Influence of Mycobacterium tuberculosis on differential activation of helper T-cells

Host defence against tuberculosis infection involves T-lymphocyte mediated cellular immune responses. In this study we assessed T-cell activation by studying the early signal transduction events and production of cytokines by human CD4+ T-cells. The study constituted of five groups of subjects: (a) untreated acid fast bacilli (AFB)+ve TB patients who have not started anti-tuberculosis therapy (ATT) [New]; (b) patients who have taken ATT for two months [2T]; (c) patients who have taken ATT for six months [6T]; (d) mantoux positive healthy controls [T+ve]; (e) mantoux negative healthy controls [T-ve]. We found that mantoux positive healthy controls produced significantly higher levels of IP3, intracellular Ca2+ and presented increased PKC activity when CD4+ T-cells were stimulated with M. tuberculosis H37Rv cell lysate as compared to mantoux negative controls. Furthermore, decreased expression of CD54 (ICAM-1) and reduced [Ca2+]i were seen in TB patients as compared to T+ve healthy controls. TB patients showed significantly lower levels of IL-2 and IFNgamma and higher levels of IL-4 as compared to normal healthy controls, suggesting a diminished Th1 response. Thus, the reciprocal changes in cytokines, reduced [Ca2+]i levels, and CD54 expression in patients imply phenotype shifting of Th precursors to Th2 type in TB patients.     

Superantigen-induced T cell responses in acute rheumatic fever and chronic rheumatic heart disease patients

CD4+ and CD8+ T cells from healthy donors, acute rheumatic fever (ARF) and chronic rheumatic heart disease (CRHD) patients responded variably to a superantigen from Streptococcus pyogenes--Streptococcal pyrogenic erythrogenic toxin A (SPE-A). In vitro culture of CD4+ T cells from ARF patients (CD4-ARF) with SPE-A exhibited a Th1 type of response as they produced high levels of IL-2, while CD4+ T cells from CRHD patients (CD4-RHD) secreted IL-4 and IL-10 in large amounts, i.e. Th2 type of cytokine profile. The skewing of human CD4+ T cells (in response to SPE-A stimulation) to Th1 or Th2 type reflects the role of the two subsets in a disorder with differing intensities at the two extremes of the spectrum. Moreover, the anergy induction experiments revealed that CD8-ARF and CD8-RHD undergo anergy (to different extents), whereas CD4+ T cells do not, in response to re-stimulation by SPE-A. These results initially demonstrate that both CD4+ and CD8+ T cells respond differentially to SPE-A, and hence it is an important observation with respect to the pathogenesis of ARF/CRHD. Anergy in CD8+ T cells in the presence of SPE-A in vitro goes a step further to show the clinical relevance of these cells and their possible role in suppression of the disease.     

Microsmatic primates: reconsidering how and when size matters

The terms "microsmatic" and "macrosmatic" refer to species with lesser or greater levels, respectively, of olfactory function. Historically, primates are considered microsmats (olfactory sense reduced) with a concomitant increased emphasis on vision. The olfactory bulbs (forebrain centers that receive peripheral olfactory input) are proportionately smaller in primates compared to most other mammals. Similarly, the regions of the nasal cavity that are covered with olfactory epithelium (containing receptor cells) have proportionately less surface area in primates than other mammals. Thus, the generalization that primates are microsmatic is most frequently stated in terms of the proportional rather than absolute size of olfactory structures. Yet the importance of scaling to body size is unclear in regard to the chemical senses such as the olfactory or vomeronasal systems-do chemosensory structures such as olfactory bulbs and olfactory epithelium exhibit the same neural relationship to body mass that is seen for neural tissues that supply innervation to musculature or the skin? Previous studies examining neuronal density, volume, and/or surface area of the olfactory epithelium illustrate that different conclusions may be supported based on the parameter used. Plots of olfactory bulb volume versus body mass that generated for large-scale taxonomic studies or growth studies benefit from body mass (or total brain volume) with a comparative perspective. However, our examination of proportional versus absolute measurements implies that in comparisons within taxa, body size adjustments needlessly distort the data. As a final consideration, another embryonic derivative of the nasal placode, the vomeronasal organ, may warrant consideration regarding a definition of microsomia versus macrosomia.     

Anthrax toxin

Anthrax is primarily a disease of herbivores caused by gram-positive, aerobic, spore-forming Bacillus anthracis. Humans are accidental hosts through the food of animal origin and animal products. Anthrax is prevelant in most parts of the globe, and cases of anthrax have been reported from almost every country. Three forms of the disease have been recognized: cutaneous (through skin), gastrointestinal (through alimentary tract), and pulmonary (by inhalation of spores). The major virulence factors of Bacillus anthracis are a poly-D glutamic acid capsule and a three-component protein exotoxin. The genes coding for the toxin and the enzymes responsible for capsule production are carried on plasmid pXO1 and pXO2, respectively. The three proteins of the exotoxin are protective antigen (PA, 83 kDa), lethal factor (LF, 90 kDa), and edema factor (EF, 89 kDa). The toxins follow the A-B model with PA being the B moeity and LF/EF, the alternative A moeities. LF and EF are individually nontoxic, but in combination with PA form two toxins causing different pathogenic responses in animals and cultured cells. PA + LF forms the lethal toxin and PA + EF forms the edema toxin. During the process of intoxication, PA binds to the cell surface receptor and is cleaved at the sequence RKKR (167) by cell surface proteases such as furin generating a cell-bound, C-terminal 63 kDa protein (PA63). PA63 possesses a binding site to which LF or EF bind with high affinity. The complex is then internalized by receptor-mediated endocytosis. Acidification of the vesicle leads to instertion of PA63 into the endosomal membrane and translocation of LF/EF across the bilayer into the cytosol where they exert their toxic effects. EF has a calcium- and calmodulin-dependent adenylate cyclase activity. Recent reports indicate that LF is a protease that cleaves the amino terminus of mitogen-activated protein kinase kinases 1 and 2 (MAPKK1 and 2), and this cleavage inactivates MAPKK1 and thus inhibits the mitogen-activated protein kinase signal transduction pathway. We describe in detail the studies so far done on unraveling the molecular mechanisms of pathogenesis of Bacillus anthracis.     

Interactions between polymerized human albumin,hepatitis B surface antigen,and complement: II. involvement of Clq in or near the hepatitis B surface antigen receptor for polyalbumin

A species-specific receptor for polymerized human albumin (PHALB) has been reported on hepatitis B surface antigen (HBsAg)-carrying particles. Our previous observations that human Clq also binds PHALB in a species-restricted manner led us to investigate the possibility that HBsAg-associated Clq is involved in the PHALB receptor on HBsAg particles. The temperature, ionic strength, and pH requirements necessary for binding of PHALB to both Clq and HBsAg were compared and found to be similar. Normal human serum and purified Clq inhibited the PHABL-HBsAg interaction; the inhibition was markedly reduced in heat-inactivated and Clq-depleted serum. Heat-denatured or reduced and alky-lated Clq failed to inhibit the PHALB-HBsAg binding. Moreover, human Clq was found to be present in purified preparations of HBsAg and the quantity detected paralleled the degree of PHALB-HBsAg binding. While anti-Clq inhibited the PHALB-HBsAg interaction, anti-Clr, -Cls, -C3, and -Ig were not inhibitory. Collagenase treatment of purified HBsAg reduced both PHALB-binding activity and the degree of HBsAg-associated Clq. These observations provide evidence that HBsAg-associated Clq is involved in or near the HBsAg-binding site for PHALB.     

p-Dimethoxy-substituted trans-octahydrobenzo[f]- and -[g]quinolines: synthesis and assessment of dopaminergic agonist effects

The N-n-propyl homologues of the title compounds were prepared for further assessment of the ability of the "p-dimethoxy" moiety to confer dopaminergic agonism upon a variety of ring systems. Both the angularly and the linearly annulated trans-benzoquinoline ring derivatives displayed prominent DA2 dopaminergic effects on the peripheral sympathetic nerve terminal and displayed postjunctional dopamine receptor agonist properties in the striatum. It is speculated that the angular octahydrobenzo[f]quinoline derivative (but not the linear octahydrobenzo[g]quinoline derivative) may owe its dopamine-like effects to metabolic activation phenomena. In contrast, the cis-fused isomer of the angularly annulated benzoquinoline was inactive, as was the simple benzene derivative N,N-di-n-propyl-beta-(2,6-dimethoxyphenyl)ethylamine.     

Occupational stress in migraine is weekend headache a myth or reality?

To determine whether or not the frequency of migraine attacks increased at weekends in employed patients and if so, whether or not this was related to the type of migraine, 35 female patients prospectively recorded the presence or absence of migraine attacks daily over a six-week period. They were also asked to estimate the frequency with which emotional factors predisposed to their migraine attacks and to provide details of their occupation. A diagnosis of common (migraine without aura) or classical migraine (migraine with aura) was made according to both the criteria of the Ad Hoc Committee on the Classification of Headache and those of the International Headache Society. Eleven percent and 6% of patients, respectively, felt that emotional factors "usually" or "always" predisposed to migraine attacks. There was no significant increase in the frequency of migraine attacks at weekends in either the total group or in the employed patients. Similarly, the type of migraine made no difference to the results. There was therefore no evidence for a delayed onset of migraine at weekends related to the weekday stress of employment.     

Gastric polyposis caused by multiple carcinoids and early carcinoma.

A case of gastric polyposis caused by multiple carcinoids with concurrent gastric carcinoma is reported in a 70 year old woman with severe atrophic gastritis and intestinal metaplasia. On microscopic examination, the carcinoids and gastric carcinoma arose separately thus representing "double primaries". Long-standing hypergastrinaemia probably plays a causative role in the development of carcinoma and carcinoids. Carcinoid tumours, although of low malignant potential, may be important as indicators of other unrelated high risk malignancies. Patients with carcinoids should be followed closely, especially as the incidence of these tumours seems to be on the increase.     

Nutritional correlates of acute respiratory infections

During October 1992 to June 1993 in eight villages covered by the Primary Health Center Machhra in Meerut District, India, interviews with mothers and examinations of 1600 children aged less than 5 years (under-fives) were conducted to examine the relationship between acute respiratory infection (ARI) and malnutrition. 42.25% of all children had an ARI within the last 15 days. Most ARIs (73.4%) were considered mild (cough and cold with no pneumonia). Pneumonia accounted for 19.5% of all ARI cases, which were considered moderate. The remaining ARI cases were severe (severe and very severe pneumonia). 57.5% of all children suffered from protein energy malnutrition (PEM). 78.6% of children aged 12-14 months had PEM. ARI was more common among malnourished children than well-nourished children (52.2% vs. 28.8%; p 0.001). The incidence of ARI increased as the nutritional status deteriorated (p 0.05). It also increased as the midarm circumference decreased (p 0.001). These findings confirm the synergistic action between malnutrition and infection, in this case ARI. Malnourished children suffer considerable impairment in immunity, especially cellular immunity, which makes them more prone to ARI. These findings reinforce the need to strengthen the quality, quantity, and accessibility of nutritional services, particularly promotion of breast feeding and vitamin A supplementation.     

Bile-duct diameter at the porta hepatis and liver biopsies in Indian children with biliary atresia

Fibrous remnants from the porta hepatis and wedge biopsies of the liver were studied in 60 patients with biliary atresia. The patients were divided into three groups on the basis of bile duct diameter — I: no ducts; II: <50 m; III: >50 m. The liver damage was classified into three grades on the basis of ductular and parenchymal histopathologic changes and extent of inflammatory pathology. There was no correlation between severity of hepatic damage and duct diameter, although the levels of serum bilirubin and alkaline phosphatase varied in direct proportion to the degree of hepatic damage. There was an inverse relationship between age and duct diameter, but neither correlated with bile flow at surgery or in the postoperative period. The data suggest that Indian children with biliary atresia follow a different clinical course compared to those from Japan and Western countries. Correspondence to: V. Bhatnagar