Role of lymphokines in immunoregulatory function of mucosal T cells in humans and nonhuman primates

The findings presented above and in other studies provide substantial evidence that lymphocytes in the intestinal lamina propria differ from lymphocyte populations in the circulation or in other tissue sites in a number of ways. First, lamina propria lymphocytes are phenotypically distinct and have evidence of activation. Lymphocytes in the intestinal lamina propria are different in their potential for expression of lymphokine gene products, since activated cells from the lamina propria have high expression of mRNA for IL-2, IL-4, IL-5 and IFN-gamma in comparison to circulating lymphocytes. Mesenteric lymph node T cells also differ from circulating lymphocytes in their high expression of IL-4 and IL-5 mRNA. A further difference between mesenteric lymph node and lamina propria T cells is that the former are capable of proliferating in response to IL-4, whereas the latter are not. These phenotypic and mRNA differences of lamina propria lymphocytes also correlate well with their high helper activity in vitro for immunoglobulin synthesis in the pokeweed mitogen system. Finally, lamina propria T cells at a site of inflammation are able to provide high helper activity in response to specific antigens. These observations are all consistent with the conclusion that T cells in the lamina propria are pleomorphic, but are highly enriched for subpopulations of activated memory cells that are geared for effector functions. These functions are likely to be critical in maintaining normal host defense in the mucosal environment.     

Characterization of creatinine error in ketotic patients. A prospective comparison of alkaline picrate methods with an enzymatic method

Creatinine measurement by alkaline picrate reagents is subject to positive interference by acetoacetate. Enzymatic reagents avoid this interference and have been adapted to instruments such as the Ektachem-400 (Kodak). By documenting the discrepancy between alkaline picrate and Ektachem determinations for creatinine, the authors prospectively identified ketotic patients in whom the presence of ketones was responsible for a significant creatinine error. During their three-month survey, they identified 50 such ketotic inpatients. Those admitted to the medicine service represented almost 5% of all medicine admissions over this time. Of the total specimens, the mean discrepancy was 14 +/- 8 mg/L with a range of 4-44 mg/L. The greater the ketosis, the greater the discrepancy. Two-thirds of the samples were normal on the Ektachem but greater than normal by picrate methods. In addition to diabetes or ethanol abuse, 17% of the ketotic patients had severe or terminal illness that was generally associated with malnutrition.     

Effect of hydrostatic pressure on ADH induced osmotic water flow in toad bladder

The effect of hydrostatic pressure (HP) on antidiuretic hormone (ADH) stimulated osmotic water flow (Jv) across the toad urinary bladder was evaluated. Jv for ADH-stimulated bladders was significantly reduced by an elevation of the serosal HP gradient to 1 cm H₂O. Subsequent elimination of the HP gradient resulted in a recovery of Jv. Serosal HP also caused a reversible increase in sucrose permeability (P sucrose). For ADH-treated bladders fixed with glutaraldehyde during serosal HP exposure, subsequent exposure to a mucosal or serosal HP gradient caused acceleration or inhibition of Jv, respectively. The reduction in ADH-associated Jv with serosal HP was apparently caused by a back-flux of water through a paracellular pathway. Jv and P sucrose were not affected by mucosal HP during ADH stimulation. The results suggest a specific sensitivity of a paracellular pathway to a small serosal HP gradient in bladders with ADH-stimulated water flow. The reversibility of this effect on P sucrose suggests that the elements comprising the apical junctions are dynamic structures capable of recovering at least some of their permeability properties.     

Immunohistochemical localization of pepsinogen A and C containing cells in Barrett's oesophagus

Summary No data are available on the localization of Pepsinogen A (PGA=PG I) and Pepsinogen C (PGC=PG II) positive cells in Barrett's epithelium. Endoscopic biopsy specimens were taken from the columnar epithelium from 23 patients (n=93), and in addition from the cardia from eight healthy control subjects (n=38). The tissue was stained by the immunoperoxidase technique with specific anti-pepsinogen antisera, and double immunostained for PGA and PGC. In the Barrett's epithelium PGA was found in 28 out of 93 biopsy specimens (30.1%) and PGC in 55 out of 93 (59.1%). Chief cells always stained both for PGA and PGC, while clear mucous cells were often PGA– and PGC+. PGA+ and PGC+ cells were found each in 100% of the biopsy specimens with fundic type epithelium, in 21.7% and 70.7% of biopsy specimens with junctional type, in 0% and 26.1% of biopsy specimens with specialized epithelium and in 12.5% and 43.5% of biopsy specimens with mixed junctional/specialized features respectively. Dysplastic epithelium stained always negatively with both anti-pepsinogen antisera. In most control cardia biopsy specimens PGA as well as PGC were demonstrable; occasionally clear mucous glands were PGA– and PGC+.It is concluded that pepsinogen-containing cells can be accurately identified in the Barrett's epithelium; their presence seems related to the histological cell type. Identification of pepsinogen positive cells may contribute to a more accurate morphological classification of the Barrett's epithelium.Presented in part at the Annual Meeting of the American Gastroenterological Association, San Francisco, May 1986     

Abeta-degrading endopeptidase,neprilysin, in mouse brain: synaptic and axonal localization inversely correlating with Abeta pathology

Metabolism of amyloid-beta peptide (Abeta) is closely associated with the pathology and etiology of Alzheimer's disease (AD). Since neprilysin is the only rate-limiting catabolic peptidase proven by reverse genetics to participate in Abeta metabolism in vivo, we performed detailed immunohistochemical analysis of neprilysin in mouse brain using neprilysin-deficient mice as a negative control. The aim was to assess, at both the cellular and subcellular levels, where Abeta undergoes neprilysin-dependent degradation in the brain and how neprilysin localization relates to Abeta pathology in amyloid precursor protein (APP)-transgenic mice. In hippocampus, neprilysin was present in the stratum pyramidale and stratum lacunosum-moleculare of the CA1-3 fields and the molecular layer of the dentate gyrus. Confocal double immunofluorescence analyses revealed the subcellular localization of neprilysin along axons and at synapses. This observation suggests that after synthesis in the soma, neprilysin, a type II membrane-associated protein, is axonally transported to the terminals, where Abeta degradation is likely to take place. Among various cell types, GABAergic and metabotropic glutamate 2/3 receptor-positive neurons but not catecholaminergic or cholinergic neurons, expressed neprilysin in hippocampus and neocortex, implying the presence of a cell type-specific mechanism that regulates neprilysin gene expression. As expected, Abeta deposition correlated inversely with neprilysin expression in TgCRND8 APP-transgenic mice. These observations not only support the notion that neprilysin functions as a major Abeta-degrading enzyme in the brain but also suggest that down-regulation of neprilysin activity, which may be caused by aging, is likely to elevate local concentrations of Abeta at and around neuronal synapses.     

Foreign bodies,exogenous & endogenous triggering mechanical effects,good/bad,in the airways. The anesthesiologist as the diagnostician

Fifty odd years ago, in his historic book, 'The Silent World,' Jacques Cousteau told us that scuba divers breathing compressed air were apt to get a 'high,' which he called, 'Rapture of the Deep,' and a form of cerebral arrest, which he termed, 'Nitrogen Narcosis'. Furthermore, these submarine soloists, also like persons under general anesthesia, are prone to mysterious sudden death. All this reminds us of 'ether parties,' and contemporary snorters and huffers, sniffing such foreign bodies as, glue, cocaine, paint-thinner, gasoline, spray-can-propellant, etc. Relevant is the fact that the endogenous and other soporifics which arise within the body proper (endo-integumentarily) do not induce general anesthesia, which is cerebral arrest, until they have entered the extra-integumentary mucosal compartments called airways. Nitrogen is an inert gas, so its actions are neither toxic nor chemical, but mechanical. The effects of endogenous soporifics such as acetone, carbon dioxide, alcohol, and ammonia, are usually assumed to be toxic and endo-integumentary. Therefore, I must emphasize the fact that they do not cause 'Highs,' somnolence, nor deaths until/unless they have entered the extra-integumentary airways. Certainly those agents may also have some endo-integumentary actions. I must also stress the fact that foreign bodies in the airways which do not pierce the integument to enter the body proper, such as endotracheal or tracheostomy tubes, lumps of meat, mucus plugs (boogers), etc., can also occasionally trigger cerebral, respiratory and even cardiac arrests locally and mechanically in the airways, depending on which trigger points they stimulate and how powerfully. Four points explain the mechanism of general anesthesia: (a) Endogenous soporifics do not induce sleep until they have entered the extra-integumentary airways, and contacted the mural mucosa; (b) however administered, intravenously, rectally, or by inhalation, exogenous general agents do not anesthetize until they enter the airways and contact the extra-integumentary mucosa; (c) other foreign bodies, e.g., mishandled endotubes in the airways, which cannot pierce the integument to enter the body proper, can and do trigger cerebral/respiratory/cardiac arrest locally, mechanically, and extra-integumentarily. These effects are neither toxic, nor chemical; (d) Some agents, which can and do pierce the integument, having induced anesthesia, will later exit the body chemically unchanged by their endo-integumentary sojourn, which suggests that their modus operandi is mechanical.     

More training needed in chronic care: a survey of US physicians.

PURPOSE: Although more than 125 million North Americans have one or more chronic conditions, medical training may not adequately prepare physicians to care for them. The authors evaluated physicians' perceptions of the adequacy of their chronic illness care training to and the effects of training on their attitudes toward care of persons with chronic conditions. METHOD: In November 2000 through June 2001, the authors surveyed by telephone a random sample of U.S. physicians who had > or =20 hours of patient contact per week. The interview instrument examined demographics, career satisfaction, practice characteristics, perceived adequacy of chronic illness care training in ten competencies (geriatric syndromes, chronic pain, nutrition, developmental milestones, end-of-life care, psychosocial issues, patient education, assessment of caregiver needs, coordination of services, and interdisciplinary teamwork), and effect of training on attitudes toward chronic illness care. RESULTS: Of 1,905 eligible physicians, 1,236 (65%) responded (270 family or general practitioners, 231 internists, 129 pediatricians, 335 nonsurgical specialists, and 271 surgeons). Most physicians reported their chronic disease training was less than adequate for all ten competencies. Family practitioners were more likely (p <.05) to report adequate training in seven competencies compared with internists, and in two to four competencies when compared with pediatricians, nonsurgical specialists, or surgeons. Most physicians reported that training had a positive effect on attitudes toward care of people with chronic conditions, including the ability to make a difference in their lives (74-84%). CONCLUSIONS: Physicians perceived their medical training for chronic illness care was inadequate. Medical schools and residencies may need to modify curricula to better prepare physicians to treat the growing number of people with chronic conditions.     

Allergen immunotherapy induces a suppressive memory response mediated by IL-10 in a mouse asthma model

BACKGROUND: Human studies have demonstrated that allergen immunotherapy induces memory suppressive responses and IL-10 production by allergen-specific T cells. Previously, we established a mouse model in which allergen immunotherapy was effective in the suppression of allergen-induced asthma manifestations. OBJECTIVE: In this study, we examined whether immunotherapy induces a long-lasting effect and investigated the role of IL-10 in successful immunotherapy. METHODS: Ovalbumin-sensitized BALB/c mice were treated with 3 injections of ovalbumin (1 mg, subcutaneous) on alternate days. After a short interval (1 week) and after a long interval (5 weeks), mice were challenged by ovalbumin inhalation, and subsequently, airway reactivity, airway eosinophilia, ovalbumin-specific IgE, and T(H)2 cytokine profile were measured. Flow cytometry and blocking of IL-10 receptors in vivo were used to gain insight in the role of IL-10 in the beneficial effects of allergen immunotherapy. RESULTS: After a long interval between ovalbumin immunotherapy and ovalbumin challenge, the development of airway eosinophilia and hyperresponsiveness to methacholine were as strongly suppressed as after a short interval. These suppressive effects coincided with significantly reduced serum ovalbumin-specific IgE levels and T(H)2 cytokine production. On immunotherapy, the IL-5:IL-10 ratio in the bronchoalveolar lavage fluid shifted toward IL-10. In ovalbumin-restimulated lung cell and thoracic lymph node cultures from these mice, IL-5 levels dramatically decreased, whereas the percentage of IL-10(+)CD4(+) T cells was not affected. Finally, in mice treated with mAb against IL-10 receptors, the beneficial effects of immunotherapy were largely abrogated. CONCLUSION: These data demonstrate that allergen immunotherapy induces a memory suppressive effect in which IL-10 is essential.     

Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming

Naive T cells are stimulated by antigen-presenting dendritic cells (DCs) in secondary lymphoid organs, but whether other types of cell participate in T cell priming is unclear. Here we show in mice that natural killer (NK) cells, which are normally excluded from lymph nodes, are rapidly recruited in a CCR7-independent, CXCR3-dependent manner to lymph nodes on stimulation by the injection of mature DCs. Recruitment of NK cells is also induced by some, but not all, adjuvants and correlates with the induction of T helper cell type 1 (T(H)1) responses. NK cell depletion and reconstitution experiments show that NK cells provide an early source of interferon-gamma (IFN-gamma) that is necessary for T(H)1 polarization. Taken together, our results identify an induced pathway of NK cell migration in antigen-stimulated lymph nodes and a mechanism by which some adjuvants may facilitate T(H)1 responses.     

High risk pregnancies in hypopituitary women

BACKGROUND: Various short papers have suggested that pregnancies in women with hypopituitarism are high risk but no formal assessment of pregnancy outcome has yet been reported. METHODS: An audit was carried out concerning the outcome of 18 pregnancies in nine women who underwent ovulation induction in a single centre over 20 years. RESULTS: The live birth rate was 61%, miscarriage rate 28% and mid-trimester uterine death rate 11% with no survivors from four sets of twins. The Caesarian section rate was 100% and half of the live births were on or below the 10th centile for weight. One woman successfully breast-fed. CONCLUSIONS: Women with hypopituitarism have high-risk pregnancies, perhaps because of a uterine defect secondary to endocrine deficiency. Fertility treatment must strive for singleton pregnancies with application of particularly strict criteria to avoid twin pregnancies. Early elective Caesarian section is probably warranted in this group.