Network approach reveals preferential T-cell and macrophage association with α-linked ß-cells in early stage of insulitis in NOD mice.

One of the challenges in studying islet inflammation-insulitis-is that it is a transient phenomenon. Traditional reporting of the insulitis progression is based on cumulative, donor-averaged values of leucocyte density in the vicinity of pancreatic islets, that hinder intra- and inter-islet heterogeneity of disease progression. Here, we aimed to understand why insulitis is non-uniform, often with peri-insulitis lesions formed on one side of an islet. To achieve this, we demonstrated the applicability of network theory in detangling intra-islet multi-cellular interactions during insulitis. Specifically, we asked the question "What is unique about regions of the islet that interact with immune cells first". This study utilized the non-obese diabetic mouse model of type one diabetes and examined the interplay among α-, ß-, T-cells, myeloid cells, and macrophages in pancreatic islets during the progression of insulitis. Disease evolution was tracked based on the T/ß cell ratio in individual islets. In the early stage, we found that immune cells are preferentially interacting with α-cell-rich regions of an islet. At the islet periphery α-linked ß-cells were found to be targeted significantly more compared to those without α-cell neighbors. Additionally, network analysis revealed increased T-myeloid, and T-macrophage interactions with all ß-cells.

Network approach reveals preferential T-cell and macrophage association with α-linked ß-cells in early stage of insulitis in NOD mice.

One of the challenges in studying islet inflammation - insulitis - is that it is a transient phenomenon. Traditional reporting of the insulitis progression is based on cumulative, donor-averaged values of leucocyte density in the vicinity of pancreatic islets, that hinders intra- and inter-islet heterogeneity of disease progression. Here, we aimed to understand why insulitis is non-uniform, often with peri-insulitis lesions formed on one side of an islet. To achieve this, we demonstrated applicability of network theory in detangling intra-islet multi-cellular interactions during insulitis. Specifically, we asked the question "what is unique about regions of the islet which interact with immune cells first". This study utilized the non-obese diabetic mouse model of type one diabetes and examined the interplay among α-, ß-, T-cells, myeloid cells, and macrophages in pancreatic islets during the progression of insulitis. Disease evolution was tracked based on T/ß cell ratio in individual islets. In the early stage, we found that immune cells are preferentially interacting with α-cell-rich regions of an islet. At the islet periphery α-linked ß-cells were found to be targeted significantly more compared to those without α-cell neighbors. Additionally, network analysis revealed increased T-myeloid, and T-macrophage interactions with all ß-cells.

Employing neural density functionals to generate potential energy surfaces.

CONTEXT: With the union of machine learning (ML) and quantum chemistry, amid the debate between machine-learned functionals and human-designed functionals in density functional theory (DFT), this paper aims to demonstrate the generation of potential energy surfaces using computations with machine-learned density functional approximation (ML-DFA). A recent research trend is the application of ML in quantum sciences in the design of density functionals such as DeepMind's Deep Learning model (DeepMind21, DM21). Though science reported the state-of-the-art performance of DM21, the opportunity to utilize DeepMind's pretrained DM21 neural networks in computations in quantum chemistry has not yet been tapped. So far in the literature, the Deep Learning density functionals (DM21) have not been applied to generate potential energy surfaces. While the superior accuracy of DM21 has been reported, there is still a scarcity of publications that apply DM21 in calculations in the field. In this context, for the first time in literature, neural density functionals inferring 2D potential energy surfaces (ML-DFA-PES) based on machine-learned DFA-based computational method is contributed in this paper. This paper reports the ML-DFA-generated PES for C4H8, H2O, H2, and H2+ by employing a pretrained DM21m TensorFlow model with cc-pVDZ basis set. In addition, we also analyze the long-range behavior of DM21 based PES to investigate the ability to describe a system at long ranges. Furthermore, we compare PES diagrams from DM21 with popular DFT functionals (b3lyp/ PW6B95) and CCSD(T). METHODS: In this method, 2D potential energy surfaces are obtained using a method that relies upon the neural network's ability to accurately learn the mapping between 3D electron density and exchange-correlation potential. By inserting Deep Learning inference in DFT with a pretrained neural network, self-consistent field (SCF) energy at different geometries along the coordinates of interest is computed, and then, potential energy surfaces are plotted. In this method, first, the electron density is computed mathematically, and this computed 3D electron density is used as a ML feature vector to predict the exchange correlation potential as a ML inference computed by a forward pass of pre-trained DM21 TensorFlow computational graph, followed by the computation of self-consistent field energy at multiple geometries, and then, SCF energies at different bond lengths/angles are plotted as 2D PES. We implement this in a python source code using frameworks such as PySCF and DM21. This paper contributes this implementation in open source. The source code and DM21-DFA-based PES are contributed at https://sites.google.com/view/MLfunctionals-DeepMind-PES .

Comparison of peritoneal transport characteristics at the second week and at six months of peritoneal dialysis commencement.

Peritoneal equilibration test (PET) is an important tool for managing peritoneal dialysis (PD) prescription. The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines suggest that the first PET be performed 4-8 weeks after PD commencement. The main reason for this delay is because of the peritoneal membrane might change its character once it is exposed to the glucose based dialysate. In this study, we compared PET 2 weeks after PD commencement to PET after 6 months to evaluate the changes in the peritoneal membrane character with time. This study included 126 patients who underwent PD initiation between March 2007 and December 2011. The PET was performed as per the standard protocol at 2(nd) week and 6(th) month after PD initiation. Transport status was categorized as low, low average, high average, and high as per the standard definition. There was no change in transport character in 115 patients (91.2%) between the two PET measurements. When the Early PET at 2(nd) week and 6(th) month PET data were analyzed, no significant changes were observed in measured D/P creatinine (0.59 ± 0.14 vs. 0.62 ± 0.14 respectively P = 0.26) and D/D0 Glucose (0.46 ± 0.12 vs. 0.46 ± 0.11, P = 0.65). Using the Bland-Altman analysis the repeatability coefficients were 0.27 and 0.25 for creatinine and glucose values respectively. In our study, the PET performed at the 2(nd) week are similar to that of the 6(th) month PET in 91.2% of our patients and the test did not significantly change with time. In conclusion, we could do PET early at 2(nd) week to assess the peritoneal membrane character and this would help in proper dialysis prescription to the patients.

Synthesis and biological evaluation of delavayin-C.

The synthesis of a cyclic heptapeptide, delavayin-C, cyclo(gly-tyr-tyr-tyr-pro-val-pro) is described. The structure of this compound was established on the basis of analytical IR, (1)H NMR and FAB mass spectral data. The antibacterial and antifungal activities of this peptide are also described.

Omenn's Syndrome: A rare primary immunodeficiency disorder.

Over the last 17 years different forms of severe combined immunodeficiency have been diagnosed at Sultan Qaboos University Hospital, Muscat. Omenn's syndrome is a rare autosomal recessive form of severe combined immunodeficiency. We report a 6 weeks old Omani infant who presented with the characteristic clinical and immunological phenotype of Omenn's syndrome. We take the opportunity to discuss and review the immunological aspect of this rare syndrome.

Nodular Lymphocyte Predominant Hodgkin's Lymphoma Presenting as Severe Hypercalcaemia: A Case Report.

Nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) is a recently described type of Hodgkin's lymphoma (HL) and accounts for 5-6% of all the cases of HL. Here we report the case of an elderly man who presented to Sultan Qaboos University Hospital, Oman, with severe hypercalcemia, and was diagnosed to have stage IV NLPHL. Although the incidence of hypercalcemia is estimated to be between 1-5% in classical HL, to our knowledge this is the first report of NLPHL presenting with severe hypercalcemia. The patient responded to the anti-CD20 monoclonal antibody, Rituximab, and has been in clinical remission for more than 3 years.

Pattern of chronic diarrhoea in children: a prospective analysis of causes, clinical features and outcome.

OBJECTIVES: To determine the pattern of chronic diarrhoea in children in Oman. STUDY DESIGN: This is a prospective study carried out over a 7 year period at the Sultan Qaboos University Hospital, Muscat, Oman. SUBJECTS: Sixty two children (37 M:25 F), aged 3 months to 13 years who presented with chronic diarrhoea, defined as diarrhoea persisting for more than 4 weeks, were studied. RESULTS: Principal identifiable causes in the study population include post-gastroenteritis syndrome in 50% of cases, enteric infections and infestations in 27%, and coeliac disease in 13%. On presentation 63% were malnourished, 27% were anaemic while 39% were dehydrated. The median duration of hospital admission was 50 days. Majority of the patients responded to conservative therapy with correction of dehydration, and careful nutritional supplementation, in addition to specific therapy where necessary. Mortality was low (1.5%) resulting from immunodeficiency and gram-negative septicaemia. CONCLUSION: Chronic diarrhoea remains an important cause of morbidity especially malnutrition in children and early and adequate nutritional rehabilitation plays a pivotal role in the management.

The prognostic determinants of gastric cancer treatment outcome in Omani Arab patients.

BACKGROUND: Gastric cancer is the most common cancer in Oman and a leading cause of cancer death. The variation in survival rates between countries and ethnic groups has been attributed to early detection policies, differences in clinicopathological features, treatment approaches, and biological characteristics. There were no previous reports on gastric cancer from Oman and very few studies on Asian Arabs. AIM: To evaluate the impact of clinicopathological and treatment variables on the survival prospects of Omani Arab patients diagnosed with gastric cancer. METHODS: The medical records of 339 Omani Arab patients diagnosed with invasive gastric adenocarcinoma during the period 1993-2004 were retrospectively reviewed. The relative importance of clinicopathological features and surgical and medical treatments were assessed using univariate and multivariate analyses. RESULTS: Most patients had distal ulcerating-type gastric cancer and presented at advanced stages. The median survival time for the entire cohort was 12 months (95% CI 9.7-14.4) with a 5-year overall survival rate of 16.7%. On univariate analysis of 237 patients who underwent surgical resection, the following positive prognostic factors emerged as significant: early overall TNM stage, early T stage, negative lymph nodes, tumor size <5 cm, ulcerating macroscopic appearance, and curative surgical attempt. The independent prognostic factors on multivariate analysis were T stage and lymph node involvement. CONCLUSION: The overall T and N stages are the most important determining factor for survival in Omani Arab patients. More efforts need to be made for the early detection of gastric cancer in developing countries such as Oman, while continuing to employ the standard surgical and medical treatments.

The prognostic significance of p53, p27 kip1, p21 waf1, HER-2/neu, and Ki67 proteins expression in gastric cancer: a clinicopathological and immunohistochemical study of 121 Arab patients.

BACKGROUND: The variability of prognosis within a pathological stage of gastric cancer (GC) at presentation, underscores the need for specific biological markers to identify subgroups of patients with aggressive course for intensive treatment. To our knowledge, this is the first study from an Arab population reporting on the relationship of p53, p27 kip1, p21 waf1, HER-2/neu, and Ki67 expression, and clinicopathological features and their prognostic significance. METHODS: Formalin-fixed paraffin-embedded tumors were studied by immunohistochemistry, using monoclonal antibodies to p53, p27 kip1, p21 waf1, HER-2/neu, and Ki67. The results were correlated with clinicopathological features and survival. RESULTS: M:F = 80:41; median age = 60 years; stage III and IV = 71%; and median follow-up = 34.4 months. Positive expression rates of p53, p27 kip1, p21 waf1, Ki67, and HER-2/neu were 54%, 40%, 8.3%, 70%, and 12% respectively. p53 expression correlated with age <60 years (P = 0.03), tumor size >5 cm (P = 0.01), p27 kip1 and Ki67 expression (P = 0.0001), and HER-2/neu (P = 0.04). p21 waf1 correlated inversely with T-stage (P = 0.008) and Her-2/neu expression correlated with histological grade (P = 0.04) and T-stage (P = 0.008). Univariate analysis showed that p53 overexpression (P = 0.01), fungating and infiltrative macroscopic appearance (P = 0.02), size >5 cm (P = 0.0001), lymph node metastasis (P = 0.0001), p T3 and T4 disease (P = 0.01), and overall stage III and IV (P = 0.0001) disease were adverse prognostic factors. Patients with tumor profiles p53 (-)/p27 (+) had better survival than those with p53 (+)/p27 kip1 (-)(P = 0.02). On multivariate analysis by Cox regression model, the expression of p53 (P = 0.03) and lymph node involvement (P = 0.01) were significant adverse prognostic factors for overall survival. CONCLUSIONS: The expression of p53 in Arab patients with GC correlates with aggressive tumor characteristics and is an independent prognostic factor. The combined analysis of p53 and p27 kip1 is of added prognostic value.

Pattern of chronic liver disease in Omani children--a clinicopathological review.

OBJECTIVE: To determine the pattern of chronic liver disease in Omani children. STUDY DESIGN: Seventy six children [43M : 33F] aged 4 days to 10 years, referred to the Paediatric Gastroenterology clinic of the Sultan Qaboos University Hospital, Muscat, Oman, between 1995--2000 for evaluation of liver disease were studied. Liver biopsies were performed in all and tissues obtained processed and examined for histological lesions. RESULT: The main histological diagnoses were neonatal hepatitis (22) biliary atresia (9) biliary hypoplasia (7), cirrhosis (7) and congenital hepatic fibrosis (5). Hepatomegaly with or without jaundice was the indication for liver biopsy in the majority of patients studied. CONCLUSION: The study has provided background information on the occurrence of specific liver diseases in Omani children. Neonatal hepatitis syndrome was the most common diagnosis before the age of 2 years.

The outcome of treatment of breast cancer in a developing country--Oman.

The aim of the present study was to evaluate the outcome of treatment of breast cancer in Oman with an analysis of clinico-pathological features, treatment modalities utilized, and prognostic factors. One hundred fifty-two breast cancer patients diagnosed between January 1996 and June 2002 were evaluated retrospectively. Their mean age was 48.5 (S.D. +/- 10.8) years, and 48% of the female patients were premenopausal. The mean tumor size according to pathology was 4.6 (S.D. 3.29)cm, and 34.9% and 15.8% of patients had stage III or IV disease, respectively. Only 26.3% of the patients had breast-conserving surgery, and neoadjuvant chemotherapy was underutilized. The overall 5-year relapse-free survival (RFS) and overall (OS) survival rates were 62% and 64%, respectively. On multivariate analysis, axillary lymph node involvement and tumor differentiation were predictive of RFS and OS, respectively. Thus, breast cancer patients in Oman present with advanced stages of the disease at younger ages than their counterparts in the West and have lower survival rates. Increasing awareness and the introduction of screening programs and of a multidisciplinary approach are essential in Oman and other developing countries to improve the outcome of treatment.

Significance of p53, Bcl-2, and HER-2/neu protein expression in Omani Arab females with breast cancer.

Racial disparity in the presentation of breast cancer and the outcome of its treatment is well established. However, the causes remain unexplained. The scarcity of reports about the prognostic significance of p53, bcl-2, and HER-2/neu in Arab females with breast cancer has been the impetus to this study. We evaluated the prognostic significance of altered expression of p53, bcl-2, HER-2/neu in Omani Arab females with non-metastatic breast cancer with correlation to other established prognostic factors. We have retrospectively analyzed the immunohistochemical expression of p53, HER-2/neu and bcl-2 in paraffin embedded blocks of 72 females diagnosed with invasive breast cancer between 1992 and 2002. The expression of the above proteins was correlated with other prognostic factors and univariate and multivariate analysis was carried out for all prognostic factors. Overexpression of p53 significantly correlated with younger age (<40), pre-menopausal status, poor differentiation with inverse correlation with bcl-2 expression. Expression of bcl-2 immunopostivity significantly correlated to low histological grade and positive estrogen and progesterone receptor status. On univariate and multivariate p53 overexpression and lack of bcl-2 immunostaining resulted in worse survival outcome, but not Her-2/neu overexpression. Expression patterns of p53 and bcl-2 are independent predictors of survival in Omani Arab population which may help to stratify these patients into different risk groups.

Are scintigraphy and ultrasonography necessary before fine-needle aspiration cytology for thyroid nodules?

OBJECTIVE: To evaluate the efficacy of scintigraphy, ultrasound and fine-needle aspiration in thyroid nodules and to establish the best diagnostic pathway in detecting thyroid cancer. METHOD: Two hundred and sixteen patients with thyroid nodules were examined using high-resolution ultrasonography, 99mTc thyroid scintigraphy and ultrasound-guided fine-needle aspiration. Of these, 113 patients subsequently underwent thyroidectomy. The remaining 103 were followed up for two years without any evidence of malignancy. RESULTS: Cytopathology classified 71% of the aspirate as benign, 3% as positive for malignancy, 21% as suspected neoplasia and 5% as unsatisfactory. Fine-needle aspiration cytology had a sensitivity of 87.5% and specificity of 80%. On ultrasound 33% of malignant nodules were hypo-echoic and on scintigraphy 16% of solitary cold nodules were malignant. Neither test could reliably diagnose thyroid cancer. CONCLUSION: Ultrasound-guided fine-needle aspiration cytology should be the first test performed in euthyroid patients with a thyroid nodule. Scintigraphy and ultrasound imaging should be reserved for follow-up studies and patients who have suppressed levels of thyroid stimulating hormone.