Calibrating a network meta-analysis of diabetes trials of sodium glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor analogues and dipeptidyl peptidase-4 inhibitors to a representative routine population: a systematic review protocol.

INTRODUCTION: Participants in randomised controlled trials (trials) are generally younger and healthier than many individuals encountered in clinical practice. Consequently, the applicability of trial findings is often uncertain. To address this, results from trials can be calibrated to more representative data sources. In a network meta-analysis, using a novel approach which allows the inclusion of trials whether or not individual-level participant data (IPD) is available, we will calibrate trials for three drug classes (sodium glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) receptor analogues and dipeptidyl peptidase-4 (DPP4) inhibitors) to the Scottish diabetes register. METHODS AND ANALYSIS: Medline and EMBASE databases, the US clinical trials registry (clinicaltrials.gov) and the Chinese Clinical Trial Registry (chictr.org.cn) will be searched from 1 January 2002. Two independent reviewers will apply eligibility criteria to identify trials for inclusion. Included trials will be phase 3 or 4 trials of SGLT2 inhibitors, GLP1 receptor analogues or DPP4 inhibitors, with placebo or active comparators, in participants with type 2 diabetes, with at least one of glycaemic control, change in body weight or major adverse cardiovascular event as outcomes. Unregistered trials will be excluded.We have identified a target population from the population-based Scottish diabetes register. The chosen cohort comprises people in Scotland with type 2 diabetes who either (1) require further treatment due to poor glycaemic control where any of the three drug classes may be suitable, or (2) who have adequate glycaemic control but are already on one of the three drug classes of interest or insulin. ETHICS AND DISSEMINATION: Ethical approval for IPD use was obtained from the University of Glasgow MVLS College Ethics Committee (Project: 200160070). The Scottish diabetes register has approval from the Scottish A Research Ethics Committee (11/AL/0225) and operates with Public Benefit and Privacy Panel for Health and Social Care approval (1617-0147). PROSPERO REGISTRATION NUMBER: CRD42020184174.

Acute and sub-chronic toxicological evaluation of Averrhoa carambola leaves in Sprague Dawley rats.

Averrhoa carambola is a species of tree native to tropical Southeast Asia. It possesses antioxidant and anti-hyperlipidemia effects and has traditionally been used to treat a variety of ailments. However, the presence of oxalic acid in its fruits might restrict its consumption by individuals suffering from kidney disease, and caramboxin can cause neurotoxicity. In this study, we evaluated the acute and sub-chronic toxicity of the methanolic extract of A. carambola leaves (MEAC) in male and female rats. In the acute study, female rats were given a single oral dose of 5000 mg/kg of MEAC and closely examined for distinct indications of toxic effects during the first 4 h, periodically for 48 h, and daily thereafter for 14 days. Rats of both sexes were employed in the sub-chronic investigation for the 28-day repeated dose oral toxicity study. Results of the acute study revealed the safety of MEAC up to a dose of 5000 mg/kg where the rats did not show changes or signs of toxicity. In the sub-chronic toxicity study, MEAC (250, 500, and 1000 mg/kg) administration did not affect the body weight, food, and water consumption, motor coordination, behavior, or mental alertness in the treated rats. In addition, no variations in hematological or biochemical markers were found in MEAC-treated rats. In conclusion, these findings pinpoint the safety of MEAC at doses up to 5000 mg/kg. The leaves of A. carambola could be safely consumed by people with kidney disease to treat other ailments.

Association between type 1, type 2 cytokines, diabetic autoantibodies and 25-hydroxyvitamin D in children with type 1 diabetes.

PURPOSE: Vitamin D may play a role in the pathogenesis of type 1 diabetes (T1D). The aim of the current study was to determine the possible association between 25-hydroxyvitamin D [25(OH)D] levels and circulating levels of type 1 and type 2 cytokines, as well as the pathophysiology of T1D in children. METHODS: A total of 250 T1D patients and 250 sex- and age-matched T1D-free controls were screened for 25(OH)D, hemoglobin A1c (HbA1c), type 1 and type 2 cytokines, C-reactive protein (CRP) and bone mineral metabolism, as well as antibodies against insulin, glutamic acid decarboxylase (anti-GAD 65) and islet cells. RESULTS: Our data showed that the plasma level of 25(OH)D was significantly lower in T1D patients and that there was a significant negative correlation between 25(OH)D levels and HbA1c values. There was a significant association between deficient levels of 25(OH)D and higher levels of cytokines (IFN-γ, TNF-α, IL-6, IL-1ß, IL-4 and IL-10) and CRP. Total blood hemoglobin, the hematocrit percentage, body mass index SDS values, phosphate and magnesium levels were significantly lower in T1D patients than in T1D-free subjects. The levels of parathyroid hormone and alkaline phosphatase were significantly higher in T1D patients. Higher levels of cytokines were significantly associated with deficient levels of 25(OH)D. Moreover, in T1D patients, higher levels of islet antibodies, anti-GAD antibodies and anti-insulin antibodies were significantly associated with deficient levels of 25(OH)D. CONCLUSIONS: In type 1 diabetic children, deficient levels of 25(OH)D are associated with high levels of HbA1c, circulatory cytokines and antibody markers.

An assessment of diabetes-related knowledge among registered nurses working in hospitals in Jordan.

BACKGROUND: Nurses play a vital role in caring for people with diabetes where knowledge constitutes the cornerstone of this care. AIM: This study assessed the level of Jordanian nurses' perceived and actual knowledge of diabetes and examined the relationship between nurses' actual knowledge of diabetes and their different characteristics. METHODS: A cross-sectional descriptive design was used to report knowledge regarding diabetes. Registered nurses were asked to complete self-administered questionnaires. The Diabetes Self-Report Tool and the Modified Diabetes Basic Knowledge Test were used to assess nurses' perceived and actual knowledge of diabetes. RESULTS: A total of 277 out of the 450 eligible registered nurses accepted to participate and returned questionnaires from seven hospitals in Jordan. Nurses in this study mostly demonstrated a knowledge deficit in clinical and theoretical-based topics, such as initial treatment of hypoglycaemia, insulin storage and preparation; meal planning and duration of action with hypoglycaemic agents. Nurses' actual knowledge of diabetes was positively correlated with their perceived knowledge, perceived competence and level of education. LIMITATIONS: Study participants were selected using convenience sampling. The length of time needed for nurses exceeded 50 min to complete study questionnaires. CONCLUSIONS: This study examined current knowledge among Jordanian registered nurses regarding diabetes. A knowledge deficit regarding diabetes was demonstrated by the nurses who participated in this study. The role of continuing education is essential to supporting nurses' knowledge of complex clinical conditions, such as diabetes. Adequate implementation and dissemination of evidence-based guidelines on caring for people with diabetes is a prerequisite to improve the nurses' knowledge. IMPLICATION FOR NURSING AND HEALTH POLICY: Promoting continuing education in diabetes for nurses requires continuous effort and creativity. Healthcare system administrators must acknowledge and prioritize the need for this education.

Viral hepatitis E outbreak in Al-Sadr city, Baghdad, Iraq.

Hepatitis E virus (HEV) is a major cause of acute hepatitis in many developing countries. This study describes an outbreak of HEV infection in Al-Sadr city, Baghdad. Blood samples obtained from patients with jaundice attending 19 primary health care centres in AI-Sadr city during a 6-month period in 2005 were tested for HEV. HEV (IgM) antibodies were detected in 38.1% of 268 patients. The association of HEV infection with unacceptable residual chlorine concentrations and/or bacteriologically unsafe water samples was significant. High rates of HEV infection, low chlorine concentrations and unsafe water were reported in June. Gross isruption of sanitation and water supplies was the most likely contributing factor.

Predictive value of assessment of different modalities in the diagnosis of infantile cholestasis.

This study investigated the relative accuracy and roles of abdominal ultrasonography, hepatobiliary scintigraphy and liver biopsy in the diagnosis of infantile cholestasis. A total of 50 infants (27 females) aged 1 - 12 months were classified into those with intrahepatic causes of cholestasis (n = 22) and those with extrahepatic causes (n = 28). Cholestasis is caused by a wide range of conditions and diagnosis requires meticulous history taking, thorough clinical examination and many laboratory tests. The most common cause of intrahepatic cholestasis was found to be idiopathic neonatal hepatitis (54.5%), followed by infectious hepatitis (9.1%), metabolic liver diseases (9.1%), intrahepatic biliary atresia (9.1%) and Alagille syndrome (4.5%). The most common cause of extrahepatic cholestasis was extrahepatic biliary atresia (96.4%). The incidence of choledochal cyst was low (3.6%). The cornerstone of the diagnosis of infantile cholestasis was found to be liver biopsy, which was associated with a high degree of accuracy.

Viral hepatitis E outbreak in Al Sadr city, Baghdad, Iraq

Hepatitis E virus [HEV] is a major cause of acute hepatitis in many developing countries. This study describes an outbreak of HEV infection in Al-Sadr city, Baghdad. Blood samples obtained from patients with jaundice attending 19 primary health care centres in Al-Sadr city during a 6-month period in 2005 were tested for HEV. HEV [IgM] antibodies were detected in 38.1% of 268 patients. The association of HEV infection with unacceptable residual chlorine concentrations and/or bacteriologically unsafe water samples was significant. High rates of HEV infection, low chlorine concentrations and unsafe water were reported in June. Gross disruption of sanitation and water supplies was the most likely contributing factor

Metoclopramide protection of cholinesterase from paraoxon inhibition.

This study evaluated the protective effect of the benzamide compound metoclopramide (MCP) against inhibition by paraoxon (POX) as assessed by red blood cell acetylcholinesterase (RBC-AChE) activity. Three groups of 6 rats each were used. All substances were applied ip daily for 5 d, followed by a 2-d rest. The 7-d cycle was repeated 6 times. Group 1 received 100 nM POX, Group 2 received 50 microM MCP. Group 3 received 100 nM POX + 50 microM MCP. Red blood cell acetylcholinesterase measurements were performed at base line and then after each 7-d cycle. Enzyme activities were compared using the Mann-Whitney rank order test. Metoclopramide conferred significant in vivo protection from inhibition of RBC-AChE by POX.

Paraoxon induces apoptosis in EL4 cells via activation of mitochondrial pathways.

The toxicity of organophosphorus compounds, such as paraoxon (POX), is due to their anticholinesterase action. Recently, we have shown that, at noncholinergic doses (1 to 10 nM), POX (the bioactive metabolite of parathion) causes apoptotic cell death in murine EL4 T-lymphocytic leukemia cell line through activation of caspase-3. In this study, by employing caspase-specific inhibitors, we extend our observations to elucidate the sequence of events involved in POX-stimulated apoptosis. Pretreatment of EL4 cells with the caspase-9-specific inhibitor zLEHD-fmk attenuated POX-induced apoptosis in a dose-dependent manner, whereas the caspase-8 inhibitor zIETD-fmk had no effect. Furthermore, the activation of caspase-9, -8, and -3 in response to POX treatment was completely inhibited in the presence of zLEHD-fmk, implicating the involvement of caspase 9-dependent mitochondrial pathways in POX-stimulated apoptosis. Indeed, under both in vitro and in vivo conditions, POX triggered a dose- and time-dependent translocation of cytochrome c from mitochondria into the cytosol, as assessed by Western blot analysis. Investigation of the mechanism of cytochrome c release revealed that POX disrupted mitochondrial transmembrane potential. Neither this effect nor cytchrome c release was dependent on caspase activation, since the general inhibitor of the caspase family zVAD-fmk did not influence both processes. Finally, POX treatment also resulted in a time-dependent up-regulation and translocation of the proapoptotic molecule Bax to mitochondria. Inhibition of this event by zVAD-fmk suggests that the activation and translocation of Bax to mitochondria is subsequent to activation of the caspase cascades. The results indicate that POX induces apoptosis in EL4 cells through a direct effect on mitochondria by disrupting its transmembrane potential, causing the release of cytochrome c into the cytosol and subsequent activation of caspase-9. Inhibition of this specific pathway might provide a useful strategy to minimize organophosphate-induced poisoning.

Increase in neuronal nitric oxide synthase content of the gastroduodenal tract of diabetic rats.

This study examined the changes occurring in the pattern of distribution and expression of neuronal nitric oxide synthase (nNOS)-positive nerves in the gastroduodenal tract of streptozotocin-induced diabetic rats. The ganglion cells of the myenteric plexus of the gastric antrum of normal rats contain nNOS. We also observed nNOS-positive neurons and fibres in the myenteric plexus of the duodenum of normal rats. After the onset of diabetes, the number and intensity of staining of nNOS-positive nerve profiles in the gastric antrum and duodenum did not change significantly. However, Western blotting showed a significant increase in the expression of nNOS after the onset of diabetes. In conclusion, diabetes of 4 and 32 weeks duration induced an increase in the tissue content of nNOS in the gastroduodenum of rat. The increase in the level of nNOS in the gastroduodenum of diabetic rats may explain why impaired gastric emptying is common in patients with diabetes.

Influence of paraoxon (POX) and parathion (PAT) on apoptosis: a possible mechanism for toxicity in low-dose exposure.

The acute effects of poisoning with organophosphorus compounds (OPCs) are well known and have been described extensively. Most of the clinical symptoms are due to inhibition of acetylcholinesterase. Although acute OPC poisoning is a well-established clinical entity, the existence of chronic poisoning due to exposure to low levels of OPC (below the threshold required for cholinergic clinical symptoms) is a hotly debated issue. Recent studies have suggested the involvement of OPCs in apoptotic processes. However, the mechanisms by which they modulate this process are poorly investigated. In the present study we evaluated the toxic effect of different concentrations of paraoxon (POX) and parathion (PAT) in murine EL4 T lymphocytes. We examined cellular responses, including induction of apoptosis, involvement of a caspase cascade, the activity of effector caspase (caspase-3) and the biochemical and morphological changes that are the hallmarks of classical apoptosis. The results of our study indicate that at doses below IC(50) POX is a potent inducer of apoptosis, as opposed to PAT that shows little apoptotic effect.

Effect of malathion on apoptosis of murine L929 fibroblasts: a possible mechanism for toxicity in low dose exposure.

While acute organophosphorous compound poisoning due to inhibition of acetylcholinesterase is a well-established clinical entity, the existence of chronic poisoning due to exposure to low levels of organophosphorous compounds (below the threshold required for cholinergic clinical symptoms) is a hotly debated issue. In this study, we have evaluated the effects of noncholinergic doses of malathion (0.01-20 microM) on apoptosis of murine L929 fibroblasts. Employing flow cytometric and caspase activation analyses we demonstrate that malathion induces apoptosis in L929 cells in a dose- and time-dependent manner. The initiator caspases (caspase-8 and caspase-9) as well as the effector caspase (caspase-3) were activated by the treatment of L929 cells with malathion. Exposure of L929 cells to malathion in the presence of a general inhibitor of caspase, z-VAD-FMK abolished the apoptotic effect of the compound. In addition, malathion induced an increase in the expression of the pro-apoptotic protein p53. However, the induction of p53 expression was subsequent to activation of the caspase cascades. The present findings suggest, that the cytotoxicity of malathion at noncholinergic doses is mediated through caspase-dependent apoptosis.

Laparoscopy versus laparotomy management of tubal pregnancy.

OBJECTIVE: To compare laparoscopy versus laparotomy management of tubal pregnancy and the reproductive outcome. METHODS: A retrospective chart review of 81 patients admitted for management of tubal pregnancy was carried out at Riyadh Armed Forces Hospital from January 1998 until January 2000. The patients were divided according to surgical procedure performed into: Group I (33 patients) laparoscopy and group II (48 patients) laparotomy. We evaluated pre and postoperative serum b-human chorionic gonadotrophin levels, total operating time, total blood loss or blood transfusion or both, duration of hospital stay, recurrence rates of ectopic pregnancy and future fertility outcome for all patients. RESULTS: No differences were found between both groups in patient age, parity, size of adnexal mass, condition at the time of presentation, site of tubal pregnancy, previous history of ectopic, pre and postoperative serum b-human chorionic gonadotrophin and the total operating time. There were significant reductions of total blood loss, number of blood transfusion units, and duration of hospital stay, in the laparoscopic group compared to the laparotomy group. A total of 54 patients desired pregnancy, 23 patients in the laparoscopy and 31 patients in the laparotomy group. No significant differences were found in the fertility outcome between both groups. The rates of subsequent intrauterine pregnancy were 74% (17/23) in the laparoscopy group and 61%, (19/31) in the laparotomy group and the rates of subsequent ectopic pregnancy were 4% (1/23) in the laparoscopy group and 10% (3/31) in the laparotomy group. CONCLUSION: Laparoscopic treatment of ectopic pregnancy in hemodynamically stable patients offers major economic benefits superior to laparotomy in terms of less need for blood transfusion, shorter duration of hospital stay and convalescence.

Protective effect of folinic acid on low-dose methotrexate genotoxicity.

INTRODUCTION: Methotrexate (MTX) is an antineoplastic agent widely used in low dose to treat patients with rheumatoid arthritis (RA). Its side effects can partly be explained by folate antagonism. Folinic acid (Leucovorin) is generally administered with MTX to decrease MTX-induced toxicity. However information regarding the inhibitory effect of folinic acid against cytogenetic damage caused by MTX is limited. The aim of this study was to assess the protective effect of folinic acid against MTX-genotoxicity. METHODS: This study was done on Wistar albino rats and in patients with RA. Forty rats of both sexes were randomized into four equal groups and dosed in the following way: Group-I, distilled water vehicle; Group-II, 0.5 mg/kg folinic acid; Group-III, 0.5 mg/kg MTX; Group-IV, 0.5 mg/kg folinic acid plus 0.5 mg/kg MTX. Doses were given i.p., once daily for 8 consecutive days. A bone marrow chromosomal study and a micronucleus test were performed for each rat. Twenty patients with RA (5 males and 15 females) on a 10 mg weekly dose of MTX, i.m., for one month, were administered the same dose of MTX in addition to 10 mg of folinic acid as a single dose 4 hours after MTX administration, i.m., every week for another 4 weeks. Chromosomal studies as well as a micronucleus test were evaluated for each patient. RESULTS: MTX produced a significant genetic injury as proved by the increased incidence of chromosomal aberration and micronuclei formation in Group-III animals. Inversely, folinic acid (group IV) produced a significant protection against genetic damages induced by MTX. In RA patients, folinic acid provides satisfactory improvement of MTX-induced genetic damage. CONCLUSION: Folinic acid has a protective affect against MTX genotoxicity in human as well as in animal models.

Stillbirths in Qatar: a review of 83 cases.

To evaluate the aetiology, diagnostic procedures and current management of stillbirths in Qatar, 83 stillbirths with a birth weight of more than 500 g were studied. The validity of the cause of death was classified as certain, probable and unexplained. Frequency and descriptive statistics were used. The stillbirth rate was 8.15 per 1000. The cause of death was certain in 29%, probable in 62% and remained entirely unexplained in 9% of the cases. The major factors that might be the causes of fetal death were intrauterine growth retardation (23%), abruptio placentae (16.3%), congenital anomalies (13.3%), gestational diabetes (9.6%) and hydrops fetalis (7.2%). The cause of death was found unavoidable in 24 cases (29%). The autopsy rate was terribly low (1/80) and far away from the recommended rate of 75%. The introduction of a stillbirth programme, that includes post-mortem autopsy, in any maternity hospital, is considered crucial to reach a specific diagnosis for almost all stillbirths and to prevent fetal death in future pregnancies. However, if the patient or her family refused autopsy, a combination of patience and learned communication can pave the way to their understanding and acceptance of the procedure. Postmortem magnetic resonance imaging may be used as alternative to autopsy if it is refused.

Mechanism of H(+)-coupled formate transport in rabbit renal microvillus membranes.

It has been proposed that a major fraction of Cl- absorption in the mammalian proximal tubule occurs by Cl-/formate exchange across the apical membrane with recycling of formate by nonionic diffusion. The purpose of this study was to characterize the mechanism of formate recycling in rabbit renal microvillus membrane vesicles. Formate uptake was stimulated by an inside-alkaline pH gradient. When external pH (pH alpha) was varied at constant internal pH (pHi), the initial rate of formate uptake was less than predicted for nonionic diffusion of formic acid at constant formic acid permeability. When pHi was varied at constant pHi, the initial rate of formate uptake exhibited cooperative and saturable kinetics with respect to pHi, in contrast to the pHi independence predicted for nonionic diffusion. pH gradient-stimulated [14C]formate uptake was stimulated by internal formate, indicating formate/formate exchange. pH gradient-stimulated formate influx was sensitive to inhibition by 1 mM 4,4'-diisothiocyanostilbene-2, 2'-disulfonic acid but not by furosemide or hydroxycinnamate. We conclude that pH gradient-stimulated formate uptake takes place by a carrier-mediated process of H(+)-formate cotransport, OH-/formate exchange, or facilitated formic acid diffusion, rather than solely by passive nonionic diffusion through the lipid bilayer.

Electrophoretic polymorphism in rabbit tear lysozyme.

Rabbit tears were found to contain two lysozymes which differed in their electrophoretic mobility and were designated tear lysozymes 1 and 2. Rabbit tear lysozyme 1 was purified to homogeneity by conventional purification methods. It was found to be distinct from other known mammalian c-type lysozymes, rabbit tear lysozyme 2 and the major rabbit gastrointestinal lysozyme. The activity profile is centered around the neutral region with an optimum of 7 which is slightly lower than that for chicken lysozyme. The thermal stability as well as inhibition profiles by the substrate analogues, N-acetylglucosamine (NAG) and chitotetraose (NAG)4 are comparable to those of chicken lysozyme. Based on its molecular weight and catalytic properties this isozyme is classified as a c-type lysozyme.

Papillary immature metaplasia of the cervix: a distinct subset of exophytic cervical condyloma associated with HPV-6/11 nucleic acids.

A subset of exophytic cervical precursor lesions are composed of immature metaplastic cells that differ from conventional condylomata by the virtual absence of koilocytotic atypia and the presence of slender filiform papillae. We evaluated a series of exophytic cervical lesions containing this morphology for HPV nucleic acids and compared the associated HPV types with conventional exophytic condylomata of the cervix. Six of six exophytic condylomata and five of six papillary immature metaplasias (PIM), respectively, contained HPV type 6/11 by in situ hybridization. Subtyping of three PIM by polymerase chain reaction combined with direct sequencing revealed nucleic acid sequences consistent with HPV 6/11. PIM were distinguished from high-grade squamous intraepithelial lesions by the rarity of mitoses and by the uniformity of nuclear size and staining intensity with multiple chromocenters. However, these lesions tended to involve the more cephalad region of the cervical transformation zone, and three cases extended deeply into the endocervix with two requiring conization for a definitive diagnosis. Although their bland morphology and association with HPV 6/11 nucleic acids suggest a benign process, their location within the endocervical canal implies that these variants of condyloma may differ biologically from conventional exophytic condylomas of the cervix. The differential diagnosis of PIM and potential explanations for their distinctive morphology, are discussed.

Intracellular H+ buffering power and its dependency on intracellular pH.

Intracellular hydrogen ion (H+) buffering power, conventionally defined as the amount of acid or base that would have to be introduced into the cell cytosol to decrease or increase ipH by one pH unit, is generally said to increase as intracellular pH (ipH) decreases. This implies that the cell has a lesser capability to resist acute acid or base perturbations at its steady state ipH than at any lower ipH. We re-examined this notion, reasoning that the logarithmic nature of the pH unit could limit the validity of the conventional expression of buffering power in imparting physiologic insight into the mechanisms of cellular H+ homeostasis. The mathematical derivation of the formula, delta i[NH4+]/delta ipH, conventionally used to estimate buffering power using the NH4Cl technique, revealed that this parameter is, by design, inversely proportional to the exponential of ipH. This a priori dependence on pH dictates an increase in buffering power with decreasing ipH, and thereby interferes with the assessment of the physiologic capability of the intracellular milieu to buffer protons at different ipH levels. To circumvent this problem, buffering power was defined as the amount of hydrogen ions that would have to be added to or removed from the cell to effect a change in the concentration of H+ in the cell cytosol of 1 mM (a term heretofore referred to as the cell H+ buffering coefficient). The mathematical derivation of the formula used to calculate the cell H+ buffering coefficient, delta i[NH4+]/delta[H+]i, does not suffer from an a priori dependence on ipH.(ABSTRACT TRUNCATED AT 250 WORDS)