Biglycan protects cardiomyocytes against hypoxia/reoxygenation injury: Role of nitric oxide

Biglycan, a proteoglycan component of extracellular matrix, has been suspected to contribute to the development of atherosclerosis, but overexpression of biglycan in transgenic mice has been shown to induce cardioprotective genes including nitric oxide (NO) synthases in the heart. Therefore, here we hypothesized if exogenous administration of biglycan exerts cytoprotection. Primary cardiomyocytes from neonatal rats were subjected to 150 min hypoxia and 2 h reoxygenation. Mortality of cardiomyocytes was dose-dependently attenuated by pretreatment with 1-100 nM biglycan. Biglycan enhanced eNOS mRNA and protein, and significantly increased NO content of cardiomyocytes. The NO synthase inhibitor l-nitro-arginine-methyl-ester significantly attenuated the cytoprotective effect of biglycan. This is the first demonstration that biglycan leads to cytoprotection against hypoxia/reoxygenation injury, and that this phenomenon is partially mediated by an NO-dependent mechanism.     

Bsx, a novel hypothalamic factor linking feeding with locomotor activity, is regulated by energy availability

We recently reported that the hypothalamic homeobox domain transcription factor Bsx plays an essential role in the central nervous system control of spontaneous physical activity and the generation of hyperphagic responses. Moreover, we found Bsx to be a master regulator for the hypothalamic expression of key orexigenic neuropeptide Y and agouti gene-related protein. We now hypothesized that Bsx, which is expressed in the dorsomedial and arcuate nucleus (ARC) of the hypothalamus, is regulated by afferent signals in response to peripheral energy balance. Bsx expression was analyzed using in situ hybridization in fed vs. fasted (24 h) and ghrelin vs. leptin-treated rats, as well as in mice deficient for leptin or the ghrelin signaling. Ghrelin administration increased, whereas ghrelin receptor antagonist decreased ARC Bsx expression. Leptin injection attenuated the fasting-induced increase in ARC Bsx levels but had no effect in fed rats. Dorsomedial hypothalamic nucleus Bsx expression was unaffected by pharmacological modifications of leptin or ghrelin signaling. Obese leptin-deficient (ob/ob) mice, but not obese melanocortin 4 receptor-knockout mice, showed higher expression of Bsx, consistent with dependency from afferent leptin rather than increased adiposity per se. Interestingly, exposure to a high-fat diet triggered Bsx expression, consistent with the concept that decreased leptin signaling due to a high-fat diet induced leptin resistance. Our data indicate that ARC Bsx expression is specifically regulated by afferent energy balance signals, including input from leptin and ghrelin. Future studies will be necessary to test if Bsx may be involved in the pathogenesis of leptin resistance.     

Divergent effects of human lymphokine derived oligopeptides on PMNLs function of young and aged healthy subjects

The effects of low molecular weight lymphokine-derived oligopeptides (LK-OPs) on PMNLs effector functions and receptor mediated biochemical events were studied in the case of healthy young and aged subjects. In the case of young subjects the low mol. wt. LK-OPs stimulated the Fc gamma receptor-mediated effector functions of PMNLs, whereas an inhibition was observed in PMNLs of the elderly (extracellular cytotoxicity and intracellular killing). The underlying biochemical events, induced by low mol. wt. LK-OPs stimulation, were also investigated. In PMNLs of young subjects the oxidative metabolism was stimulated (enhanced O2 consumption, O2 and H2O2 production) by low mol. wt. LK-OPs, while in elderly subjects it was inhibited. The cyclic nucleotides regulating the Fc gamma receptor mediated effector functions and the oxygen radicals formation showed an altered dynamic response under low mol. wt. LK-OPs stimulation with aging i.e. the cGMP level could not be changed at all. Our results suggest that low mol. wt. LK-OPs induced inhibition of Fc gamma receptor mediated effector functions with aging could be partly explained by an altered post receptorial coupling switch and as a consequence the lymphokines could not play their role of immunomodulators further impairing the altered immune response with aging.     

No difference in symptoms of irritable bowel syndrome between healthy subjects and patients with recurrent depression in remission

There is bidirectional comorbidity between anxiety/depression and irritable bowel syndrome (IBS). To investigate the prevalence of IBS symptoms, and factors associated with gastrointestinal symptoms in patients with recurrent depressive disorder. Patients (n = 95) with recurrent type of major depression according to DSM-IV criteria and sex- and age-matched controls (n = 190) were sent questionnaires investigating symptoms of IBS [Gastrointestinal Symptom Rating Scale (GSRS)-IBS] and symptoms of anxiety and depression [Hospital Anxiety and Depression Scale (HADS)]. Medical records were checked over a 10-year period for chronic somatic symptoms or diseases. Seventy-three patients with unipolar disorder (mean age 63.6 years SD 13.8; range 23-86 years) and 156 controls (mean age 59.2 years SD 11.6, range 21-85 years) responded. Patients with recurrent depression had higher GSRS-IBS scores and showed a strong correlation between symptoms of IBS and anxiety-depression (r(s) = 0.54; P < 0.001). IBS symptoms were also associated with multiple pain symptoms, higher health-seeking behaviour and selective-serotonin-reuptake inhibitor intake. However, patients with recurrent depression (n = 46) in remission (HADS-Depression score <8) did not have more symptoms of IBS than controls (GSRS-IBS median score 6.0 vs 6.5; P = 0.46). There is a strong association between symptoms of IBS and symptoms of anxiety and depression, whereas depressive patients in remission do not have more IBS symptoms than controls.     

Investigation of the role of adrenergic and non-nitrergic, non-adrenergic neurotransmission in the sheep isolated internal anal sphincter

Abstract Nitric oxide is widely established as an important neurotransmitter in the control of anal sphincter tone; although, a number of other transmitters have also been tentatively implicated. Whilst α‐adrenoceptor antagonists reduce anal sphincter pressure in man, the role of noradrenaline as a possible transmitter is poorly characterised. We have investigated the contribution of these transmitters to neurogenic relaxations, and evaluated the possible role of a non‐nitrergic, non‐adrenergic transmitter. The magnitude and duration of neurogenic responses were examined by measuring responses to electrical field stimulation (EFS) in segments of sheep internal anal sphincter following the development of spontaneous myogenic tone. Neurogenic relaxations induced by EFS were significantly reduced in the presence of Np>Gp>‐nitro‐L‐arginine methyl ester (l ‐NAME) suggesting major involvement of nitric oxide as a neurotransmitter. The duration of neurogenic relaxations was inversely related to the frequency of EFS, with contractile responses often manifest at higher frequencies. The duration of relaxations at high frequencies of EFS was increased by bretylium (adrenergic neurone blocker) and prazosin (α₁‐adrenoceptor antagonist). At higher frequencies of EFS, 60% of preparations also produced a residual non‐nitrergic, non‐adrenergic, apamin‐sensitive relaxation which was unaffected by vasoactive intestinal polypeptide (VIP) and inhibitors of purinergic responses [suramin, pyridoxal‐phosphate‐6‐azophenyl 2′,4′ disulfonic acid (PPADS) and α,β‐methylene adenosine triphosphate (ATP)]. However, MRS2179 (P2Y₁ receptor antagonist) showed a modest inhibitory effect. We conclude that endogenous noradrenaline acts via postjunctional α₁‐adrenoceptors to antagonize neurogenic relaxations that are largely mediated by nitric oxide. Our results indicate the involvement of a non‐nitrergic, non‐adrenergic, apamin‐sensitive transmitter which is inhibited by MRS2179, suggesting a possible role for purines.     

Oncological outcomes of IBD-associated versus sporadic colorectal cancer in modern era: a matched case-control study

Aim

Inflammatory bowel diseases (IBD) are associated with an increased risk for colorectal cancer (CRC). However and despite significant advances in the management of IBD and CRC, the prognosis of IBD-related CRC (IBD-CRC) remains controversial. The aim of the present case-control study was to compare the prognosis of IBD-CRC to sporadic CRC.

Methods

Consecutive patients operated for IBD-CRC from 2004 to 2014 were recruited and matched with sporadic CRC (ratio 3:1) from the same center. Matching was performed on gender, tumor stage, and location and period of surgery. Endpoints were postoperative morbidity (Dindo-Clavien III-V), quality of surgery, and long-term oncological outcomes.

Results

Among 1498 CRC patients operated during the study period, 21 patients were identified with IBD-CRC and matched to 63 patients with sporadic CRC (S-CRC). Patients with IBD-CRC were significantly younger (p?&amp;lt;?0.001), had multifocal lesions more frequently (p?=?0.04), and undergone abdominoperineal excision and coloproctectomy more often (p?=?0.001). Postoperative morbidity was not significantly different between the two groups (25 vs. 14%; p?=?0.309), as well as the rate of R0 resection (86 vs. 95%; p?=?0.162). Five-year disease-free and overall survival were 71 and 81% in patients with IBD-CRC and 69% (p?=?0.801) and 78% (p?=?0.845) in those with S-CRC, respectively.

Conclusion

In a case-control study of patients operated for CRC within the last decade, the prognosis of cancer associated with IBD is similar to sporadic cancer.

     

Sensitivity and specificity of the fine needle aspiration biopsy of the thyroid: clinical point of view

INTRODUCTION: The rates of sensitivity and specificity of fine needle aspiration biopsy (FNAB) for the diagnosis of thyroid malignancy differ considerably among various reported series. These values are influenced by three factors: (a) whether only clearly positive and negative results are considered, or whether the commonly encountered 10-20% of indeterminate/suspicious ones are included; (b) whether adenomas are considered as neoplasms in one group with carcinomas; and (c) whether only histologically proven cases are used in calculations or whether patients with benign clinical follow-up are included. AIM: The aim of the study was to evaluate the sensitivity and specificity of FNABs performed at this institution in the last 7 years from the clinical point of view, considering only benign vs. suspicious/malignant FNAB results (indicating surgery), and benign (including adenomas) vs. malignant definitive histology. STUDY DESIGN: Retrospective study comparing pre-operative FNAB results with definitive histological examination after operation. PATIENTS: A total of 2492 FNABs were performed in 2100 patients (1875 women and 225 men); their ages ranged from 9 to 85 years, with a median of 46 years. Clinical diagnosis was multinodular goitre in 1330, single nodule in 591, Hashimoto's thyroiditis in 147 and subacute thyroiditis in 32 cases. In 148 instances, the nodule was cystic. A history of previous treatment for carcinoma of the thyroid was present in 12 patients. Five hundred and thirty-six patients subsequently underwent thyroid surgery. STATISTICS: The values of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy were calculated. RESULTS: The sensitivity was 86%, specificity 74%, PPV 34%, NPV 97% and diagnostic accuracy 75%. CONCLUSIONS: The specificity and positive predictive value are low when fine needle aspiration biopsy results are divided into two categories only (these being indication for surgery or not), and when only suspicious/malignant fine needle aspiration biopsies with subsequent malignant histology are considered to be true positive. Nevertheless, the ability to discriminate 11.7% of patients with a 34% probability of malignancy (suspicious/malignant cytology) from 81.2% of patients (benign cytology) with a probability of only 3% is very helpful.