IgG2 associated hypergammaglobulinaemia in some Nigerians with HIV infection

Concentrations of immunoglobulins (IgA, IgG and IgM) were measured in Nigerians with (HIV) infection. Considerable elevations up to two-fold the reference values were observed for IgG and IgM in the patient group as a whole but elevations in IgA concentration were least marked albeit significantly different from the healthy subjects. Elevation of a particular isotype was not always concomitant with elevation of the other major classes in the same patient. Overall, these elevations were observed in both symptomatic and asymptomatic infected subjects. Further analysis of IgG hyperglobulinemia showed that increases in this major class may be due to increased IgG2 subclass concentrations. It is suggested that elevation of IgG2 subclass in Nigerians with HIV infection and not IgG1 or IgG3 may be due to genetic and environmental factors rather than variation in the strain of the virus.     

The influence of blood volume changes on leucocyte and lymphocyte subpopulations in elite swimmers following interval training of varying intensities

BACKGROUND: Current staging systems for unresectable or metastatic neuroblastoma do not reliably predict responses to chemotherapy in infants under 1 year of age. Previous studies have indicated that the DNA content, or ploidy, of malignant neuroblasts can discriminate between good and poor responders in this group of patients, but the clinical utility of ploidy assessment has remained in question. PURPOSE: We tested, in a prospective nonrandomized study, the hypothesis that neuroblast ploidy could be used as the sole guide for treatment selection in infants with unresectable or metastatic tumors and could differentiate between those who would respond to our previous standard regimen and those who would benefit from an immediate switch to another therapy. METHODS: One hundred seventy-seven infants were enrolled in this trial. Five of these infants were subsequently excluded (two ineligible, two lacking ploidy information, and one protocol violation); therefore, 172 patients were included in the study. One hundred thirty infants with hyperdiploid tumors (DNA index > 1.0; better prognosis in retrospective studies) were treated with a well-tolerated regimen of cyclophosphamide (150 mg/m2 per day orally or intravenously on days 1-7) and doxorubicin (35 mg/m2 intravenously on day 8). Forty-two infants with diploid tumors (DNA index = 1.0; worse prognosis in retrospective studies) received cisplatin (90 mg/m2 intravenously on day 1) and teniposide (100 mg/ m2 intravenously on day 3) after an initial course of cyclophosphamide plus doxorubicin. Statistical end points were response and long-term survival. In addition, we assessed within each ploidy group (i.e., patients with hyperdiploid tumors and those with diploid tumors) the prognostic significance of NMYC gene copy number, tumor stage, and other variables commonly measured in this disease. RESULTS: Of the 127 assessable infants with hyperdiploid tumors, 115 (91%) had complete responses--85 after receiving five courses of cyclophosphamide plus doxorubicin and 30 after receiving further therapy including cisplatin plus teniposide. The 3-year survival estimate for the entire hyperdiploid group was 94% (95% confidence interval [CI] = 89%-98%). Nineteen (46%) of 41 assessable infants with diploid tumors were complete responders. The overall 3-year survival estimate for this group was 55% (95% CI = 39%-70%). Prognostic factor analysis indicated that NMYC gene amplification and an elevated serum lactate dehydrogenase level were statistically significant markers of higher risk disease within the diploid group (two-sided P values of .005 and .003, respectively). Only NMYC was predictive in the hyperdiploid group (P = .003). CONCLUSION: Use of a prognostic staging system based on tumor cell ploidy, augmented with the NMYC gene copy number and serum level of lactate dehydrogenase, would very likely improve the treatment of infants with unresectable or metastatic neuroblastoma. Patients with diploid tumors characterized by an amplified NMYC locus represent a particularly unfavorable risk group that may benefit from innovative new therapies.     

Isolation and characterization of a novel gene from human glioblastoma multiforme tumor tissue

The therapeutic application of high-dose interleukin (IL) 2 in human malignancy is limited by severe multiorgan toxicities that are mediated, in part, by tumor necrosis factor (TNF) and IL-1. CT1501R (lisofylline; LSF) is one of several methyl xanthine congeners that inhibit the effects of TNF by the interruption of specific signal transduction pathways. This randomized, placebo-controlled trial was designed to assess the activity of LSF in reducing the toxicities of high-dose IL-2 therapy. Fifty-three patients with metastatic renal cancer or malignant melanoma were treated with i.v. bolus IL-2, 600, 000 IU/kg every 8 h for 5 days (14 doses), followed by 9 days of rest and another 5-day course of IL-2. Patients were randomly assigned to LSF, 1.5 mg/kg i.v. bolus, or placebo every 6 h during IL-2 therapy. All patients were to be treated to individual maximum tolerance of IL-2 at the intensive care unit level of support. The end points for statistical analysis were the number of IL-2 doses administered during the first cycle of treatment (maximum, 28) and the toxicities experienced by each group after the first 8 planned IL-2 doses. There was no difference between the LSF and placebo groups in the mean number of IL-2 doses tolerated in the entire first cycle of therapy (19.6 +/- 5.4 versus 19.5 +/- 5.8, P = 0.86) or in the first or second 5-day course of IL-2. The only significant difference in toxicities occurring through the eighth dose of IL-2 was in the maximum elevation of serum creatinine (mean, 1.7 +/- 0.8 for placebo versus 1.5 +/- 0.6 mg/dl for LSF, P = 0.013). A Monte Carlo analysis of major toxicities over the first 14-dose course of therapy showed a statistically significant difference favoring the LSF-treated group (P = 0.025). LSF was well tolerated, associated only with mildly increased nausea (P = 0.006 after eight IL-2 doses, but not significant for the entire first cycle). The antitumor activity was comparable in both groups (objective responses, 2 of 28 with LSF versus 4 of 24 with placebo). The mean peak plasma concentrations of LSF on days 1, 5, and 19 were 6.24, 3.83, and 5.04 micromol/liter, respectively. In conclusion, with this dose and schedule, LSF did not alter the toxicities of high-dose i.v. IL-2 sufficiently to impact the overall dose intensity of IL-2. Successful IL-2 toxicity modulation may require the use of higher doses of LSF, the development of agents with more potent anti-TNF activity, and/or combined modulating agents that function via distinct mechanisms to interrupt cytokine-mediated signaling.     

Idiopathic constipation in childhood is associated with thickening of the internal anal sphincter

This study was undertaken to search for a rational basis for the use of anal dilatation and internal sphincterotomy as the treatment for chronic intractable constipation in children. Sixteen children, age 5 months to 13 years, who had constipation resistant to conservative treatment were compared with 39 age-matched controls. History and current symptoms were assessed using a standard questionnaire. Internal and external and sphincter morphology was assessed on clinical examination and by anal endosonography, using a 10-MHz rotating endoprobe to provide accurate measurement of the various components of the anal canal. The control group showed a linear correlation between the thickness of the internal anal sphincter and both age and weight, increasing from 0.4 mm in infancy to 0.9 mm in adolescence. Children who had constipation displayed significant thickening of the internal sphincter (range, 0.5 to 1.9 mm, P = .005) which was independent of the length of the history (P = .103). There was no difference in the morphology of the external anal sphincters between the groups. The finding of a hypertrophied internal anal sphincter could provide a rational basis for anal dilatation and internal sphincterotomy as treatment for idiopathic constipation.     

Direct and collateral effects of restraints and restraint fading

Mechanical restraints are commonly used to reduce the risks associated with severe self-injurious behavior (SIB), but may result in movement restriction and adverse side effects (e.g., bone demineralization). Restraint fading may provide a method for decreasing SIB while increasing movement and reducing these side effects. In the current investigation, rigid arm sleeves and restraint fading (gradually reducing the rigidity of the sleeves) were used with 3 clients who engaged in hand-to-head SIB. Restraints and fading reduced the hand-to-head SIB of all clients. However, for 1 client, the addition of a water mist procedure further reduced SIB to near-zero levels. For a 2nd client, another form of SIB developed that was not prevented by the rigid sleeves. For a 3rd client, a topography of SIB that was not physically prevented by the rigid sleeves was also reduced when restraints and fading were introduced.     

Estrogen modulation: tiered testing for human hazard evaluation. American Industrial Health Council, Reproductive and Developmental Effects Subcommittee

Recent concerns about the potential of certain chemicals to modulate estrogen-regulated processes have led to questions as to how chemicals should be tested for such effects. Therefore, AIHC has developed a comprehensive, resource-efficient, and flexible tiered strategy for estrogen modulation (EM) testing. Levels of evaluation include Tier 0, in which exposure, along with alerts based on structure-activity, persistence, bioaccumulation, and other data, are assessed to prioritize chemicals for preliminary testing. In Tier I, short term in vitro, ex vivo, and/or in vivo assays are used to obtain a preliminary indication of EM potential. Among these, an in vivo response assay is considered the most reliable at this time. However, none of these tests are intended for risk assessment, but rather to aid in choosing chemicals for further testing and in guiding the extent of that testing. Tier II is aimed at risk assessment and involves whole animal tests that contain EM-sensitive end points (e.g., two-generation reproduction study). Tier III consists of hypothesis-driven research reserved for situations where targeted research can reduce levels of uncertainty. This tiered approach provides a framework for the strategic and effective application of EM test methods to address specific information needs on a case by case basis.     

Complex segregation analyses: uses and limitations

It is sometimes difficult to visualize the luminal borders of the vessel even by intracoronary ultrasound (ICUS), especially after coronary intervention. In this study, we evaluated the potential for improving visualization at intervention sites using contrast-enhanced ICUS and the suitable contrast agents for this procedure in humans. In 37 patients, ICUS (30 MHz) was performed with intracoronary injection (3 ml) of 7 different contrast preparations and without the contrast agents (control) after coronary intervention. The contrast agents used were as follows: saline solution, standard iomeprol, standard ioxaglate, sonicated iomeprol, sonicated ioxaglate, 50% Albunex, and 100% Albunex. Vessel wall delineation, contrast homogeneity (Grade 0-3), peak contrast intensity and shadowing were examined. Homogeneous and complete opacification of the vessel lumen and false lumen was observed with sonicated ioxaglate, 50% and 100% Albunex. Shadowing was not observed at all with sonicated ioxaglate and was uncommon with 50% Albunex, whereas 100% Albunex caused shadowing in all cases. The coronary delineation rate with the other contrast agents was only 50-70 %, and the homogeneity and peak intensity were relatively low. Thus, sonicated ioxaglate and 50 % Albunex both achieved good visualization, but the former is cheaper, stable and takes shorter to prepare. Large dissection in 5 patients were found by contrast-enhanced ICUS' whereas they were not detected by coronary angiography. All of them needed additional interventional therapy due to the results of contrast-enhanced ICUS. In conclusion, contrast-enhanced ICUS is useful for evaluation of the results by intervention therapy, and of the agents we studied sonicated ioxaglate is best for contrast-enhanced ICUS.     

Inhibition of shivering increases core temperature afterdrop and attenuates rewarming in hypothermic humans

During severe hypothermia, shivering is absent. To simulate severe hypothermia, shivering in eight mildly hypothermic subjects was inhibited with meperidine (1.5 mg/kg). Subjects were cooled twice (meperidine and control trials) in 8 degrees C water to a core temperature of 35.9 +/- 0.5 (SD) degrees C, dried, and then placed in sleeping bags. Meperidine caused a 3.2-fold increase in core temperature afterdrop (1.1 +/- 0.6 vs. 0.4 +/- 0.2 degree C), a 4.3-fold increase in afterdrop duration (89.4 +/- 31.4 vs. 20.9 +/- 5.7 min), and a 37% decrease in rewarming rate (1.2 +/- 0.5 vs. 1.9 +/- 0.9 degrees C/h). Meperidine inhibited overt shivering. Oxygen consumption, minute ventilation, and heart rate decreased after meperidine injection but subsequently returned toward preinjection values after 45 min postimmersion. This was likely due to the increased thermoregulatory drive with the greater afterdrop and the short half-life of meperidine. These results demonstrate the effectiveness of shivering heat production in attenuating the postcooling afterdrop of core temperature and potentiating core rewarming. The meperidine protocol may be valuable for comparing the efficacy of various hypothermia rewarming methods in the absence of shivering.