Localization and behaviors in null mice suggest that ASIC1 and ASIC2 modulate responses to aversive stimuli.

Acid-sensing ion channels (ASICs) generate H(+) -gated Na(+) currents that contribute to neuronal function and animal behavior. Like ASIC1, ASIC2 subunits are expressed in the brain and multimerize with ASIC1 to influence acid-evoked currents and facilitate ASIC1 localization to dendritic spines. To better understand how ASIC2 contributes to brain function, we localized the protein and tested the behavioral consequences of ASIC2 gene disruption. For comparison, we also localized ASIC1 and studied ASIC1(-/-) mice. ASIC2 was prominently expressed in areas of high synaptic density, and with a few exceptions, ASIC1 and ASIC2 localization exhibited substantial overlap. Loss of ASIC1 or ASIC2 decreased freezing behavior in contextual and auditory cue fear conditioning assays, in response to predator odor and in response to CO2 inhalation. In addition, loss of ASIC1 or ASIC2 increased activity in a forced swim assay. These data suggest that ASIC2, like ASIC1, plays a key role in determining the defensive response to aversive stimuli. They also raise the question of whether gene variations in both ASIC1 and ASIC2 might affect fear and panic in humans.

Effect of primer selection on estimates of GB virus C (GBV-C) prevalence and response to antiretroviral therapy for optimal testing for GBV-C viremia.

GB virus C (GBV-C; also called hepatitis G virus) is a common cause of infection associated with prolonged survival among HIV-infected individuals. The prevalences of GBV-C viremia vary widely in different studies, and there has been poor agreement among different laboratories performing GBV-C RNA detection in quality control studies. To determine the optimal method of measuring GBV-C RNA in clinical samples, samples obtained from 939 HIV-infected subjects were studied using reverse transcription (RT)-PCR methods amplifying four separate regions of the GBV-C genome. Primers amplifying the E2 coding region were 100% specific; however, their sensitivity was only 76.6%. In contrast, primers amplifying three additional conserved regions of the GBV-C genome (the 5' nontranslated region and the nonstructural protein-coding regions 3 and 5A) were more sensitive but produced higher rates of false-positive results. Using low-specificity primer sets influenced the significance of association between GBV-C viremia and response to antiretroviral therapy. Using a quantitative GBV-C RNA method, the GBV-C RNA concentration did not correlate with baseline or set point HIV RNA levels; however, a correlation between negative, low, and high GBV-C RNA levels and increasing reduction in HIV RNA following antiretroviral therapy was observed. Subjects with both GBV-C E2 antibody and viremia had significantly lower GBV-C RNA levels than did viremic subjects without E2 antibody. These studies demonstrate that accurate detection of GBV-C RNA by nested RT-PCR requires the use of primers representing multiple genome regions. Analyses based on testing with single primers do not lead to reliable conclusions about the association between GBV-C infection and clinical outcomes.

Effect of early and late GB virus C viraemia on survival of HIV-infected individuals: a meta-analysis.

OBJECTIVES: To conduct a meta-analysis to synthesize the evidence regarding the effect of co-infection with GB virus C (GBV-C) on survival of HIV-infected individuals, and to estimate the effect. METHODS: A Bayesian meta-analysis was conducted to synthesize evidence from eligible studies. Prospective survival studies of HIV-1-infected individuals, with outcome defined as time from baseline to all-cause death, were included and classified by whether GBV-C status was determined in early or late HIV disease. The primary measure was the hazard ratio (HR) of death for HIV-infected individuals with GBV-C infection versus those without GBV-C infection. RESULTS: Eleven studies from eight publications met the inclusion criteria. For studies with GBV-C status measured 2 years or less after HIV seroconversion (912 subjects), the combined HR was 0.88 [95% credible interval (CI) 0.30, 1.50]. For studies with GBV-C status measured more than 2 years after HIV seroconversion (1294 subjects), the combined HR was 0.41 (95% CI 0.23, 0.69). CONCLUSIONS: No conclusive evidence was found of an association between survival and GBV-C infection early in HIV disease. However, when GBV-C infection was present later in HIV disease, a significant reduction in the hazard for mortality was observed for those with co-infection. Potential explanations for this difference include a non-proportional benefit of GBV-C over time, possibly related to clearance of GBV-C infection early in HIV disease. The timing of GBV-C infection appears to account for the contradictory results of studies on the effect of GBV-C coinfection on survival of HIV-infected people.

A Bayesian stopping rule for a single arm study: With a case study of stem cell transplantation.

Continuous monitoring of treatment failures is an important issue in clinical studies of a single experimental treatment for high risk therapy such as hematopoietic stem cell transplantation. The sequential probability ratio test (SPRT) of Wald in 1947 and various alternative stopping rules have been proposed for sequential monitoring of adverse events. It is natural to use prior information to improve stopping rules and statistical analysis. A Bayesian stopping rule is developed and applied to an example of an umbilical cord blood transplant study performed at the University of Minnesota. Two strata, based on the number of nucleated cells per kg recipient body weight (the 'dose') are monitored separately and different rules are constructed for each stratum using different prior distributions. It is believed that patients in the lower dose group have a greater chance of graft failure than those in the higher dose group. A program, written in R, is also presented for calculating the stopping rule using the prior beliefs. The program is an improvement upon existing programs and it can be used for larger studies.

Effect of GB virus C on response to antiretroviral therapy in HIV-infected Brazilians.

OBJECTIVES: GB virus C (GBV-C) infection is associated with delayed mortality in HIV-infected people in most, but not all, studies. Previous investigations of the effect of GBV-C viraemia on response to antiretroviral therapy (ART) were inconclusive. To determine the effect of GBV-C on ART, we retrospectively analysed plasma samples taken from patients in a prospective randomized clinical trial of ART in HIV-positive Brazilians. METHODS: GBV-C viraemia was characterized by testing stored serum samples from 175 participants by reverse transcriptase-polymerase chain reaction (RT-PCR). Subjects were randomized to receive indinavir (n=59), zidovudine and lamivudine (n=58), or zidovudine, lamivudine and indinavir (n=58). The effect of GBV-C viraemia on the average change in HIV viral load and CD4 count following initiation of therapy was evaluated in a multiple regression analysis. RESULTS: The prevalence of GBV-C viraemia was similar to that observed in previous studies (24%). HIV viral load decreased following ART to a significantly greater extent in patients with GBV-C viraemia (by 0.48 log(10) HIV-1 RNA copies/mL, P=0.009, adjusting for age, ART group, and baseline CD4 count). Although there was no significant difference in change in CD4 count between individuals with and without GBV-C viraemia overall, CD4 counts were higher following 48 weeks of therapy in GBV-C viraemic individuals receiving the least potent ART regimen (zidovudine and lamivudine) compared with those without GBV-C infection. CONCLUSIONS: GBV-C viraemia is associated with an enhanced reduction of HIV viral load in response to ART. In this study of treatment-naive individuals during 48 weeks of follow up, patients with GBV-C viraemia had reductions in HIV viral load that were approximately 0.5 log copies/mL greater than those found in patients without GBV-C viraemia. This is similar to reductions observed with nucleoside reverse transcriptase inhibitors.

The safety and efficacy of adefovir dipivoxil in patients with advanced HIV disease: a randomized, placebo-controlled trial.

OBJECTIVE: Efficacy and safety of adefovir dipivoxil (adefovir) added to background antiretroviral therapy in advanced HIV disease. DESIGN: Randomized, double-blind, placebo-controlled multicenter trial. SETTING: Fifteen clinical trial units providing HIV primary care. PARTICIPANTS: Adults with CD4 cell count < or = 100 x 10(6)/l, or 101-200 x 10(6)/l with prior nadir < or = 50 x 10(6)/l. INTERVENTIONS: Oral adefovir or placebo 120 mg once daily. MAIN OUTCOME MEASURES: Survival, cytomegalovirus (CMV) disease, plasma HIV-RNA, CD4 cell count, grade 4 drug toxicity, permanent drug discontinuation due to toxicity. RESULTS: Among the 253 patients assigned adefovir and the 252 assigned placebo, respectively, 17 and 16 died (P = 0.88), and four and eight experienced CMV disease (P = 0.25). Mean change in log(10) plasma HIV-RNA in the adefovir and placebo groups, respectively, was 0.09 and -0.03 copies/ml at 6 months (P = 0.22) and 0.06 and -0.02 at 12 months (P = 0.87). Changes in CD4 cell counts were not different between groups. At 12 months the cumulative percent with proximal renal tubular dysfunction (PRTD) was 17% in the adefovir group and 0.4% in the placebo group (P < 0.0001, log rank test). Median time to resolution of PRTD was 15 weeks among patients assigned adefovir, and 16% of patients did not resolve completely 41 weeks after onset. More drug discontinuations occurred in the adefovir group than in the placebo group. CONCLUSIONS: No virologic or immunologic benefit was observed when adefovir was added to background antiretroviral therapy in advanced HIV disease, and adefovir was associated with considerable nephrotoxicity. This study does not support the use of adefovir for treatment of advanced HIV disease in pretreated patients.

Quantifying and documenting prior beliefs in clinical trials.

Collecting and documenting subjective prior beliefs from knowledgeable clinicians about the potential results of a clinical trial has many advantages. Two large trials of prophylactic treatments in an HIV-positive population are used as examples. The trials recruited patients of primary care physicians and compared treatments which were in use in clinical practice. Opinions about these trials were elicited from 58 practising HIV clinicians. It is shown how the documented opinions can be used to augment the monitoring process; the prior opinions are updated with interim data using approximate Bayesian methods to give posterior opinions incorporating interim results. These posterior opinions can be used by the monitoring board to anticipate the clinicians' reaction to the results. Eliciting prior beliefs is also ethically important for documenting the nature of the uncertainty or equipoise. Important information is provided for the informed consent process and Institutional Review Board (IRB).

Older persons' opinions about life-sustaining procedures in the face of dementia.

OBJECTIVE: To investigate the attitudes of cognitively normal older adults toward various life-sustaining procedures in the face of dementia. METHODS: Participants were 84 cognitively normal men and women (70% response rate), 65 years and older, from a variety of urban and suburban settings, including private homes, assisted-living apartments, transitional care facilities, and nursing homes. In-person interviews were conducted with each participant to obtain information about demographic characteristics, life and health, and desire for various life-sustaining procedures for 4 hypothesized levels of dementia. RESULTS: Approximately three fourths of participants said they would not want cardiopulmonary resuscitation, use of a respirator, or parenteral or enteral tube nutrition with the milder forms of dementia, and 95% or more of participants would not want these procedures with severe dementia. In addition, only one third or fewer participants thought they would want to be hospitalized or given antibiotics if they were severely demented. Logistic regression analysis showed a relationship between participants' desire for life-sustaining procedures and having less education, greater independence, and a higher perceived quality of life. CONCLUSIONS: Most surveyed individuals did not desire life-sustaining treatments with any degree of dementia, and the proportion of individuals not desiring such treatments increased with the projected severity of dementia. These findings indicate a need for including dementia in advance directives planning.

Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: a randomized controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS.

CONTEXT: Peripheral neuropathy is common in persons infected with the human immunodeficiency virus (HIV) but few data on symptomatic treatment are available. OBJECTIVE: To evaluate the efficacy of a standardized acupuncture regimen (SAR) and amitriptyline hydrochloride for the relief of pain due to HIV-related peripheral neuropathy in HIV-infected patients. DESIGN: Randomized, placebo-controlled, multicenter clinical trial. Each site enrolled patients into 1 of the following 3 options: (1) a modified double-blind 2 x 2 factorial design of SAR, amitriptyline, or the combination compared with placebo, (2) a modified double-blind design of an SAR vs control points, or (3) a double-blind design of amitriptyline vs placebo. SETTING: Terry Beirn Community Programs for Clinical Research on AIDS (HIV primary care providers) in 10 US cities. PATIENTS: Patients with HIV-associated, symptomatic, lower-extremity peripheral neuropathy. Of 250 patients enrolled, 239 were in the acupuncture comparison (125 in the factorial option and 114 in the SAR option vs control points option), and 136 patients were in the amitriptyline comparison (125 in the factorial option and 11 in amitriptyline option vs placebo option). INTERVENTIONS: Standardized acupuncture regimen vs control points, amitriptyline (75 mg/d) vs placebo, or both for 14 weeks. MAIN OUTCOME MEASURE: Changes in mean pain scores at 6 and 14 weeks, using a pain scale ranging from 0.0 (no pain) to 1.75 (extremely intense), recorded daily. RESULTS: Patients in all 4 groups showed reduction in mean pain scores at 6 and 14 weeks compared with baseline values. For both the acupuncture and amitriptyline comparisons, changes in pain score were not significantly different between the 2 groups. At 6 weeks, the estimated difference in pain reduction for patients in the SAR group compared with those in the control points group (a negative value indicates a greater reduction for the "active" treatment) was 0.01 (95% confidence interval [CI], -0.11 to 0.12; P=.88) and for patients in the amitriptyline group vs those in the placebo group was -0.07 (95% CI, -0.22 to 0.08; P=.38). At 14 weeks, the difference for those in the SAR group compared with those in the control points group was -0.08 (95% CI, -0.21 to 0.06; P=.26) and for amitriptyline compared with placebo was 0.00 (95% CI, -0.18 to 0.19; P=.99). CONCLUSIONS: In this study, neither acupuncture nor amitriptyline was more effective than placebo in relieving pain caused by HIV-related peripheral neuropathy.

Growth of Hmong children.

OBJECTIVE: To investigate the growth of a group of young Hmong children. DESIGN: In this descriptive, comparative study, length and weight measures of Hmong children were abstracted from medical charts for each previous clinic visit (newborn to most recent visit) where both measures had been recorded, and measures were compared with National Center for Health Statistics (NCHS) standard percentiles. Visits occurred from 1988 to 1994. PARTICIPANTS AND SETTING: Participants were 579 Hmong children, ages 0 to 5 years, who were active patients at a family practice residency clinic. MAIN OUTCOME MEASURES: Length and weight. RESULTS: This group of Hmong children showed lengths similar to those of the NCHS reference population for the first 6 to 12 months of life, after which they lagged behind reference lengths. By the 24th month, median length for Hmong girls and boys was less than the NCHS 25th percentile. The Hmong children's average weight was slightly higher than the NCHS median until about 8 months of age, after which the distributions were similar. CONCLUSIONS: Compared with children who comprise the NCHS reference population, the Hmong children in this study were slightly heavier in the first several months of life, and shorter thereafter. Therefore, in general, the Hmong children were proportionately heavier than other children of similar height.

Women's postpartum maternity benefits and work experience.

BACKGROUND: This study was conducted to describe women's perceptions of their maternity leave policy and its implementation, maternity leave benefits, postpartum work experience, and factors that relate to returning to work. METHODS: Surveys were mailed to 436 married, recently employed, first-time mothers at 1, 3, 6, 9 and 12 months postpartum. RESULTS: Most respondents said they had written maternity leave policies they could understand, but they were not completely satisfied with their policies. The average 11.1-week maternity leave was considerably shorter than their 8-month ideal, and only 25.5% had the option of working part-time. A minority (35.8%) were allowed to use personal days to care for a sick infant. Most women were distressed about making child care arrangements. Compared with women who remained at home, those who returned to work complained of more respiratory, gynecologic, and breast symptoms. CONCLUSIONS: Relatively little is known about women's postpartum work experience. In this study, return to work after delivery was related to several demographic, occupational, and social factors and was associated with health problems and concerns about child care. With a majority of new mothers now returning to work, attention has recently been directed to factors that facilitate the merger of work and parenting roles. One such important factor is women's parental or maternity leave benefits, the focus of this study.

Family practice residents' maternity leave experiences and benefits.

BACKGROUND: A growing number of residents are having babies during residency training. While many businesses are working to improve maternity conditions and benefits for their employees, residency programs are often not prepared to accommodate pregnant residents. This study was conducted to examine the maternity leave experiences of women who delivered infants during their family practice residency training. METHODS: Program directors from each of the 394 family practice residency programs listed in the 1993 Directory of Family Practice Residency Programs were asked to distribute surveys to female residents who gave birth during their residency training and had returned to work by the time of the study. RESULTS: Of 199 known eligible residents, 171 (86%) completed surveys; these women represented 127 programs located in 36 states and Puerto Rico. Only 56.8% of women were aware of their program having a written maternity leave policy. The average length of maternity leave was 8 weeks; 76% had leaves of 10 weeks or less. For many, the maternity leave was derived from more than one source, including vacation, sick time, or a mother-child elective. Nearly all (88.3%) the women breast-fed, and the mean duration of breast-feeding was more than 19 weeks. In general, participants believed that having a baby during residency was somewhat difficult. Problems frequently encountered by women after their return to work included sleep deprivation and tiredness, difficulty arranging for child care, guilt about child care, and breast-feeding. Factors that detracted most from the childbirth experience were too little sleep, problems arranging for child care, and lack of support from the partner, residency faculty, and other residents. CONCLUSIONS: Having a baby during residency is somewhat difficult for the average female resident. Factors that may ease this difficulty include getting adequate sleep and receiving support from one's partner, faculty, and other residents.

The relationship of women's postpartum mental health to employment, childbirth, and social support.

BACKGROUND: This study was conducted to examine changes in women's mental health over the first postpartum year and factors that are associated with mental health. METHODS: Participants included women who were married, employed, English-speaking, and giving birth to their first child at one of two hospitals in St Paul, Minnesota. Women who were eligible and willing to participate were mailed questionnaires at 1, 3, 6, 9, and 12 months postpartum. RESULTS: There were significant changes in mothers' general mental health, depression, and anxiety over the first postpartum year (P < or = .01), with least favorable outcomes at 1 month and most favorable outcomes at 12 months postpartum. Poor mental health was related to work factors, such as longer work hours and maternity leave of less than 24 weeks, and to variables often associated with recent childbirth, such as maternal fatigue, loss of sleep, concerns about appearance, and infant illnesses. In addition, postpartum symptoms were predicted by physical illness, previous mental problems, poor general health, poor social support, fewer recreational activities, young age, and low income (R2 = 37% to 57%). CONCLUSIONS: In this select group of women, postpartum mental health was found to be least favorable 1 month after delivery and related to factors associated with employment, recent delivery, and level of social support.

Mothers' experience with household roles and social support during the first postpartum year.

This prospective, longitudinal study was conducted to investigate the changes in the division of household labor, and in the emotional and practical support received by new mothers during the first postpartum year. Questionnaires were completed by 436 married, recently employed mothers at 1, 3, 6, 9, and 12 months after they had delivered their first child. Results showed that women assumed primary responsibility for the majority of household tasks studied, and that they perceived declines over time in their husbands' participation in household chores, their husbands' and others' expressions of caring, and in the frequency with which friends and relatives "helped out" during the year. Women who had had cesarean sections (versus those with vaginal deliveries) and who returned to work (versus those who stayed home) believed their husbands participated more in traditionally feminine household chores. Women's satisfaction with their husbands' contribution to household activities was significantly related to their own mental health, delivery type (cesarean section), job status (being at home vs. back at work), and family income; and to their husbands' occupation, expressions of caring, and participation in child care and certain household chores (house cleaning, grocery shopping, cooking, washing clothes and dishes, household repairs, car maintenance, and garbage removal). Overall, these findings showed diminishing levels of emotional and practical support for women at a time when the need for support was likely greater: following the birth of their first child.

Optimum experimental designs for properties of a compartmental model.

Three properties of interest in bioavailability studies using compartmental models are the area under the concentration curve, the maximum concentration, and the time to maximum concentration. Methods are described for finding designs that minimize the variance of the estimates of these quantities in such a model. These methods use prior information. Both prior estimates and prior distributions are used. The designs for an open one-compartment model are compared with the corresponding D theta-optimum design for all parameters and also with designs that minimize the sum of the scaled variances of the individual properties.

Changes in women's physical health during the first postpartum year.

OBJECTIVE: To examine changes in women's physical health during the first postpartum year. DESIGN: Participants completed surveys at 1, 3, 6, 9, and 12 months post partum. PARTICIPANTS AND SETTING: Four hundred thirty-six first-time mothers who gave birth at one of two St Paul, Minn, hospitals during a 12-month period and who met the criteria for the study. MAIN OUTCOME MEASURES: Physical symptoms and number of illness days experienced within the previous 2 weeks. RESULTS: Physical problems seen at a higher prevalence at 1 month post partum included breast symptoms, vaginal discomfort, fatigue, hemorrhoids, poor appetite, constipation, increased sweating, acne, hand numbness or tingling, dizziness, hot flashes, and illness days. Several of these disorders--hemorrhoids, dizziness, fatigue, and constipation--persisted beyond 1 month and were joined by other "late" problems, including respiratory symptoms, sexual concerns, and hair loss. Women who returned to the work force noted more symptoms of respiratory infections, and women with vaginal deliveries had a higher prevalence of hemorrhoids, vaginal discomfort, pain with intercourse, difficulty reaching orgasm, sinus problems, and acne. CONCLUSIONS: Recovery from childbirth often requires more than the 6 weeks traditionally allotted, and postpartum health appears to be affected by delivery type and work status.