Immune reconstitution inflammatory syndrome in association with HIV/AIDS and tuberculosis: Views over hidden possibilities

Background  

CD4+ T lymphocyte (CD4) cell count testing is the standard method for determining eligibility for antiretroviral therapy (ART), but is not widely available in sub-Saharan Africa. Total lymphocyte counts (TLCs) have not proven sufficiently accurate in identifying subjects with low CD4 counts. We developed clinical algorithms using TLCs, hemoglobin (Hb), and body mass index (BMI) to identify patients who require ART.     

The immune dysregulatory compound mercuric chloride induces integrin-mediated T-lymphocyte adhesion

Exposure of Brown Norway rats to mercuric chloride induces systemic autoimmunity, involving T- and B-lymphocyte activation, (auto-)antibody production and multiorgan inflammation. Several divalent metal ions, such as Mg2+ and Mn2+, can activate binding of integrins to their ligands, thus causing lymphocyte adhesion. To test the hypothesis that Hg2+ acts in a similar way, we studied the effect of HgCl2 on integrin-mediated T-cell adhesion. HgCl2 induced cell-cell aggregation of human T lymphoblasts. Exposure of a human T-cell clone to HgCl2 for 1 hr enhanced, in a dose-dependent way, cell binding to fibronectin (FN) and to intercellular adhesion molecules (ICAM) -1, -2 and -3. Furthermore, HgCl2 induced strong binding of Jurkat T cells to FN. These effects of HgCl2 were of similar magnitude as the effects of phorbol 12-myristate 13-acetate (PMA) or MnCl2. Studies using blocking antibodies indicated the involvement of CD11a in binding to ICAMs, and of CD49d, CD49e, and CD29 in binding to FN. Adhesion to FN induced by HgCl2 or by PMA, but not by MnCl2, was dependent on temperature and on extracellular Ca2+ or Mg2+. Addition of cytochalasin B enhanced synergistically the FN adhesion induced by MnCl2, whereas the effects of PMA and HgCl2 were not modified. These results indicate that Hg2+ is a potent activator of T-cell adhesion, mediated by several integrins and ligands. In contrast to the effect of MnCl2, HgCl2-induced cell adhesion probably involves an intracellular pathway. Activation of integrins by HgCl2 may play an important role in activation and migration of leucocytes involved in HgCl2-induced immune dysregulation in vivo.     

Late denervation in patients with antecedent paralytic poliomyelitis

The development of new weakness, fatigue, and pain decades after acute paralytic poliomyelitis is a recognized syndrome. We conducted a controlled study of this syndrome by analyzing clinical, electromyographic, and muscle-biopsy features in 18 patients with a history of poliomyelitis--13 reporting 1 to 20 years of new weakness and 5 without new symptoms. The patients with new weakness also reported new muscle atrophy (9 of 13) and fatigue (10 of 13), symptoms not reported by the controls. The age at the time of acute poliomyelitis, severity of poliomyelitis, residual disability, number of years since acute poliomyelitis, and age at the time of study were comparable in the weakening and control groups. Evidence of remote denervation consistent with antecedent poliomyelitis was demonstrated in all patients by electromyography or muscle biopsy or both. In addition, active denervation (as evidenced by spontaneous activity on conventional electromyography, increased jitter on single-fiber electromyography, or atrophic myofibers) was found in 12 patients in the weakening group and in all 5 controls. Immunohistochemical detection of myofibers expressing the neural-cell adhesion molecule corroborated ongoing denervation in both patient groups. When muscle data from both groups were pooled, correlations were observed between the extent of past reinnervation and the degree of ongoing motor-unit instability. We conclude that the extensive reinnervation of denervated muscle that occurs in paralytic poliomyelitis may be followed by late denervation of the previously reinnervated muscle fibers. Electromyographic and muscle-biopsy evidence of ongoing denervation does not distinguish between stable patients with prior paralytic poliomyelitis and those with new weakness.     

Histological,immunohistochemical, and ultrastructural features of a rat medullary thyroid carcinoma transfected with a corticotropin-releasing hormone cDNA expression vector

Clonal cell lines producing corticotropin-releasing hormone (CRH) have been generated by transfection of the W2 rat medullary thyroid carcinoma (MTC) cell with a CRH-encoding CMV/ SV40 expression vector. Here, we report the morphological, immunohistochemical, and ultrastructural features of rat tumors derived by implantation of CRH-producing W2CRH-7 cells and compare them with non-CRH-producing W2 MTCs. Both types of tumors grew rapidly and consisted of sheets and nests of pleomorphic cells infiltrating adjacent adipose tissue. Immunohistochemistry revealed CRH in only W2CRH-7 tumors; scattered cells in these tumors also were immunoreactive for chromogranin and for vasoactive intestinal peptide. Otherwise, the two tumor types exhibited similar profiles of various neuroendocrine markers, including neuron-specific enolase, synaptophysin, calcitonin, and somatostatin. Ultrastructurally, the tumors contained abundant dilated rough endoplasmic reticulum, a prominent Golgi apparatus, and numerous lysosomes. Very few secretory granules were noted in the W2 tumors; by contrast, secretory granules, although still not numerous in the majority of W2CRH-7 cells, were more abundant in scattered cells of those tumors. The positive immunostaining for CRH is consistent with the observations of increased plasma CRH and pituitary-adrenal activation induced by these transplanted tumors. This system provides a valuable model for CRH excess mimicking tumoral CRH-dependent Cushing’s syndrome in human patients.     

Age at onset in Huntington''s disease: effect of line of inheritance and patient''s sex.

The Leiden Roster for Huntington's disease (HD) contained data on 2617 cases up to July 1988. The age at onset (AO) was known in 1084 cases and in 1020 of these both their AO and the sex of the affected parent was known. The mean AO was higher for females than for males and higher for maternal than for paternal cases. However, in the group born before 1925 only females with maternal inheritance had a higher mean AO. Data on influence of sex and line of inheritance were present for the grandparents as well as for the great grandparents. Influence of the line of inheritance from the grandparents was particularly present for the grandmother-father (MP) lineage; regarding the great grandparents a significant difference was found between the MPM and PMP lineage. The results obtained for juvenile HD cases were comparable to those previously published. In late onset cases (over 50 years) no maternal preponderance in inheritance was found.     

CD4+CD25+ T lymphocytes in human tonsils suppress the proliferation of CD4+CD25- tonsil cells

Animal studies define CD4+CD25+ T cells as a subset that protect against autoimmune inflammation. We wanted to investigate whether CD4+CD25+ T cells from patients with recurrent tonsillitis could suppress the proliferation of other tonsil cells, in vitro, as this immunological tissue also may serve as a model for chronic inflammation. Tonsil CD4+CD25+ cells markedly suppressed the proliferation of CD4+CD25- T cells in Concanavalin A-stimulated cocultures compared with cultures containing CD4+CD25- T cells only. The suppression exerted by the CD4+CD25+ cells was abrogated if these cells were irradiated before coculture or if interleukin (IL)-2 was added to the culture medium. CD4+CD25+ T cells proliferated poorly in response to mitogen, when cultured alone. Substitution with CD4+CD25+ T cells isolated from peripheral blood, enriched by similar methods, did not downregulate the proliferation of CD4+CD25- responder cells from tonsils. The augmented suppressive ability of tonsil CD4+CD25+ T cells compared with cells of this phenotype from blood, on CD4+CD25- responder cells from tonsils, suggests that there may be a functional difference between CD25+ cells from the two locations. In conclusion, CD4+CD25+ T cells from inflamed tonsils distinctly suppressed T-cell responses to mitogen in vitro, pointing to a regulatory role for CD4+CD25+ cells retrieved from inflammatory reactions in humans.     

Influence of gastrostomy on the colonization of the stomach: Impact on neonatal septicaemia

Summary Quantitative bacterial counts were carried out on 161 gastric aspirates of 65 neonates with gastrostomy. In comparison to 101 controls — cultures of premature infants without gastrostomy —Enterobacteriaceae, enterococci,Pseudomonas andCandida were found far more frequently (p<0.01). The colonization of the stomach was influenced by the duration of gastrostomy and by the pH of the gastric juice but not by systemic antibiotic therapy or the kind of food. Six newborns with gastrostomy developed septicaemia caused by the same organisms as we had found in elevated numbers in their gastric aspirates. The influence of non-absorbable antibiotics was studied prospectively in 72 gastric aspirates and 48 stool specimens. There was no highly significant difference between infants who had been treated with these antibiotics and those who had not.

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Einflu der Gastrostomie auf die Kolonisation des Magens — Sepsisquelle beim Neugeborenen?

Zusammenfassung Es wird über 161 quantitative bakteriologische Untersuchungen des Mageninhalts bei 65 gastrostomierten Neugeborenen berichtet. Im Vergleich zu 101 Untersuchungen an nichtgastrostomierten Frühgeborenen fanden sich hochsignifikant häufigerEnterobacteriaceae, Enterokokken,Pseudomonas undCandida (p<0.01). Die Kolonisation des Magens wurde von der Dauer der Gastrostomie und dem pH-Wert des Magensaftes beeinflußt, nicht aber von intravenöser Antibiotika-Gabe oder der Art der Ernährung. Sechs gastrostomierte Kinder erkrankten an einer Sepsis mit dem gleichen Erreger in der Blutkultur, der sich auch in hoher Konzentration im Mageninhalt zeigte. Der Einfluß schwer resorbierbarer Antibiotika wurde prospektiv an 72 Aspiraten von Mageninhalt und 48 Stuhlproben untersucht. Hierbei zeigten sich keine hochsignifikanten Unterschiede zwischen behandelten und nictbehandelten Kindern.

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This paper is dedicated to Prof. Dr. med.W. Marget on the occasion of his 65th birthday.     

The role of interleukin-2 in proliferative responses in vitro of T cells from patients after bone marrow transplantation. Evidence that minor defects can lead to in vitro unresponsiveness

We have studied lectin-induced interleukin-2 (IL-2) production and proliferation of peripheral blood mononuclear cells from patients who had undergone a successful allogeneic bone marrow transplantation. Shortly after transplantation, the T cells show a decreased proliferative response and a decreased IL-2 production. However, addition to the culture of exogenous IL-2 does not result in restoration of the proliferative response, which indicates that the low proliferative response is not due to decreased IL-2 production alone. Longitudinal studies show a substantial variation between patients in the time in which the capacity to produce IL-2 is restored; however, in all patients there is a period in which IL-2 production is still diminished, but the proliferative capacity, as measured upon addition of exogenous IL-2 to the culture, is almost within the normal range. Also during this period, the proliferative response of the T cells can be restored by the addition of irradiated "feeder cells" obtained from the bone-marrow donors, as these cells secrete IL-2 without consuming it. Because peripheral blood samples from patients after bone marrow transplantation show great imbalances in the distribution of T4/T8 subpopulations, we have studied the influence of an artificially produced "reverse T4/T8" ratio on the proliferative response to mitogen and (allos-)antigen stimulation of healthy donor T lymphocytes. Even at very low proportions of T4 cells, normal responses were obtained in the proliferation assays with polyclonal mitogens. Only the response to soluble antigens, such as tetanus toxoid, was impaired. However, a low proportion of T4 cells resulted in a low IL-2 production so that, when IL-2 is a limiting factor due to intrinsic defects of patient cells, an inverse T4/T8 ratio can cause a nonresponsiveness in in-vitro assays.     

Cervical cytology screening after tubal ligation

Tubal ligation has become one of the most frequently performed surgical procedures, and estimates suggest that over 50 percent of all women will undergo surgical sterilization by age 45. Preventive health procedures such as Pap tests are often performed when women visit physicians for family planning and obstetric care. Since women do not visit physicians for these reasons following tubal ligation, it is important to know how their physician contact and Pap test coverage is affected by this surgery. We used data from the Manitoba Health Services Commission to construct health-services-use histories for the two years before and the two years after surgery for all women aged 25-44 who underwent tubal ligation in 1974 (n = 4,553) and for a comparison group of women who did not have the surgery (n = 5,161). Women visited physicians after surgery at the same rate as they had before surgery. However, the proportion of women receiving Pap tests fell in the years after surgery for the tubal ligation women but remained the same for the comparison group. The reasons for this decline in testing were a decline in the number of visits for gynecologic and obstetric reasons and a decline in testing because of high rates of "screening" prior to surgery. This study demonstrates both the importance of the one-time surgical event as an opportunity to offer Pap tests to women who might otherwise not visit physicians and the possibility of overtesting among some women.