Showing papers by "University of Texas Medical Branch published in 2001"

Molecular basis of mechanotransduction in living cells

Abstract: The simplest cell-like structure, the lipid bilayer vesicle, can respond to mechanical deformation by elastic membrane dilation/thinning and curvature changes. When a protein is inserted in the lip...

The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins.

Abstract: To maintain quality control in cells, mechanisms distinguish among improperly folded peptides, mature and functional proteins, and proteins to be targeted for degradation. The molecular chaperones, including heat-shock protein Hsp90, have the ability to recognize misfolded proteins and assist in their conversion to a functional conformation. Disruption of Hsp90 heterocomplexes by the Hsp90 inhibitor geldanamycin leads to substrate degradation through the ubiquitin-proteasome pathway, implicating this system in protein triage decisions. We previously identified CHIP (carboxyl terminus of Hsc70-interacting protein) to be an interaction partner of Hsc70 (ref. 4). CHIP also interacts directly with a tetratricopeptide repeat acceptor site of Hsp90, incorporating into Hsp90 heterocomplexes and eliciting release of the regulatory cofactor p23. Here we show that CHIP abolishes the steroid-binding activity and transactivation potential of the glucocorticoid receptor, a well-characterized Hsp90 substrate, even though it has little effect on its synthesis. Instead, CHIP induces ubiquitylation of the glucocorticoid receptor and degradation through the proteasome. By remodelling Hsp90 heterocomplexes to favour substrate degradation, CHIP modulates protein triage decisions that regulate the balance between protein folding and degradation for chaperone substrates.

The Comorbidity of Major Depression and Anxiety Disorders: Recognition and Management in Primary Care

Abstract: BACKGROUND: Depressive and anxiety disorders commonly occur together in patients presenting in the primary care setting. Although recognition of individual depressive and anxiety disorders has increased substantially in the past decade, recognition of comorbidity still lags. The current report reviews the epidemiology, clinical implications, and management of comorbidity in the primary care setting. METHOD: Literature was reviewed by 2 methods: (1) a MEDLINE search (1980-2001) using the key words depression, depressivedisorders, and anxietydisorders; comorbidity was also searched with individual anxiety diagnoses; and (2) direct search of psychiatry, primary care, and internal medicine journals over the past 5 years. RESULTS: Between 10% and 20% of adults in any given 12-month period will visit their primary care physician during an anxiety or depressive disorder episode (although typically for a nonpsychiatric complaint); more than 50% of these patients suffer from a comorbid second depressive or anxiety disorder. The presence of depressive/anxiety comorbidity substantially increases medical utilization and is associated with greater chronicity, slower recovery, increased rates of recurrence, and greater psychosocial disability. Typically, long-term treatment is indicated, although far less research is available to guide treatment decisions. Selective serotonin reuptake inhibitor antidepressants are the preferred treatment based on efficacy, safety, and tolerability criteria. Knowledge of their differential clinical and pharmacokinetic profiles can assist in optimizing treatment. CONCLUSION: Increased recognition of the high prevalence and negative psychosocial impact of depression and anxiety disorder comorbidity will lead to more effective treatment. While it is hoped that early and effective intervention will yield long-term benefits, research is needed to confirm this.

Reversal of catabolism by beta-blockade after severe burns.

Abstract: Background The catecholamine-mediated hypermetabolic response to severe burns causes increased energy expenditure and muscle-protein catabolism. We hypothesized that blockade of β-adrenergic stimulation with propranolol would decrease resting energy expenditure and muscle catabolism in patients with severe burns. Methods Twenty-five children with acute and severe burns (more than 40 percent of total body-surface area) were studied in a randomized trial. Thirteen received oral propranolol for at least two weeks, and 12 served as untreated controls. The dose of propranolol was adjusted to decrease the resting heart rate by 20 percent from each patient's base-line value. Resting energy expenditure and skeletal-muscle protein kinetics were measured before and after two weeks of beta-blockade (or no therapy, in controls). Body composition was measured serially throughout hospitalization. Results Patients in the control group and the propranolol group were similar with respect to age, weight, percentage of tota...

Timing of amino acid-carbohydrate ingestion alters anabolic response of muscle to resistance exercise

Abstract: The present study was designed to determine whether consumption of an oral essential amino acid-carbohydrate supplement (EAC) before exercise results in a greater anabolic response than supplementa...

p47phox is required for atherosclerotic lesion progression in ApoE–/– mice

Abstract: NADPH oxidase is upregulated in smooth muscle cells (SMCs) in response to growth factor stimulation, concomitant with increased reactive oxygen species (ROS) production. We investigated the role of ROS production by NADPH oxidase in SMC responses to growth factors and in atherosclerotic lesion formation in ApoE(-/-) mice. SMCs from wild-type, p47phox(-/-), and gp91phox(-/-) mice differed markedly with respect to growth factor responsiveness and ROS generation. p47phox(-/-) SMCs had diminished superoxide production and a decreased proliferative response to growth factors compared with wild-type cells, whereas the response of gp91phox(-/-) SMCs was indistinguishable from that of wild-type SMCs. The relevance of these in vitro observations was tested by measuring atherosclerotic lesion formation in genetically modified (wild-type, p47phox(-/-), ApoE(-/-), and ApoE(-/-)/p47phox(-/-)) mice. ApoE(-/-)/p47phox(-/-) mice had less total lesion area than ApoE(-/-) mice, regardless of whether mice were fed standard chow or a high-fat diet. Together, these studies provide convincing support for the hypothesis that superoxide generation in general, and NADPH oxidase in particular, have a requisite role in atherosclerotic lesion formation, and they provide a rationale for further studies to dissect the contributions of ROS to vascular lesion formation.

Association of hyperglycemia with increased mortality after severe burn injury.

Abstract: Background: Hyperglycemia is commonly associated with the hypermetabolic stress response. However, persistent hyperglycemia may adversely affect wound healing and immunity. The purpose of this study was to assess any relationship between hyperglycemia and clinical outcome after severe burn injury. Methods: Survey of the medical records from January 1996 to July 1999 identified 58 pediatric patients with burns ≥ 60% body surface. Patients were categorized as having poor glucose control (n = 33) if ≥ 40% of all plasma glucose determinations were ≥ 7.8 mmol/L (140 mg/dL) and compared with patients deemed to have adequate glucose control (n = 25) in whom ≤ 40% of all glucose values were ≥ 7.8 mmol/L. Results: Despite similar age, burn size, caloric intake, and frequency of wound infection, patients categorized with poor glucose control had a significantly greater incidence of positive blood cultures (positive blood cultures/length of stay days, 0.42 ± 0.04 for hyperglycemia patients vs. 0.30 ± 0.03 for normoglycemia patients; mean ± SEM, p ≤ 0.05). This finding was especially prominent for blood cultures positive for yeast. Hyperglycemia patients had significantly less percentage of skin graft take than did the normoglycemic patients (percent take/operative procedure, 64 ± 9 for hyperglycemia patients vs. 88 ± 5 for normoglycemia patients; p < 0.05). Nine patients (27%) with persistent hyperglycemia died compared with only one death (4%) in patients with adequate glucose control (p ≤ 0.05). Conclusion: This association between poor glucose control, bacteremia/ fungemia, reduced skin graft take, and subsequent mortality in severely burned children may be related to a hyperglycemia-induced detriment in antimicrobial defense. Although this report fails to establish cause and effect, these findings suggest that aggressive maneuvers to normalize plasma glucose in critically injured patients may be warranted.

Latency and duration of stimulation of human muscle protein synthesis during continuous infusion of amino acids.

Abstract: 1. The aim of this study was to describe the time course of the response of human muscle protein synthesis (MPS) to a square wave increase in availability of amino acids (AAs) in plasma. We investigated the responses of quadriceps MPS to a approximately 1.7-fold increase in plasma AA concentrations using an intravenous infusion of 162 mg (kg body weight)(-1) h(-1) of mixed AAs. MPS was estimated from D3-leucine labelling in protein after a primed, constant intravenous infusion of D3-ketoisocaproate, increased appropriately during AA infusion. 2. Muscle was separated into myofibrillar, sarcoplasmic and mitochondrial fractions. MPS, both of mixed muscle and of fractions, was estimated during a basal period (2.5 h) and at 0.5-4 h intervals for 6 h of AA infusion. 3. Rates of mixed MPS were not significantly different from basal (0.076 +/- 0.008 % h(-1)) in the first 0.5 h of AA infusion but then rose rapidly to a peak after 2 h of approximately 2.8 times the basal value. Thereafter, rates declined rapidly to the basal value. All muscle fractions showed a similar pattern. 4. The results suggest that MPS responds rapidly to increased availability of AAs but is then inhibited, despite continued AA availability. These results suggest that the fed state accretion of muscle protein may be limited by a metabolic mechanism whenever the requirement for substrate for protein synthesis is exceeded.

Basal muscle amino acid kinetics and protein synthesis in healthy young and older men.

Abstract: ContextSarcopenia is associated with loss of strength and function, eventually leading to loss of independence. Some studies suggest that basal muscle protein turnover is reduced with aging, but other studies do not confirm this finding.ObjectiveTo determine if aging per se affects basal muscle protein turnover in men.Design and SettingCross-sectional study conducted from June 1997 to July 2000 in a general US community.ParticipantsTwenty-six young (mean [SE] age, 28 [2] years) and 22 older (mean [SE] age, 70 [1] years) men, who were healthy and independent based on activities of daily living, physical examinations, and screening tests. Subjects were excluded if they had cardiac, pulmonary, liver, or kidney disease; any impairment in activities of daily living; or steroid use.Main Outcome MeasuresWe measured basal muscle protein and amino acid kinetics, based on stable isotope techniques with femoral arteriovenous catheterization and muscle biopsies. Three models (arteriovenous balance, three-pool, and fractional synthesis rate) were used to estimate the metabolic parameters.ResultsMean (SE) total leg volume was 9.60 (0.32) L in older men vs 10.83 (0.43) L in younger men, which suggests muscle loss in the older men. Net muscle protein balance was similar in both groups (older men, − 19 [2] nmol/min per 100 mL of leg volume vs younger men, − 21 [2] nmol/min per 100 mL of leg volume; P = .51). Small differences were found in mean (SE) muscle protein synthesis in comparisons of older vs younger men: arteriovenous balance, 48 (5) nmol/min per 100 mL of leg volume vs 32 (3) nmol/min per 100 mL of leg volume; P = .004; three-pool, 58 (5) nmol/min per 100 mL of leg volume vs 43 (4) nmol/min per 100 mL of leg volume; P = .04; and fractional synthesis rate, 0.0601 (0.0046) %/h vs 0.0578 (0.0047) %/h; P = .73. Small differences were also found in mean (SE) muscle protein breakdown: arteriovenous balance, 66 (5) nmol/min per 100 mL of leg volume in older vs 53 (4) nmol/min per 100 mL of leg volume in younger men, P = .045; and three-pool, 76 (6) nmol/min per 100 mL of leg volume vs 64 (5) nmol/min per 100 mL of leg volume, P = .14.ConclusionDifferences in basal muscle protein turnover between older and younger men do not appear to explain muscle loss that occurs with age.

Psychometric properties of an Italian version of the Barratt Impulsiveness Scale-11 (BIS-11) in nonclinical subjects

Abstract: To assess the psychometric properties of the Italian translation of the Barratt Impulsiveness Scale-11 (BIS-11), the scale was administered to 763 college undergraduates. Based on analyses using item-total correlations and t-tests for differences between the top and the bottom total score quartiles, all items from the English version of the BIS-11 were retained in the Italian version. Cronbach's alpha for internal consistency was.79 and two-month test-retest reliability was.89. An exploratory principal-components analysis replicated the six first-order factors and three oblique second-order factors, consistent with the number identified in the English version. However, subfactor item loadings differed between the English and Italian versions. The overall item pool was consistent in being a homogeneous measure of impulsiveness. The BIS-11 total score was correlated significantly with aggression and ADHD measures. The BIS-11 also significantly differentiated between high and low levels of binge eating, alcohol consumption, and cigarette smoking.

Stimulation of human 8-oxoguanine-DNA glycosylase by AP-endonuclease: potential coordination of the initial steps in base excision repair

Abstract: 8-Oxoguanine-DNA glycosylase 1 (OGG1), with intrinsic AP lyase activity, is the major enzyme for repairing 7,8-dihydro-8-oxoguanine (8-oxoG), a critical mutagenic DNA lesion induced by reactive oxygen species. Human OGG1 excised the damaged base from an 8-oxoG. C-containing duplex oligo with a very low apparent k(cat) of 0.1 min(-1) at 37 degrees C and cleaved abasic (AP) sites at half the rate, thus leaving abasic sites as the major product. Excision of 8-oxoG by OGG1 alone did not follow Michaelis-Menten kinetics. However, in the presence of a comparable amount of human AP endonuclease (APE1) the specific activity of OGG1 was increased approximately 5-fold and Michaelis-Menten kinetics were observed. Inactive APE1, at a higher molar ratio, and a bacterial APE (Nfo) similarly enhanced OGG1 activity. The affinity of OGG1 for its product AP.C pair (K:(d) approximately 2.8 nM) was substantially higher than for its substrate 8-oxoG.C pair (K:(d) approximately 23. 4 nM) and the affinity for its final ss-elimination product was much lower (K:(d) approximately 233 nM). These data, as well as single burst kinetics studies, indicate that the enzyme remains tightly bound to its AP product following base excision and that APE1 prevents its reassociation with its product, thus enhancing OGG1 turnover. These results suggest coordinated functions of OGG1 and APE1, and possibly other enzymes, in the DNA base excision repair pathway.

The association between emotional well-being and the incidence of stroke in older adults.

Abstract: Objective Individuals with high levels of depressive symptoms have an increased risk of many illnesses, including stroke. Measures of depressive symptoms include questions about the presence of negative affect, such as sadness, as well as the absence of positive affect, such as happiness and optimism. We assessed whether positive or negative affect, or both, predicted risk of stroke. Methods Data were from a 6-year prospective cohort study of a population-based sample of 2478 older whites and blacks from five counties in North Carolina who reported no history of stroke at the baseline interview. Baseline, in-person interviews were conducted to gather information on sociodemographic, psychosocial, and health-related characteristics of subjects. Thereafter interviews were conducted annually for 6 years. Results Increasing scores on the modified version of the Center for Epidemiological Studies Depression Scale (CES-D) were significantly associated with stroke incidence for the overall sample (relative risk [RR] = 1.04 for each one-point increase, 95% confidence interval [CI] = 1.01-1.09) over the 6-year follow-up period after adjusting for sociodemographic characteristics, blood pressure, body mass index, smoking status, and selected chronic diseases. Positive affect score demonstrated a strong inverse association with stroke incidence (RR = 0.74, 95% CI = 0.62-0.88). Conclusions Increasing scores on the modified CES-D are related to an increased risk of stroke, whereas high levels of positive affect seem to protect against stroke in older adults.

Prevalence of neuroendocrine dysfunction in patients recovering from traumatic brain injury.

Abstract: Although hypopituitarism is a known complication of head injury, it may be underrecognized due to its subtle clinical manifestations. The nonspecific symptoms may be masked by and may contribute to the physical and psychological sequelae of brain trauma. This study examines the prevalence of neuroendocrine abnormalities in patients rehabilitating from traumatic brain injury. Seventy adults (mean age, 31.5 +/- 1.1 yr; range, 18--58; 46 men and 24 women) with traumatic brain injury an average of 49 +/- 8 months before the study (median, 13 months) underwent a series of standard endocrine tests, including serum levels of TSH, free T(4), insulin-like growth factor I, PRL, testosterone (males), and cosyntropin stimulation. Abnormal results of these tests were followed by dynamic tests of gonadotropin, TSH, and GH secretion. Glucagon stimulation testing in 48 subjects revealed GH deficiency (peak, <3 microg/L) in 14.6%. Free T(4) (n = 6; 8.6%), TSH (n = 7; 10%), or both (n = 2; 2.9%) were low in 21.7%, whereas 87% had both TSH and free T(4) below the midnormal level. Basal morning cortisol was below normal in 45.7% of subjects, whereas cosyntropin-stimulated levels were insufficient (peak, <500 nmol/L) in 7.1%. Hypogonadism and hyperprolactinemia were uncommon. In summary, pituitary hormone deficiencies were identified in a substantial proportion of patients with previous brain injury. GH deficiency, found in 15% by glucagon stimulation testing, may compound the physical and psychological complications of traumatic brain injury and interfere with rehabilitation.

Evolutionary Relationships and Systematics of the Alphaviruses

Abstract: Partial E1 envelope glycoprotein gene sequences and complete structural polyprotein sequences were used to compare divergence and construct phylogenetic trees for the genus Alphavirus. Tree topologies indicated that the mosquito-borne alphaviruses could have arisen in either the Old or the New World, with at least two transoceanic introductions to account for their current distribution. The time frame for alphavirus diversification could not be estimated because maximum-likelihood analyses indicated that the nucleotide substitution rate varies considerably across sites within the genome. While most trees showed evolutionary relationships consistent with current antigenic complexes and species, several changes to the current classification are proposed. The recently identified fish alphaviruses salmon pancreas disease virus and sleeping disease virus appear to be variants or subtypes of a new alphavirus species. Southern elephant seal virus is also a new alphavirus distantly related to all of the others analyzed. Tonate virus and Venezuelan equine encephalitis virus strain 78V3531 also appear to be distinct alphavirus species based on genetic, antigenic, and ecological criteria. Trocara virus, isolated from mosquitoes in Brazil and Peru, also represents a new species and probably a new alphavirus complex.

Synaptically released zinc: Physiological functions and pathological effects

Abstract: In addition to its familiar role as a component of metalloproteins, zinc is also sequestered in the presynaptic vesicles of a specialized type of neurons called ‘zinc-containing’ neurons. Here we review the physiological and pathological effects of the release of zinc from these zinc-containing synaptic terminals. The best-established physiological role of synaptically released zinc is the tonic modulation of brain excitability through modulation of amino acid receptors; prominent pathological effects include acceleration of plaque deposition in Alzheimer’s disease and exacerbation of excitotoxic neuron injury. Synaptically released zinc functions as a conventional synaptic neurotransmitter or neuromodulator, being released into the cleft, then recycled into the presynaptic terminal. Beyond this, zinc also has the highly unconventional property that it passes into postsynaptic neurons during synaptic events, functioning analogously to calcium in this regard, as a transmembrane neural signal. To stimulate comparisons of zinc signals with calcium signals, we have compiled a list of the important parameters of calcium signals and zinc signals. More speculatively, we hypothesize that zinc signals may loosely mimic phosphate ‘signals’ in the sense that signal zinc ions may commonly bind to proteins in a lasting manner (i.e., ‘zincylating’ the proteins) with consequential changes in protein structure and function.

Mechanical load increases muscle IGF-I and androgen receptor mRNA concentrations in humans

Abstract: The mechanism(s) of load-induced muscle hypertrophy is as yet unclear, but increasing evidence suggests a role for locally expressed insulin-like growth factor I (IGF-I). We investigated the effect...

Roles of yeast DNA polymerases delta and zeta and of Rev1 in the bypass of abasic sites.

Abstract: Abasic (AP) sites are one of the most frequently formed lesions in DNA, and they present a strong block to continued synthesis by the replicative DNA machinery. Here we show efficient bypass of an AP site by the combined action of yeast DNA polymerases delta and zeta. In this reaction, Poldelta inserts an A nucleotide opposite the AP site, and Polzeta subsequently extends from the inserted nucleotide. Consistent with these observations, sequence analyses of mutations in the yeast CAN1s gene indicate that A is the nucleotide inserted most often opposite AP sites. The nucleotides C, G, and T are also incorporated, but much less frequently. Enzymes such as Rev1 and Poleta may contribute to the insertion of these other nucleotides; the predominant role of Rev1 in AP bypass, however, is likely to be structural. Steady-state kinetic analyses show that Polzeta is highly inefficient in incorporating nucleotides opposite the AP site, but it efficiently extends from nucleotides, particularly an A, inserted opposite this lesion. Thus, in eukaryotes, bypass of an AP site requires the sequential action of two DNA polymerases, wherein the extension step depends solely upon Polzeta, but the insertion step can be quite varied, involving not only the predominant action of the replicative DNA polymerase, Poldelta, but also the less prominent role of various translesion synthesis polymerases.

Effectiveness of St John's wort in major depression: A randomized controlled trial

Abstract: ContextExtracts of St John's wort are widely used to treat depression. Although more than 2 dozen clinical trials have been conducted with St John's wort, most have significant flaws in design and do not enable meaningful interpretation.ObjectiveTo compare the efficacy and safety of a standardized extract of St John's wort with placebo in outpatients with major depression.Design and SettingRandomized, double-blind, placebo-controlled clinical trial conducted between November 1998 and January 2000 in 11 academic medical centers in the United States.ParticipantsTwo hundred adult outpatients (mean age, 42.4 years; 67.0% female; 85.9% white) diagnosed as having major depression and having a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 20.InterventionParticipants completed a 1-week, single-blind run-in of placebo, then were randomly assigned to receive either St John's wort extract (n = 98; 900 mg/d for 4 weeks, increased to 1200 mg/d in the absence of an adequate response thereafter) or placebo (n = 102) for 8 weeks.Main Outcome MeasuresThe primary outcome measure was rate of change on the HAM-D over the treatment period. Secondary measures included the Beck Depression Inventory (BDI), Hamilton Rating Scale for Anxiety (HAM-A), the Global Assessment of Function (GAF) scale, and the Clinical Global Impression–Severity and –Improvement scales (CGI-S and CGI-I).ResultsThe random coefficient analyses for the HAM-D, HAM-A, CGI-S, and CGI-I all showed significant effects for time but not for treatment or time-by-treatment interaction (for HAM-D scores, P<.001, P = .16, and P = .58, respectively). Analysis of covariance showed nonsignificant effects for BDI and GAF scores. The proportion of participants achieving an a priori definition of response did not differ between groups. The number reaching remission of illness was significantly higher with St John's wort than with placebo (P = .02), but the rates were very low in the full intention-to-treat analysis (14/98 [14.3%] vs 5/102 [4.9%], respectively). St John's wort was safe and well tolerated. Headache was the only adverse event that occurred with greater frequency with St John's wort than placebo (39/95 [41%] vs 25/100 [25%], respectively).ConclusionIn this study, St John's wort was not effective for treatment of major depression.

Systemic lupus erythematosus in three ethnic groups. VIII. Predictors of early mortality in the LUMINA cohort

Abstract: Objective To determine the features associated with mortality in a multiethnic US cohort of patients with systemic lupus erythematosus (SLE) within 5 years of study onset. Methods Socioeconomic and demographic features (age, gender, ethnicity, marital status, education, occupation, poverty, and health-related behaviors [drinking, smoking, exercising]), clinical and immunologic features (disease duration, disease onset type, disease activity according to the Systemic Lupus Activity Measure [SLAM], disease damage according to the Systemic Lupus International Collaborating Clinics [SLICC] Damage Index [SDI], number of American College of Rheumatology criteria at diagnosis, organ system manifestations, fatigue and pain ratings, and medication usage and autoantibodies), immunogenetic features (HLA class II genotypes), and behavioral and psychosocial features (social support, illness-related behaviors, and helplessness), as obtained at enrollment into the study, were compared between survivors and deceased patients. Logistic regression analysis was used to determine significant independent risk factors for mortality. Results Within 5 years of study onset, 34 of 288 patients have died. Fourteen deaths could be directly attributed to SLE and 11 to infections. In 1 patient the cause of death could not be determined. In the remaining 8 patients the cause of death was neither infectious nor disease-related. There were 10 deaths among Hispanics, 18 among African Americans, and 6 among Caucasians (P< 0.05). Variables associated with mortality in the univariable analyses included poverty, less than full-time employment, difficulty in accessing health care, shorter disease duration, cardiovascular and renal involvement, higher serum creatinine levels and lower hematocrit values, higher SLAM and SDI scores, lower use of antimalarial drugs, and higher use of (some) immunosuppressants. Specific autoantibodies and class II HLA genotypes were not associated with mortality. Poverty and higher baseline SLAM and SDI scores were independently associated with mortality in the multivariable analyses. Conclusions Disease activity, disease damage, and poverty appear to be the most important determinants of mortality in this multiethnic US cohort of SLE patients. These results have applicability to the management of patients with SLE, a disease that more severely affects disadvantaged minority population groups.

Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women.

Abstract: ContextHerpes simplex virus type 2 (HSV-2) is one of the most common sexually transmitted infections in the United States. No prospective study has shown the ability of condoms to reduce transmission of HSV-2.ObjectiveTo evaluate risk factors for HSV-2 acquisition and efficacy of condoms in prevention of HSV-2 transmission.DesignAnalysis of data from a randomized, double-blind, placebo-controlled trial conducted December 13, 1993, to June 28, 1996, of an ineffective candidate HSV-2 vaccine with 18 months of follow-up.SettingEighteen clinical trial centers in the United States.ParticipantsA total of 528 monogamous couples discordant for HSV-2 infection, including an HSV-2–susceptible population of 261 men and 267 women.Main Outcome MeasureAcquisition of HSV-2 infection by susceptible partners, compared with those remaining free of HSV-2 with regard to demographic characteristics, sexual activity, and condom use.ResultsTwenty-six women (9.7%) vs 5 men (1.9%) acquired HSV-2, for a rate per 10 000 sex acts (episodes of sexual intercourse) of 8.9 vs 1.5, respectively (P<.001). In multivariable analysis, younger age (adjusted hazard ratio [HR] per 5 years, 1.57; 95% confidence interval [CI], 1.22-2.04), seropositivity for HSV-1 and HSV-2 vs HSV-2 alone in the source partner (adjusted HR, 2.34; 95% CI, 1.14-4.82), and more frequent sexual activity (adjusted HR per additional sex act per week, 1.10; 95% CI, 1.01-1.19) were associated with higher risk of HSV-2 acquisition. Condom use during more than 25% of sex acts was associated with protection against HSV-2 acquisition for women (adjusted HR, 0.085; 95% CI, 0.01-0.67) but not for men (adjusted HR, 2.02; 95% CI, 0.32-12.50). Risk of HSV-2 transmission declined from 8.5 per 100 person-years in the initial 150-day interval to 0.9 per 100 person-years in the final 150-day interval (P = .002 for trend), concurrent with a decrease in sexual activity and proportion of sex acts occurring when the source partner had genital lesions.ConclusionsCondom use offers significant protection against HSV-2 infection in susceptible women. Changes in sexual behavior, correlated with counseling about avoiding sex when a partner has lesions, were associated with reduction in HSV-2 acquisition over time. These data suggest that identification of discordant couples can reduce transmission of HSV-2, especially for heterosexual couples in which the male partner has HSV-2 infection.

Metabotropic glutamate receptors: novel targets for pain relief.

Abstract: Metabotropic glutamate receptors (mGluRs) are a relatively new family of G-protein coupled receptors that can be activated by the major excitatory neurotransmitter, L-glutamate. The eight known mGluR subtypes are classified into three groups based on their sequence homology, signal transduction mechanisms and receptor pharmacology. Extensive research has implicated mGluRs in neuroplasticity associated with normal brain functions, but also in various neurological and psychiatric disorders. Evidence is accumulating to suggest an important role of mGluRs in nociception and pain. With the availability in recent years of selective pharmacological tools, behavioral and electrophysiological studies have shown that mGluR subgroups and subtypes mediate and modulate nociceptive processing at different levels of the nervous system: periphery, spinal cord and brain. Thus, mGluRs may provide important novel therapeutic targets for the relief of pain associated with altered neurotransmission and neuronal excitability.