Rate Limiting Factors in Sympathetic Neurotransmitter Secretion

Isolated superfused field stimulated preparations of guinea-pig vas deferens, in which the neural stores of noradrenaline (NA) had been labelled by preincubation with tritium-marked (-)-NA, were used to study the factors regulating the amount of NA secreted from the nerves, per applied shock. The results indicate that ‘stimulation secretion coupling’ in this tissue is subject to 2 different kinds of facilitation, one independent and one dependent on nerve stimulation frequency. Kinetic analysis of the calcium dependence of transmitter secretion, after removal of α-adrenoceptor mediated negative feedback control, suggests that there is a definite upper limit to the amount of transmitter which can be secreted, per pulse, from each ‘secretory area’ of the nerves. The low Q₁₀ value of this apparent V_max suggests that the rate limiting factor is non-enzymatic in nature. It is proposed that the ultimately rate limiting factor in NA secretion may rather be the number of vesicles in each potential ‘secretory area’ which are in a suitable position within the nerve for active participation in the secretion of transmitter.     

Influence of sodium deoxycholate on morphology, net fluid transport and motility in the small intestine of the rat

Intestinal fluid secretion and motility were induced by luminal perfusion of rat small intestine with sodium deoxycholate, a dihydroxy bile salt for 1-3 h. Changes in intestinal morphology were studied simultaneously with the changes in fluid transport and motility. The results suggest that the bile salt causes epithelial lesions which may lead to a reduced fluid absorption in the villi, thereby explaining part of the total change in net fluid transport caused by the bile salt. Pyrilamine and indomethacin did not influence the bile salt-induced secretion. Based on earlier studies, it is proposed that the major part of the bile salt-evoked secretion is mediated via activation of intramural nervous reflex(es), which also stimulate the intestinal smooth muscle cells.     

A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children

BACKGROUND: Bacterial signals play an important role in the maturation of the immune system. Polymorphisms in genes coding for receptors to bacterial components can alter the immune responsiveness of the host to microbial agents and may indicate the development of aberrant immune responses that are associated with immune-mediated diseases such as atopic diseases. OBJECTIVE: The study's objective was to investigate the relationship between TLR4 and CD14 gene polymorphisms, the LPS responsiveness of PBMCs, and the presence of asthma and allergic rhinoconjunctivitis in children. METHODS: The TLR4 (Asp299Gly) and CD14/-159 polymorphisms were determined in 115 Swedish children aged 8 and 14 years. LPS-induced IL-12(p70), IL-10, and IFN-gamma responses of PBMCs from 69 of the children were analyzed by means of ELISA. The levels of soluble CD14 in serum samples were analyzed by means of ELISA, and the total IgE levels were analyzed by means of UniCAP Total IgE (Pharmacia Diagnostics, Uppsala, Sweden). RESULTS: Decreased LPS-induced IL-12(p70) and IL-10 responses were associated with the TLR4 (Asp299Gly) polymorphism and independently with asthma, especially atopic asthma. The TLR4 (Asp299Gly) polymorphism was associated with a 4-fold higher prevalence of asthma in school-aged children (adjusted odds ratio 4.5, 95% CI 1.1-17.4) but not to allergic rhinoconjunctivitis. CONCLUSION: A TLR4 polymorphism modifies innate immune responses in children and may be an important determinant for the development of asthma. This may influence the outcome of intervention studies that use microbial stimuli as immune modulators.     

Expression and localization of mutant p16 proteins in melanocytic lesions from familial melanoma patients

Little is known about the correlation between the loss of p16 expression and tumor progression in familial melanoma; no systematic study has been conducted on p16 expression in melanocytic tumors from patients carrying germline CDKN2A mutations. We analyzed 98 early primary lesions from familial patients, previously tested for germline CDKN2A status, by quantitative immunohistochemistry using 3 p16 antibodies. We found that p16 expression was inversely correlated with tumor progression and was significantly lower in melanomas, including in situ lesions, than in nevi. Of other features analyzed, tumor thickness showed the most significant correlation with p16 levels. Lesions from mutation-negative patients displayed combined nuclear and cytoplasmic staining. However, some mutation-positive lesions (ie, G101W, 113insR, M53I, R24P, and 33ins24), including benign nevi, showed nuclear mislocalization, confirming previous studies suggesting that subcellular distribution indicates functional impairment of p16.     

Transforming growth factor-beta (TGF-beta) and tissue transglutaminase expression in the small intestine in children with coeliac disease

The production of cytokines from T cells and macrophages is of potential importance for the histological changes apparent in coeliac disease (CoD). Small intestinal biopsy specimens from children with CoD and disease control subjects were investigated for their content of cytokines and tissue transglutaminase (tTG). The transforming growth factor-beta1 (TGF-beta1) expression was increased in the lamina propria of children with villous atrophy. In contrast, TGF-beta3 was expressed at a higher level in the epithelium and the lamina propria of the disease control subjects. The tTG expression was increased in the small intestine of CoD patients as compared with that in subjects. Interleukin-4 (IL-4) was detected in the lamina propria of both CoD patients and controls, and some of the investigated biopsy specimens also showed IL-4 expression in the epithelium. We conclude that children with active CoD could have an altered expression of TGF-beta and tTG in the small intestine and that a disturbed regulation of TGF-beta may be of importance in the immune pathogenesis of CoD.     

Etiopathogenetic aspects of hepatitis A. I. Excretion of hepatitis A virus, biochemistry of liver function, and humoral immune response in patients with hepatitis A on admission to hospital

The excretion of hepatitis A virus (HAV) in stools from 30 patients with clinically overt hepatitis A infection on the day of their admission to the hospital was determined and compared with the dynamics and values of biochemical indices of hepatocyte injury as well as with the immune response to HAV. Virus was found in 16 out of 30 stools (53%) collected within 1 week after the appearance of clinical symptoms. In sera obtained on the day of hospitalization both IgM and IgA anti-HAV were detected in all of the 30 patients, while IgG anti-HAV were found in 20 (67%). There was a correlation between HAV excretion and increasing SGPT upon admission to hospital, while the level of SGPT or bilirubin as well as presence or absence of IgG anti-HAV did not correlate with excretion of HAV. HAV from stools was characterized morphologically and physicochemically. The majority of particles visualized by immune electron microscopy had electrondense appearance, while electron-lucid particles were only occasionally encountered. Isopycnic banding of HAV in CsCl revealed a broad range of densities with HAV activity. Rebanding of pooled fractions containing HAV revealed peak amounts of the virus in fractions with densities 1.32-1.33 gm/cm3.     

Analysis of family resemblance for lipids and lipoproteins

A path analysis of published reports on family resemblance reveals an important role for genetic factors in all lipids and lipoproteins, with no evidence of a discrepancy between twins and other relatives (which might be due to dominance or epistasis) nor between studies which used environmental indices and those which did not. Family environment within population is less important and is significantly greater for twins than for other relatives.