Excess prevalence of fasting and postmethionine-loading hyperhomocysteinemia in stable renal transplant recipients

Hyperhomocysteinemia, either fasting or after methionine loading, may contribute to the increased incidence of cardiovascular disease events experienced by renal transplant recipients. Limited data are available on fasting homocysteine (Hcy) levels, and none on postmethionine-loading Hcy levels, in these patients. We assessed the prevalence and potential determinants of fasting and postmethionine-loading hyperhomocysteinemia in 29 stable renal transplant recipients and 58 age- and sex-matched, population-based controls free of renal disease with serum creatinine levels of 1.5 mg/dL or less. Total (t) plasma Hcy was determined fasting and 2 hours after methionine loading, along with fasting determinations of the B-vitamin cofactors/substrates for Hcy metabolism, ie, pyridoxal 5'-phosphate, B-12, and folate and serum creatinine. Geometric mean fasting (18.1 versus 9.8 microM, P < .001) and postmethionine-loading increase (22.0 versus 15.2, P = .001) in tHcy levels were significantly greater in the renal transplant recipients, as were the prevalence odds (with 95% confidence intervals) for fasting [14.8 (3.4-64.7)], postmethionine loading [6.9 (1.5-32.8)], combined fasting and postmethionine-loading [18.0 (2.3-142.1)] hyperhomocysteinemia, and inadequate circulating folate [4.2 (1.1-16.5)] or pyridoxal 5'-phosphate [3.2 (0.9-11.0) status. Correlation analyses suggested important potential relationships between creatinine and both fasting (+0.64, P < .001) and postmethionine-load increase (+0.38, P = .045) in tHcy, folate and fasting (-0.41, P = .025) tHcy, and pyridoxal 5'-phosphate and postmethionine-loading increase (-0.33, P = .091) in tHcy. We conclude that there is an excess prevalence of fasting and postmethionine-loading hyperhomocysteinemia in stable renal transplant recipients. Renal function is related to both fasting and postmethionine loading-hyperhomocysteinemia, inadequate folate status is associated with fasting hyperhomocysteinemia, and inadequate vitamin B-6 status may be related to postmethionine-loading hyperhomocysteinemia in this patient population.     

The National Cancer Data Base report on non-Hodgkin's lymphoma

BACKGROUND: The National Cancer Data Base (NCDB) has reported on many malignancies occurring in men and women in the U. S. from >1400 contributing hospitals. The current report on non-Hodgkin's lymphoma (NHL) is a companion to an upcoming Patient Care Evaluation study of this relatively common and serious cancer. METHODS: This report is comprised of all NHL cases submitted to the NCDB divided into two diagnostic-year groups: 1985-1988 and 1990-1993. Variables routinely collected by hospital cancer registries have been analyzed to report on patterns of diagnosis and treatment. RESULTS: High grade NHL cases were more likely to be Stage IV (40.8%) than were low or intermediate grade cases (34.8% and 32.5%, respectively). Patients with NHL arising from lymph node sites tended to present with more advanced disease (55.8% with Stages III and IV disease), whereas patients with NHL arising from extranodal sites and non-lymph node nodal sites presented at an earlier stage (64.7% and 74.0%, respectively, with Stage I or Stage II disease). Approximately 67% of all patients underwent chemotherapy, whereas only 25% underwent surgery or radiation. By histology, 5-year survival was 68.8% for low grade disease, 51.9% for intermediate grade disease, and 45.8% for high grade disease; by stage, survival rates ranged from 73.5% for Stage I to 42.9% for Stage IV disease. CONCLUSIONS: To the authors' knowledge, the 91,306 cases in this study represent the largest contemporary sample of NHL patients. The material reported here may serve as a reference with which to compare local patterns with national data. The Working Formulation's ability to stratify patients' survival rates confirms its utility for NHL. Stage according to the American Joint Committee on Cancer also was accurate in predicting survival.     

Intravenous immunoglobulin prophylaxis in neonates on artificial ventilation

The efficacy of the prophylactic use of intravenous immunoglobulin (Ig) was evaluated in a double-blind placebo-controlled trial of 21 pairs of ventilated neonates weighing more than 1,500 g. Each infant received 0.4 g/kg/day of intravenous Ig or a similar volume of placebo daily for 5 days. Criteria used to assess the efficacy of intravenous Ig were the number of infections, the duration of ventilation therapy and time to clinical recovery. There were no significant differences in the treated and placebo groups with regard to the frequency of positive blood cultures (28.6% and 14.3%), endotracheal cultures (57.1% and 66.7%) and abnormal white cell counts (52.4% and 57.1%). On entry to the study there was no significant difference in IgG levels between the treated (974.5 mg/dl; SD 575.3) and placebo groups (818 mg/dl; SD 516.9). However, on day 6 the treated group had a mean level of 1,400.3 mg/dl (SD 426.7) versus 710.9 mg/dl (SD 377.4) in the placebo group (P < 0.05). Clinical improvement occurred within 3 days in both groups. Ventilatory support was required for 11.8 days (SD 8.3) in the treated and 11.8 days (SD 7.3) in the placebo group. Both groups required 3-4 antibiotic treatments over a period of 14-15 days. Two patients died in the treated and 4 in the placebo group, with 1 infant in each group developing bronchopulmonary dysplasia. The patients who recovered did so within 14 days. Analyses of subgroups of patients with different diagnoses revealed no differences except a trend suggesting fewer infections in term babies treated with intravenous Ig. The organisms cultured in the intravenous Ig groups were Pseudomonas, Klebsiella, Escherichia coli and Staphylococcus and in the placebo group Pseudomonas, Klebsiella and Enterobacter. The above has shown that, except for a trend in the older neonates, intravenous Ig is not of prophylactic benefit in ventilated neonates. Newer adjuncts in immunotherapy such as hyperimmune gammaglobulin or monoclonal antibodies may prove of greater value in the treatment of neonatal sepsis.     

Evaluating multiple alternative hypotheses for the origin of Bilateria: an analysis of 18S rRNA molecular evidence

Six alternative hypotheses for the phylogenetic origin of Bilateria are evaluated by using complete 18S rRNA gene sequences for 52 taxa. These data suggest that there is little support for three of these hypotheses. Bilateria is not likely to be the sister group of Radiata or Ctenophora, nor is it likely that Bilateria gave rise to Cnidaria or Ctenophora. Instead, these data reveal a close relationship between bilaterians, placozoans, and cnidarians. From this, several inferences can be drawn. Morphological features that previously have been identified as synapomorphies of Bilateria and Ctenophora, e.g., mesoderm, more likely evolved independently in each clade. The endomesodermal muscles of bilaterians may be homologous to the endodermal muscles of cnidarians, implying that the original bilaterian mesodermal muscles were myoepithelial. Placozoans should have a gastrulation stage during development. Of the three hypotheses that cannot be falsified with the 18S rRNA data, one is most strongly supported. This hypothesis states that Bilateria and Placozoa share a more recent common ancestor than either does to Cnidaria. If true, the simplicity of placozoan body architecture is secondarily derived from a more complex ancestor. This simplification may have occurred in association with a planula-type larva becoming reproductive before metamorphosis. If this simplification took place during the common history that placozoans share with bilaterians, then placozoan genes that contain a homeobox, such as Trox2, should be explored, for they may include the gene or genes most closely related to Hox genes of bilaterians.     

An outbreak of urticarial form of swine erysipelas in a medium-scale piggery in Kiambu District, Kenya

The influence which female sexual steroids, especially estrogen, have on the development of cancer has not only been shown epidemiologically, but also by experimental findings. Hormones, in spite of a known marginal increase in the risk of thrombosis and endometrial cancer, play an important role in the preventive cancer medication (oral contraceptives: ovarian and endometrial cancer; chemoprevention: high-risk breast cancer patients). Basically, hormone replacement therapy should be administered to all patients suffering from gynecological malignomas. In the case of patients suffering from breast cancer, the advantages of hormone replacement therapy (e.g., less risk of cardiovascular complications) need to be weighed against the disadvantages.     

Development of autologous, oligoclonal, poorly functioning T lymphocytes in a patient with autosomal recessive severe combined immunodeficiency caused by defects of the Jak3 tyrosine kinase

Defects of the common gamma chain subunit of the cytokine receptors (gamma c) or of Jak3, a tyrosine kinase required for gamma c signal transduction, result in T-B+ severe combined immunodeficiency (SCID). However, atypical cases, characterized by progressive development of T lymphocytes, have been also reported. We describe a child with SCID caused by Jak3 gene defects, which strongly but not completely affect Jak3 protein expression and function, who developed a substantial number (> 3,000/microL) of autologous CD3+CD4+ T cells. These cells showed a primed/activated phenotype (CD45R0+ Fas+ HLA-DR+ CD62L(lo)), defective secretion of T-helper 1 and T-helper 2 cytokines, reduced proliferation to mitogens, and a high in vitro susceptibility to spontaneous (caused by downregulation of bcl-2 expression) as well as activation-induced cell death. A restricted T-cell receptor repertoire was observed, with oligoclonal expansion within each of the dominant segments. These features resemble those observed in gamma c-/y and in Jak3-/- mice, in which a population of activated, anergic T cells (predominantly CD4+) also develops with age. These results suggest that residual Jak3 expression and function or other Jak3-independent signals may also permit the generation of CD4+ T cells that undergo in vivo clonal expansion in humans; however, these mechanisms do not allow development of CD8+ T cells, nor do they fully restore the functional properties of CD4+ T lymphocytes.     

Structure-based design of new constrained cyclic agonists of the cholecystokinin CCK-B receptor

New constrained cyclic pseudopeptide cholecystokinin-B (CCK-B) agonists have been designed on the basis of conformational characteristics of the potent and selective CCK-B agonist Boc-Trp-(NMe)Nle-Asp-Phe-NH2 (Ki = 0.8 nM, selectivity ratio CCK-A/CCK-B > 6000) (Goudreau et al. Biopolymers, 1994, 34, 155-169). These compounds are among the first successful examples of macrocyclic constrained CCK4 analogs endowed with agonist properties and as such may be of value for the development of nonpeptide CCK-B agonists. The affinities and selectivities of these compounds for CCK-B and CCK-A receptors have been determined in vitro by measuring the displacement of [3H]pCCK8 binding to guinea pig cortex and pancreas membranes, respectively. The most potent compound, 8b, N-(cycloamido)-alpha-Me(R)Trp-[(2S)-2-amino-9- ((cycloamido)carbonyl)nonanoyl]-Asp-Phe-NH2, has a Ki value of 15 +/- 1 nM for guinea pig cortex membranes with a good CCK-B selectivity ratio (CCK-A/CCK-B = 147). Furthermore, 8b behaved as a potent and full agonist in a functional assay which measures the stimulation of inositol phosphate accumulation in CHO cells transfected with the rat CCK-B receptor (EC50 = 7 nM). The in vivo affinity of 8b for mouse brain CCK-B receptors was determined following intracerebroventricular injection (ID50 approximately 29 nmol/kg). 8b was also shown to cross the blood-brain barrier (0.16%), after intravenous administration in mice. 8b also increased gastric acid secretion measured in anesthetized rats after intravenous injection. Therefore, 8b appears to be an interesting pharmacological tool and is currently under investigation as a lead for further development of nonpeptide CCK-B agonists.