Activation of androgen receptor-expressing neurons in the posterior medial amygdala is associated with stress resistance in dominant male hamsters.

Social stress is a negative emotional experience that can increase fear and anxiety. Dominance status can alter the way individuals react to and cope with stressful events. The underlying neurobiology of how social dominance produces stress resistance remains elusive, although experience-dependent changes in androgen receptor (AR) expression is thought to play an essential role. Using a Syrian hamster (Mesocricetus auratus) model, we investigated whether dominant individuals activate more AR-expressing neurons in the posterior dorsal and posterior ventral regions of the medial amygdala (MePD, MePV), and display less social anxiety-like behavior following social defeat stress compared to subordinate counterparts. We allowed male hamsters to form and maintain a dyadic dominance relationship for 12 days, exposed them to social defeat stress, and then tested their approach-avoidance behavior using a social avoidance test. During social defeat stress, dominant subjects showed a longer latency to submit and greater c-Fos expression in AR+ cells in the MePD/MePV compared to subordinates. We found that social defeat exposure reduced the amount of time animals spent interacting with a novel conspecific 24 h later, although there was no effect of dominance status. The amount of social vigilance shown by dominants during social avoidance testing was positively correlated with c-Fos expression in AR+ cells in the MePV. These findings indicate that dominant hamsters show greater neural activity in AR+ cells in the MePV during social defeat compared to their subordinate counterparts, and this pattern of neural activity correlates with their proactive coping response. Consistent with the central role of androgens in experience-dependent changes in aggression, activation of AR+ cells in the MePD/MePV contributes to experience-dependent changes in stress-related behavior.

Virological and immunological outcomes at 3 years after starting antiretroviral therapy with regimens containing non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or both in INITIO: open-label randomised trial.

BACKGROUND: Antiretroviral therapy has greatly reduced HIV mortality and morbidity. However, the best sequence of regimens and implications of initial regimen for long-term therapeutic success are not well defined. METHODS: In INITIO, a large international randomised trial, we compared antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors (didanosine+stavudine) plus either a non-nucleoside reverse transcriptase inhibitor (efavirenz, EFV) or a protease inhibitor (nelfinavir, NFV), or both (EFV/NFV), in patients with HIV-1 infection who had not previously received antiretroviral drugs. Primary outcomes were proportion with undetectable HIV RNA in plasma, and change in CD4 count from baseline at 3 years. Analyses were by intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN44582462. FINDINGS: We followed up 911 participants (297 EFV, 311 NFV, 303 EFV/NFV). At 3 years, the proportion with HIV RNA less than 50 copies per mL was highest in the EFV group (188 [74%] EFV, 162 [62%] NFV, 155 [62%] EFV/NFV; p=0.004). Mean (95% CI) increases in CD4 count were 316x10(6) cells per L (288-343) for EFV, 289x10(6) cells per L (262-316) for NFV, and 274x10(6) cells per L (231-291) for EFV/NFV (p=0.1). Fewer participants in the EFV group than in the other groups stopped adequate antiretroviral therapy for more than 30 days (p=0.005). Participants in the EFV/NFV group had shorter time to stopping the initial regimen (p<0.0001) and to a treatment modifying adverse event (p=0.04) than those in the other groups. INTERPRETATION: Starting antiretroviral therapy with a three-drug/two-class regimen including efavirenz was better than starting with regimens including nelfinavir or efavirenz plus nelfinavir in terms of virological suppression and durability of the initial regimen. The shorter time on adequate antiretroviral therapy or to a treatment-modifying adverse event might explain the absence of additional benefit for the four-drug regimen.

Magnetic resonance imaging in a military setting: a utilization analysis.

A prospective study was conducted to evaluate the use of magnetic resonance imaging (MRI) by orthopedic surgeons and residents versus the use of MRI by non-orthopedically trained health care providers in diagnosing knee pathology. Fifty patients initially evaluated by members of one of these groups who underwent subsequent knee MRI evaluation were selected to participate. Two orthopedic examiners individually examined all patients, recording clinical diagnosis and the merit of MRI evaluation in each case. Clinical accuracy, sensitivity, and specificity were compared between groups based on MRI findings. Diagnostic accuracy was similar; however, the orthopedic group displayed greater sensitivity, suggesting better clinical assessment. The study examiners observed both groups using MRI equally inappropriately and found 62% of the imaging studies unjustified. We conclude that knee MRI is used inappropriately in the current military setting. An algorithm is proposed to guide the future use of MRI in the diagnosis and management of knee pathology.

Comparison of a point mutation assay with a line probe assay for the detection of the major mutations in the HIV-1 reverse transcriptase gene associated with reduced susceptibility to nucleoside analogues.

This study compares the performance of a line probe assay (LiPA) for the detection of the major mutations associated with reduced sensitivity to nucleoside analogues with a well characterised point mutation assay (PMA). Plasma samples obtained from patients in a trial of four reverse transcriptase inhibitors (MRC Quattro Trial) were tested by both LiPA and PMA at baseline, 32nd and 64th weeks for the presence of drug resistance associated mutations in the reverse transcriptase (RT) gene. HIV-1 RNA was extracted from plasma by the Boom method and amplified by RT-PCR prior to being tested by LiPA or PMA. Assay discrepancies were further investigated by sequencing of the RT gene. Of 275 samples available from 98 trial subjects, 246 samples were successfully amplified by PCR and analysed by LiPA and PMA for six mutations. Of the 1476 individual codons analysed, LiPA successfully assayed 1444 (97.8%) and PMA gave a result with 1418 (96.1%). LiPA failed to give a result for 32 codons from 22 samples and PMA failed with 58 codons from 38 samples. Gross differences between the two assays, in which one scored a codon as wild-type only and the other as mutant only or vice versa, occurred at 28 codons analysed (1.9%) representing 26 samples from 20 subjects. Sequencing of 22 of the 26 samples confirmed the LiPA result in nine cases, the PMA result in 11 and detected a novel variant at codon 215 in four cases. The PMA and LiPA approach to the detection of the major mutations that are genotypically associated with reduced sensitivity to nucleoside analogues can correctly detect mutations in 97% of the cases.

How generalizable are the results of large randomized controlled trials of antiretroviral therapy?

OBJECTIVES: To examine the generalizability of two large randomized controlled clinical trials of antiretroviral therapy in HIV-infected individuals. METHODS: The demographic, clinical and laboratory characteristics of HIV-infected participants in two antiretroviral trials (Concorde and Delta) at three study sites were compared with those of two other groups of patients to whom the trial results would be applicable: eligible patients who were screened for the trials but who did not enrol, and eligible patients who were not approached or screened for the trials. RESULTS: Among enrolled participants in the Concorde and Delta trials there was an under-representation of patients who had acquired HIV infection heterosexually (P = 0.014) or through injecting drug use (P = 0.03), and a greater representation of homosexual men (P < 0.001) compared to non-enrolled participants. Trial participants in Concorde had significantly less advanced immunosuppression compared to non-trial participants (P = 0.0001), while in Delta the converse was true. Concorde participants were also much less likely to be lost to follow-up for more than a year (9%) compared to eligible but unscreened patients (40%) (P < 0.001), and screened but unenrolled patients (22%) (P = 0.035). CONCLUSIONS: In applying the findings of large randomized clinical trials, it is important to establish whether there are systematic differences between the characteristics of trial participants and eligible non-participants, which might affect the generalizability of the study results. A log of the characteristics of enrolled as well as eligible but non-enrolled patients should be maintained so that the representativeness of the trial population can be evaluated.

Serum vitamin B12 and transcobalamin levels in early HIV disease.

A cohort of asymptomatic human immunodeficiency virus (HIV) seropositive patients was followed over a 2 1/2-year period, to establish changes in serum vitamin B12 (B12) concentrations. Serum B12, CD4 count, and clinical progression to acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) were measured. The unsaturated B12 binding capacities of the transcobalamins were also determined at the start of the study and compared to those from a homosexual HIV seronegative control group. The geometric mean of serum B12 in 218 asymptomatic HIV seropositive patients was significantly lower than of a homosexual HIV seronegative control group (P = 0.02) and the unsaturated B12 binding capacities of transcobalamins I and II were significantly higher in the asymptomatic patients compared with the same control group (P < 0.03, P < 0.0001, respectively). Fifty-nine of the asymptomatic HIV seropositive patients were followed over a 2 1/2-year period during which most had falling serum B12 levels (64%). Twelve patients progressed clinically to ARC or AIDS, of which nine had repeat serum B12 estimation prior to progression. All nine patients had or developed falling serum B12 levels without any evidence of an HIV-related bowel disorder. All patients progressing had falling CD4 counts. Subnormal serum B12 levels are common in HIV disease and occur at an early stage. B12 levels fall in most patients with time and may help predict those patients whose disease will progress the most rapidly.

Beta 2-adrenergic agonist as adjunct therapy to levodopa in Parkinson's disease.

We studied the effect of the beta 2-adrenergic agonist albuterol on Parkinson's disease (PD) patients receiving chronic levodopa treatment. The albuterol-treated patients demonstrated reduced parkinsonian symptoms and an increased ability to tap their index finger between two points 20 cm apart, and were able to perform a "walk test" in 70% of their control time. Three patients currently on chronic albuterol therapy still show amelioration of their parkinsonian symptoms, and two have reduced their daily levodopa dose. This study suggests that beta 2-adrenergic agonists as adjunct therapy to levodopa may be beneficial in PD.

Whose health is it? Views about decision-making and information-seeking from people with HIV infection and their professional carers.

The views of people with HIV and their professional carers about patients' views on involvement in decision-making and information-seeking were studied, using a standardized self-report instrument. Patients and staff reported high levels of desire for patients' involvement in their care, but there were important differences between groups. Staff had higher preference for patients' involvement in decision-making than the patients themselves, while the opposite was the case for information-seeking. There were differences between professional groups and symptomatic and asymptomatic patients, social workers generally reporting higher preference for patients' autonomy, while doctors reported lower levels. Symptomatic patients tended to have lower preference for autonomy than asymptomatic ones. The significance and practical implications of the findings are discussed.

Pharmacokinetics of 2-fluorodideoxycytidine (2FddC) in patients infected with human immunodeficiency virus.

1. The aim of this study was to estimate an oral dosage regimen of 2FddC giving peak plasma drug concentrations close to the antiretroviral IC50 of 150 ng ml-1. 2. A total of 55 doses (40 intravenous infusions and 15 oral solutions) were given to 21 patients. One group (n = 6-11) received single doses of 0.01 mg kg-1 intravenously (i.v.), 0.1 mg kg-1 i.v. and 0.1 mg kg-1 orally (p.o.) in that order. The other group (n = 8-10) received single doses of 0.03 mg kg-1 i.v., 0.3 mg kg-1 i.v. and 0.3 mg kg-1 p.o. in that order. Blood and urine samples were collected up to 24 h after each dose for drug assay by h.p.l.c.-u.v. 3. The peak plasma concentrations of 2FddC were proportional to dosage across the range 0.03 to 0.3 mg kg-1. After intravenous dosing, the mean (%CV) volume of distribution was 60 (28) 1 and the mean (CV%) plasma clearance was 23 (23) 1 h-1. On average, 71% of the dose was recovered unchanged in urine and renal clearance exceeded concurrent creatinine clearance. 4. Plasma concentrations reached mean peaks of 37 and 96 ng ml-1 after oral doses of 0.1 and 0.3 mg kg-1, respectively. The mean absolute bioavailability was 50% within a 95% confidence interval of 20 to 80%. 5. The adverse events were usually mild or moderate in severity and were generally attributed to the disease rather than the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Transmission of HIV to heterosexual partners of infected men and women.

Future heterosexual spread of HIV will in part depend on the efficiency of transmission from men to women and from women to men. We studied seventy-eight female sexual partners of men infected with HIV and 18 male sexual partners of infected women. Participants were interviewed concerning sexual practices, use of contraception and other risk factors for HIV infection. Fifteen out of 78 (19.2%) female partners and one out of eighteen (5.5%) male partners were seropositive for HIV antibody. All couples had practised vaginal intercourse. Seropositive female partners did not differ significantly from seronegative partners with regard to length of relationship, number of acts of vaginal intercourse, other sexual practices, stage of clinical disease in the index case, or numbers of other sexual partners in the last five years. In two women, seroconversion was documented after one act of unprotected sexual intercourse. The majority of infected female partners (eight out of 15) had sexual relationships with men who were asymptomatic and did not practice anal intercourse. Biological factors such as variability in infectivity of the index case and susceptibility of the contact, as well as behavioural variables may be important in determining transmission.

Disabled-worker beneficiaries under OASDI: comparison with severely disabled PA recipients.

The 1972 Survey of Disabled and Nondisabled Adults found that more than 1 million severely disabled persons aged 20-64 were receiving payments under Federal-State public assistance programs. To determine the reasons why most of these individuals did not qualify for disabled-worker benefits under the social security program, their characteristics were compared with those of the approximately 1.5 million disabled-worker beneficiaries. The public assistance recipients were found to be younger and less well educated than their disabled-worker beneficiary counterparts. A greater proportion of them were women and more were members of minority races. Public assistance recipients became disabled at an earlier age and had been disabled longer. Compared with disabled-worker beneficiaries, they had held less skilled jobs, had earned less money, and had had a weaker attachment to the labor force. These characteristics greatly reduced their chances of qualifying for disabled-worker benefits. Lack of knowledge about the program was also an important contributing factor.

Loss of protective antigen, histamine-sensitising factor and envelope polypeptides in cultural variants of Bordetella pertussis.

Five Bordetella pertussis strains of phase I were grown in conventional casamino-acid medium and in media modified by adding high concentrations of MgSO4 or nicotinic acid. Cells grown in high-magnesium media (in the C-mode) had only about 4% of the protective antigen (PA) and 6% of the histamine-sensitising factor (HSF) of cells from the normal medium. Envelopes from C-mode organisms when examined by SDS-PAGE showed a loss of 28K and 30K polypeptide bands. Similar parallel losses of PA, HSF and 28K and 30K bands were found with cells from the high-nicotinic-acid medium. A medium with a high concentration of nicotinamide gave cells with normal amounts of PA, HSF and 28K and 30K bands. Growth in high concentrations of Na2SO4 caused partial losses of PA, HSF and 28K and 30K bands, while a high-succinate medium gave cells with somewhat diminished PA and HSF but without appreciable attenuation of the 28K and 30K bands. Because of the close correlation between the presence or absence of PA, HSF and 28K and 30K envelope polypeptides, it is suggested that the latter may represent or be closely associated with the components responsible for PA and HSF activities.