Latent autoimmune diabetes in adults: A distinct but heterogeneous clinical entity

Latent autoimmune diabetes in adults (LADA) accounts for 2%-12% of all cases of diabetes. Patients are typically diagnosed after 35 years of age and are often misdiagnosed as type II Diabetes Mellitus (DM). Glycemic control is initially achieved with sulfonylureas but patients eventually become insulin dependent more rapidly than with type II DM patients. Although they have a type II DM phenotype, patients have circulating beta (β) cell autoantibodies, a hallmark of type I DM. Alternative terms that have been used to describe this condition include type 1.5 diabetes, latent type I diabetes, slowly progressive Insulin Dependent Diabetes Mellitus, or youth onset diabetes of maturity. With regards to its autoimmune basis and rapid requirement for insulin, it has been suggested that LADA is a slowly progressive form of type I DM. However, recent work has revealed genetic and immunological differences between LADA and type I DM. The heterogeneity of LADA has also led to the proposal of criteria for its diagnosis by the Immunology of Diabetes Society. Although many workers have advocated a clinically oriented approach for screening of LADA, there are no universally accepted criteria for autoantibody testing in adult onset diabetes. Following recent advances in immunomodulatory therapies in type I DM, the same strategy is being explored in LADA. This review deals with the contribution of the genetic, immunological and metabolic components involved in the pathophysiology of LADA and recent approaches in screening of this distinct but heterogeneous clinical entity.     

Non‐stress‐related factors associated with maternal corticotrophin‐releasing hormone (CRH) concentration

Kramer MS, Lydon J, Séguin L, Goulet L, Kahn SR, McNamara H, Genest J, Sharma S, Meaney MJ, Libman M, Dahhou M, Platt RW. Non‐stress‐related factors associated with maternal corticotrophin‐releasing hormone (CRH) concentration. Paediatric and Perinatal Epidemiology 2010. During pregnancy, most maternal corticotrophin‐releasing hormone (CRH) is secreted by the placenta, not the hypothalamus. Second trimester maternal CRH concentration is robustly associated with the subsequent risk of preterm birth, and it is often assumed that physiological and/or psychological stress stimulates placental CRH release. Evidence supporting the latter assumption is weak, however, and other factors affecting maternal CRH have received little attention from investigators. We carried out a case–control study nested within a large, multicentre prospective cohort of pregnant women to examine potential ‘upstream’ factors associated with maternal CRH concentration measured at 24–26 weeks of gestation. The predictors studied included maternal age, parity, birthplace (as a proxy for ethnic origin), pre‐pregnancy body mass index, height, smoking, bacterial vaginosis and vaginal fetal fibronectin (FFN) concentration. Women with high (above the median) plasma CRH concentration were significantly less likely to have been born in Sub‐Saharan Africa or the Caribbean, less likely to be overweight or obese, and more likely to be smokers. Associations with maternal birthplace and BMI persisted in logistic regression analyses controlling for potential confounding variables and when restricted to term controls. A strong (but imprecise and statistically non‐significant) association was also observed with high vaginal FFN concentration. Further studies are indicated both in animal models and human populations to better understand the biochemical and physiological pathways to CRH secretion and their aetiological role, if any, in preterm birth.     

1,3-Bis(2-chloroethyl)-1-nitrosourea enhances the inhibitory effect of Resveratrol on 5-fluorouracil sensitive/ resistant colon cancer cells

AIM:To study the mechanism of 5-fluorouracil(5-FU)resistance in colon cancer cells and to develop strategies for overcoming such resistance by combination treatment.METHODS:We established and characterized a 5-FU resistance(5-FU-R)cell line derived from continuous exposure(25μmol/L)to 5-FU for 20 wk in 5-FU sensitive HCT-116 cells.The proliferation and expression of different representative apoptosis and anti-apoptosis markers in 5-FU sensitive and 5-FU resistance cells were measured by the MTT assay and by Western blotting,respectively,after treatment with Resveratrol(Res)and/or 1,3-Bis(2-chloroethyl)-1-nitrosourea(BCNU).Apoptosis and cell cycle arrest was measured by 4’,6’-diamidino-2-phenylindole hydrochloride staining and fluorescence-activated cell sorting analysis,respectively.The extent of DNA damage was measured by the Comet assay.We measured the visible changes in the DNA damage/repair cascade by Western blotting.RESULTS:The widely used chemotherapeutic agents BCNU and Res decreased the growth of 5-FU sensitive HCT-116 cells in a dose dependent manner.Combined application of BCNU and Res caused more apoptosis in5-FU sensitive cells in comparison to individual treatment.In addition,the combined application of BCNU and Res caused a significant decrease of major DNA base excision repair components in 5-FU sensitive cells.We established a 5-FU resistance cell line(5-FU-R)from 5-FU-sensitive HCT-116(mismatch repair deficient)cells that was not resistant to other chemotherapeutic agents(e.g.,BCNU,Res)except 5-FU.The 5-FU resistance of 5-FU-R cells was assessed by exposure to increasing concentrations of 5-FU followed by the MTT assay.There was no significant cell death noted in5-FU-R cells in comparison to 5-FU sensitive cells after5-FU treatment.This resistant cell line overexpressed anti-apoptotic[e.g.,AKT,nuclear factorκB,FLICE-like inhibitory protein),DNA repair(e.g.,DNA polymerase beta(POL-β),DNA polymerase eta(POLH),protein Flap endonuclease 1(FEN1),DNA damage-binding protein 2(DDB2)]and 5-FU-res     

Gamma irradiation of medicinally important plants and the enhancement of secondary metabolite production

Purpose: The profitable production of some important plant-based secondary metabolites (ginsenosides, saponins, camptothecin, shikonins etc.) in vitro by gamma irradiation is a current area of interest. We reviewed different types of secondary metabolites, their mode of synthesis and effect of γ-radiation on their yield for different plants, organs and in vitro cultures (callus, suspension, hairy root). Special effort has been made to review the biochemical mechanisms underlying the increase in secondary metabolites. A comparison of yield improvement with biotic and abiotic stresses was made.

Results: Phenolic compounds increase with γ-irradiation in whole plants/plant parts; psoralen content in the common herb babchi (Psoralea corylifolia) was increased as high as 32-fold with γ-irradiation of seeds at 20 kGy. The capsaicinoids, a phenolic compound increased about 10% with 10 kGy in paprika (Capsicum annum L.). The in vitro studies show all the three types of secondary metabolites are reported to increase with γ-irradiation. Stevioside, total phenolic and flavonoids content were slightly increased in 15?Gy-treated callus cultures of stevia (Stevia rebaudiana Bert.). In terpenoids, total saponin and ginsenosides content were increased 1.4- and 1.8-fold, respectively, with 100?Gy for wild ginseng (Panax ginseng Meyer) hairy root cultures. In alkaloids, camptothecin yield increased as high as 20-fold with 20?Gy in callus cultures of ghanera (Nothapodytes foetida). Shikonins increased up to 4-fold with 16?Gy in suspension cultures of purple gromwell (Lithospermum erythrorhizon S.). The enzymes associated with secondary metabolite production were increased with γ-irradiation of 20?Gy; namely, phenylalanine ammonia-lyase (PAL) for phenolics, chalcone synthase (CHS) for flavonoids, squalene synthase (SS), squalene epoxidase (SE) and oxidosqualene cyclases (OSC) for ginsenosides and PHB (p-hydroxylbenzoic acid) geranyl transferase for shikonins.

Conclusions: An increase in secondary metabolites in response to various biotic and abiotic stresses is compared with ionizing radiation. A ～5- to 20-fold increase is noted with ～20?Gy irradiation dose. It increases the yield of secondary metabolites by enhancing the activity of certain key biosynthetic enzymes. Identification of the optimum dose is the important step in the large-scale production of secondary metabolites at industrial level.     

Impurity profile study of loratadine

Three unknown impurities in loratadine bulk drug at levels below 0.1% (ranging from 0.05 to 0.1%) were detected by a simple isocratic reversed-phase high performance liquid chromatography (HPLC). These impurities were isolated from mother liquor sample of loratadine using reversed-phase preparative HPLC. Based on the spectral data (IR, NMR and MS) the structures of these impurities were characterized as 11-(N-carboethoxy-4-piperidylidene)-6,11-dihydro-5H-benzo(5,6) cyclopenta(1,2-b)-pyridine (I), 8-bromo-11-(N-carboethoxy-4-piperidylidene)-6,11-dihydro-5H-benzo(5,6) cyclopenta (1,2-b)-pyridine (II) and 8-chloro-11-(N-carboethoxy-4-piperidylidene)-5H-benzo(5,6) cyclopenta (1,2-b)-pyridine (III). The synthesis of these impurities was discussed.     

Hypertension and catecholamine levels in sleep apnoea

Background

Sleep-disordered breathing has been strongly associated with systemic hypertension. Increased sympathetic activity in sleep-disordered breathing may be responsible for this association.

Method

In this sleep clinic-based study, 82 newly diagnosed patients of sleep-disordered breathing were evaluated for hypertension, and their plasma and urinary levels of catecholamines were measured. Catecholamine levels were then compared separately with the severity of sleep apnoea and blood pressure (BP).

Results

The prevalence of hypertension in the study population was 46.3%. The BP showed a strong and statistically significant correlation with apnoea-hypopnoea index (diastolic, r = 0.65, P < 0.001 and systolic, r = 0.60, P < 0.001) which was maintained even after the results were analysed separately for obese and non-obese subjects. Both plasma and urinary levels of catecholamines were greater in patients with severe sleep apnoea (compared to nonsevere cases) and in those with hypertension compared to normotensives. However, statistical significance was achieved only for urine catecholamines and not for plasma catechol-amines in both the cases.

Conclusion

Hypertension is highly prevalent among Indian subjects with obstructive sleep apnoea. Catecholamine levels are significantly higher in hypertensive than in normotensive apnoeics and are also directly related to the severity of obstructive sleep apnoea. Twenty-four hour urinary catecholamine levels are more valid measures of sympathetic activity than spot plasma samples.     

Case report: Bilateral simultaneous central retinal vein occlusion in Waldenström's macroglobulinemia

BackgroundWe report a case of bilateral simultaneous central retinal vein occlusion (CRVO) in Waldenström's macroglobulinemia.MethodsWe report the case of a 60-year-old woman who presented with decreased vision in both eyes.ResultsOphthalmoscopic examination showed scattered retinal hemorrhages and venous tortuosity with macular edema bilaterally. The patient had a history of hypertension and was under investigation for lethargy, recurrent epistaxis, and fainting episodes. Serum protein electrophoresis showed an M-spike in the gamma region. Bone marrow trephine biopsy confirmed the diagnosis of Waldenström's macroglobulinemia. The patient was treated with plasmapheresis and subsequent chemotherapy, resulting in improvement of ocular and systemic symptoms.ConclusionsWe report this case to emphasize that in any case of bilateral CRVO, hyperviscosity should be suspected. Serum electrophoresis along with coagulation profiles should be performed as a standard practice in patients with bilateral simultaneous CRVO.