The intestinal and rectal epithelial lymphocyte in AIDS. An electron-microscopic study

Injury to the gastrointestinal tract may be mediated in part by the intraepithelial lymphocyte. In this study, we utilized electron microscopy to define the morphological appearance of 86 intestinal and 55 rectal intraepithelial lymphocytes observed in 11 patients with acquired immunodeficiency syndrome (AIDS), and one patient with AIDS-related lymphadenopathy syndrome. The data obtained from intraepithelial lymphocytes of AIDS are compared to those from 106 normal intestinal epithelial lymphocytes and 52 untreated celiac sprue epithelial lymphocytes. The AIDS epithelial lymphocyte possesses more organelles and appears "activated." Eighty-four percent of AIDS epithelial lymphocytes and 44% of normal epithelial lymphocytes possess lysosomal granules. There are 3.3 lysosomal granules/AIDS epithelial lymphocyte and 1.0 lysosomal granule/normal epithelial lymphocyte. Lymphocytes in AIDS usually possess multiple surface projections, which indent and make point contact with adjacent epithelial cells. Thirty-four percent of AIDS epithelial lymphocytes, 23% of sprue epithelial lymphocytes, and 2% of normal epithelial lymphocytes appear "activated." Lymphocytes in AIDS are "activated" in both the presence and absence of gastrointestinal pathogens. Epithelial lymphocytes are increased in intestinal, but not in rectal, AIDS tissue. Mucosal injury, including single cell necrosis, is minimal in the AIDS tissue. We speculate that the "activated" epithelial lymphocyte in AIDS, often possessing large lysosomes, could function as a cytotoxic effector in the development of gastrointestinal immune injury reported to be present in some patients with AIDS.     

Expression of an alternatively spliced ercc1 messenger-RNA species, is related to reduced DNA-repair efficiency in human T-lymphocytes

We have previously shown that in non-drug-selected human T lymphocytes, DNA repair is the primary determinant of cellular resistance to cisplatin (1). In this system, we have assessed mRNA levels of expression of the nucleotide excision repair (NER) genes ERCC1 and XPA, as well as the alternatively spliced species of ERCC1 which lacks exon VIII. The focus of these studies, was to try to identify the possible relative roles of normal XPA, full-length ERCC1, and alternatively spliced ERCC1, in a system where DNA repair is a clear determinant of cisplatin resistance. ERCC1 expression was directly related to cisplatin-DNA adduct repair capability, as well as directly related to cisplatin resistance, suggesting a primary role for ERCC1 in effecting DNA repair. XPA expression was approximately equivalent in each cell line, regardless of the level of DNA repair activity, suggesting a helper role for the product of this gene. The mRNA levels of the alternatively spliced species of ERCC1 were strongly inversely related to DNA repair activity, suggesting a possible inhibitory influence on the DNA repair process. This interpretation is consistent with alternative splicing of several known oncogenes, where the alternatively spliced species has an inhibitory effect on the full-length gene product. The NER pathway appears to be vitally important in effecting cisplatin resistance in non-drug-selected T lymphocytes. Further, it appears that NER may have at least one inhibitory regulatory component.     

Auditing paediatric diabetes care and the impact of a specialist nurse trained in paediatric diabetes

AIMS: To define outcome measures for auditing the clinical care of children and adolescents with insulin dependent diabetes mellitus (IDDM) and to assess the benefit of appointing a dedicated paediatric trained diabetes specialist nurse (PDSN). METHODS: Retrospective analysis of medical notes and hospital records. Glycaemic control, growth, weight gain, microvascular complications, school absence, and the proportion of children undergoing an annual clinical review and diabetes education session were assessed. The effect of the appointment of a PDSN on the frequency of hospital admission, length of inpatient stay, and outpatient attendance was evaluated. RESULTS: Children with IDDM were of normal height and grew well for three years after diagnosis, but grew suboptimally thereafter. Weight gain was above average every year after diagnosis. Glycaemic control was poor at all ages with only 16% of children having an acceptable glycated haemoglobin. Eighty five per cent of patients underwent a formal annual clinical review, of whom 16% had background retinopathy and 20% microalbuminuria in one or more samples. After appointing the PDSN the median length of hospital stay for newly diagnosed patients decreased from five days to one day, with 10 of 24 children not admitted. None of the latter was admitted during the next year. There was no evidence of the PDSN affecting the frequency of readmission or length of stay of children with established IDDM. Non-attendance at the outpatient clinic was reduced from a median of 19 to 10%. CONCLUSIONS: Outcome measures for evaluating the care of children with IDDM can be defined and evaluated. Specialist nursing support markedly reduces the length of hospital stay of newly diagnosed patients without sacrificing the quality of care.     

Early stage nasopharyngeal carcinoma: radiotherapy dose and time factors in tumor control

OBJECTIVE: To evaluate radiotherapy dose and length of treatment in the control of early stage nasopharyngeal carcinoma (NPC) treated with a combination of external radiotherapy and brachytherapy, MATERIALS & METHODS: We reviewed the records of 133 patients with early stage nasopharyngeal carcinoma (stage I or II, AJC/UICC staging system) who received definitive radiotherapy in Chang Gung Memorial Hospital from 1979 to 1991. The median follow-up time was 7.1 years with a minimum of 2 years. All patients were treated with megavoltage external radiotherapy to the nasopharynx area (63-72 Gy) followed by high dose rate intracavitary brachytherapy (5-16.5 Gy in one to three fractions, spaced 1-2 weeks apart). The median total dose and time of irradiation was 75 Gy (69.8-81.4 Gy) and 11.6 weeks (7.8-20 weeks) respectively. Survival analysis was used to examine the effect of several variables on prognosis. RESULTS: The 5-year rates were 86.4% for local control, 84.7% for disease free survival, 88.5% for actuarial survival and 84.2% for overall survival. The treatment group (combination of time and dose of irradiation) was the most important prognostic factor according to Cox's proportional hazard model. Patients receiving radiation at a total dose of < or = 75 Gy completed in < 12 weeks showed the best prognosis. CONCLUSION: Treatment time and total treatment dose are both important factors in treating early stage NPC. Decreasing the total radiation time to < 12 weeks and not exceeding a radiation dose of 75 Gy gave the best results.      

Expression and Significance of Coxsackie and Adenovirus Receptor in Renal-Cell Carcinoma

OBJECTIVE To investigate the expression of Coxsackie and Adenovirus receptor (CAR) in renal-cell carcinoma and the relationship of the CAR to the biological behavior of the carcinomas.METHODS The immunohistochemical SP method was used to detect the expression of Coxsaekie and Adenovirus receptor in 48 cases of renalcell carcinoma and in 12 cases of normal renal tissue 2 cm away from the tumor tissue.RESULTS The positive rates of CAR were 100% in 12 cases of para-tumcr normal renal tissue and 35.4% in 48 cases of renal-cell carcinoma respectively. The difference of CAR expression between them was significant (P＜0.05). The grades of the tumor were as follows: 22 in Grade Ⅰ, 17in Grade Ⅱ and 9 in Grade Ⅲ with the CAR positive rate being 54.5%,23.5% and 11.1%, respectively. There was a negative correlation between CAR expression and tumor grading (P＜0.05). In addition, the number of the cases in stages Ⅰ to ⅣV were 19, 13, 11 and 5 respectively, with the respective positive rates being 57.9%, 30.8%, 18.2% and 0.0%, i.e. there also was a negative relationship between CAR expression and the stage (P＜0.05).CONCLUSION CAR expression is down-regulated in renal-cell carcinoma compared with normal tissue. The level of CAR may be a sensitive predictor of differentiation, invasion and metastasis. Loss of CAR expression correlates with the invasive phenotype in our analysis of renal-cell carcinoma.     

Deleterious effects of irradiation and bone marrow transplantation therapy in the genetically anemic an/an mouse

The efficacy and outcome of bone marrow transplantation therapy following lethal irradiation were examined in syngeneic mice that had a hereditary macrocytic anemia (an/an) or were genotypically normal (+/+). Successful RBC and WBC replacement, based on blood cell parameters and donor genetic markers, were observed in all combinations of transplant therapy. Nevertheless, the an/an mice died prematurely several months after treatment, whether they received +/+ or an/an marrow cells. In contrast, the +/+ recipients of either +/+ or an/an marrow cells survived for at least 1 year after transplantation. Premature death of the an/an mice was associated with lymphopenia, anemia, kidney lesions, and severe pathogen-free pneumonitis. On the basis of our results, we hypothesize that the premature deaths of an/an mice are caused by a kind of chronic irradiation damage to which an/an mice are especially susceptible.     

Surveillance of Creutzfeldt Jakob disease in the United Kingdom

By the end of May 2000, 54 definite cases and 13 probable cases of vCJD had been notified in the United Kingdom by the National CJD Surveillance Unit set up in 1990. All definite cases for whom data are available are methionine homozygous at codon 129 of     

Mechanism of intestinal secretion: effect of cyclic AMP on rabbit ileal crypt and villus cells.

Cyclic AMP-dependent secretagogues such as cholera toxin inhibit the coupled absorption of Na+ and Cl- and stimulate the secretion of HCO3- and Cl- in the ileum. Aside from Cl- secretion, little is known about the mechanism of these cyclic AMP-mediated effects. We therefore determined the effect of forskolin, an agent known to increase intracellular cyclic AMP by stimulation of adenylyl cyclase, on Na+/H+ and Cl-/HCO3- exchange in isolated crypt and villus cells from rabbit ileum. Forskolin increased cyclic AMP in the villus cells and decreased intracellular pH. The effect of forskolin on pH in villus cells was HCO3- independent, Na+ dependent, and amiloride sensitive. Further, the rate of recovery from an acid load was decreased by forskolin. These data suggest that increasing cyclic AMP inhibits Na+/H+ exchange in villus cells. In crypt cells also, forskolin increased cyclic AMP; however, forskolin increased intracellular pH in these cells. The effect of forskolin in crypt cells was also HCO3- independent, Na+ dependent, and amiloride sensitive. However, the rate of recovery from an acid load was increased by forskolin, the opposite effect of that seen in villus cells. These data suggest that increasing cyclic AMP in crypt cells stimulates Na+/H+ exchange. Inhibition of Na+/H+ exchange on the brush border membrane in villus cells would be expected to inhibit coupled NaCl absorption (which occurs by coupling of Na+/H+ and Cl-/HCO3- exchange). Stimulation of Na+/H+ exchange in crypt cells, present only on the basolateral membrane, alkalinizes the cell, which would be expected to stimulate HCO3- secretion by stimulating the Cl-/HCO3- exchanger on the brush border membrane. Thus, these results provide a mechanism for some of the previously unexplained in vivo and in vitro effects of cyclic AMP on ileal electrolyte transport.     

Knockout mice lacking steroidogenic factor 1 are a novel genetic model of hypothalamic obesity.

Knockout (KO) mice lacking steroidogenic factor 1 (SF-1) exhibit a phenotype that includes adrenal and gonadal agenesis, impaired gonadotropin expression, and abnormalities of the ventromedial hypothalamic nucleus (VMH). Studies in rodents with lesions of the ventromedial hypothalamus have implicated the VMH in body weight regulation, suggesting that SF-1 KO mice may provide a genetic model of obesity. To prevent death, SF-1 KO mice were rescued with corticosteroid injections, followed by syngeneic adrenal transplants from wild-type (WT) littermates. Corticosterone and ACTH levels in WT and SF-1 KO mice were indistinguishable, documenting restoration of hypothalamic-pituitary-adrenal function. Although weights at earlier ages did not differ significantly from WT littermates, SF-1 KO mice were significantly heavier by 8 wk of age and eventually weighed almost twice as much as WT controls. Obesity in SF-1 KO mice predominantly resulted from decreased activity rather than increased food intake. Leptin was increased markedly, insulin was modestly elevated, and glucose was indistinguishable from WT mice. Although sex steroids in rodents affect weight, ovariectomy did not abolish the weight difference between WT and SF-1 KO mice. These SF-1 KO mice are a genetic model of late-onset obesity that may help elucidate the role of the VMH in weight regulation.