Antioxidant status, lipid peroxidation and nitric oxide end products in patients of type 2 diabetes mellitus with nephropathy

OBJECTIVES: Oxidative stress is considered to be a unifying link between diabetes mellitus (DM) and its complications including nephropathy. The aim of the present study was to evaluate oxidative stress status in Asian Indian patients of type 2 DM with nephropathy. DESIGN AND METHODS: Serum levels of malondialdehyde (MDA) and nitric oxide end products (nitrite and nitrate), activities of erythrocyte superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH) content were estimated in controls, patients of type 2 DM without nephropathy (group 1) and with nephropathy (group 2). RESULTS: Serum MDA concentration was significantly high in both the groups of diabetic patients as compared to controls, (p < 0.05), with group 2 having a significantly higher value than group 1 (p < 0.05). Significantly elevated serum nitrite levels were found in diabetic patients as compared to controls (p < 0.001), however, no significant difference was found between group 1 and group 2. Moreover, serum nitrate as well as nitrite + nitrate levels were significantly higher in group 2 as compared to controls (p < 0.05). Activity of erythrocyte SOD and CAT was significantly reduced in both groups as compared to controls (p < 0.001) with catalase activity in group 2 being significantly lower than group 1 (p < 0.05). Erythrocyte GSH content was significantly lower in group 2 as compared to controls (p < 0.05) and group 1 (p < 0.05). CONCLUSIONS: Results of the present study indicate that oxidative stress is increased and antioxidant defenses are compromised in type 2 DM. These derangements are of a higher magnitude in patients of type 2 DM with nephropathy.     

Significance of advanced atrioventricular block in acute inferior myocardial infarction--a study based on ventricular function and Holter monitoring

Eighty-two consecutive patients with a first inferior wall acute myocardial infarction were evaluated by radionuclide angiography and 24-hour Holter monitoring during their hospital stay. The patients were divided into two groups. The first group (n = 28) had advanced atrioventricular block, while the second group (n = 54) were without atrioventricular block. The patients with advanced block had lower left ventricular (49 +/- 12% vs. 55 +/- 14%, P less than 0.05) and right ventricular ejection fraction (26 +/- 10% vs. 43 +/- 11%, P less than 0.001) than those with normal atrioventricular conduction. The atrioventricular block disappeared spontaneously in all of them. The hospital mortality of the patients with advanced block and those without advanced block was 10.7 and 5.5%, respectively (P = NS). Pre-discharge 24-hour Holter monitoring done in all survivors revealed isolated ventricular ectopics (Lown grade I, II, III) in 44% of patients who had had advanced block and 43.1% of patients without advanced block (P = NS). Complex ventricular ectopics (Lown grade IVa, IVb), however, were recorded in significantly more patients with advanced block as compared to patients without advanced block (36 vs. 7.8%, P less than 0.01). Most patients with complex ventricular ectopics in both groups had impaired left or right ventricular function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biliary endogenous inorganic phosphate, D-glucose, IgA and transferrin are differentially altered by hydrostatic pressure.

Our objective was to determine the effects of hydrostatic biliary pressure on excretion patterns of endogenous solutes which reflect various pathways of bile formation. A stable in vivo model was developed using anesthetized rats intraduodenally infused with taurocholate to maintain bile flow. Bile was collected during a 2-h basal period, a 4-h pressure period where elevation of the bile duct cannula decreased bile flow to 1/3 the basal rate, and a 2-h period after release of hydrostatic biliary pressure. During pressure treatment, bile salt concentration gradually increased approximately 3-fold, biliary inorganic phosphate concentrations rapidly rose approximately 5-fold, and biliary glucose concentration progressively rose approximately 17-fold. Concentrations of proteins in bile were affected differently with extreme decreases in IgA, moderate decreases in total protein and leucine aminopeptidase, and minimal change in transferrin. By 2 h after pressure release, only the alterations in biliary glucose and IgA persisted. The observed striking and persisting increases in biliary glucose are tentatively explained as an impaired reabsorption of glucose by the biliary tract.     

Immunohistochemical characterisation of Aschoff nodules and endomyocardial inflammatory infiltrates in left atrial appendages from patients with chronic rheumatic heart disease

Fifty left atrial appendages collected fresh during closed mitral valvotomy in patients with chronic rheumatic heart disease, were analysed to determine the frequency of Aschoff nodules and characteristics of mononuclear inflammatory infiltration. Fifty-six percent of specimens demonstrated Aschoff nodules with no clinical or laboratory evidence of acute rheumatic activity in the patients undergoing surgery. Endomyocardial infiltration contained predominantly T cells and occasionally B cells. The relative proportions of T helper-inducer, T suppressor-cytotoxic lymphocytes and macrophages were 45.1 +/- 7.6, 23.5 +/- 4.8 and 29.3 +/- 9.6%, respectively. Frequent presence of Aschoff nodules and heavy mononuclear infiltrates in chronic rheumatic heart disease suggests a possibility of subclinical ongoing carditis.     

Surgical experience with intracardiac myxomas

Eighteen patients underwent surgery for intracardiac myxoma (16 left atrial and 2 right atrial) during the last 10 years. Seventeen patients had tumour stalk attached to the oval fossa. The myxoma was excised along with a cuff of the atrial septum, which was reconstructed using a Dacron patch in 15 patients and by direct suture in 2 patients. In the remaining case the myxoma was attached to the left atrial wall and adjacent atrioventricular junction. There was only one early death in a patient who underwent a concomitant lobectomy for lung abscess and one late death due to a noncardiac cause. During the follow-up period of 3-96 months (average 36 months) all the survivors were in New York Heart Association Class I. Scanning electron microscopy of tumour tissue was done in 8 cases. The morphological findings did not help in categorizing the tumours into any pathological subgroups. Postoperative cardiac catheterization done in 3 patients (30-50 months postoperatively) showed return of haemodynamics to normal. Echocardiographic studies done postoperatively have not revealed recurrence of tumour in any patient. Surgical excision of myxomas is possible with very gratifying long-term results.     

A phase I trial of intrapleural recombinant human interferon α (rHuIFNα2b) in patients with malignant pleural effusions

The use of intrapleural sclerosing agents to control reaccumulation of pleural fluid in patients with malignant effusions has been widely investigated. A phase I trial of intrapleural recombinant human interferon (rHuIFN2b) was initiated to determine the toxicity and maximal tolerated dose in this group of patients. rHuIFN2b was instilled as a single dose following chest tube (15/16) or percutaneous (1/16) drainage of cytologically proven malignant effusions. Doses of rHuIFN2b were escalated from 25×10⁶ to 200×10⁶ U/m² in cohorts of three to four patients. Toxicity was mild to moderate, and included chills, fever and chest pain, and resembled that produced by systemic administration of rHuIFN2b. Dose-limiting toxicity occurred at 200×10⁶ U/m² and consisted of hepatic enzyme elevations and renal failure. Partial control of the effusions was noted in two patients, with two additional patients having stable disease. Phase II trials of rHuIFN2b should utilize up to 150×10⁶ U/m² for intrapleural instillation.Abbreviation IFN interferon - MPE malignant pleural effusions Supported in part by a grant from the Schering Corporation, Kenilworth, N.J.     

A role for deregulated c-Myc expression in apoptosis of Epstein-Barr virus-immortalized B cells.

When deprived of autocrine growth factors, Epstein-Barr virus (EBV)-immortalized B cells stop growing and die. In this study, we show that death of EBV-immortalized cells deprived of autocrine growth factors occurred by apoptosis. Cycloheximide, a protein synthesis inhibitor, inhibited apoptosis, suggesting that de novo protein synthesis is required. Because p53, Bcl-2, and c-Myc were previously implicated in the induction or prevention of apoptosis in other systems, we assessed their possible involvement here. Unlike normal cells that respond to growth factor deprivation by down-regulating c-Myc expression, EBV-immortalized cells continued to express c-Myc, p53, and Bcl-2 at levels comparable to those measured prior to starvation. Consistent with data demonstrating that c-Myc expression is sufficient to drive quiescent cells into the cell cycle, autocrine growth factor-deprived EBV-immortalized cells did not undergo growth arrest but rather continued to proliferate until death, which occurred randomly throughout the cell cycle. In contrast to EBV-immortalized B cells, normal peripheral blood B cells activated in vitro with anti-CD40 monoclonal antibody and interleukin 4 rapidly down-regulated c-Myc expression and underwent growth arrest in response to growth factors and serum deprivation. These findings demonstrated that c-Myc expression is deregulated in EBV-immortalized cells. Addition of antisense oligonucleotides to c-Myc specifically promoted the survival of starved EBV-immortalized cells and suppressed growth of nonstarved EBV-immortalized cells. Thus, deregulated expression of c-Myc in EBV-immortalized cells promotes proliferation and apoptosis following autocrine growth factor deprivation.     

Smad7 alters cell fate decisions of human hematopoietic repopulating cells

Intracellular Smad proteins mediate signal transduction of the transforming growth factor-beta (TGF-beta) superfamily that play pleiotropic roles in hematopoietic development, suggesting that intracellular Smad proteins may play key roles in hematopoietic regulation. Although inhibitory Smad7, which negatively regulates TGF-beta signaling, has been implicated in the development of mature hematopoietic cells, a role for Smad7 in regulating more primitive hematopoietic cells has yet to be examined. Here, Smad7 was overexpressed in primary human severe combined immunodeficient (SCID) repopulating cells (SRCs), representing a common myeloid/lymphoid precursor cell with the functional capacity to repopulate the bone marrow of nonobese diabetic (NOD)/SCID recipient mice. Retroviral transduction of Smad7 into human umbilical cord blood (CB)-SRCs caused a shift from lymphoid dominant engraftment toward increased myeloid contribution, and increased the myeloid-committed clonogenic progenitor frequency in reconstituted mice. Neither myeloid nor B-lymphoid lineage developmental stages were compromised by Smad7 overexpression, suggesting Smad7 regulates cell fate commitment decisions of myeloid/lymphoid precursors by augmenting myeloid differentiation at the expense of lymphoid commitment. In addition, global gene expression analysis using microarray was used to identify potential target genes regulated by Smad7 in primitive hematopoietic cells that may control this process. Our study demonstrates a novel and unexpected role for Smad7 in modulating the cell fate decisions of primary multipotent human repopulating cells and establishes a role for Smad7 in the development of primitive human hematopoietic cells.     

Ras mutations in United Kingdom examples of oral malignancies are infrequent

Point mutations in codons 12, 13 or 61 of the oncogenes Ha-ras, Ki-ras or N-ras have been identified in human malignancies of many types. Using the PCR (polymerase chain reaction) technique for DNA amplification in vitro and stringent probing of the amplified DNA on dot blots with a library of specific oligonucleotides, we have screened for the presence of ras mutations in oral and para-oral malignancies and some associated lesions. The material, from UK patients, consisted of 22 oral squamous-cell carcinomas including 5 neck metastases, 1 oral mucosal dysplasia, 1 proliferative verrucous leukoplakia, 1 antral and 1 tonsillar carcinoma, 1 basal-cell carcinoma, 1 salivary adenocarcinoma, 1 salivary adenoid cystic carcinoma and 1 lung adenocarcinoma metastatic to the gingiva. Genomic DNA was extracted from tissues which were fresh or preserved in liquid nitrogen. Two DNA samples contained point mutations in codon 61 of Ki-ras. One of these mutations was in the lymphocytes infiltrating a retromolar SCC. The other mutation (CAA to CAU; substitution of glutamine by histidine) was in the lung adenocarcinoma metastasis. The absence of ras mutations in the epithelium of primary oral squamous-cell carcinomas is of considerable interest as other work in our Department on Indian cases of oral carcinomas associated with chewing tobacco (quid) revealed that 35% of these had a codon 12, 13 or 61 mutation in Ha-ras. While ras activations arising from point mutations may occur in a high proportion of oral malignancies associated with chewing tobacco (quid), this was not the case in UK oral malignancies, even where tobacco was smoked.     

X-Linked Parkinsonism: Phenotypic and Genetic Heterogeneity

X-linked parkinsonism encompasses rare heterogeneous disorders mainly inherited as a recessive trait, therefore being more prevalent in males. Recent developments have revealed a complex underlying panorama, including a spectrum of disorders in which parkinsonism is variably associated with additional neurological and non-neurological signs. In particular, a childhood-onset encephalopathy with epilepsy and/or cognitive disability is the most common feature. Their genetic basis is also heterogeneous, with many causative genes and different mutation types ranging from “classical” coding variants to intronic repeat expansions. In this review, we provide an updated overview of the phenotypic and genetic spectrum of the most relevant X-linked parkinsonian syndromes, namely X-linked dystonia-parkinsonism (XDP, Lubag disease), fragile X-associated tremor/ataxia syndrome (FXTAS), beta-propeller protein-associated neurodegeneration (BPAN, NBIA/PARK-WDR45), Fabry disease, Waisman syndrome, methyl CpG-binding protein 2 (MeCP2) spectrum disorder, phosphoglycerate kinase-1 deficiency syndrome (PGK1) and X-linked parkinsonism and spasticity (XPDS). All clinical and radiological features reported in the literature have been reviewed. Epilepsy occasionally represents the symptom of onset, predating parkinsonism even by a few years; action tremor is another common feature along with akinetic-rigid parkinsonism. A focus on the genetic background and its pathophysiological implications is provided. The pathogenesis of these disorders ranges from well-defined metabolic alterations (PGK1) to non-specific lysosomal dysfunctions (XPDS) and vesicular trafficking alterations (Waisman syndrome). However, in other cases it still remains poorly defined. Recognition of the phenotypic and genetic heterogeneity of X-linked parkinsonism has important implications for diagnosis, management, and genetic counseling. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society