Pharmacological studies of behavioral influences on cardiovascular function

Squirrel monkeys, prepared with chronic arterial and venous catheters, responded (pressed a key) under fixed-ratio schedules of termination of a stimulus associated with electric shock or under fixed-ratio schedules of food presentation. Although there was no necessary correlation between schedule-controlled responding and cardiovascular changes, pronounced elevations in both heart rate and blood pressure occurred during and just after brief periods of fixed-ratio responding. These episodic increases in blood pressure and heart rate were as marked under schedules of food presentation as under schedules of stimulus-shock termination. Thus, these episodic changes appear to be more dependent upon the schedule-controlled behavior than upon the type of event maintaining the behavior. Pharmacological studies indicated that under the conditions of the behavioral experiments the squirrel monkey has a relatively high degree of cardiac sympathetic tone; however, blood pressure elevations produced by administration of l-norepinephrine were associated with an increased parasympathetic tone and decreased heart rate. The reflex bradycardia induced by l-norepinephrine was inhibited during periods of schedule-controlled responding, suggesting that environmental and behavioral factors can not only modulate the parameters of physiological variables but also modulate this basic cardiovascular control system.     

The management of acute oesophageal obstruction from a food bolus. Can we be more conservative?

The objective was to assess the number of patients with acute oesophageal bolus obstruction that resolves spontaneously and to aid the identification of the best practice. This prospective and retrospective case series study at a teaching hospital and a district general hospital in Scotland, UK, involved 37 patients with acute oesophageal obstruction from a food bolus who were observed for 24 h from the beginning of symptoms. The bolus passed spontaneously in 54% of the patients during the observational period. A short observational period following the admission of patients with acute food bolus obstruction is reasonable as it may reduce exposure to surgical morbidity and decrease inpatient stay.     

Race/ethnicity and insurance status as factors associated with ADHD treatment patterns

Using data from the 1997-2000 Medical Expenditure Panel Survey (MEPS), disparities in different stages of attention-deficit/hyperactivity disorder (ADHD) health care were investigated, from initial detection to follow-up physician visits and psychotherapy appointments. Differences in ADHD diagnoses, stimulant usage, and health-care visits were examined by age, race/ethnicity, region, and type of insurance. Major significant findings were: (1) children without insurance had lower levels of care in all stages relative to children with insurance, (2) Hispanic-American and African-American children were less likely to be diagnosed with ADHD by parent report than were white American children, and (3) African-American youths with ADHD were less likely to initiate stimulant medication relative to white American children. Implications for expanding childhood health insurance coverage, and for future work on minority mental health care in regard to ADHD, are discussed.     

The diversity of dolichol-linked precursors to Asn-linked glycans likely results from secondary loss of sets of glycosyltransferases

The vast majority of eukaryotes (fungi, plants, animals, slime mold, and euglena) synthesize Asn-linked glycans (Alg) by means of a lipid-linked precursor dolichol-PP-GlcNAc2Man9Glc3. Knowledge of this pathway is important because defects in the glycosyltransferases (Alg1-Alg12 and others not yet identified), which make dolichol-PP-glycans, lead to numerous congenital disorders of glycosylation. Here we used bioinformatic and experimental methods to characterize Alg glycosyltransferases and dolichol-PP-glycans of diverse protists, including many human pathogens, with the following major conclusions. First, it is demonstrated that common ancestry is a useful method of predicting the Alg glycosyltransferase inventory of each eukaryote. Second, in the vast majority of cases, this inventory accurately predicts the dolichol-PP-glycans observed. Third, Alg glycosyltransferases are missing in sets from each organism (e.g., all of the glycosyltransferases that add glucose and mannose are absent from Giardia and Plasmodium). Fourth, dolichol-PP-GlcNAc2Man5 (present in Entamoeba and Trichomonas) and dolichol-PP- and N-linked GlcNAc2 (present in Giardia) have not been identified previously in wild-type organisms. Finally, the present diversity of protist and fungal dolichol-PP-linked glycans appears to result from secondary loss of glycosyltransferases from a common ancestor that contained the complete set of Alg glycosyltransferases.     

A new variant cytotoxic T lymphocyte escape mutation in HLA-B27-positive individuals infected with HIV type 1

The immune response in HIV-infected individuals who carry HLA-B27 is characterized by an immunodominant cytotoxic T lymphocyte (CTL) response to a conserved epitope corresponding to amino acids 263-272 of HIV-1 p24 gag. The arginine at position 264 is a crucial anchor residue. Amino acid substitution at 264 from arginine (R) to glycine (G), lysine (K), or threonine (T) results in a low affinity peptide that binds to HLA-B27 inefficiently and is poorly recognized by T cells that respond to the wild-type peptide. These mutants have been characterized as CTL escape mutations. We studied the plasma virus of 20 HLA-B27 longterm nonprogressors: 14 were wild type and 6 were found to be mutant. Five of these carried known escape mutations coding for K or G at position 264. One patient demonstrated a previously undescribed R264Q mutation in 30/31 clones. This altered epitope failed to elicit an IFN-gamma response from PBMC isolated from any of four HLA-B27-positive individuals with strong responses to wild-type peptide. A peptide binding assay confirmed that the R264Q mutant peptide had 30-fold lower binding affinity to HLA-B27 compared to wild type. Therefore, the R264Q variant is a likely novel escape mutation in HLA-B27-positive individuals.     

Adequacy of androgen replacement influences bone density response to testosterone in androgen-deficient men

OBJECTIVE: Androgen deficiency (AD) leads to bone loss and contributes to osteoporotic fractures in men. Although low bone mineral density (BMD) in AD men is improved by testosterone replacement, the responses vary between individuals but the determinants of this variability are not well defined. DESIGN AND METHODS: Retrospective review of dual energy X-ray absorptiometry (DEXA) of the lumbar spine and proximal femur in men with established AD requiring regular androgen replacement therapy (ART). After a DEXA scan all men were treated with testosterone implants (800 mg, approximately 6 month intervals). Patients were classified as having a congenital, childhood, or post-pubertal onset, as well as according to the adequacy of treatment prior to their first DEXA scan as untreated, partially treated or well treated. RESULTS: Men with AD requiring regular ART (n = 169, aged 46.3+/-1.1 years, range 22-84 years) underwent a DEXA scan prior to being treated with testosterone implants (800 mg, approximately 6 month intervals). In cross-sectional analysis at the time of the first DEXA scan untreated men (n = 24) had significantly reduced age-adjusted BMD at all four sites (L1-L4, femoral neck, Ward's triangle and trochanter). Well-treated men (n = 77) had significantly better age-adjusted BMD at all four sites compared with those who were partially treated (n = 66) or untreated (n = 24) with their age-adjusted BMD being normalized. In a longitudinal assessment of men (n = 60) who had two or more serial DEXA scans, at the second DEXA scan after a median of 3 years, men who were previously partially treated (n = 19) or untreated (n = 11) had proportionately greater improvements in BMD, significantly for Ward's triangle (P = 0.025) and the trochanter (P = 0.044) compared with men (n = 30) previously well treated. CONCLUSIONS: The present study demonstrates a positive relationship between adequacy of testosterone replacement and BMD in men with overt organic AD. Additionally, the BMD of well-treated AD men approximates that of age-matched non-AD controls. The greatest BMD gains are made by those who have been either untreated or partially treated, and optimal treatment over time (median 3 years) normalizes BMD to the level expected for healthy men of the same age.