Selective attenuation of neuropeptide-Y-mediated contractile responses in blood vessels from patients with diabetes mellitus

Vascular smooth muscle contractile responses to neuropeptide Y, ,ß-methyleneATP and noradrenaline were studied in circular segments of isolated vessels with intact endotheliumin vitro from 12 patients with diabetes mellitus type 2 (NIDDM) and 12 control subjects. The dilatory effect of acetylcholine was used to test the function of the endothelium. Subcutaneous arteries and veins (diameter 0.1–1.1 mm) were obtained during surgery. There was no difference in contractile responses to noradrenaline or ,ß-methyleneATP between diabetic and control vessels. The contractile response to neuropeptide Y, however, was markedly reduced in the diabetic group. The maximal contractile effect (46.0 ± 14.0%,p < 0.05) but not the sensitivity to neuropeptide Y was significantly less in diabetic veins compared to control (107.5 ± 19.6%). Thus, the attenuation of neuropeptide Y responses was present in humans as previously observed in alloxan-induced diabetes mellitus in rabbits. There was no difference in the dilator effect of acetylcholine between the diabetic and the control group in any of the vessel types, indicating that the difference in vascular reactivity to neuropeptide Y was not endothelium-dependent. In conclusion, the present study has shown that the postjunctional effects of neuropeptide Y, a co-transmitter of the peripheral sympathetic nervous system, is selectively attenuated in diabetes mellitus.     

Molecular genetic studies of early breast cancer evolution

Summary In the past few years there has been an explosion in the number of patients diagnosed with hyperplastic breast disease andin situ breast cancer. Based on epidemiological data, these morphologically defined lesions may be categorized as those with little malignant potential (e.g. typical hyperplasia or proliferative disease without atypia [PDWA]), those with significant malignant potential which may already be initiated (e.g. atypical ductal hyperplasia [ADH]), and early transformed lesions which are malignant but not yet invasive (e.g. ductal carcinomain situ [DCIS]). They may represent sequential evolutionary stages in the ontogeny of invasive breast cancer, with each morphologically defined stage resulting from accumulating genetic changes culminating in a transformed clonal lineage capable of invasion and metastasis. Using loss-of-heterozygosity (LOH) analysis, we are studying the genetic changes associated with these lesions in archival tissue samples. 50% (6/12) of the proliferative lesions (PDWA and ADH) and 80% of the DCIS shared their LOH patterns with more advanced lesions from the same breast, strongly supporting a precursor/product relationship between these lesions and the cancers they accompany.     

Role of T lymphocytes in secretory response to an enteric nematode parasite

Athymic (nude) rats have been used to assess the role of thymus-dependent T cells in the control of the intestinal response following infection with the enteric parasite,Nippostrongylus brasiliensis. Tissues from infected rats were excised on days 4, 7, 10, and 21 postinfection (p-i) for physiological and morphological studies; uninfected (day 0) rats served as controls. In response to the worm burden, jejunal tissues displayed a secretory response, indicated by an elevated baseline short-circuit current (I _sc ) on days 7 and 10 p-i, and were more responsive to histamine than control tissues. Despite this enhanced secretory response, 35% of the worm burden was still present on day 21 p-i (compared with expulsion of >95% by day 14 p-i in normal rats). Mast cell activation and hyperplasia, increased goblet cell (implying increased mucus synthesis) and intraepithelial leukocyte numbers, and abnormalities inI _sc responses after electrical stimulation of enteric nerves were identified following infection. These events in nude rats were attenuated or delayed in onset as compared with conventional immunocompetent rats. Our results support the postulate that thymus-dependent T cells regulate the timing and/or nature of the mucosal response to enteric parasitic infections. However, ion secretion was not altered in the absence of T cells and, therefore, is more likely to be a consequence of mast cell activation.This work was conducted with financial support from The Canadian Medical Research Council and the National Institutes of Health (NS 29536).     

Role of calcium in thromboxane B2-mediated injury to rabbit gastric mucosal cells

A sustained increase in cytosolic Ca²⁺ can damage gastric mucosal cells. The present study has examined the role of Ca²⁺ in thromboxane B₂ (TXB₂)-mediated damage of rabbit isolated gastric mucosal cells. Cells were isolated from rabbit oxyntic mucosa by collagenase-EDTA digestion. Cell metabolic activity and cell damage were estimated by alamar blue dye absorbance and trypan blue uptake, respectively. Cellular Ca²⁺ was monitored by indo-1 dye fluorescence. Addition of TXB₂ (10^–6 and 10^–8 M) to the cell suspension resulted in a decrease in metabolic activity, and this effect was reduced when Ca²⁺ was removed from the incubation Ca²⁺ and incubation of cells with the intracellular Ca²⁺ chelator, BAPTA-AM (20 M), reduced cell injury in response to TXB₂. Incubation of cells with the Ca²⁺ ionophore A23187 (1–25 M) resulted in a dose-dependent increase in trypan blue uptake and a reduction in cell metabolism. Cell unjury in response to A23187 were exacerbated by addition of TXB₂ (10^–8 M) to the cell suspension. TXB₂ treatment reduced cellular content of reduced glutathione (GSH), while exogenous GSH addition (10 mM) reduced TXB₂-mediated cell injury. These data demonstrate that TXB₂ can directly injure gastric mucosal cells. Gastric mucosal cellular damage in response to TXB₂ is mediated in part by a disruption of Ca²⁺ homeostasis as well as a reduction in cellular GSH content.This work was supported by a grant from the Medical Research Council of Canada MT6426.     

Mechanisms of oral sensation

Sensory nerves that supply mechanoreceptors in the mucosal lining of the oral cavity, pharynx, and larynx provide the substrate for a variety of sensations. They are essential for the perception of complex or composite sensory experiences including oral kinesthesia and oral stereognosis. Relevant to the concerns of the oral health care delivery specialist they also contribute to initiation of reflexes and coordination and timing of patterned motor behaviors. The response of oral mechanoreceptors to natural stimuli is determined to a large degree by morphological factors such as the nature of the relationship between nerve ending and certain cellular specializations, their distribution in the mucosa, the diameter of their primary afferent nerve fibers, and the central distribution of these fibers in the brainstem. Because of morphological similarities to certain cutaneous mechanoreceptors, the mucosal lining may be considered as an internal continuation of the large receptor sheet for localization and detection of mechanical stimuli. In some regions of the oral, pharyngeal, and laryngeal mucosa, this analogy is appropriate whereas in others, existing data suggest a different role consistent with regionally specific demands (i.e., initiation of protective reflexes).     

Blue toe syndrome from a “coral reef” aorta

An endoaortic calcified mass, sometimes referred to as a coral reef aorta, is an unusual cause of distal leg microembolization. When discovered it is usually in the suprarenal aorta. We present an unusual case of infrarenal coral reef aorta with symptoms of distal atheroembolism. A review of the literature is also presented.     

The Effects of Fat Distribution on Resting Energy Expenditure in Premenopausal Morbidly Obese Females

Background: upper body, or abdominal, distribution of body fat is associated with a number of metabolic and hormonal aberrations that could influence resting energy expenditure REE. The purpose of our study was to examine the effects of fat distribution on REE of 96 morbidly obese premenopausal females. Methods: the study population consisted of three groups of study subjects, 32 with lower body fat distribution (LBD) and waist-to-hip circumference ratios WHR < 0.80, 20 with intermediate (INT) fat distribution and WHR between 0.80 and 0.85 and 34 females with upper body distribution of fat (UBD) and WHR > 0.85. Indices measured included: (1) REE; (2) maximal oxygen consumption during an exercise tolerance test (VO_2max); (3) basal respiratory quotient (RQ); (4) fasting blood glucose; and (5) serum cholesterol and triglycerides. Results: we found that morbidly obese women who store fat abdominally (WHR > 0.80) have significantly (p < 0.01) higher REE (kcal per h per BSA) than those with lower body obesity. Levels of triglyceride and glucose of the UBD group were also higher than those of the LBD subjects, i.e. 35% and 23%, respectively. VO_2max and RQ were similar between the study groups, suggesting that the elevated REE of the patients with abdominal adiposity were likely not the result of their greater muscle mass or differences in substrate utilization. Conclusion: fat distribution affects REE in morbidly obese premenopausal females, and further research is needed to identify the various entities regulating REE in the morbidly obese.     

Gastric Banding: Advantages and Complications. A 5- and 10-Year Follow-up

Background: Gastric banding is one of the simplest surgical procedures for the treatment of morbid obesity. We performed more than 150 ‘laparotomy’ (open) gastric bandings and more than 50 ‘laparoscopic’ bandings in the last 10 years. Methods: In most procedures we used non-adjustable bands, but since the beginning of 1995 we have used adjustable silicone banding. Results: The 5- and 10-year follow-up weight loss results are encouraging. The average long-term weight loss was 35.5 kg. Since 1993, we performed all the procedures laparoscopically, and the postoperative complications decreased from 18.5% in the ‘laparotomy’ group to 9.5% in the ‘laparoscopic’ group, with the majority being esophagitis and outlet area irritation. Conclusion: Gastric banding itself and especially the minimally invasive laparoscopic approach is an easy technical procedure. The long-term weight loss results and the reoperation rate are acceptable for bariatric surgery criteria.     

The Effect of Basic Fibroblast Growth Factor on the Reversion of Omental Adipocytes from Lean and Obese Patients

Background: this study was designed to characterize some of the biochemical and molecular genetic changes during reversion of human fat cells. Methods: mature adipocytes were isolated from greater omental fat tissue of eight lean and 14 massively obese persons by established methodology. Results: at day 7 of adherence to Leighton tubes, there was appreciable depletion of triacylglycerol, as well as assumption of an elongated contour. Relatedly, there was an increase in the expression of β-actin mRNA and a significant decrease in the specific activity of cytosolic glycerophosphate dehydrogenase. The decrement in the specific activity of glycerophosphate dehydrogenase, after 7 days in culture, was significant at p < 0.001. Basic fibroblast growth factor at 10 ngml^-1 accelerated significantly (p < 0.03) the decrease in the specific activity of glycerophosphate dehydrogenase in adipose cells from lean subjects. In contrast, basic fibroblast growth factor had no significant influence on cells from massively obese persons. Conclusion: such resistance may contribute to the intractability of massive obesity.