Polymorphism of the thiopurine S-methyltransferase gene in African- Americans

The molecular basis for the genetic polymorphism of thiopurine S - methyltransferase (TPMT) has been estab-lished for Caucasians, but it remains to be elucidated in African populations. In the current study, we determined TPMT genotypes in a population of 248 African-Americans and compared it with allele frequencies in 282 Caucasian Americans. TPMT genotype was determined in all individuals with TPMT activity indicative of a heterozygous genotype (</=10.1 U/ml pRBC, n = 23African- Americans, n = 21 Caucasians) and a control group with TPMT activity indicative of a homozygous wild-type genotype (>10.2 U/ml pRBC, n = 23 African-Americans, n = 21 Caucasians). No mutant alleles were found in the high activity control groups. The overall mutant allele frequencies were similar in African-Americans and Caucasians (4.6 and 3.7% of alleles, respectively). However, while TPMT*3C was the most prevalent mutant allele in African-Americans (52.2% of mutant alleles), it represented only 4.8% of mutant alleles in Caucasians ( P < 0.001). In contrast, TPMT*3A and TPMT*2 were less common in African-Americans (17.4 and 8.7% of mutant alleles), whereas TPMT*3A was the most prevalent mutant allele in Caucasians (85.7% of mutant alleles). A novel allele ( TPMT*8 ), containing a single nucleotide transition (G644A), leading to an amino acid change at codon 215 (Arg-->His), was found in one African-American with intermediate activity. These data indicate that the same TPMT mutant alleles are found in American black and white populations, but that the predominant mutant alleles differ in these two ethnic groups.      

Changing acute renal failure treatment from intermittent hemodialysis to continuous hemofiltration: impact on azotemic control.

BACKGROUND: Continuous renal replacement therapy is increasingly used in the management of acute renal failure in critically ill patients. The advantages of continuous renal replacement therapy (CRRT) over intermittent hemodialysis (IHD), however, are not yet fully documented. In particular, it is unknown whether continuous veno-venous hemodiafiltration (CVVHDF) provides better control of azotemia than IHD. OBJECTIVES: To study the effect on azotemic control of changing acute renal failure treatment from IHD to CVVHDF. SETTINGS: Tertiary intensive care unit. PATIENTS: Forty seven consecutive critically ill patients with multiorgan failure and acute renal failure treated with IHD and 47 similar patients treated with CVVHDF. METHODS: Analysis of daily morning urea and creatinine concentrations over the period of renal replacement therapy in the ICU. Statistical comparison of data. RESULTS: The two groups of patients were comparable for mean age (55 years for IHD vs. 60 years for CVVHDF; NS) and number of failing organs prior to therapy (mean of 4.2 for IHD vs. 3.7 for CVVHDF; NS). Severity of illness at admission as assessed by APACHE II score, however, was greater for patients receiving CVVHDF (29.4 vs 25.7; p<0.003). CVVHDF was associated with a significantly lower plasma urea (p < 0.0001) and serum creatinine (p < 0.01) level at 24 hours of treatment despite similar levels at the start of therapy Throughout the duration of therapy, mean urea levels (35.0 mmol/L for IHD vs 23.4 mmol/L for CVVHDF) and mean serum creatinine levels (513 micromoles/L for IHD and 263 micromoles/L for CVVHDF) showed significantly (p <0.0001) better control of uremia with CRRT. CONCLUSIONS: Changing the form of renal replacement therapy from intermittent hemodialysis to continuous hemofiltration is associated with improved control of azotemia. The superior adequacy of small solute clearance achieved during CVVHDF provides additional support for its preferential use in the management of acute renal failure in the ICU.     

Anionic Synthesis of Epoxy End‐Capped Polymers

The reaction of living anions of polystyrene (PS) or poly(methyl methacrylate) (PMMA) with epibromohydrin for the synthesis of well‐defined epoxy end‐functionalized polymers is reported. Polyanions were reacted with an excess of epibromohydrin in tetrahydrofuran (THF) at ?78 °C. The functionalities of the resulting polymers were analyzed by matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS), NMR, and size exclusion chromatography (SEC). The epoxy end groups were reacted with 1,1‐diphenyl‐ hexyllithium, and MALDI‐TOF MS and NMR before and after this chemical modification were used to determine the presence of the epoxy end groups. The presence of the epoxy end group was confirmed by anionically polymerizing ethylene oxide from these epoxy end group. The formation of a block copolymer due to the epoxy end groups was proved by SEC analysis. The combined MALDI‐TOF MS, ¹H NMR, and SEC results indicate that epoxy end‐capped PS was obtained in quantitative yield. The method was extended to the synthesis of epoxy end‐capped PMMA. With this polymer the extent of end‐functionalization was high but not quantitative, with non‐dimeric byproducts detected by MALDI‐TOF MS.

     

Renin angiotensin system and ASCVD

The renin angiotensin system was first described over 100 years ago and is still the focus of intense clinical and basic science investigation. The renin angiotensin system was demonstrated to play a major pathogenetic role in hypertension. The development of inhibitors of angiotensin-converting enzyme and specific receptor blockers for angiotensin-II represent a major advance in the treatment of elevated blood pressure. However, the renin angiotensin system is intimately involved in a number of conditions that increase the risk for atherosclerosis. Components of the renin angiotensin system have demonstrated to play a significant role in the initial phases of atherosclerosis. Additionally, plaque vulnerability and the potential for an acute atherosclerotic event are also modulated by the renin angiotensin system. Angiotensin-II plays a significant role in the balance between intravascular clot formation and fibrinolytic potential. Therefore, blocking the generation of angiotensin-II or inhibiting its binding to specific receptors may decrease the subsequent risk for unstable angina and acute myocardial infarction. Increased renin activity has been correlated as a statistical risk factor for coronary heart disease and converting enzyme inhibition has been demonstrated to decrease the incidence of acute ischemic events. This review will center on the role of modulation of the renin angiotensin system as a means to alter the clinical course of coronary atherosclerosis.     

Intriguing issues of EGFR targeting in head and neck cancer

We have read the recent comprehensive review by Cruz et al.[1] regarding the targeting of receptor tyrosine kinases andtheir therapeutic perspectives in head and neck squamous cellcarcinomas (HNSCC). The major focus of this report was epidermalgrowth factor receptor (EGFR) biology and targeting. However,we feel     

Carcass composition and resistance to fasting in neonatal piglets born of sows immunized against somatostatin and/or receiving growth hormone-releasing factor injections during gestation.

Thirty-eight gestating sows were either immunized against somatostatin (SRIF) and/or injected with growth hormone-releasing factor (GRF). Treatment effects on carcass composition and resistance of newborn piglets to a 60-hour fast were investigated. Protein content of carcasses at birth was increased in piglets of sows receiving GRF or immunized against SRIF, however, when sows received both treatments there was a reduction in carcass protein content (p = 0.01). Other carcass components were unaltered by treatments, and none of the treatments affected metabolic or endocrine profiles of piglets at birth. Concentrations of GH, IGF-I (p less than 0.01), glucagon and cortisol (p less than 0.05) increased linearly with duration of fast, whereas glucose values decreased. Resistance to fasting was unaltered in piglets from any treatment thereby suggesting that exogenous GRF and/or SRIF immunization of sows during gestation are unlikely to improve survival of newborn piglets.     

High prevalence of genital tract papillomavirus infection in female adolescents

To investigate clinical condyloma, abnormal cervical cytologic findings, and evidence of human papillomavirus infections, 89 adolescent girls were examined. Cellular DNAs extracted from exfoliated cervical cells were examined for human papillomavirus genomic sequences by Southern transfer hybridization using 32P-labeled human papillomavirus DNA probes. Human papillomavirus sequences were detected in 12 (13%) young women, abnormal cytologic specimens in 21 (24%), and vulvar condylomas in 12 (13%). The human papillomavirus types identified included HPV-6/11 (four instances), which is known to be associated with benign lesions, and HPV-16, -18, and -31 (eight instances) which are considered to have oncogenic potential. Two young women were infected with both HPV-16 and -31. Human papillomavirus sequences were found in 48% of the young women with abnormal cytologic findings and in 3% of patients with normal cytologic findings (P less than .0001). Condylomatous changes in the cervical smear were associated with the presence of HPV-6/11 and mild dysplasia with the presence of HPV-16, -18, and -31. The presence of vulvar condylomas correlated with condylomatous changes in the cervical smear and with the recovery of HPV-6/11 from the cervical epithelium. The results indicate that the prevalence of human papillomavirus infections in this population is high and that a majority of the infections are with viruses associated with lower genital tract malignancies.