Calciphylaxis in uraemic and nonuraemic settings: clinical risk factors and histopathological findings.

BACKGROUND: Calciphylaxis is a life-threatening cutaneous ulcerative/necrotic disease characterized by vascular calcification/occlusion. It occurs most commonly in end-stage kidney disease (ESKD), known as uraemic calciphylaxis (UC) but can also occur in patients with chronic kidney disease (CKD) and normal kidney function (nonuraemic calciphylaxis; NUC). There are few large series of NUC in the literature. AIM: To compare the clinicopathological features of UC and NUC. METHODS: We retrospectively compared the clinicopathological features of 35 patients with NUC during the period 2010-2020 with those of 53 patients with UC (control group). Cases were classified as NUC in the absence of all of the following: ESKD, significant CKD (defined as serum creatinine > 3 mg/dL or creatinine clearance < 15 mL/min) and acute kidney injury requiring kidney replacement therapy or kidney transplantation. RESULTS: NUC represented 40% of the total cases, and there was a higher number of women (P < 0.01) and a higher median body mass index (P = 0.06) compared with the control UC group. Elevated parathyroid hormone was present in 44% of patients with NUC. Most of the tested patients were positive for lupus anticoagulants (56%). NUC biopsies showed a higher rate of extravascular calcium deposits (73% vs. 47%, P = 0.03). Dermal reactive vascular proliferation was the most common dermal change (32%). CONCLUSIONS: NUC is more common than previously reported and shows a higher predilection for obese postmenopausal women. Undiagnosed hyperparathyroidism shows a possible association with NUC. Lupus anticoagulants were positive in most patients. NUC biopsies are more likely than UC biopsies to display extravascular calcium deposition.

Desulphurisation kinetics of thiophenic compound by sulphur oxidizing Klebsiella oxytoca SOB-1.

AIMS: The major aims of this study are to determine the capability of sulphur oxidizing bacterium (SOB-1) to desulphurize dibenzothiophene (DBT) and crude oil, detection of the reaction kinetics and identify the proposed pathway of DBT desulphurization. METHODS AND RESULTS: The isolate was genetically identified based on 16S rRNA gene sequencing as Klebsiella oxytoca and deposited in the Genebank database under the accession number: MT355440. The HPLC analysis of the remaining DBT concentration revealed that, SOB-1 could desulphurize 90% of DBT (0·25 mmol l-1 ) within 96 h. The maximum production of sulphate ions from the desulphurization of DBT (0·36 mmol l-1 ) and crude oil (0·4 mmol l-1 ) could be quantitatively detected after 48 h of incubation at 30°C. The high values of correlation coefficient (R2 ) obtained at all studied concentrations; suggested that biodesulfurization kinetics of DBT follows the first-order reaction model. The kinetics studies showed that, DBT may have an inhibitory effect on SOB-1 when the initial concentration exceeded 0·75 mmol l-1 . The GC-MS analysis exhibited four main metabolites rather than DBT. The most important ones are 2-hydroxybiphenyl (2-HBP) and methoxybiphenyl n(2-MBP). CONCLUSIONS: Klebsiella oxytoca SOB-1 catalyzes the desulphurization of DBT through 4S pathway and forms four main metabolic products. The release of sulphate ion and formation of 2-HBP indicating the elimination of sulphur group without altering the carbon skeleton of DBT. The bacterial strain could also catalyzes desulphurization of crude oil. The desulphurization kinetics follows the first-order reaction model. SIGNIFICANCE AND IMPACT OF THE STUDY: Klebsiella oxytoca SOB-1 could be used as a promising industrial and environmental biodesulfurizing agent as it is not affecting carbon skeleton of thiophenic compounds and forming less toxic metabolic product (2-MBP).

COVID-19 in people living with diabetes: An international consensus.

The COVID-19 pandemic has added an enormous toll to the existing challenge of diabetes care world-wide. A large proportion of patients with COVID-19 requiring hospitalization and/or succumbing to the disease have had diabetes and other chronic conditions as underlying risk factors. In particular, individuals belonging to racial/ethnic minorities in the U.S. and other countries have been significantly and disproportionately impacted. Multiple and complex socioeconomic factors have long played a role in increasing the risk for diabetes and now for COVID-19. Since the pandemic began, the global healthcare community has accumulated invaluable clinical experience on providing diabetes care in the setting of COVID-19. In addition, understanding of the pathophysiological mechanisms that link these two diseases is being developed. The current clinical management of diabetes is a work in progress, requiring a shift in patient-provider interaction beyond the walls of clinics and hospitals: the use of tele-medicine when feasible, innovative patient education programs, strategies to ensure medication and glucose testing availability and affordability, as well as numerous ideas on how to improve meal plans and physical activity. Notably, this worldwide experience offers us the possibility to not only prepare better for future disasters but also transform diabetes care beyond the COVID-19 era.

Managing People with Diabetes Fasting for Ramadan During the COVID-19 Pandemic: A South Asian Health Foundation Update.

The month of Ramadan forms one of the five pillars of the Muslim faith. Adult Muslims are obligated to keep daily fasts from dawn to sunset, with exceptions. This year Ramadan is due to begin on 23 April 2020 and the longest fast in the UK will be approximately 18 hours in length. In addition, due to the often high-calorie meals eaten to break the fast, Ramadan should be seen as a cycle of fasting and feasting. Ramadan fasting can impact those with diabetes, increasing the risk of hypoglycaemia, hyperglycaemia and dehydration. This year, Ramadan will occur during the global COVID-19 pandemic. Reports show that diabetes appears to be a risk factor for more severe disease with COVID-19. In addition, the UK experience has shown diabetes and COVID-19 is associated with dehydration, starvation ketosis, diabetic ketoacidosis and hyperosmolar hyperglycaemic state. This makes fasting in Ramadan particularly challenging for those Muslims with diabetes. Here, we discuss the implications of fasting in Ramadan during the COVID-19 pandemic and make recommendations for those with diabetes who wish to fast.

The South Asian Health Foundation (UK) guidelines for managing diabetes during Ramadan.

BACKGROUND: Fasting in the holy month of Ramadan is among the five pillars of Islam and is considered as a religious obligation by the Muslim population. People with diabetes observing the practice of fasts are at a higher risk of complications such as hypoglycaemia, hyperglycaemia and ketoacidosis due to changes in eating patterns and circadian rhythms. With the objective of mitigating these complications, the South Asian Health Foundation (UK) has developed the present guidelines based on robust evidence derived from epidemiological studies and clinical trials. METHODS: We have highlighted the role of pre-Ramadan risk stratification and counselling by healthcare professionals with emphasis on the need for advice on adequate dietary and fluid intake, blood glucose monitoring and awareness of when to break the fast. RESULTS: We reviewed the current literature and have given clinically-relevant recommendations on lifestyle modifications and glucose-lowering therapies such as metformin, sulphonylureas, dipeptidyl peptidase-4 inhibitors, sodium glucose co-transporter-2 inhibitors, thiazolidinediones, glucagon-like peptide-1 receptor agonists and insulin. CONCLUSIONS: An individualised patient-centric treatment plan is essential to not only achieve optimal glycaemic outcomes but also enable people with diabetes to observe a risk-free month of fasting during Ramadan.

Multi-country retrospective observational study of the management and outcomes of patients with Type 2 diabetes during Ramadan in 2010 (CREED).

AIM: To describe the characteristics and management of patients with diabetes who chose to fast during Ramadan in 2010. METHODS: This was a multi-country, retrospective, observational study, supplemented with physician and patient questionnaires, with data captured before, during and after Ramadan. A total of 508 physicians in 13 countries enrolled 3777 patients and a total of 3394 evaluable cases were analysed. We report on the subset of patients with Type 2 diabetes, which included 3250 patients (95.8%). RESULTS: Oral anti-hyperglycaemic therapy was the predominant pre-Ramadan therapy for most patients (76.6%). The treatment regimen was modified before Ramadan for 39.3% of all patients (34.9% for patients on oral drugs alone, 47.1% for patients on injectable drugs alone). Almost all physicians (96.2%) reported providing fasting-specific advice to patients and 62.6% report using guidelines or recommendations for the management of diabetes during Ramadan. In all, 64% of patients reported fasting everyday of Ramadan and 94.2% fasted for at least 15 days. CONCLUSIONS: Physicians have increasingly adopted multiple approaches to the management of fasting during Ramadan, including the adoption of international and/or national guidelines, providing fasting-specific advice and adjusting treatment regimens, such that patients are able to fast for a greater number of days without acute complications. Additional research is needed to explore physician and patient beliefs and practices to inform the evidence-based management of diabetes while fasting, both during and outside of Ramadan, and to identify and address barriers to the universal uptake of techniques to facilitate that management.

Assessment of physical inactivity and perceived barriers to physical activity among health college students, south-western Saudi Arabia.

Physical inactivity is a public health problem in Saudi Arabia. A cross-sectional study was carried out to evaluate the pattern of physical activity, predictors of physical inactivity and perceived barriers to physical activity among health college students in King Khalid University. A total of 1257 students (426 males and 831 females) were recruited. The Arabic short form of the International Physical Activity Questionnaire was used. Overall, 58.0% of the students were physically inactive. Only 13.4% of the students performed vigorous physical activity, 14.8% moderate-intensity physical activity and 29.9% walking activities which met World Health Organization criteria of health-enhancing physical activities. The prevalence of inactive leisure time was 47.5%. The independent predictors of physical inactivity were non-membership of sports clubs and being a medical student. The top reported barrier to physical activity among inactive students was time limitations (51.3%). Overcoming perceived barriers may increase physical activity among students.

Treatment adherence with vildagliptin compared to sulphonylurea as add-on to metformin in Muslim patients with type 2 diabetes mellitus fasting during Ramadan.

OBJECTIVE: To assess treatment adherence to dipeptidyl peptidase-4 inhibitor vildagliptin compared with sulphonylureas (SU) in Muslim patients with type 2 diabetes mellitus who were fasting during Ramadan in the UK. RESEARCH DESIGN AND METHODS: This prospective, observational cohort study was conducted in four UK centres. Patients already taking vildagliptin (50 mg twice a day) or an SU as add-on therapy to metformin were followed up for ≤16 weeks. They were asked to record all missed doses of anti-diabetes medications. RESULTS: Of the 72 patients enrolled (vildagliptin, n = 30; SU, n = 41; not allocated to treatment, n = 1), 59 (81.9%) completed the study (vildagliptin, n = 23; SU, n = 36), including one patient in the SU arm who completed but failed to provide information on missed doses; all patients in the SU arm were taking gliclazide. In the vildagliptin arm one patient (4.3%) missed a total of four doses while in the SU arm 10 patients (27.8%) missed a total of 266 doses (mean [SD] number of doses missed per patient: 26.6 [16.5]). The mean (SD) proportions of doses missed during fasting were 0.2% (0.9) and 10.4% (21.7) in the vildagliptin and SU arms, respectively, with a significant mean between-group difference of -10.2% (95% CI: -19.3%, -1.1%; p = 0.0292). There were no patients in the vildagliptin arm who missed more than 20% of OAD doses compared with 19.4% in the SU arm (p = 0.0358). Of the patients receiving an SU, 15 (42%) collectively reported 34 hypoglycaemic events (HEs) and one grade 2 HE; of these, fewer were non-adherent (n = 6, 40%) than adherent (n = 9, 60%). No patients reported HEs in the vildagliptin arm. CONCLUSION: During Ramadan fasting, treatment with vildagliptin resulted in better treatment adherence compared with SU in Muslim patients with type 2 diabetes mellitus. Study limitations are the sample size and the lack of diet and exercise data.

Ramadan Education and Awareness in Diabetes (READ) programme for Muslims with Type 2 diabetes who fast during Ramadan.

BACKGROUND AND AIMS: During Ramadan, Muslims fast from dawn to dusk for one lunar month. The majority of Muslim diabetic patients are unaware of complications such as hypoglycaemia during fasting. The safety of fasting has not been assessed in the UK Muslim population with diabetes. The aim of this study was to determine the impact of Ramadan-focused education on weight and hypoglycaemic episodes during Ramadan in a Type 2 diabetic Muslim population taking oral glucose-lowering agents. METHODS: We retrospectively analysed two groups. Group A attended a structured education programme about physical activity, meal planning, glucose monitoring, hypoglycaemia, dosage and timing of medications. Group B did not. Hypoglycaemia was defined as home blood glucose < 3.5 mmol/l. RESULTS: There was a mean weight loss of 0.7 kg after Ramadan in group A, compared with a 0.6-kg mean weight gain in group B (P < 0.001). The weight changes observed were independent of the class of glucose-lowering agents used. There was a significant decrease in the total number of hypoglycaemic events in group A, from nine to five, compared with an increase in group B from nine to 36 (P < 0.001). The majority were in patients treated with short-acting sulphonylureas (group A-100%, group B-94%). At 12 months after attending the programme, glycated haemoglobin (HbA(1c)) reduction were sustained in group A. CONCLUSIONS: Ramadan-focused education in diabetes can empower patients to change their lifestyle during Ramadan. It minimizes the risk of hypoglycaemic events and prevents weight gain during this festive period for Muslims, which potentially benefits metabolic control.

Comparison of Humalog Mix 50 with human insulin Mix 30 in type 2 diabetes patients during Ramadan.

AIMS: To compare hypoglycaemic events, glycated haemoglobin (HbA1c) and changes in body weight in Muslim patients with Type 2 diabetes receiving Humalog Mix 50 and human Mixtard 30 twice daily during Ramadan fasting. METHODS: Data were collected from Muslim patients with Type 2 diabetes attending primary care practices in North-West London, who were on Mixtard 30 insulin twice daily before Ramadan. Group 1 had their evening insulin changed to Humalog Mix 50 (n = 26) 2 weeks before Ramadan, i.e. taking Mixtard 30 at predawn meal and Humalog Mix 50 at the sunset meal during Ramadan. As the major proportion of the daily caloric intake was consumed at the sunset meal, the rationale of switching the evening dose from human Mixtard 30 to Humalog Mix 50 was to provide more rapid-acting insulin that has shorter time of onset and peak time for the large evening meal to improve the postprandial glucose control without increasing the risk of hypoglycaemia. Group 2 continued on Mixtard 30 twice daily (n = 26). All patients received structured education about how to identify and manage hypoglycaemia during Ramadan. RESULTS: Group 1 had a mean HbA1c reduction of 0.48% (p = 0.0001) before and after Ramadan, whereas group 2 had a mean HbA1c increase of 0.28% (p = 0.007). Group 1 was associated with a small reduction of 0.04 (p = 0.81) in the mean number of hypoglycaemic events during Ramadan compared with before Ramadan, whereas group 2 was associated with an increase of 0.15 (p = 0.43), although these differences between the groups were not statistically significant following adjustment for baseline factors [LSM difference between groups = 0.135, p = 0.36, 95% confidence limits (-0.16, 0.43)]. CONCLUSION: Changing to humalog Mix 50 during Ramadan resulted in improvement in glycaemic control without increasing the incidence of hypoglycaemia.

Chronic hepatitis C virus infection: prevalence of cryoglobulinemia and renal affection in the Egyptian patients.

The association between mixed cryoglobulinemia (MC), chronic hepatitis C virus (CHC), and renal insufficiency was documented. This paper aimed to determine the prevalence of cryoglobulinemia (CG), and renal affection drug-naïve Egyptian patients suffering from CHC-in a cross-sectional study So, 53 patients with CHC and 20 healthy controls were included. Parameters investigated covered; HCV antibodies, HCV RNA, liver profile (AST, ALT, serum albumin, total bilirubin, prothrombin time), renal profile (urea, uric acid, creatinine clearance, urinary albumin), CG, C3, C4, & three MDRD equations to calculate the GFR. The results showed that CG was found in all patients, but none in controls. The renal markers showed that none of the patients suffered frank nephropathy, but were at increased risk for developing kidney disease.

Vildagliptin therapy and hypoglycaemia in Muslim type 2 diabetes patients during Ramadan.

AIMS: To compare hypoglycaemic events, glycated haemoglobin (HbA(1c)) and changes in bodyweight in metformin-treated Muslim patients with type 2 diabetes receiving adjunctive treatment with vildagliptin or gliclazide during Ramadan fasting. METHODS: Data were collected from Muslim patients with type 2 diabetes attending primary care practices in North West London, whose HbA(1c) was > 8.5% despite treatment with metformin 2 g daily before Ramadan and who received gliclazide 160 mg twice daily (n = 26) or vildagliptin 50 mg twice daily (n = 26) in addition to metformin. Hypoglycaemic events, HbA(1c) and weight were recorded 2 weeks before and 10 days after the Ramadan fast. All patients received education about how to identify and manage hypoglycaemia during Ramadan. RESULTS: During Ramadan, at least one hypoglycaemic event (defined as blood glucose < 3.5 mmol/l with or without symptoms) was recorded in two patients receiving vildagliptin (7.7%) and 16 patients receiving gliclazide [61.5%; difference between groups -53.8%, 95% confidence interval (CI) -74.9 to -26.3, p < 0.001]. Vildagliptin was associated with a reduction in the mean number of hypoglycaemic events during Ramadan compared with before Ramadan, whereas gliclazide was associated with an increase (least squares mean difference between groups -0.66, 95% CI -1.20 to -0.13, p = 0.0168). Both gliclazide and vildagliptin were associated with similar reductions in HbA(1c) and a small, but insignificant, increase in weight. CONCLUSIONS: Appropriate treatment adjustments can lead to improved diabetes management during Ramadan, with avoidance of significant weight gain and improved glucose control without hypoglycaemia. The addition of vildagliptin to metformin therapy during Ramadan in Muslim patients with type 2 diabetes was associated with a reduction in the incidence of hypoglycaemia.

Protein processing by the placental protease, cathepsin P.

Cathepsin P is a member of a family of placentally expressed cathepsins (PECs). The closest human homolog of cathepsin P is cathepsin L, a broad specificity enzyme that has functions in many tissues in addition to placenta. The gene duplications that gave rise to the PECs provide a rare opportunity to define proteolytic functions in placenta, a transient organ unique to mammals. Peptidyl substrate and inhibitor libraries have shown that cathepsin P has evolved an unusually restricted preference for substrates containing hydrophobic amino acids. Proteomic techniques were used to probe for substrates of this enzyme. Recombinant cathepsin P was incubated with rat choriocarcinoma (Rcho-1) cell proteins to identify substrates using two-dimensional difference gel electrophoresis. Substrate proteins were excised from gels and characterized by trypsin digestion and MALDI MS/MS. Two endoplasmic reticulum (ER) proteins, gp96 and calreticulin, emerged as potential substrates, and western blotting showed that these proteins are processed by cathepsin P from their C-terminus, removing the KDEL ER retention signal. Immunohistochemistry showed that a portion of cathepsin P co-localizes with calreticulin in Rcho-1 cells. Extracellular calreticulin induces differentiation of Rcho-1 cells, indicating a potential role of cathepsin P in processing and secretion of calreticulin during differentiation of trophoblast giant cells.

Role of cathepsins in blastocyst hatching in the golden hamster.

The mammalian embryo is encased in a glycoproteinaceous coat, the zona pellucida (ZP) during preimplantation development. Prior to implantation, the blastocyst must undergo 'hatching' or ZP escape. In hamsters, there is a thinning of the ZP followed by a focal lysis and a complete dissolution of the ZP during blastocyst hatching. Earlier studies from our laboratory have indicated a role for cysteine proteases in the hatching phenomenon. In this study, we tested the effect of specific inhibitors of the three classes of cysteine protease on blastocyst hatching. Cystatin, an endogenous cathepsin inhibitor, blocked blastocyst hatching. Similarly, Fmoc-Tyr-Ala-diazomethane, a synthetic cathepsin inhibitor, blocked hatching. Both showed dose-dependent and temporal inhibition of hatching. However, Z-Val-Ala-Asp-fluoromethylketone, a synthetic caspase inhibitor, and calpastatin, an endogenous calpain inhibitor, had no effect on hatching. The cathepsins were localized to blastocyst cells. Exogenous addition of cathepsins L, P or B to cultured 8-cell embryos caused a complete ZP dissolution. The expression of mRNA and protein of cathepsins L and P was observed in peri-hatching blastocysts. Cathepsins L and P were detected in trophectodermal projections and in the ZP of peri-hatching blastocysts. These data provide the first evidence that blastocyst-derived cathepsins are functionally involved as zonalytic factors in the hatching of blastocysts in the golden hamster.

Expression of cathepsin P mRNA, protein and activity in the rat choriocarcinoma cell line, Rcho-1, during giant cell transformation.

Lysosomal proteases perform critical functions in protein turnover and are essential for normal growth and development. Cathepsin P is a member of a newly discovered family of lysosomal cysteine proteases uniquely expressed in rodent placenta (PECs), and is closely related to human cathepsin L. Using the rat choriocarcinoma cell line model, Rcho-1, mRNA for the PECs cathepsins P, M, Q, R, 1, 2 was found to increase in expression during differentiation into a trophoblast giant cell phenotype. By contrast, expression of cathepsin L was not regulated. A specific enzyme assay was developed to show that activity of cathepsin P mirrored mRNA expression during differentiation. Cathepsin P protein co-localizes with cathepsin B, indicating that the enzyme probably functions in the endosomal-lysosomal compartment. This study demonstrates that the PEC genes produce functional proteases that can perform specific placental roles that are probably performed by broader specificity proteases in human placenta.

An unusual cause of diabetic ketoacidosis and fulminant septicaemia.

BACKGROUND: Diabetic ketoacidosis (DKA) is a common medical emergency. Resistant and recurrent DKA can be due to underlying infection, and a detailed travel history may be important in determining the cause in such cases. We report here a case of unusual DKA and fulminant septicaemia in a Caucasian male with Type 1 diabetes 2 years after returning from living in Thailand. CASE REPORT: A 39-year-old Caucasian male was diagnosed with Type 1 diabetes whilst working in Thailand where he also subsequently developed a cavitating lung lesion diagnosed locally as pulmonary tuberculosis. Two years after returning to the UK he was admitted with DKA and septicaemia. Despite correction of his DKA his condition deteriorated and he developed a fluid collection anterior to the left hip on computed tomography scanning. Blood and fluid aspirate cultures confirmed a diagnosis of melioidosis, a rare fulminant septicaemia in the UK, but endemic in South-east Asia and tropical Australia. Full recovery followed changing antibiotics to intravenous ceftazidime with no relapse 3 years after acute episode. CONCLUSIONS: Physicians as well as microbiologists should consider melioidosis in anyone presenting with septicaemia and/or resistant DKA, especially if the history includes travel to endemic areas or if the cultures suggest Pseudomonas-like organism. With increasing international travel, it is crucial to remember that good travel history could be life-saving in some cases of septicaemia.