Search results for: renal malignancy

Authors: Ramanpreet, Gursatej Gandhi

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Background: Dependence on electromagnetic radiations involved in communication and information technologies has incredibly increased in the personal and professional world. Among the numerous radiations, sources are fixed site transmitters, mobile phone base stations, and power lines beside indoor devices like cordless phones, WiFi, Bluetooth, TV, radio, microwave ovens, etc. Rather there is the continuous emittance of radiofrequency radiations (RFR) even to those not using the devices from mobile phone base stations. The consistent and widespread usage of wireless devices has build-up electromagnetic fields everywhere. In fact, the radiofrequency electromagnetic field (RF-EMF) has insidiously become a part of the environment and like any contaminant may pose to be health-hazardous requiring assessment. Materials and Methods: In the present study, cytogenetic damage was assessed using the Buccal Micronucleus Cytome (BMCyt) assay as a function of radiation exposure after Institutional Ethics Committee clearance of the study and written voluntary informed consent from the participants. On a pre-designed questionnaire, general information lifestyle patterns (diet, physical activity, smoking, drinking, use of mobile phones, internet, Wi-Fi usage, etc.) genetic, reproductive (pedigrees) and medical histories were recorded. For this, 24 hour-personal exposimeter measurements (PEM) were recorded for unrelated 60 healthy adults (40 cases residing in the vicinity of mobile phone base stations since their installation and 20 controls residing in areas with no base stations). The personal exposimeter collects information from all the sources generating EMF (TETRA, GSM, UMTS, DECT, and WLAN) as total RF-EMF uplink and downlink. Findings: The cases (n=40; 23-90 years) and the controls (n=20; 19-65 years) matched for alcohol drinking, smoking habits, and mobile and cordless phone usage. The PEM in cases (149.28 ± 8.98 mV/m) revealed significantly higher (p=0.000) electric field strength compared to the recorded value (80.40 ± 0.30 mV/m) in controls. The GSM 900 uplink (p=0.000), GSM 1800 downlink (p=0.000),UMTS (both uplink; p=0.013 and downlink; p=0.001) and DECT (p=0.000) electric field strength were significantly elevated in the cases as compared to controls. The electric field strength in the cases was significantly from GSM1800 (52.26 ± 4.49mV/m) followed by GSM900 (45.69 ± 4.98mV/m), UMTS (25.03 ± 3.33mV/m), DECT (18.02 ± 2.14mV/m) and was least from WLAN (8.26 ± 2.35mV/m). The higher significantly (p=0.000) increased exposure to the cases was from GSM (97.96 ± 6.97mV/m) in comparison to UMTS, DECT, and WLAN. The frequencies of micronuclei (1.86X, p=0.007), nuclear buds (2.95X, p=0.002) and cell death parameter (condensed chromatin cells) were significantly (1.75X, p=0.007) elevated in cases compared to that in controls probably as a function of radiofrequency radiation exposure. Conclusion: In the absence of other exposure(s), any cytogenetic damage if unrepaired is a cause of concern as it can cause malignancy. Larger sample size with the clinical assessment will prove more insightful of such an effect.

Keywords: Buccal micronucleus cytome assay, cytogenetic damage, electric field strength, personal exposimeter

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Authors: Faris Alkhalil, Rana Bitar, Amer Azaz, Hisham Natour, Noora Almeraikhi, Mohamad Miqdady

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Background: Children with liver transplantation are achieving very good survival and so there is now a need to concentrate on achieving good health in these patients and preventing disease. Immunosuppressive medications have side effects that need to be monitored and if possible avoided. Glucocorticoids and calcineurin inhibitors are detrimental to bone and mineral homeostasis in addition steroids can also affect linear growth. Steroid sparing regimes in renal transplant children has shown to improve children’s height. Aim: We aim to review the growth and bone health of children post liver transplant by measuring bone mineral density (BMD) using dual energy X-ray absorptiometry (DEXA) scan and assessing if there is a clear link between poor growth and impaired bone health and use of long term steroids. Subjects and Methods: This is a single centre retrospective Cohort study, we reviewed the medical notes of children (0-16 years) who underwent a liver transplantation between November 2000 to November 2016 and currently being followed at our centre. Results: 39 patients were identified (25 males and 14 females), the median transplant age was 2 years (range 9 months - 16 years), and the median follow up was 6 years. Four patients received a combined transplant, 2 kidney and liver transplant and 2 received a liver and small bowel transplant. The indications for transplant included, Biliary Atresia (31%), Acute Liver failure (18%), Progressive Familial Intrahepatic Cholestasis (15%), transplantable metabolic disease (10%), TPN related liver disease (8%), Primary Hyperoxaluria (5%), Hepatocellular carcinoma (3%) and other causes (10%). 36 patients (95%) were on a calcineurin inhibitor (34 patients were on Tacrolimus and 2 on Cyclosporin). The other three patients were on Sirolimus. Low dose long-term steroids was used in 21% of the patients. A considerable proportion of the patients had poor growth. 15% were below the 3rd centile for weight for age and 21% were below the 3rd centile for height for age. Most of our patients with poor growth were not on long term steroids. 49% of patients had a DEXA scan post transplantation. 21% of these children had low bone mineral density, one patient had met osteoporosis criteria with a vertebral fracture. Most of our patients with impaired bone health were not on long term steroids. 20% of the patients who did not undergo a DEXA scan developed long bone fractures and 50% of them were on long term steroid use which may suggest impaired bone health in these patients. Summary and Conclusion: The incidence of impaired bone health, although studied in limited number of patients; was high. Early recognition and treatment should be instituted to avoid fractures and improve bone health. Many of the patients were below the 3rd centile for weight and height however there was no clear relationship between steroid use and impaired bone health, reduced weight and reduced linear height.

Keywords: bone, growth, pediatric, liver, transplantation

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Authors: Neha Batra Bali, Monika Tomar, Vinay Gupta

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A reagentless biosensor for detection of urea based on ZnO-CuO composite thin film is presented in following work. Biosensors have immense potential for varied applications ranging from environmental to clinical testing, health care, and cell analysis. Immense growth in the field of biosensors is due to the huge requirement in today’s world to develop techniques which are both cost effective and accurate for prevention of disease manifestation. The human body comprises of numerous biomolecules which in their optimum levels are essential for functioning. However mismanaged levels of these biomolecules result in major health issues. Urea is one of the key biomolecules of interest. Its estimation is of paramount significance not only for healthcare sector but also from environmental perspectives. If level of urea in human blood/serum is abnormal, i.e., above or below physiological range (15-40mg/dl)), it may lead to diseases like renal failure, hepatic failure, nephritic syndrome, cachexia, urinary tract obstruction, dehydration, shock, burns and gastrointestinal, etc. Various metal nanoparticles, conducting polymer, metal oxide thin films, etc. have been exploited to act as matrix to immobilize urease to fabricate urea biosensor. Amongst them, Zinc Oxide (ZnO), a semiconductor metal oxide with a wide band gap is of immense interest as an efficient matrix in biosensors by virtue of its natural abundance, biocompatibility, good electron communication feature and high isoelectric point (9.5). In spite of being such an attractive candidate, ZnO does not possess a redox couple of its own which necessitates the use of electroactive mediators for electron transfer between the enzyme and the electrode, thereby causing hindrance in realization of integrated and implantable biosensor. In the present work, an effort has been made to fabricate a matrix based on ZnO-CuO composite prepared by pulsed laser deposition (PLD) technique in order to incorporate redox properties in ZnO matrix and to utilize the same for reagentless biosensing applications. The prepared bioelectrode Urs/(ZnO-CuO)/ITO/glass exhibits high sensitivity (70µAmM⁻¹cm⁻²) for detection of urea (5-200 mg/dl) with high stability (shelf life ˃ 10 weeks) and good selectivity (interference ˂ 4%). The enhanced sensing response obtained for composite matrix is attributed to the efficient electron exchange between ZnO-CuO matrix and immobilized enzymes, and subsequently fast transfer of generated electrons to the electrode via matrix. The response is encouraging for fabricating reagentless urea biosensor based on ZnO-CuO matrix.

Keywords: biosensor, reagentless, urea, ZnO-CuO composite

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Authors: Niklas Ravn-Boess, Nainita Bhowmick, Takamitsu Hattori, Shohei Koide, Christopher Park, Dimitris Placantonakis

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Background: Glioblastoma (GBM) is the most common and deadly primary brain malignancy in adults. Tumor propagation, brain invasion, and resistance to therapy critically depend on GBM stem-like cells (GSCs); however, the mechanisms that regulate GSC self-renewal are incompletely understood. Given the aggressiveness and poor prognosis of GBM, it is imperative to find biomarkers that could also translate into novel drug targets. Along these lines, we have identified a cell surface antigen, CD97 (ADGRE5), an adhesion G protein-coupled receptor (GPCR), that is expressed on GBM cells but is absent from non-neoplastic brain tissue. CD97 has been shown to promote invasiveness, angiogenesis, and migration in several human cancers, but its frequency of expression and functional role in regulating GBM growth and survival, and its potential as a therapeutic target has not been investigated. Design: We assessed CD97 mRNA and protein expression in patient derived GBM samples and cell lines using publicly available RNA-sequencing datasets and flow cytometry, respectively. To assess CD97 function, we generated shRNA lentiviral constructs that target a sequence in the CD97 extracellular domain (ECD). A scrambled shRNA (scr) with no predicted targets in the genome was used as a control. We evaluated CD97 shRNA lentivirally transduced GBM cells for Ki67, Annexin V, and DAPI. We also tested CD97 KD cells for their ability to self-renew using clonogenic tumorsphere formation assays. Further, we utilized synthetic Abs (sAbs) generated against the ECD of CD97 to test for potential antitumor effects using patient-derived GBM cell lines. Results: CD97 mRNA expression was expressed at high levels in all GBM samples available in the TCGA cohort. We found high levels of surface CD97 protein expression in 6/6 patient-derived GBM cell cultures, but not human neural stem cells. Flow cytometry confirmed downregulation of CD97 in CD97 shRNA lentivirally transduced cells. CD97 KD induced a significant reduction in cell growth in 3 independent GBM cell lines representing mesenchymal and proneural subtypes, which was accompanied by reduced (~20%) Ki67 staining and increased (~30%) apoptosis. Incubation of GBM cells with sAbs (20 ug/ ml) against the ECD of CD97 for 3 days induced GSC differentiation, as determined by the expression of GFAP and Tubulin. Using three unique GBM patient derived cultures, we found that CD97 KD attenuated the ability of GBM cells to initiate sphere formation by over 300 fold, consistent with an impairment in GSC self-renewal. Conclusion: Loss of CD97 expression in patient-derived GBM cells markedly decreases proliferation, induces cell death, and reduces tumorsphere formation. sAbs against the ECD of CD97 reduce tumorsphere formation, recapitulating the phenotype of CD97 KD, suggesting that sAbs that inhibit CD97 function exhibit anti-tumor activity. Collectively, these findings indicate that CD97 is necessary for the proliferation and survival of human GBM cells and identify CD97 as a promising therapeutically targetable vulnerability in GBM.

Keywords: adhesion GPCR, CD97, GBM stem cell, glioblastoma

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Authors: Mariam Khaled, Noha Farag, Ghada Mohamed Abdel Salam, Khaled Abu-Aisha, Mohamed El-Azizi

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Gastric and colorectal cancers are among the most frequent causes of cancer-associated mortalities in Africa. They have been considered as a global public health concern, as nearly one million new cases are reported per year. IL-1β is a pro-inflammatory cytokine-produced by activated macrophages and monocytes- and a member of the IL-1 family. The inactive IL-1β precursor is cleaved and activated by caspase-1 enzyme, which itself is activated by the assembly of intracellular structures defined as NLRP3 (Nod Like receptor P3) inflammasomes. Activated IL-1β stimulates the Interleukin-1 receptor type-1 (IL-1R1), which is responsible for the initiation of a signal transduction pathway leading to cell proliferation. It has been proven that the IL-1β gene is a highly polymorphic gene in which single nucleotide polymorphisms (SNPs) may affect its expression. It has been previously reported that SNPs including base transitions between C and T at positions, -511 (C-T; dbSNP: rs16944) and -31 (C-T; dbSNP: rs1143627), from the transcriptional start site, contribute to the pathogenesis of gastric and colorectal cancers by affecting IL-1β levels. Altered production of IL-1β due to such polymorphisms is suspected to stimulate an amplified inflammatory response and promote Epithelial Mesenchymal Transition leading to malignancy. Allele frequency distribution of the IL-1β-31 and -511 SNPs, in different populations, and their correlation to the incidence of gastric and colorectal cancers, has been intriguing to researchers worldwide. The current study aims to investigate allele distributions of the IL-1β SNPs among gastric and colorectal cancers Egyptian patients. In order to achieve to that, 89 Biopsy and surgical specimens from the antrum and corpus mucosa of chronic gastritis subjects and gastric and colorectal carcinoma patients was collected for DNA extraction followed by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). The amplified PCR products of IL-1β-31C > T and IL-1β-511T > C were digested by incubation with the restriction endonuclease enzymes ALu1 and Ava1. Statistical analysis was carried out to determine the allele frequency distribution in the three studied groups. Also, the effect of the IL-1β -31 and -511 SNPs on nuclear factor binding was analyzed using Fluorescence Electrophoretic Mobility Shift Assay (EMSA), preceded by nuclear factor extraction from gastric and colorectal tissue samples and LPS stimulated monocytes. The results of this study showed that a significantly higher percentage of Egyptian gastric cancer patients have a homozygous CC genotype at the IL-1β-31 position and a heterozygous TC genotype at the IL-1β-511 position. Moreover, a significantly higher percentage of the colorectal cancer patients have a homozygous CC genotype at the IL-1β-31 and -511 positions as compared to the control group. In addition, the EMSA results showed that IL-1β-31C/T and IL-1β-511T/C SNPs do not affect nuclear factor binding. Results of this study suggest that the IL-1β-31 C/T and IL-1β-511 T/C may be correlated to the incidence of gastric cancer in Egyptian patients; however, similar findings couldn’t be proven in the colorectal cancer patients group for the IL-1β-511 T/C SNP. This is the first study to investigate IL-1β -31 and -511 SNPs in the Egyptian population.

Keywords: colorectal cancer, Egyptian patients, gastric cancer, interleukin-1β, single nucleotide polymorphisms

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Authors: Thao Nguyen, Maximiliano Hyon, Sany Rajagukguk, Anna Melkonyan

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Introduction: Type 2 Diabetes is a well-established risk factor for severe SARS-CoV-2 infection. Uncontrolled hyperglycemia in patients with established or newly diagnosed diabetes is associated with poor outcomes, including increased mortality and hospital length of stay. Objectives: Our study aims to compare three different glycemic management strategies and their association with clinical outcomes in patients hospitalized for moderate to severe SARS-CoV-2 infection. Identifying optimal glycemic management strategies will improve the quality of patient care and improve their outcomes. Method: This is a retrospective observational study on patients hospitalized at Adventist Health White Memorial with severe SARS-CoV-2 infection from 11/1/2020 to 02/28/2021. The following inclusion criteria were used: positive SARS-CoV-2 PCR test, age >18 yrs old, diabetes or random glucose >200 mg/dL on admission, oxygen requirement >4L/min, and treatment with glucocorticoids. Our exclusion criteria included: ICU admission within 24 hours, discharge within five days, death within five days, and pregnancy. The patients were divided into three glycemic management groups: Group 1, managed solely by the Primary Team, Group 2, by Pharmacy; and Group 3, by Endocrinologist. Primary outcomes were average glucose on Day 5, change in glucose between Days 3 and 5, and average insulin dose on Day 5 among groups. Secondary outcomes would be upgraded to ICU, inpatient mortality, and hospital length of stay. For statistics, we used IBM® SPSS, version 28, 2022. Results: Most studied patients were Hispanic, older than 60, and obese (BMI >30). It was the first CV-19 surge with the Delta variant in an unvaccinated population. Mortality was markedly high (> 40%) with longer LOS (> 13 days) and a high ICU transfer rate (18%). Most patients had markedly elevated inflammatory markers (CRP, Ferritin, and D-Dimer). These, in combination with glucocorticoids, resulted in severe hyperglycemia that was difficult to control. Average glucose on Day 5 was not significantly different between groups primary vs. pharmacy vs. endocrine (220.5 ± 63.4 vs. 240.9 ± 71.1 vs. 208.6 ± 61.7 ; P = 0.105). Change in glucose from days 3 to 5 was not significantly different between groups but trended towards favoring the endocrinologist group (-26.6±73.6 vs. 3.8±69.5 vs. -32.2±84.1; P= 0.052). TDD insulin was not significantly different between groups but trended towards higher TDD for the endocrinologist group (34.6 ± 26.1 vs. 35.2 ± 26.4 vs. 50.5 ± 50.9; P=0.054). The endocrinologist group used significantly more preprandial insulin compared to other groups (91.7% vs. 39.1% vs. 65.9% ; P < 0.001). The pharmacy used more basal insulin than other groups (95.1% vs. 79.5% vs. 79.2; P = 0.047). There were no differences among groups in the clinical outcomes: LOS, ICU upgrade, or mortality. Multivariate regression analysis controlled for age, sex, BMI, HbA1c level, renal function, liver function, CRP, d-dimer, and ferritin showed no difference in outcomes among groups. Conclusion: Given high-risk factors in our population, despite efforts from the glycemic management teams, it’s unsurprising no differences in clinical outcomes in mortality and length of stay.

Keywords: glycemic management, strategies, hospitalized, SARS-CoV-2, outcomes

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Authors: Yang Yang, Luciana Magalhães Rebelo Alencar, Martha Sahylí Ortega Pijeira, Beatriz da Silva Batista, Alefe Roger Silva França, Erick Rafael Dias Rates, Ruana Cardoso Lima, Sara Gemini-Piperni, Ralph Santos-Oliveira

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Radium-²²³ dichloride ([²²³Rₐ]RₐCl₂) is an alpha particle-emitting radiopharmaceutical currently approved for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease. [²²³Rₐ]RₐCl₂ is bone-seeking calcium mimetic that bonds into the newly formed bone stroma, especially osteoblastic or sclerotic metastases, killing the tumor cells by inducing DNA breaks in a potent and localized manner. Nonetheless, the successful therapy of osteosarcoma as primary bone tumors is still a challenge. Nanomicelles are colloidal nanosystems widely used in drug development to improve blood circulation time, bioavailability, and specificity of therapeutic agents, among other applications. In addition, the enhanced permeability and retention effect of the nanosystems, and the renal excretion of the nanomicelles reported in most cases so far, are very attractive to achieve selective and increased accumulation in tumor site as well as to increase the safety of [²²³Rₐ]RₐCl₂ in the clinical routine. In the present work, [²²³Rₐ]RₐCl₂ nanomicelles were produced, characterized, in vitro evaluated, and compared with pure [²²³Rₐ]RₐCl2 solution using SAOS2 osteosarcoma cells. The [²²³Rₐ]RₐCl₂ nanomicelles were prepared using the amphiphilic copolymer Pluronic F127. The dynamic light scattering analysis of freshly produced [²²³Rₐ]RₐCl₂ nanomicelles demonstrated a mean size of 129.4 nm with a polydispersity index (PDI) of 0.303. After one week stored in the refrigerator, the mean size of the [²²³Rₐ]RₐCl₂ nanomicelles increased to 169.4 with a PDI of 0.381. Atomic force microscopy analysis of [223Rₐ]RₐCl₂ nanomicelles exhibited spherical structures whose heights reach 1 µm, suggesting the filling of 127-Pluronic nanomicelles with [²²³Rₐ]RₐCl₂. The viability assay with [²²³Rₐ]RₐCl₂ nanomicelles displayed a dose-dependent response as it was observed using pure [²²³Rₐ]RₐCl2. However, at the same dose, [²²³Rₐ]RₐCl₂ nanomicelles were 20% higher efficient in killing SAOS2 cells when compared with pure [²²³Rₐ]RₐCl₂. These findings demonstrated the effectiveness of the nanosystem validating the application of nanotechnology in targeted alpha therapy with [²²³Ra]RₐCl₂. In addition, the [²²³Rₐ]RaCl₂nanomicelles may be decorated and incorporated with a great variety of agents and compounds (e.g., monoclonal antibodies, aptamers, peptides) to overcome the limited use of [²²³Ra]RₐCl₂.

Keywords: nanomicelles, osteosarcoma, radium dichloride, targeted alpha therapy

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Authors: Angelis P. Barlampas

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Introduction: The term phantom lung mass describes the ovoid collection of fluid within the interlobular fissure, which initially creates the impression of a mass. The problem of correct differential diagnosis is great, especially in plain radiography. A case is presented with three nodular pulmonary foci, the shape, location, and density of which, as well as the presence of chronic loculated pleural effusions, suggest the presence of multiple phantom tumors of the lung. Purpose: The aim of this paper is to draw the attention of non-experienced and non-specialized physicians to the existence of benign findings that mimic pathological conditions and vice versa. The careful study of a radiological examination and the comparison with previous exams or further control protect against quick wrong conclusions. Methods: A hospitalized patient underwent a non-contrast CT scan of the chest as part of the general control of her situation. Results: Computed tomography revealed pleural effusions, some of them loculated, increased cardiothoracic index, as well as the presence of three nodular foci, one in the left lung and two in the right with a maximum density of up to 18 Hounsfield units and a mean diameter of approximately five centimeters. Two of them are located in the characteristical anatomical position of the major interlobular fissure. The third one is located in the area of the right lower lobe’s posterior basal part, and it presents the same characteristics as the previous ones and is likely to be a loculated fluid collection, within an auxiliary interlobular fissure or a cyst, in the context of the patient's more general pleural entrapments and loculations. The differential diagnosis of nodular foci based on their imaging characteristics includes the following: a) rare metastatic foci with low density (liposarcoma, mucous tumors of the digestive or genital system, necrotic metastatic foci, metastatic renal cancer, etc.), b) necrotic multiple primary lung tumor locations (squamous epithelial cancer, etc. ), c) hamartomas of the lung, d) fibrotic tumors of the interlobular fissures, e) lipoid pneumonia, f) fluid concentrations within the interlobular fissures, g) lipoma of the lung, h) myelolipomas of the lung. Conclusions: The collection of fluid within the interlobular fissure of the lung can give the false impression of a lung mass, particularly on plain chest radiography. In the case of computed tomography, the ability to measure the density of a lesion, combined with the provided high anatomical details of the location and characteristics of the lesion, can lead relatively easily to the correct diagnosis. In cases of doubt or image artifacts, comparison with previous or subsequent examinations can resolve any disagreements, while in rare cases, intravenous contrast may be necessary.

Keywords: phantom mass, chest CT, pleural effusion, cancer

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Authors: Sandra Smieszek, Jonathan Haines

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Introduction: Numerous research efforts have focused on searching for ‘longevity genes’. However, attempting to decipher the genetic component of the longevous phenotype have resulted in limited success and the mechanisms governing longevity remain to be explained. We conducted a genome-wide homozygosity analysis (GWHA) of the founder population of the Amish community in central Ohio. While genome-wide association studies using unrelated individuals have revealed many interesting longevity associated variants, these variants are typically of small effect and cannot explain the observed patterns of heritability for this complex trait. The Amish provide a large cohort of extended kinships allowing for in depth analysis via family-based approach excellent population due to its. Heritability of longevity increases with age with significant genetic contribution being seen in individuals living beyond 60 years of age. In our present analysis we show that the heritability of longevity is estimated to be increasing with age particularly on the paternal side. Methods: The present analysis integrated both phenotypic and genotypic data and led to the discovery of a series of variants, distinct for stratified populations across ages and distinct for paternal and maternal cohorts. Specifically 5437 subjects were analyzed and a subset of 893 successfully genotyped individuals was used to assess CHIP heritability. We have conducted the homozygosity analysis to examine if homozygosity is associated with increased risk of living beyond 90. We analyzed AMISH cohort genotyped for 614,957 SNPs. Results: We delineated 10 significant regions of homozygosity (ROH) specific for the age group of interest (>90). Of particular interest was ROH on chromosome 13, P < 0.0001. The lead SNPs rs7318486 and rs9645914 point to COL4A2 and our lead SNP. COL25A1 encodes one of the six subunits of type IV collagen, the C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. COL4A2 mutations have been reported with a broader spectrum of cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities. The second region of interest points to IRS2. Furthermore we built a classifier using the obtained SNPs from the significant ROH region with 0.945 AUC giving ability to discriminate between those living beyond to 90 years of age and beyond. Conclusion: In conclusion our results suggest that a history of longevity does indeed contribute to increasing the odds of individual longevity. Preliminary results are consistent with conjecture that heritability of longevity is substantial when we start looking at oldest fifth and smaller percentiles of survival specifically in males. We will validate all the candidate variants in independent cohorts of centenarians, to test whether they are robustly associated with human longevity. The identified regions of interest via ROH analysis could be of profound importance for the understanding of genetic underpinnings of longevity.

Keywords: regions of homozygosity, longevity, SNP, Amish

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Authors: Shiamaa Eltantawy, Gihan Sobhy, Alif Alaam

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Wilson disease, or hepatolenticular degeneration, is an autosomal recessive disease that results in excess copper buildup in the body. It primarily affects the liver and basal ganglia of the brain, but it can affect other organ systems. Musculoskeletal abnormalities, including premature osteoarthritis, skeletal deformity, and pathological bone fractures, can occasionally be found in WD patients with a hepatic or neurologic type. The aim was to assess the prevalence of osteoporosis and osteopenia in Wilson’s disease patients. This case-control study was conducted on ninety children recruited from the inpatient ward and outpatient clinic of the Paediatric Hepatology, Gastroenterology, and Nutrition department of the National Liver Institute at Menofia University, aged from 1 to 18 years. Males were 49, and females were 41. Children were divided into three groups: (Group I) consisted of thirty patients with WD; (Group II) consisted of thirty patients with chronic liver disease other than WD; (Group III) consisted of thirty age- and sex-matched healthy The exclusion criteria were patients with hyperparathyroidism, hyperthyroidism, renal failure, Cushing's syndrome, and patients on certain drugs such as chemotherapy, anticonvulsants, or steroids. All patients were subjected to the following: 1- Full history-taking and clinical examination. 2-Laboratory investigations: (FBC,ALT,AST,serum albumin, total protein, total serum bilirubin,direct bilirubin,alkaline phosphatase, prothrombin time, serum critine,parathyroid hormone, serum calcium, serum phosphrus). 3-Bone mineral density (BMD, gm/cm2) values were measured by dual-energy X-ray absorptiometry (DEXA). The results revealed that there was a highly statistically significant difference between the three groups regarding the DEXA scan, and there was no statistically significant difference between groups I and II, but the WD group had the lowest bone mineral density. The WD group had a large number of cases of osteopenia and osteoporosis, but there was no statistically significant difference with the group II mean, while a high statistically significant difference was found when compared to group III. In the WD group, there were 20 patients with osteopenia, 4 patients with osteoporosis, and 6 patients who were normal. The percentages were 66.7%, 13.3%, and 20%, respectively. Therefore, the largest number of cases in the WD group had osteopenia. There was no statistically significant difference found between WD patients on different treatment regimens regarding DEXA scan results (Z-Score). There was no statistically significant difference found between patients in the WD group (normal, osteopenic, or osteoporotic) regarding phosphorus (mg/dL), but there was a highly statistically significant difference found between them regarding ionised Ca (mmol/L). Therefore, there was a decrease in bone mineral density when the Ca level was decreased. In summary, Wilson disease is associated with bone demineralization. The largest number of cases in the WD group in our study had osteopenia (66.7%). Different treatment regimens (zinc monotherapy, Artamin, and zinc) as well as different laboratory parameters have no effect on bone mineralization in WD cases. Decreased ionised Ca is associated with low BMD in WD patients. Children with WD should be investigated for BMD.

Keywords: wilson disease, Bone mineral density, liver disease, osteoporosis

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Authors: Karolina Wieczorek, Zofia Przypaśniak

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Climate change is a rapidly growing threat to global health, and part of the responsibility to combat it lies within the healthcare sector itself, including adequate education of future medical professionals. To mitigate the consequences, the General Medical Council (GMC) has equipped medical schools with a list of outcomes regarding sustainability teaching. Students are expected to analyze the impact of the healthcare sector’s emissions on climate change. The delivery of the related teaching content is, however, often inadequate and insufficient time is devoted for exploration of the topics. Teaching curricula lack in-depth exploration of the learning objectives. This study aims to assess the extent and characteristics of climate change and sustainability subjects teaching in the curriculum of a chosen UK medical school (Barts and The London School of Medicine and Dentistry). It compares the data to the national average scores from the Climate Change and Sustainability Teaching (C.A.S.T.) in Medical Education Audit to draw conclusions about teaching on a regional level. This is a single-center audit of the timetabled sessions of teaching in the medical course. The study looked at the academic year 2020/2021 which included a review of all non-elective, core curriculum teaching materials including tutorials, lectures, written resources, and assignments in all five years of the undergraduate and graduate degrees, focusing only on mandatory teaching attended by all students (excluding elective modules). The topics covered were crosschecked with GMC Outcomes for graduates: “Educating for Sustainable Healthcare – Priority Learning Outcomes” as gold standard to look for coverage of the outcomes and gaps in teaching. Quantitative data was collected in form of time allocated for teaching as proxy of time spent per individual outcomes. The data was collected independently by two students (KW and ZP) who have received prior training and assessed two separate data sets to increase interrater reliability. In terms of coverage of learning outcomes, 12 out of 13 were taught (with the national average being 9.7). The school ranked sixth in the UK for time spent per topic and second in terms of overall coverage, meaning the school has a broad range of topics taught with some being explored in more detail than others. For the first outcome 4 out of 4 objectives covered (average 3.5) with 47 minutes spent per outcome (average 84 min), for the second objective 5 out of 5 covered (average 3.5) with 46 minutes spent (average 20), for the third 3 out of 4 (average 2.5) with 10 mins pent (average 19 min). A disproportionately large amount of time is spent delivering teaching regarding air pollution (respiratory illnesses), which resulted in the topic of sustainability in other specialties being excluded from teaching (musculoskeletal, ophthalmology, pediatrics, renal). Conclusions: Currently, there is no coherent strategy on national teaching of climate change topics and as a result an unstandardized amount of time spent on teaching and coverage of objectives can be observed.

Keywords: audit, climate change, sustainability, education

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Authors: Surachart Koyadun

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Introduction: Plasmodium knowlesi (P. knowlesi) malaria is a zoonotic disease that is classified as type 5 of human malaria. Commonly found in macaques (Macaca fascicularis) and (Macaca nemestrina), P. knowlesi is capable of resulting in both uncomplicated and severe malaria in humans. Situation of P. knowlesi malaria in Phang-Nga province for the past 3 years from 2020 – 2022 revealed no case report in 2020, however, a total of 14 cases had been reported in 2021 - 2022. This research aimed to 1) study the epidemiology of P. knowlesi, 2) examine the clinical manifestations of P. knowlesi patients, 3) analyze the ecology and entomology of P. knowlesi, and 4) analyze the diagnosis and treatment of P. knowlesi. Method: This research was a retrospective descriptive study/case report. The study was conducted in 14 patients with P. knowlesi malaria between 2021 and 2022 in 4 districts of Phang-Nga Province, Thailand including Thapput, Kapong, Takuapa and Khuraburi. Results: The study subjects of P. knowlesi malaria were all males. Most of them were working age groups as farmers and worked in forest or plantation areas. All had no history of blood transfusions. Most of the patients did not use mosquito nets and had a history of camping in the forest prior to the onset of fever. An analysis of all 14 sources of infection unveiled the area is home to macaques, and that area has detected Anopheles mosquito, which is the carrier of the disease. Majority of them got sick in the dry season of Thailand (December-April). The main symptoms brought to the hospital were fever, chills, headache, body aches. Laboratory findings on the first day of diagnosis were as follows: The white blood cell count was found within the normal range. In the proportion of white blood cells, eosinophils were found to be slightly higher than normal. Slight anemia was found on early examination. The platelet count was found to be below normal in all cases. Severely low platelet count (2,000 cells/mm3) was found in severe cases with multiple complications. No patient was found dead but 85.7% of complications were found, with acute renal failure being the most common. Patients with delayed diagnosis and treatment of malaria (inaccurate diagnosis or late access to the hospital) had the highest severity and complications than those who had seen the doctor since the first 3-4 days of illness or the screening of symptoms and risk history by the malaria clinic staff at vector-borne disease control unit. Conclusion and Recommendation: P. knowlesi malaria is an emerging infectious disease transmitted from animals to humans. There are challenges in epidemiology, entomology, ecology for effective surveillance, prevention and control. Early diagnosis and treatment would reduce complications and prevent death.

Keywords: malaria, plasmodium knowlesi, epidemiology, ecology, entomology, diagnosis, treatment

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Authors: Hansraj Bookun, Rachel Xuan, Angela Tan, Kejia Wang, Animesh Singla, David Kim, Christopher Loupos, Jim Iliopoulos

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Introduction: Complex endovascular aortic aneursymal repairs with fenestrated and branched endografts require customised devices to exclude the pathology while reducing morbidity and mortality, which was historically associated with open repair of complex aneurysms. Such endovascular procedures have predominantly been performed in a large volume dedicated tertiary centres. We present here our nine year multidisciplinary experience with this technology in an Australian tertiary centre. Method: This was a cross-sectional, single-centre observational study of 670 patients who had undergone complex endovascular aortic aneurysmal repairs with conventional endografts, fenestrated endografts, and iliac-branched devices from January 2010 to July 2019. Descriptive statistics were used to characterise our sample with regards to demographic and perioperative variables. Homogeneity of the sample was tested using multivariant regression, which did not identify any statistically significant confounding variables. Results: 670 patients of mean age 74, were included (592 males) and the comorbid burden was as follows: ischemic heart disease (55%), diabetes (18%), hypertension (90%), stage four or greater kidney impairment (8%) and current or ex-smoking (78%). The main indications for surgery were elective aneurysms (86%), symptomatic aneurysms (5%), and rupture aneurysms (5%). 106 patients (16%) underwent fenestrated or branched endograft repairs. The mean length of stay was 7.6 days. 2 patients experienced reactionary bleeds, 11 patients had access wound complications (6 lymph fistulae, 5 haematoms), 11 patients had cardiac complications (5 arrhythmias, 3 acute myocadial infarctions, 3 exacerbation of congestive cardiac failure), 10 patients had respiratory complications, 8 patients had renal impairment, 4 patients had gastrointestinal complications, 2 patients suffered from paraplegia, 1 major stroke, 1 minor stroke, and 1 acute brain syndrome. There were 4 vascular occlusions requiring further arterial surgery, 4 type I endoleaks, 4 type II endoleaks, 3 episodes of thromboembolism, and 2 patients who required further arterial operations in the setting of patient vessels. There were 9 unplanned returns to the theatre. Discussion: Our numbers of 10 years suggest that we are not a dedicated high volume centre focusing on aortic repairs. However, we have achieved significantly low complication rates. This can be attributed to our multidisciplinary approach with the intraoperative involvement of skilled interventional radiologists and vascular surgeons as well as postoperative protocols with particular attention to spinal cord protection. Additionally, we have a ratified perioperative pathway that involves multidisciplinary team discussions of patient-related factors and lesion-centered characteristics, which allows for holistic, patient-centered care.

Keywords: aneurysm, aortic, endovascular, fenestrated

Procedia PDF Downloads 91

Authors: Rajeswari Raguraman, Sowmya Parameswaran, Krishnakumar Subramanian, Jagat Kanwar, Rupinder Kanwar

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Background: Tumor microenvironment has been implicated in several cancers to regulate cell growth, invasion and metastasis culminating in outcome of therapy. Tumor stroma consists of multiple cell types that are in constant cross-talk with the tumor cells to favour a pro-tumorigenic environment. Not much is known about the existence of tumor microenvironment in the pediatric intraocular malignancy, Retinoblastoma (RB). In the present study, we aim to understand the multiple stromal cellular subtypes and tumor stromal interactions expressed in RB tumors. Materials and Methods: Immunohistochemistry for stromal cell markers CD31, CD68, alpha-smooth muscle (α-SMA), vimentin and glial fibrillary acidic protein (GFAP) was performed on formalin fixed paraffin embedded tissues sections of RB (n=12). The differential expression of stromal target molecules; fibroblast activation protein (FAP), tenascin-C (TNC), osteopontin (SPP1), bone marrow stromal antigen 2 (BST2), stromal derived factor 2 and 4 (SDF2 and SDF4) in primary RB tumors (n=20) and normal retina (n=5) was studied by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blotting. The differential expression was correlated with the histopathological features of RB. The interaction between RB cell lines (Weri-Rb-1, NCC-RbC-51) and Bone marrow stromal cells (BMSC) was also studied using direct co-culture and indirect co-culture methods. The functional effect of the co-culture methods on the RB cells was evaluated by invasion and proliferation assays. Global gene expression was studied by using Affymetrix 3’ IVT microarray. Pathway prediction was performed using KEGG and the key molecules were validated using qRT-PCR. Results: The immunohistochemistry revealed the presence of several stromal cell types such as endothelial cells (CD31+;Vim+/-); macrophages (CD68+;Vim+/-); Fibroblasts (Vim+; CD31-;CD68- );myofibroblasts (α-SMA+/ Vim+) and invading retinal astrocytes/ differentiated retinal glia (GFAP+; Vim+). A characteristic distribution of these stromal cell types was observed in the tumor microenvironment, with endothelial cells predominantly seen in blood vessels and macrophages near actively proliferating tumor or necrotic areas. Retinal astrocytes and glia were predominant near the optic nerve regions in invasive tumors with sparse distribution in tumor foci. Fibroblasts were widely distributed with rare evidence of myofibroblasts in the tumor. Both gene and protein expression revealed statistically significant (P<0.05) up-regulation of FAP, TNC and BST2 in primary RB tumors compared to the normal retina. Co-culture of BMSC with RB cells promoted invasion and proliferation of RB cells in direct and indirect contact methods respectively. Direct co-culture of RB cell lines with BMSC resulted in gene expression changes in ECM-receptor interaction, focal adhesion, IL-8 and TGF-β signaling pathways associated with cancer. In contrast, various metabolic pathways such a glucose, fructose and amino acid metabolism were significantly altered under the indirect co-culture condition. Conclusion: The study suggests that the close interaction between RB cells and the stroma might be involved in RB tumor invasion and progression which is likely to be mediated by ECM-receptor interactions and secretory factors. Targeting the tumor stroma would be an attractive option for redesigning treatment strategies for RB.

Keywords: gene expression profiles, retinoblastoma, stromal cells, tumor microenvironment

Procedia PDF Downloads 357

Authors: Wonil Nam, Xiang Ren, Inyoung Kim, Masoud Agah, Wei Zhou

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Despite its ultrasensitive detection capability, surface-enhanced Raman spectroscopy (SERS) faces challenges as a quantitative biochemical analysis tool due to the significant dependence of local field intensity in hotspots on nanoscale geometric variations of plasmonic nanostructures. Therefore, despite enormous progress in plasmonic nanoengineering of high-performance SERS devices, it is still challenging to quantitatively correlate the measured SERS signals with the actual molecule concentrations at hotspots. A significant effort has been devoted to developing SERS calibration methods by introducing internal standards. It has been achieved by placing Raman tags at plasmonic hotspots. Raman tags undergo similar SERS enhancement at the same hotspots, and ratiometric SERS signals for analytes of interest can be generated with reduced dependence on geometrical variations. However, using Raman tags still faces challenges for real-world applications, including spatial competition between the analyte and tags in hotspots, spectral interference, laser-induced degradation/desorption due to plasmon-enhanced photochemical/photothermal effects. We show that electronic Raman scattering (ERS) signals from metallic nanostructures at hotspots can serve as the internal calibration standard to enable quantitative SERS analysis and improve biostatistical analysis. We perform SERS with Au-SiO₂ multilayered metal-insulator-metal nano laminated plasmonic nanostructures. Since the ERS signal is proportional to the volume density of electron-hole occupation in hotspots, the ERS signals exponentially increase when the wavenumber is approaching the zero value. By a long-pass filter, generally used in backscattered SERS configurations, to chop the ERS background continuum, we can observe an ERS pseudo-peak, IERS. Both ERS and SERS processes experience the |E|⁴ local enhancements during the excitation and inelastic scattering transitions. We calibrated IMRS of 10 μM Rhodamine 6G in solution by IERS. The results show that ERS calibration generates a new analytical value, ISERS/IERS, insensitive to variations from different hotspots and thus can quantitatively reflect the molecular concentration information. Given the calibration capability of ERS signals, we performed label-free SERS analysis of living biological systems using four different breast normal and cancer cell lines cultured on nano-laminated SERS devices. 2D Raman mapping over 100 μm × 100 μm, containing several cells, was conducted. The SERS spectra were subsequently analyzed by multivariate analysis using partial least square discriminant analysis. Remarkably, after ERS calibration, MCF-10A and MCF-7 cells are further separated while the two triple-negative breast cancer cells (MDA-MB-231 and HCC-1806) are more overlapped, in good agreement with the well-known cancer categorization regarding the degree of malignancy. To assess the strength of ERS calibration, we further carried out a drug efficacy study using MDA-MB-231 and different concentrations of anti-cancer drug paclitaxel (PTX). After ERS calibration, we can more clearly segregate the control/low-dosage groups (0 and 1.5 nM), the middle-dosage group (5 nM), and the group treated with half-maximal inhibitory concentration (IC50, 15 nM). Therefore, we envision that ERS calibrated SERS can find crucial opportunities in label-free molecular profiling of complicated biological systems.

Keywords: cancer cell drug efficacy, plasmonics, surface-enhanced Raman spectroscopy (SERS), SERS calibration

Procedia PDF Downloads 113

Authors: Anush Patric, M. Jadeyegowda, M. N. Ramesh, M. Ravikumar, C. R. Ajay

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Kodagu district which is situated in Central Western Ghats regions falls in one of the hottest of hot spots of biodiversity which is recognised by UNESCO. The district has one of the highest densities of community managed sacred forests in the world with rich floral and faunal diversity. It is a habitat for more than ten different types of Ethnic Indigenous tribal groups commonly called ‘Girijanas’ (Soligas, Yarvas, Jenukuruba, Bettakuruba etc.), who are having the rich knowledge of medicinal value of the plants that are commonly available in the forest. The tribal men of this region are the treasure house of the traditional plant knowledge and health care practices. An ethnobotanical survey was undertaken in tribal areas of the district to collect information about some of the indigenous medicinal plant knowledge of tribal people by semi-structured interviews, ranking exercises and field observations on their native habitat in order to evaluate the potential medicinal uses of local plants. The study revealed that, the ethnobotanical information of 83 plant species belonging to 45 families, of the total 83 species documented, most plants used in the treatment were trees (11 species), shrubs (41 species), herbs (22 species) and rarely climbers (9 species) which are used in the treatment of Hyperacidity, Respiratory disorders, Snake bite Abortifacient, Anthelmintic, Paralysis, Antiseptic, Fever, Chest pain, Stomachic, Jaundice, Piles, Asthma, Malaria, Renal disorders, Malaria and many other diseases. Maximum of 6 plant species each of Acanthaceae, Apiaceae and were used for drug preparation, followed by Asclepiadaceae, Liliaceae, Fabaceae, Verbenaceae, Caesalpinaceae, Bombaceae, Papilonaceae, Solanaceae, Rubiaceae, Myrtaceae, Amaranthaceae, Asteraceae, Ascelepidaceae, Cucurbitaceae, Apocyanaceae, and Solanaceae etc. In our present study, only medicinal plants and their local medicinal uses are recorded and presented. Information was obtained by local informants having the knowledge about medicinal plants. About 23 local tribes were interviewed. For each plant, necessary information like botanical name, family of plant species, local name and uses are given. Recent trend shows a decline in the number of traditional herbal healers in the tribal areas since the younger generation is not interested to continue this tradition. Hence, there is an urgent need to record and preserve all information on plants used by different ethnic/tribal communities for various purposes before it reaches to verge of extinction. In addition, several wild medicinal plants are declining in numbers due to deforestation and forest fires. There is need for phytochemical analysis and conservation measures to be taken for conserving medicinal plant species which is far better than allopathic medicines and these do not cause any side effects as they are the natural disease healers. So, conservation strategies have to be practiced in all levels and sectors by creating awareness about the value of such medicinal plants, and it is necessary to save the disappearing plants to strengthen the document and to conserve them for future generation.

Keywords: diseases, ethnic groups, folk medicine, Kodagu, medicinal plants

Procedia PDF Downloads 243

Authors: George Zhou, Yunchan Chen, Candace Chien

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Kidney replacement therapy is the current standard of care for end-stage renal diseases. In-center or home hemodialysis remains an integral component of the therapeutic regimen. Arteriovenous fistulas (AVF) make up the vascular circuit through which blood is filtered and returned. Naturally, AVF patency determines whether adequate clearance and filtration can be achieved and directly influences clinical outcomes. Our aim was to build a deep learning model for automated AVF stenosis screening based on the sound of blood flow through the AVF. A total of 311 patients with AVF were enrolled in this study. Blood flow sounds were collected using a digital stethoscope. For each patient, blood flow sounds were collected at 6 different locations along the patient’s AVF. The 6 locations are artery, anastomosis, distal vein, middle vein, proximal vein, and venous arch. A total of 1866 sounds were collected. The blood flow sounds are labeled as “patent” (normal) or “stenotic” (abnormal). The labels are validated from concurrent ultrasound. Our dataset included 1527 “patent” and 339 “stenotic” sounds. We show that blood flow sounds vary significantly along the AVF. For example, the blood flow sound is loudest at the anastomosis site and softest at the cephalic arch. Contextualizing the sound with location metadata significantly improves classification performance. How to encode and incorporate categorical metadata is an active area of research1. Herein, we study ordinal (i.e., integer) encoding schemes. The numerical representation is concatenated to the flattened feature vector. We train a vision transformer (ViT) on spectrogram image representations of the sound and demonstrate that using scalar multiples of our integer encodings improves classification performance. Models are evaluated using a 10-fold cross-validation procedure. The baseline performance of our ViT without any location metadata achieves an AuROC and AuPRC of 0.68 ± 0.05 and 0.28 ± 0.09, respectively. Using the following encodings of Artery:0; Arch: 1; Proximal: 2; Middle: 3; Distal 4: Anastomosis: 5, the ViT achieves an AuROC and AuPRC of 0.69 ± 0.06 and 0.30 ± 0.10, respectively. Using the following encodings of Artery:0; Arch: 10; Proximal: 20; Middle: 30; Distal 40: Anastomosis: 50, the ViT achieves an AuROC and AuPRC of 0.74 ± 0.06 and 0.38 ± 0.10, respectively. Using the following encodings of Artery:0; Arch: 100; Proximal: 200; Middle: 300; Distal 400: Anastomosis: 500, the ViT achieves an AuROC and AuPRC of 0.78 ± 0.06 and 0.43 ± 0.11. respectively. Interestingly, we see that using increasing scalar multiples of our integer encoding scheme (i.e., encoding “venous arch” as 1,10,100) results in progressively improved performance. In theory, the integer values do not matter since we are optimizing the same loss function; the model can learn to increase or decrease the weights associated with location encodings and converge on the same solution. However, in the setting of limited data and computation resources, increasing the importance at initialization either leads to faster convergence or helps the model escape a local minimum.

Keywords: arteriovenous fistula, blood flow sounds, metadata encoding, deep learning

Procedia PDF Downloads 52

Authors: Suliman Al-Fayoumi, Sherri Amberg, Huafeng Zhou, Jack W. Singer, James P. Dean

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Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CSF1R. In clinical studies, pacritinib was well tolerated with clinical activity in patients with myelofibrosis. The most frequent adverse events (AEs) observed with pacritinib are gastrointestinal (diarrhea, nausea, and vomiting; mostly grade 1-2 in severity) and typically resolve within 2 weeks. A human ADME mass balance study demonstrated that pacritinib is predominantly cleared via hepatic metabolism and biliary excretion (>85% of administered dose). The major hepatic metabolite identified, M1, is not thought to materially contribute to the pharmacological activity of pacritinib. Hepatic diseases are known to impair hepatic blood flow, drug-metabolizing enzymes, and biliary transport systems and may affect drug absorption, disposition, efficacy, and toxicity. This phase 1 study evaluated the pharmacokinetics (PK) and safety of pacritinib and the M1 metabolite in study subjects with mild, moderate, or severe hepatic impairment (HI) and matched healthy subjects with normal liver function to determine if pacritinib dosage adjustments are necessary for patients with varying degrees of hepatic insufficiency. Study participants (aged 18-85 y) were enrolled into 4 groups based on their degree of HI as defined by Child-Pugh Clinical Assessment Score: mild (n=8), moderate (n=8), severe (n=4), and healthy volunteers (n=8) matched for age, BMI, and sex. Individuals with concomitant renal dysfunction or progressive liver disease were excluded. A single 400 mg dose of pacritinib was administered to all participants. Blood samples were obtained for PK evaluation predose and at multiple time points postdose through 168 h. Key PK parameters evaluated included maximum plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration time curve (AUC) from hour zero to last measurable concentration (AUC0-t), AUC extrapolated to infinity (AUC0-∞), and apparent terminal elimination half-life (t1/2). Following treatment, pacritinib was quantifiable for all study participants at 1 h through 168 h postdose. Systemic pacritinib exposure was similar between healthy volunteers and individuals with mild HI. However, there was a significant difference between those with moderate and severe HI and healthy volunteers with respect to peak concentration (Cmax) and plasma exposure (AUC0-t, AUC0-∞). Mean Cmax decreased by 47% and 57% respectively in participants with moderate and severe HI vs matched healthy volunteers. Similarly, mean AUC0-t decreased by 36% and 45% and mean AUC0-∞ decreased by 46% and 48%, respectively in individuals with moderate and severe HI vs healthy volunteers. Mean t1/2 ranged from 51.5 to 74.9 h across all groups. The variability on exposure ranged from 17.8% to 51.8% across all groups. Systemic exposure of M1 was also significantly decreased in study participants with moderate or severe HI vs. healthy participants and individuals with mild HI. These changes were not significantly dissimilar from the inter-patient variability in these parameters observed in healthy volunteers. All AEs were grade 1-2 in severity. Diarrhea and headache were the only AEs reported in >1 participant (n=4 each). Based on these observations, it is unlikely that dosage adjustments would be warranted in patients with mild, moderate, or severe HI treated with pacritinib.

Keywords: pacritinib, myelofibrosis, hepatic impairment, pharmacokinetics

Procedia PDF Downloads 274

Authors: Kuo-Kai Lin, Po-Lun Chang

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Research Background and Purpose: Following the development of the Internet and multimedia, the Internet and information technology have become crucial avenues of modern communication and knowledge acquisition. The advantages of using mobile devices for learning include making learning borderless and accessible. Mobile learning has become a trend in disease management and health promotion in recent years. End-stage renal disease (ESRD) is an irreversible chronic disease, and patients who do not receive kidney transplants can only rely on hemodialysis or peritoneal dialysis to survive. Due to the complexities in caregiving for patients with ESRD that stem from their advanced age and other comorbidities, the patients’ incapacity of self-care leads to an increase in the need to rely on their families or primary caregivers, although whether the primary caregivers adequately understand and implement patient care is a topic of concern. Therefore, this study explored whether primary caregivers’ health care provisions can be improved through the intervention of an automatic speech intelligent system, thereby improving the objective health outcomes of patients undergoing long-term dialysis. Method: This study developed an automatic speech intelligent system with healthcare functions such as health information voice prompt, two-way feedback, real-time push notification, and health information delivery. Convenience sampling was adopted to recruit eligible patients from a hemodialysis center at a regional teaching hospital as research participants. A one-group pretest-posttest design was adopted. Descriptive and inferential statistics were calculated from the demographic information collected from questionnaires answered by patients and primary caregivers, and from a medical record review, a health care scale (recorded six months before and after the implementation of intervention measures), a subjective health assessment, and a report of objective physiological indicators. The changes in health care behaviors, subjective health status, and physiological indicators before and after the intervention of the proposed automatic speech intelligent system were then compared. Conclusion and Discussion: The preliminary automatic speech intelligent system developed in this study was tested with 20 pretest patients at the recruitment location, and their health care capacity scores improved from 59.1 to 72.8; comparisons through a nonparametric test indicated a significant difference (p < .01). The average score for their subjective health assessment rose from 2.8 to 3.3. A survey of their objective physiological indicators discovered that the compliance rate for the blood potassium level was the most significant indicator; its average compliance rate increased from 81% to 94%. The results demonstrated that this automatic speech intelligent system yielded a higher efficacy for chronic disease care than did conventional health education delivered by nurses. Therefore, future efforts will continue to increase the number of recruited patients and to refine the intelligent system. Future improvements to the intelligent system can be expected to enhance its effectiveness even further.

Keywords: automatic speech intelligent system for health care, primary caregiver, long-term hemodialysis, health care capabilities, health outcomes

Procedia PDF Downloads 88

Authors: A. F. C. Nassar, D. K. Tessler, L. Okuda, C. Del Fava, D. P. Chiebao, A. H. C. N. Romaldini, A. P. Alvim, M. J. Sanchez-Vazquez, M. S. Rosa, J. C. Pompei, R. Harakava, M. C. S. Araujo, G. H. F. Marques, E. M. Pituco

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Glanders is a zoonotic disease of Equidae caused by the bacterium Burkholderia mallei presented in acute or chronic clinical forms with inflammatory nodules in the respiratory tract, lymphangitis and caseous lymph nodes. There is not a treatment with veterinary drugs to this life-threatening disease; thus, its occurrence must be notified to official animal health services and any infected animal must be eliminated. This study aims to detect B. mallei from horses euthanized in outbreaks of glanders in Brazil, providing a better understanding of the bacterial characteristics and determine a proper protocol for isolation. The work was carried out with the collaboration of the Ministry of Agriculture and the Sao Paulo State Animal Health Department, while its procedures were approved by the Committee of Ethics in Animal Experimentation from the Instituto Biologico (CETEA n°156/2017). To the present time, 16 horses from farms with outbreaks of glanders detected by complement fixation test (CFT) serology method were analyzed. During the necropsy, samples of possibly affected organs (lymph nodes, lungs, heart, liver, spleen, kidneys and trachea) were collected for bacterial isolation, molecular tests and pathology. Isolation was performed using two enriched mediums, a potato infusion agar with 5% sheep blood, 4% glycerol and antibiotics (penicilin100U/ mL), and another with the same ingredients except the antibiotic. A PCR protocol was modified for this study using primers design to identify a region of the Flip gen of B. mallei. Thru isolation, 12.5% (2/16) animals were confirmed positive using only the enriched medium with antibiotic and confirmed by PCR: from mediastinal and submandibular lymph nodes and lungs in one animal and from mediastinal lymph node in the other. The detection of the bacterium using PCR showed positivity of 100% (16/16) horses from 144 samples of organs. Pathology macroscopic lesions observed were catarrhal nasal discharge, fetlock ulcers, emaciation, lymphangitis in limbs, suppurative lymphangitis, lymph node enlargement, star shaped liver, and spleen scars, adherence of the renal capsule, pulmonary hemorrhage, and miliary nodules. Microscopic lesions were suppurative bronchopneumonia with microabscesses and Langhans giant cells in lungs; lymph nodes with abscesses and intense lymphoid reaction; hemosiderosis and abscesses in spleen. Positive samples on PCR will be sequenced later and analyzed comparing with previous records in the literature. A throughout description of the recent acute cases of glanders occurring in Brazil and characterization of the bacterium related will contribute to advances in the knowledge of the pathogenicity, clinical symptoms, and epidemiology of this zoonotic disease. Acknowledgment: This project is sponsored by FAPESP.

Keywords: equines, bacterial isolation, zoonosis, PCR, pathology

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Authors: Pamela Chia, Tay Yoong Chuan

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Introduction: Severe pulmonary hypertension (PH) patients requiring non-cardiac surgery risk have increased mortality rates ranging. These patients are plagued with cardiorespiratory failure, dysrhythmias and anticoagulation potentially with concurrent sepsis and renal insufficiency, perioperative morbidity. We present a deaf-mute patient with severe idiopathic PH emergently prepared for ruptured ectopic laparotomy. Case Report: A 20 year-old female, 62kg (BMI 25 kg/m2) with severe idiopathic PH (2DE Ejection Fraction was 41%, Pulmonary Artery Systolic Pressure (PASP) 105 mmHg, Right ventricle strain and hypertrophy) and selective mutism was rushed in for emergency laparotomy after presenting to the emergency department for abdominal pain. The patient had an NYHA Class II with room air SpO2 93-95%. While awaiting lung transplant, the patient takes warfarin, Sildanefil, Macitentan and even Selexipag for rising PASP. At presentation, vital signs: BP 95/63, HR 119 SpO2 88% (room air). Despite decreasing haemoglobin 14 to 10g/dL, INR 2.59 was reversed with prothrombin concentrate, and Vitamin K. ECG revealed Right Bundle Branch Block with right ventricular strain and x-ray showed cardiomegaly, dilated Right Ventricle, Pulmonary Arteries, basal atelectasis. Arterial blood gas showed compensated metabolic acidosis pH 7.4 pCO2 32 pO2 53 HCO3 20 BE -4 SaO2 88%. The cardiothoracic surgeon concluded no role for Extracorporeal Membrane Oxygenation (ECMO). We inserted invasive arterial and central venous lines with blood transfusion via an 18G cannula before the patient underwent a midline laparotomy, haemostasis of ruptured ovarian cyst with 2.4L of clots under general anesthesia and FloTrac cardiac output monitoring. Rapid sequence induction was done with Midazolam/Propofol, remifentanil infusion, and rocuronium. The patient was maintained on Desflurane. Blood products and colloids were transfused for further 1.5L blood loss. Postoperatively, the patient was transferred to the intensive care unit and was extubated uneventfully 7hours later. The patient went home a week later. Discussion: Emergency hemostasis laparotomy in anticoagulated WHO Class I PH patient awaiting lung transplant with no ECMO backup poses tremendous stress on the deaf-mute patient and the anesthesiologist. Balancing hemodynamics avoiding hypotension while awaiting hemostasis in the presence of pulmonary arterial dilators and anticoagulation requires close titration of volatiles, which decreases RV contractility. We review the contraindicated anesthetic agents (ketamine, N2O), choice of vasopressors in hypotension to maintain Aortic-right ventricular pressure gradients and nitric oxide use perioperatively. Conclusion: Interdisciplinary communication with a deaf-mute moribund patient and anesthesia considerations pose many rare challenges worth sharing.

Keywords: pulmonary hypertension, case report, warfarin reversal, emergency surgery

Procedia PDF Downloads 182

Authors: Nautiyal Ruchira, Nautiyal Hemant, Chaudhury Devnanda, Bhargava Surbhi, Chauhan Nidhi

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Introduction: South East Asian region contributes 2.5 million cases of malaria each year to the global burden of 300 to 500 million of which 76% is reported from India. Government of India launched a national program almost half a century ago, still malaria remains a major public health challenge. Pregnant women are more susceptible to severe malaria and its fetomaternal complications. Inadequate surveillance and under-reporting underestimates the problem. Aim: Present study aimed to analyze the clinical course and pattern of malaria during pregnancy and to study the feto-maternal outcome. Methodology: This is a prospective observational study carried out at Himalayan Institute of Medical Sciences – a tertiary care center in the sub-Himalayan state of Uttarakhand, Northern India. All the pregnant women with malaria and its complications were recruited in the study during 2009 to 2014 which included referred cases from the state of western Uttar Pradesh. A thorough history and clinical examination were carried out to assess maternal and fetal condition. Relevant investigations including haemogram, platelet count, LFT, RFT, and USG was done. Blood slides and rapid diagnostic tests were done to diagnose the type of malaria.The primary outcomes measured were the type of malaria infection, maternal complications associated with malaria, outcome of pregnancy and effect on the fetus. Results: 67 antenatal cases with malaria infection were studied. 71% patients were diagnosed with plasmodium vivax infection, 25% cases were plasmodium falciparum positive and in 3% cases mixed infection was found. 38(56%) patients were primigravida and 29(43%) were multiparous. Most of the patients had already received some treatment from their local doctors and presented with severe malaria with the complications. Thrombocytopenia was the commonest manifestation seen in 35(52%) patients, jaundice in 28%, severe anemia in 18%, and severe oligohydramnios in 10% and renal failure in 6% cases. Regarding pregnancy outcome there were 44 % preterm deliveries, 22% had IUFD and abortions in 6% cases.20% of newborn were low birth weight and 6% were IUGR. There was only one maternal death which occurred due to ARDS in falciparum malaria. Although Plasmodium vivax was the main parasite considering the severity of clinical presentation, all the patients received intensive care. As most of the patients had received chloroquine therapy hence they were treated with IV artesunate followed by oral artemesinin combination therapy. Other therapies in the form of packed RBC’s and platelet transfusions, dialysis and ventilator support were provided when required. Conclusion: Even in areas with annual parasite index (API) less than 2 like ours, malaria in pregnancy could be an alarming problem. Vivax malaria cannot be considered benign in pregnancy because of high incidence of morbidity. Prompt diagnosis and aggressive treatment can reduce morbidity and mortality significantly. Increased community level research, integrating ANC checkups with the distribution of insecticide-treated nets in areas of high endemicity, imparting education and awareness will strengthen the existing control strategies.

Keywords: severe malaria, pregnancy, plasmodium vivax, plasmodium falciparum

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Authors: Luciano Tarantino

Abstract:

Gas gangrene is a rare, severe infection with a very high mortality rate caused by Clostridium species. The infection causes a non-suppurative localized producing gas lesion from which harmful toxins that impair the inflammatory response cause vessel damage and multiple organ failure. Gas gangrene of the liver is very rare and develops suddenly, often as a complication of abdominal surgery and liver transplantation. The present paper deals with a case of gas gangrene of the liver that occurred after percutaneous MW ablation of hepatocellular carcinoma, resulting in progressive liver necrosis and multi-organ failure in spite of specific antibiotics administration. The patient was successfully treated with percutaneous Radiofrequency ablation. Case report: Female, 76 years old, Child A class cirrhosis, treated with synchronous insertion of 3 MW antennae for large HCC (5.5 cm) in the VIII segment. 24 hours after treatment, the patient was asymptomatic and left the hospital . 2 days later, she complained of fever, weakness, abdominal swelling, and pain. Abdominal US detected a 2.3 cm in size gas-containing area, eccentric within the large (7 cm) ablated area. The patient was promptly hospitalized with the diagnosis of anaerobic liver abscess and started antibiotic therapy with Imipenem/cilastatine+metronidazole+teicoplanine. On the fourth day, the patient was moved to the ICU because of dyspnea, congestive heart failure, atrial fibrillation, right pleural effusion, ascites, and renal failure. Blood tests demonstrated severe leukopenia and neutropenia, anemia, increased creatinine and blood nitrogen, high-level FDP, and high INR. Blood cultures were negative. At US, unenhanced CT, and CEUS, a progressive enlargement of the infected liver lesion was observed. Percutaneous drainage was attempted, but only drops of non-suppurative brownish material could be obtained. Pleural and peritoneal drainages gave serosanguineous muddy fluid. The Surgeon and the Anesthesiologist excluded any indication of surgical resection because of the high perioperative mortality risk. Therefore, we asked for the informed consent of the patient and her relatives to treat the gangrenous liver lesion by percutaneous Ablation. Under conscious sedation, percutaneous RFA of GG was performed by double insertion of 3 cool-tip needles (Covidien LDT, USA ) into the infected area. The procedure was well tolerated by the patient. A dramatic improvement in the patient's condition was observed in the subsequent 24 hours and thereafter. Fever and dyspnea disappeared. Normalization of blood tests, including creatinine, was observed within 4 days. Heart performance improved, 10 days after the RFA the patient left the hospital and was followed-up with weekly as an outpatient for 2 months and every two months thereafter. At 18 months follow-up, the patient is well compensated (Child-Pugh class B7), without any peritoneal or pleural effusion and without any HCC recurrence at imaging (US every 3 months, CT every 6 months). Percutaneous RFA could be a valuable therapy of focal GG of the liver in patients non-responder to antibiotics and when surgery and liver transplantation are not feasible. A fast and early indication is needed in case of rapid worsening of patient's conditions.

Keywords: liver tumor ablation, interventional ultrasound, liver infection, gas gangrene, radiofrequency ablation

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Authors: Kyriaki Hatziagapiou, Eleni Kakouri, Konstantinos Bethanis, Alexandra Nikola, Eleni Koniari, Charalabos Kanakis, Elias Christoforides, George Lambrou, Petros Tarantilis

Abstract:

Medulloblastoma is a highly invasive tumour, as it tends to disseminate throughout the central nervous system early in its course. Despite the high 5-year-survival rate, a significant number of patients demonstrate serious long- or short-term sequelae (e.g., myelosuppression, endocrine dysfunction, cardiotoxicity, neurological deficits and cognitive impairment) and higher mortality rates, unrelated to the initial malignancy itself but rather to the aggressive treatment. A strong rationale exists for the use of Crocus sativus L (saffron) and its bioactive constituents (crocin, crocetin, safranal) as pharmaceutical agents, as they exert significant health-promoting properties. Crocins are water soluble carotenoids. Unlike other carotenoids, crocins are highly water-soluble compounds, with relatively low toxicity as they are not stored in adipose and liver tissues. Crocins have attracted wide attention as promising anti-cancer agents, due to their antioxidant, anti-inflammatory, and immunomodulatory effects, interference with transduction pathways implicated in tumorigenesis, angiogenesis, and metastasis (disruption of mitotic spindle assembly, inhibition of DNA topoisomerases, cell-cycle arrest, apoptosis or cell differentiation) and sensitization of cancer cells to radiotherapy and chemotherapy. The current research aimed to study the potential cytotoxic effect of crocins on TE671 medulloblastoma cell line, which may be useful in the optimization of existing and development of new therapeutic strategies. Crocins were extracted from stigmas of saffron in ultrasonic bath, using petroleum-ether, diethylether and methanol 70%v/v as solvents and the final extract was lyophilized. Identification of crocins according to high-performance liquid chromatography (HPLC) analysis was determined comparing the UV-vis spectra and the retention time (tR) of the peaks with literature data. For the biological assays crocin was diluted to nuclease and protease free water. TE671 cells were incubated with a range of concentrations of crocins (16, 8, 4, 2, 1, 0.5 and 0.25 mg/ml) for 24, 48, 72 and 96 hours. Analysis of cell viability after incubation with crocins was performed with Alamar Blue viability assay. The active ingredient of Alamar Blue, resazurin, is a blue, nontoxic, cell permeable compound virtually nonfluorescent. Upon entering cells, resazurin is reduced to a pink and fluorescent molecule, resorufin. Viable cells continuously convert resazurin to resorufin, generating a quantitative measure of viability. The colour of resorufin was quantified by measuring the absorbance of the solution at 600 nm with a spectrophotometer. HPLC analysis indicated that the most abundant crocins in our extract were trans-crocin-4 and trans-crocin-3. Crocins exerted significant cytotoxicity in a dose and time-dependent manner (p < 0.005 for exposed cells to any concentration at 48, 72 and 96 hours versus cells not exposed); as their concentration and time of exposure increased, the reduction of resazurin to resofurin decreased, indicating reduction in cell viability. IC50 values for each time point were calculated ~3.738, 1.725, 0.878 and 0.7566 mg/ml at 24, 48, 72 and 96 hours, respectively. The results of our study could afford the basis of research regarding the use of natural carotenoids as anticancer agents and the shift to targeted therapy with higher efficacy and limited toxicity. Acknowledgements: The research was funded by Fellowships of Excellence for Postgraduate Studies IKY-Siemens Programme.

Keywords: crocetin, crocin, medulloblastoma, saffron

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Authors: Claire Williams

Abstract:

Randomised controlled Trials (RCTs) of efficacy are still perceived as the gold standard for the generation of evidence, and whilst advances in data collection methods are well developed, this progress has not been matched for the reporting of adverse events (AEs). Assessment and reporting of AEs in clinical trials are fraught with human error and inefficiency and are extremely time and resource intensive. Recent research conducted into the quality of reporting of AEs during clinical trials concluded it is substandard and reporting is inconsistent. Investigators commonly send reports to sponsors who are incorrectly categorised and lacking in critical information, which can complicate the detection of valid safety signals. In our presentation, we will describe an electronic data capture system, which has been designed to support clinical trial processes by reducing the resource burden on investigators, improving overall trial efficiencies, and making trials safer for patients. This proprietary technology was developed using expertise proven in the delivery of the world’s first prospective, phase 3b real-world trial, ‘The Salford Lung Study, ’ which enabled robust safety monitoring and reporting processes to be accomplished by the remote monitoring of patients’ EHRs. This technology enables safety alerts that are pre-defined by the protocol to be detected from the data extracted directly from the patients EHR. Based on study-specific criteria, which are created from the standard definition of a serious adverse event (SAE) and the safety profile of the medicinal product, the system alerts the investigator or study team to the safety alert. Each safety alert will require a clinical review by the investigator or delegate; examples of the types of alerts include hospital admission, death, hepatotoxicity, neutropenia, and acute renal failure. This is achieved in near real-time; safety alerts can be reviewed along with any additional information available to determine whether they meet the protocol-defined criteria for reporting or withdrawal. This active surveillance technology helps reduce the resource burden of the more traditional methods of AE detection for the investigators and study teams and can help eliminate reporting bias. Integration of multiple healthcare data sources enables much more complete and accurate safety data to be collected as part of a trial and can also provide an opportunity to evaluate a drug’s safety profile long-term, in post-trial follow-up. By utilising this robust and proven method for safety monitoring and reporting, a much higher risk of patient cohorts can be enrolled into trials, thus promoting inclusivity and diversity. Broadening eligibility criteria and adopting more inclusive recruitment practices in the later stages of drug development will increase the ability to understand the medicinal products risk-benefit profile across the patient population that is likely to use the product in clinical practice. Furthermore, this ground-breaking approach to AE detection not only provides sponsors with better-quality safety data for their products, but it reduces the resource burden on the investigator and study teams. With the data taken directly from the source, trial costs are reduced, with minimal data validation required and near real-time reporting enables safety concerns and signals to be detected more quickly than in a traditional RCT.

Keywords: more comprehensive and accurate safety data, near real-time safety alerts, reduced resource burden, safer trials

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Authors: Gousilin Leandra Rocha Da Silva, Stéfani T. A. Dantas, Bruna F. Rossi, Erika R. Bonsaglia, Ivana G. Castilho, Terue Sadatsune, Ary Fernandes Júnior, Vera l. M. Rall

Abstract:

Kidney failure causes decreased diuresis and accumulation of nitrogenous substances in the body. To increase patient survival, hemodialysis is used as a partial substitute for renal function. However, contamination of the water used in this treatment, causing bacteremia in patients, is a worldwide concern. The Burkholderia cepacia complex (Bcc), a group of bacteria with more than 20 species, is frequently isolated from hemodialysis water samples and comprises opportunistic bacteria, affecting immunosuppressed patients, due to its wide variety of virulence factors, in addition to innate resistance to several antimicrobial agents, contributing to the permanence in the hospital environment and to the pathogenesis in the host. The objective of the present work was to characterize molecularly and phenotypically Bcc isolates collected from the water and dialysate of the Hemodialysis Unit and from the blood of patients at a Public Hospital in Botucatu, São Paulo, Brazil, between 2019 and 2021. We used 33 Bcc isolates, previously obtained from blood cultures from patients with bacteremia undergoing hemodialysis treatment (2019-2021) and 24 isolates obtained from water and dialysate samples in a Hemodialysis Unit (same period). The recA gene was sequenced to identify the specific species among the Bcc group. All isolates were tested for the presence of some genes that encode virulence factors such as cblA, esmR, zmpA and zmpB. Considering the epidemiology of the outbreak, the Bcc isolates were molecularly characterized by Multi Locus Sequence Type (MLST) and by pulsed-field gel electrophoresis (PFGE). The verification and quantification of biofilm in a polystyrene microplate were performed by submitting the isolates to different incubation temperatures (20°C, average water temperature and 35°C, optimal temperature for group growth). The antibiogram was performed with disc diffusion tests on agar, using discs impregnated with cefepime (30µg), ceftazidime (30µg), ciprofloxacin (5µg), gentamicin (10µg), imipenem (10µg), amikacin 30µg), sulfametazol/trimethoprim (23.75/1.25µg) and ampicillin/sulbactam (10/10µg). The presence of ZmpB was identified in all isolates, while ZmpA was observed in 96.5% of the isolates, while none of them presented the cblA and esmR genes. The antibiogram of the 33 human isolates indicated that all were resistant to gentamicin, colistin, ampicillin/sulbactam and imipenem. 16 (48.5%) isolates were resistant to amikacin and lower rates of resistance were observed for meropenem, ceftazidime, cefepime, ciprofloxacin and piperacycline/tazobactam (6.1%). All isolates were sensitive to sulfametazol/trimethoprim, levofloxacin and tigecycline. As for the water isolates, resistance was observed only to gentamicin (34.8%) and imipenem (17.4%). According to PFGE results, all isolates obtained from humans and water belonged to the same pulsotype (1), which was identified by recA sequencing as B. cepacia¸, belonging to sequence type ST-767. By observing a single pulse type over three years, one can observe the persistence of this isolate in the pipeline, contaminating patients undergoing hemodialysis, despite the routine disinfection of water with peracetic acid. This persistence is probably due to the production of biofilm, which protects bacteria from disinfectants and, making this scenario more critical, several isolates proved to be multidrug-resistant (resistance to at least three groups of antimicrobials), turning the patient care even more difficult.

Keywords: hemodialysis, burkholderia cepacia, PFGE, MLST, multi drug resistance

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Authors: Keshari Shrestha, Philip Vatterott

Abstract:

Introduction: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially fatal drug-related syndrome. DRESS classically presents with a diffuse maculopapular rash, fevers, and eosinophilia more than three weeks after drug exposure. DRESS can present with multi-organ involvement, with liver damage being the most common and severe. Pulmonary involvement is a less common manifestation and is associated with poor clinical outcomes. Chest imaging is often nonspecific, and symptoms can range from mild cough to acute respiratory distress syndrome (ARDS) . This is a case of a 49-year-old female with a history of recent clostridium difficile colitis status post treatment with oral vancomycin who presented with rash, acute liver and kidney failure, as well as diffuse nodular alveolar lung opacities concerning for DRESS syndrome with multi-organ involvement. Clinical Course: This patient initially presented to an outside hospital with clostridium difficile colitis, acute liver injury, and acute kidney injury. She developed a desquamating maculopapular rash in the setting of recent oral vancomycin, meloxicam, and furosemide initiation. She was hospitalized on two additional occasions with worsening altered mental status, liver injury, and acute kidney injury and was initiated on intermittent hemodialysis. Notably, she was found to have systemic eosinophilia (4100 cells/microliter) several weeks prior. She was transferred to this institution for further management where she was found to have encephalopathy, jaundice, lower extremity edema, and diffuse bilateral rhonchorous breath sounds on pulmonary examination. The patient was started on methylprednisolone for suspected DRESS syndrome. She underwent an evaluation for alternative causes of her organ failure. Her workup included a negative infectious, autoimmune, metabolic, toxic, and malignant work-up. Abdominal computed tomography (CT) and ultrasound were remarkable for evidence of hepatic steatosis and possible cirrhotic morphology. Additionally, a chest CT demonstrated diffuse and symmetric nodular alveolar lung opacities with peripheral sparing not consistent with acute respiratory distress syndrome or edema. Ultimately, her condition continued to decline, and she required intubation on several occasions. On hospital day 25 she succumbed to distributive shock in the setting of probable sepsis and multi-organ failure. Discussion: DRESS syndrome occurs in 1 in 1,000 to 10,000 patients with a mortality rate of around 10%. Anti-convulsant, anti-bacterial, anti-viral, and sulfonamide drugs are the most common drugs implicated in the development of DRESS syndrome; however, the list of offending agents is extensive . The diagnosis of DRESS syndrome is made after excluding other causes of disease such as infectious and autoimmune etiologies. The RegiSCAR scoring system is used to diagnose DRESS syndrome with 2-3 points indicating possible disease, 4-5 probable disease, and >5 definite disease. This patient scored a 7 on the RegiSCAR scale for eosinophilia, rash, organ involvement, and exclusion of other causes (infectious and autoimmune). While the pharmacologic trigger in this case is unknown, it is speculated to be caused by vancomycin, meloxicam, or furosemide due to the favorable timeline of initiation. Despite aggressive treatment, DRESS syndrome can often be fatal. Because of this, early diagnosis and treatment of patients with suspected DRESS syndrome is imperative.

Keywords: drug reaction with eosinophilia and systemic symptoms, multi-organ failure, pulmonary involvement, renal failure

Procedia PDF Downloads 144

Authors: Ziyad S. Haidar

Abstract:

Background: Saliva plays a major role in maintaining oral, dental, and general health and well-being; where it normally bathes the oral cavity acting as a clearing agent. This becomes more apparent when the amount and quality of saliva are significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the 5th most common malignancy worldwide, during which the salivary glands are included within the radiation field/zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely as they become malnourished and experience a significant decrease in their QoL. Accordingly, the formulation of a radio-protection/-prevention modality and development of an alternative Rx to restore damaged salivary gland tissue is eagerly awaited and highly desirable. Objectives: Assess the pre-clinical radio-protective effect and reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs, followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: cancer, head and neck, oncology, drug development, drug delivery systems, nanotechnology, nanoncology

Procedia PDF Downloads 49

Authors: Ziyad S. Haidar

Abstract:

Background: Saliva plays a major role in maintaining oral and dental health (consequently, general health and well-being). Where it normally bathes the oral cavity and acts as a clearing agent. This becomes more apparent when the amount and quality of salivare significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the fifth most common malignancy worldwide, during which the salivary glands are included within the radiation field or zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely because they become malnourished and experience a significant decrease in their quality of life. Accordingly, the development of an alternative treatment to restore or regenerate damaged salivary gland tissue is eagerly awaited. Likewise, the formulation of a radioprotection modality and early damage prevention strategy is also highly desirable. Objectives: To assess the pre-clinical radio-protective effect as well as the reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned in this experimental work for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs (in solution and powder formats), followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy (revised from our previous 15Gy model) was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: saliva, head and neck cancer, nanotechnology, controlled drug delivery, xerostomia, mucositis, biopolymers, innovation

Procedia PDF Downloads 58