Analysis of the genetic factors controlling malarial infection in man

Genetic factors have clearly been shown to play a role in controlling malarial infection in animal models. There is now also increasing evidence for the genetic control of malaria in man. We carried out a segregation analysis based on blood parasite load phenotype for a population of the town of Bobo-Dioulasso (Burkina-Faso). This analysis demonstrated a strong genetic effect. Our results were not consistent with the segregation of a major gene and thus suggest that parasite load is under the control of minor genes. The genetic effect was stronger in children than in adults. We carried out a regression analysis in children and found that there was an association between the phenotype for blood parasite load and the q31-33 region of chromosome 5. We identified a gene in this region, Pfil1 (Plasmodium falciparum infection levels 1), which accounted for almost 50% of the variance in blood parasite load and which played a fundamental role in the control of infection. The 5q31-33 region contains several genes encoding cytokines that regulate T lymphocytes. The identification of genes controlling malarial infection opens up new possibilities for preventive and treatment strategies. It should be possible in the near future to identify individuals at risk of malaria, who would derive the greatest benefit from preventive and therapeutic measures. Finally, a deeper understanding of these genes controlling protective immune responses could be of value for the development of vaccines.     

Actual 5-year survival of patients with stage IIIB breast carcinoma: phase II trial of methotrexate, vinblastine, adriamycin, cisplatin, and folinic acid.

Patients with stage IIIB breast carcinoma represent only a small proportion of women with breast cancer in western countries but may constitute up to 50% of cases in underdeveloped countries. The prognosis remains poor despite aggressive treatment. Nineteen patients (11 with inflammatory breast carcinoma) received at least three courses of neoadjuvant chemotherapy of methotrexate, vinblastine, adriamycin, cisplatin, and folinic acid (MVAC/FA) followed by mastectomy. Six months of cyclophosphamide, methotrexate, and 5-fluorouracil were given after surgery. Radiation therapy followed chemotherapy. Seventy percent of patients achieved complete and 14% partial response after MVAC/FA chemotherapy alone. Eleven patients (58%) survived 5 years, and 30% survived at least 8 years. The addition of cisplatin in combination chemotherapy used as first-line treatment for stage IIIB breast carcinoma was well tolerated, resulted in higher response rates, and appeared to have an effect on overall survival.     

Peripheral hormonal responses to D-fenfluramine as a probe of central serotonergic function in humans

We tested the hypothesis that D-fenfluramine (DFEN)-elicited cortisol (CORT) release in humans may be mediated by a direct effect on the adrenal gland by pretreating subjects with dexamethasone (DEX), to prevent release of ACTH from the pituitary, followed by a DFEN challenge test. Eight healthy subjects (four males; four female) (mean age = 38.1 ± 8.4 years (SD)] were studied > 1 week apart (same phase of menstrual cycle) and testing order was randomised. On the with-DEX day (DEX+), subjects took 2 mg DEX orally at 10 p.m.; 30 mg DFEN was then given orally at 9 a.m. and samples were taken at 0–5 h for PRL and CORT. Peak hormone responses (Δ values) were calculated by subtracting baseline values from the maximum levels post-DFEN administration. Peak and baseline hormonal values were compared between the two test conditions; DFEN-induced CORT and PRL responses were compared across all time points, with and without DEX. There was no significant difference in ΔPRL between the two test conditions (DEX−and DEX+), but Δ CORT values were significantly reduced after DEX: mean Δ CORT DEX− = 68.4 ± 26.3 nmol/l; DEX+ = 0.0 nmol/l (all blunted) (df 7,1; P = 0.03). The completely blunted peripheral cortisol response indicates that DFEN cortisol responses are of central origin only. Received: 20 March 1998/Final version: 15 July 1998     

Effect of gender on the pharmacokinetics of ofloxacin

STUDY OBJECTIVES: To assess the influence of gender on the pharmacokinetics of ofloxacin. DESIGN: Open-label study. SETTING: Academic medical center. PATIENTS: Five healthy men and seven healthy women volunteers. INTERVENTIONS: Subjects received a single oral dose of ofloxacin 400 mg, and serial blood samples were collected for 24 hours. Plasma concentrations of ofloxacin were determined by high-performance liquid chromatography and pharmacokinetic parameters were determined. Statistical comparisons between genders were made with the Wilcoxon rank sum test. MEASUREMENTS AND MAIN RESULTS: Median volume of distribution at steady state/systemic bioavailability (V(ss)/F) was significantly smaller in women than in men, although when normalized for total body weight there were no differences. Except for terminal elimination half-life, which was 10% shorter in women, no other pharmacokinetic values were significantly different between genders. Median peak concentrations, although not statistically different, were 28% higher in women. CONCLUSION: Ofloxacin V(ss)/F values were smaller in women than in men, explained by gender-related differences in weight.     

Temporal summation in hearing-impaired listeners

A study was conducted to explore variations in auditory temporal summation in listeners with normal hearing, and impairment due to otosclerosis, sensori-neural hearing loss and acoustic neuroma. Using a two-interval forced-choice procedure the detection threshold was measured for one-third octave noise bands centered at either 1000 or 4000 Hz, in combination with eight signal durations (2.5, 5, 10, 20, 40, 80, 160, and 640 ms). The results indicated that for normal listeners: (1) the slope of the function relating the detection threshold and the signal duration varied inversely with the frequency tested, and (2) the variability in the detection threshold was greater for 4000 Hz than for 1000 Hz. A comparison of performance across groups showed that the magnitude of the slope of the temporal integration function decreased as the site of lesion moved from middle ear to eighth nerve. For listeners with normal hearing and those with otosclerosis, temporal integration appeared to be incomplete at 640 ms.     

Solvent effects on coupling yields during rapid solid‐phase synthesis of CGRP(8‐37) employing in situ neutralization*

Abstract: The success of solid‐phase peptide synthesis is often dependent upon solvation of the resin and the growing resin‐bound peptide chain. We investigated the relationship between solvent properties and solvation of the resin and peptide‐resin in order to obtain satisfactory coupling yields for the rapid solid‐phase peptide synthesis, using butyloxycarbonyl‐(Boc)‐amino acid derivatives, of human‐α‐calcitonin gene‐related peptide(8‐37) (CGRP(8‐37)). Solvation of (p‐methylbenzhydrylamine)copoly(styrene–1% divinylbenzene (DVB) (resin) and resin covalently bound to the fully protected amino acid sequence of CGRP(8‐37) (peptide–resin) was correlated to solvent Hildebrand solubility (δ) and hydrogen‐bonding (δ_h) parameters. Contour solvation plots of δ_h vs. δ revealed maximum solvation regions of resin and peptide–resin. Maximum resin solvation occurred with N‐methylpyrrolidinone (NMP), NMP : dimethylsulfoxide (DMSO) (8 : 2) and DMSO. Inefficient solvation of the peptide–resin occurred with these solvents and resulted in poor syntheses with average coupling yields of 78.1, 88.9 and 91.8%, respectively. Superior peptide–resin solvation was obtained using dimethylacetamide (DMA) and dimethylformamide (DMF), resulting in significantly higher average coupling yields of 98.0 and 99.5%, respectively. Thus, the region of maximum peptide–resin solvation shifts to solvents with higher δ_h values. DMF provided the most effective peptide–resin solvation and was the only solvent from which CGRP(8‐37) was obtained as a single major product in the crude cleaved material.     

Reduction of PTEN and p27<Superscript>kip1</Superscript> expression correlates with tumor grade in prostate cancer. Analysis in radical prostatectomy specimens and needle biopsies

The extreme variability of prostate cancer implies latent disease with missing clinical symptoms in some cases. Tumor suppressors PTEN (phosphatase and tensin homolog deleted on chromosome ten) and p27^kip1 are frequently mutated in various human cancers. PTEN negatively influences cell growth and induces apoptosis, while p27^kip1 binds to cyclin-E-Cdk2 and counteracts mitosis. This study investigated the expression of PTEN and p27^kip1 in prostatectomies and needle biopsies in order to determine whether protein localization or expression levels are correlated with tumor grade and whether PTEN and p27^kip1 expression in biopsies are valuable predictive tumor markers. Analysis of PTEN demonstrated that weak expression levels were significantly more prevalent in high-grade tumors. Analysis of p27^kip1 revealed that high-grade tumors had a higher percentage of cytoplasmic localization of the protein than low-grade tumors, where nuclear localization was more frequent. Furthermore, this study indicated a positive association between PTEN and p27^kip1 levels. An increase of high-grade tumors corresponded to a progressive loss of both tumor suppressors in needle biopsies and prostatectomies. p27^kip1 and PTEN did not show a higher predictive accuracy of the tumor grade in the surgical specimen than the Gleason score. However, p27^kip1 had the same predictive value as the Gleason score in needle biopsies.     

A point mutation in beta2-microglobulin results in loss of epitope expression

A common tool in studying the structure and function of major histocompatibility complex: (MHC) class I is the generation and analysis of beta2-microglobulin (beta2m) mutations. beta2m has been shown to affect proper class I antigen presentation at the level of structural functionality. Many studies characterizing beta2m function in class I presentation have used antibody-based assays. Monitoring the effect of beta2m mutation on antibody epitope expression, therefore, is essential in being able to truly characterize the impact of a mutant interaction between beta2m and class I. Here we describe a mutant beta2m molecule, beta2m #32, that in association with class I loses reactivity with the human beta2m-specific monoclonal antibody, BBM.1. However, the BBM.1 epitope remains intact when beta2m #32 is free from class I association.     

Segregation of HLA/TNF region is linked to leprosy clinical spectrum in families displaying mixed leprosy subtypes

Each year an estimated 600000 new leprosy cases are diagnosed worldwide. The spectrum of the disease varies widely from limited tuberculoid forms to extensive lepromatous forms. A measure of the risk to develop lepromatous forms of leprosy is provided by the extent of skin reactivity to lepromin (Mitsuda reaction). To address a postulated oligogenic control of leprosy pathogenesis, we investigated in the present study linkage of leprosy susceptibility, leprosy clinical subtypes, and extent of the Mitsuda reaction to six chromosomal regions carrying known or suspected leprosy susceptibility loci. The only significant result obtained was linkage of leprosy clinical subtype to the HLA/TNF region on human chromosome 6p21 (P(corrected)=0.00126). In addition, we established that within the same family different HLA/TNF haplotypes segregate into patients with different leprosy subtypes directly demonstrating the importance of this genome region for the control of clinical leprosy presentation.