Cell-specific inhibitory modulation of sound processing in the auditory thalamus.

Inhibition along the auditory pathway is crucial for processing of acoustic information. Within the auditory thalamus, a key region in the central auditory pathway, inhibition is provided by the thalamic reticular nucleus (TRN), comprised of two large classes of inhibitory neurons, parvalbumin (PV TRN ) and somatostatin (SST TRN ) positive. In the auditory cortex, PV and SST neurons differentially shape auditory processing. We found that the ventral MGB, the thalamic region in the direct ascending auditory pathway, receives inputs predominantly from PV TRN neurons, whereas SST TRN neurons project to the dorso-medial regions of MGB. Consistently, inactivating PV TRN neurons increased sound-evoked activity in over a third of neurons in the vMGB, with another large fraction of neurons being suppressed. By contrast, inactivating SST TRN neuronal activity largely reduced tone-evoked activity in vMGB neurons. Cell type-specific computational models revealed candidate circuit mechanisms for generating the bi-directional effects of TRN inactivation on MGB sound responses. These differential inhibitory pathways within the auditory thalamus suggest a cell-specific role for thalamic inhibition in auditory computation and behavior.

Shedding light on an extremophile lifestyle through transcriptomics.

The tropical intertidal ecosystem is defined by trees - mangroves - which are adapted to an extreme and extremely variable environment. The genetic basis underlying these adaptations is, however, virtually unknown. Based on advances in pyrosequencing, we present here the first transcriptome analysis for plants for which no prior genomic information was available. We selected the mangroves Rhizophora mangle (Rhizophoraceae) and Heritiera littoralis (Malvaceae) as ecologically important extremophiles employing markedly different physiological and life-history strategies for survival and dominance in this extreme environment. For maximal representation of conditional transcripts, mRNA was obtained from a variety of developmental stages, tissues types, and habitats. For each species, a normalized cDNA library of pooled mRNAs was analysed using GSFLX pyrosequencing. A total of 537,635 sequences were assembled de novo and annotated as > 13,000 distinct gene models for each species. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) orthology annotations highlighted remarkable similarities in the mangrove transcriptome profiles, which differed substantially from the model plants Arabidopsis and Populus. Similarities in the two species suggest a unique mangrove lifestyle overarching the effects of transcriptome size, habitat, tissue type, developmental stage, and biogeographic and phylogenetic differences between them.

Proactive text messaging (GetReady2Quit) and nicotine replacement therapy to promote smoking cessation among smokers in primary care: A pilot randomized trial protocol.

INTRODUCTION: Most smokers see a physician each year, but few use any assistance when they try to quit. Text messaging programs improve smoking cessation in community and school settings; however, their efficacy in a primary care setting is unclear. The current trial assesses the feasibility and preliminary clinical outcomes of text messaging and mailed nicotine replacement therapy (NRT) among smokers in primary care. METHODS: In this single-center pilot randomized trial, eligible smokers in primary care are offered brief advice by phone and randomly assigned to one of four interventions: (1) Brief advice only, (2) text messages targeted to primary care patients and tailored to quit readiness, (3) a 2-week supply of nicotine patches and/or lozenges (NRT), and (4) both text messaging and NRT. Randomization is stratified by practice and intention to quit. The text messages (up to 5/day) encourage those not ready to quit to practice a quit attempt, assist those with a quit date through a quit attempt, and promote NRT use. The 2-week supply of NRT is mailed to patients' homes. RESULTS: Feasibility outcomes include recruitment rates, study retention, and treatment adherence. Clinical outcomes are assessed at 1, 2, 6, and 12-weeks post-enrollment. The primary outcome is ≥1self-reported quit attempt(s). Secondary clinical outcomes include self-reported past 7- and 30-day abstinence, days not smoked, NRT adherence, and exhaled carbon monoxide. CONCLUSIONS: This pilot assesses text messaging plus NRT, as a proactively offered intervention for smoking cessation support in smokers receiving primary care and will inform full-scale randomized trial planning. TRIAL REGISTRATION: ClinicalTrials.govNCT03174158.

Discussion of preferences for life-sustaining care by persons with AIDS. Predictors of failure in patient-physician communication.

OBJECTIVES: To assess the determinants of communication about resuscitation between persons with acquired immunodeficiency syndrome (AIDS) and their physician. DESIGN AND SETTING: Structured patient interview at a staff-model health maintenance organization (HMO), an internal medicine group practice at a private teaching hospital, and an AIDS clinic at a public hospital. PATIENTS: 289 persons with AIDS. MAIN RESULTS: Only 38% of patients had discussed their preferences for resuscitation with their physician. Using logistic regression, we found that patients were less likely to have discussed resuscitation with their physician if they were nonwhite (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.24 to 0.99), had never been hospitalized (OR, 0.52; 95% CI, 0.27 to 0.99), or were cared for in the HMO (OR, 0.44 relative to the private teaching hospital; 95% CI, 0.23 to 0.82). Patients were more likely to have discussed their preferences if they were not currently taking zidovudine (OR, 1.76; 95% CI, 1.02 to 3.03) and if they had decided to defer life-sustaining therapy (OR, 2.30; 95% CI, 1.35 to 3.91). Among nonwhites, those with a nonwhite physician were more likely to have discussed resuscitation (OR, 4.38; 95% CI, 1.13 to 16.93). Of patients who had not discussed their preferences for life-sustaining care, 72% wanted to do so. Patient desire for discussion of this issue did not vary by race, severity of illness, hospitalization status, use of zidovudine, or site of care. CONCLUSIONS: A majority of persons with AIDS in this study had not discussed their preferences for life-sustaining care with their physician, despite the desire to do so. Interventions to improve patient-physician communication about resuscitation for nonwhites and other groups at risk of inadequate discussion might lead to clinical decisions that are more consistent with patient preferences.

Pre-pregnancy and pregnancy-related factors and the risk of excessive or inadequate gestational weight gain.

OBJECTIVE: Gestational weight gain consistent with the Institute of Medicine's recommendations is associated with better maternal and infant outcomes. The objective was to quantify the effect of pre-pregnancy factors, pregnancy-related health conditions, and modifiable pregnancy factors on the risks of inadequate and excessive gestational weight gain. METHOD: A longitudinal cohort of pregnant women (N=1100) who completed questions about diet and weight gain during pregnancy and delivered a singleton, full-term infant. RESULTS: Gestational weight gain was inadequate for 14% and excessive for 53%. Pre-pregnancy factors contributed 74% to excessive gain, substantially more than pregnancy-related health conditions (15%) and modifiable pregnancy factors (11%). Pre-pregnancy factors, pregnancy-related health conditions, and modifiable pregnancy factors contributed fairly equally to the risk of inadequate gain. CONCLUSION: Interventions to prevent excessive gestational gain may need to start before pregnancy. Women at risk for inadequate gain would also benefit from interventions directed toward modifiable factors during pregnancy.

Risk factors for stroke in patients with nonrheumatic atrial fibrillation: a case-control study.

PURPOSE: Randomized controlled trials have demonstrated that anticoagulant therapy is very effective at preventing stroke among patients with nonrheumatic atrial fibrillation. However, these trials have reported too few strokes for powerful risk factor analysis. Observational studies may provide additional information. The purpose of this study was to identify risk factors in a larger number of patients with stroke and nonrheumatic atrial fibrillation, using case-control methodology. PATIENTS AND METHODS: We identified all patients discharged from one hospital over an 8-year period who met our case definition of nonrheumatic atrial fibrillation and ischemic stroke (n = 134), and compared them with contemporaneous control subjects who were discharged with nonrheumatic atrial fibrillation without stroke (n = 131). RESULTS: Cases and controls were similar in terms of duration of atrial fibrillation; proportion with paroxysmal atrial fibrillation; percentage with a past medical history of angina, myocardial infarction, congestive heart failure, diabetes, or smoking; and mean left atrial size. In contrast, cases were significantly older than controls (78.5 versus 74.8 years, p = 0.002) and more likely to have a history of hypertension (55% versus 38%, p = 0.0093). The relative odds for stroke was 1.91 for patients with hypertension, 1.73 for patients older than 75 years, and 3.26 for patients with both factors. CONCLUSIONS: Our analysis suggests that age and hypertension should be considered when deciding upon long-term anticoagulant therapy to prevent stroke in patients with nonrheumatic atrial fibrillation.

Influence of financial productivity incentives on the use of preventive care.

PURPOSE: We examined whether physician factors, particularly financial productivity incentives, affect the provision of preventive care. SUBJECTS AND METHODS: We surveyed and reviewed the charts of 4,473 patients who saw 1 of 169 internists from 11 academically affiliated primary care practices in Boston. We abstracted cancer risk factors, comorbid conditions, and the dates of the last Papanicolaou (Pap) smear, mammogram, cholesterol screening, and influenza vaccination. We obtained physician information including the method of financial compensation through a mailed physician survey. We used multivariable logistic regression to examine the association between physician factors and four outcomes based on Health Plan Employer Data and Information Set (HEDIS) measures: (1) Pap smear within the prior 3 years among women 20 to 75 years old; (2) mammogram in the prior 2 years among women 52 to 69 years old; (3) cholesterol screening within the prior 5 years among patients 40 to 64 years old; and (4) influenza vaccination among patients 65 years old and older. All analyses accounted for clus-tering by provider and site and were converted into adjusted rates. RESULTS: After adjustment for practice site, clinical, and physician factors, patients cared for by physicians with financial productivity incentives were significantly less likely than those cared for by physicians without this incentive to receive Pap smears (rate difference, 12%; 95% confidence interval [CI]: 5% to 18%) and cholesterol screening (rate difference, 4%; 95% CI: 0% to 8%). Financial incentives were not significantly associated with rates of mammography (rate difference, -3%; 95% CI: -15% to 10%) or influenza vaccination (rate difference, -13%; 95% CI: -28% to 2%). CONCLUSIONS: Our findings suggest that some financial productivity incentives may discourage the performance of certain forms of preventive care, specifically Pap smears and cholesterol screening. More studies are needed to examine the effects of financial incentives on the quality of care, and to examine whether quality improvement interventions or incentives based on quality improve the performance of preventive care.

Dosimetric comparison of the Fletcher family of gynecologic colpostats 1950-1980.

The Fletcher gynecologic applicator was developed for irradiation of carcinoma of the uterine cervix in the early 1950's. Since that time, numerous modifications and changes have been made in the colpostat construction and in the location of the shields that provide a reduced dose to the bladder trigone anteriorly and to the rectal wall posteriorly. The original applicators include the preload radium double colpostat and the preload radium single colpostat. In the 1960's, afterloading colpostats were manufactured as the Fletcher-Suit and the Fletcher-Green devices. With the introduction of the Delclos mini-colpostat, a new generation of applicators followed in the 1970's. The Fletcher-Suit-Delclos colpostat recently manufactured by two companies can be used as a mini-colpostat. By adding a shield-containing cap, these applicators function as the original Fletcher colpostat. With the development of new applicators over the past 30 years, numerous changes in the position of the shields and, therefore, the dose transmitted to the surrounding tissues have been made. This paper describes dosimetric evaluation of all of these applicators and the various changes that have occurred through the generations of Fletcher colpostats in an attempt to provide information for radiation therapists and gynecologists who are using these instruments in their clinical practice.

Fletcher-Suit-Delclos gynecologic applicator: evaluation of a new instrument.

A new instrument has been added to the Fletcher-Suit-Delclos group of gynecologic applicators. The colpostats can be used as mini-ovoids, but by adding a shielded cap, the instrument has the configuration of the original preload Fletcher colpostat. Dosimetric studies show that this applicator produced transmission ratios (the fraction of radiation transmitted through the tungsten shield) and isodose curves similar to the bladder trigone and anterior rectal wall of 10-25%. With the shield-containing cap removed, the mini-ovoid provides little reduction in dose to those areas and should be used with caution.

The stability of preferences for life-sustaining care among persons with AIDS in the Boston Health Study.

BACKGROUND: Clinicians recognize the importance of eliciting patient preferences for life-sustaining care, yet little is known about the stability of those preferences for patients with serious disease. OBJECTIVES: To examine the stability of preferences for life-sustaining care among persons with AIDS and to assess factors associated with changes in preferences. DESIGN: Two patient surveys and medical record reviews, administered four months apart in 1990-1991. SETTING: Three health care settings in Boston. PATIENTS: 252 of 505 eligible persons with AIDS who participated in both baseline and follow-up surveys. MAIN OUTCOME MEASURES: A single question assessing desire for cardiac resuscitation and a scale of preferences for life-extending treatment conditional on hypothetical health states. RESULTS: Approximately one-fourth of the respondents changed their minds about life-sustaining care during a four-month period. Of patients who initially desired cardiac resuscitation, 23% decided to forego it four months later, and of those who initially said they would decline care, 34% later said they would accept it. Of those who initially desired any of the life-extending treatments, 25% decided to forego them four months later, and of those who initially said they would decline life-extending care, 24% later said they would accept some treatment. Patients reporting changes in physical function, pain, or suicide ideation were more likely to modify their desires to be resuscitated (all p< or =0.05). Patients lacking an advance directive, not completing high school, or becoming more severely ill were more likely to change their preferences on the Life Extension scale (p< or =0.05). Patients who discussed their preferences with at least one physician were just as likely as others to change desires for cardiac resuscitation. Age, gender, race, emotional health, clinical severity, social support, and site of care were not significant correlates of change for either measure. CONCLUSIONS: Health care providers should periodically reassess preferences for life-sustaining care, particularly for patients with progressive disease, given the instability in patient preferences. However, predictors of instability may vary with how preferences are measured. In particular, changes in health status may be related to instability of preferences for certain types of treatments.

The effects of delay in standard treatment due to induction chemotherapy in two randomized prospective studies.

It is often suggested that tumors will respond to induction chemotherapy and result in improved survival for patients with squamous cell carcinoma of the head and neck. Two regimens of induction chemotherapy were studied in separate randomized, prospective trials over the last 6 years. Eighty-three patients with advanced disease were entered into the first study (43/chemotherapy; 40/control), and 60 into the second (27/chemotherapy; 33/control). Patient randomization was stratified by stage (III/IV) and site (oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, paranasal sinuses). The first study utilized bleomycin, Cytoxan, methotrexate and 5-fluorouracil in two cycles (one cycle if no tumor response), followed by standard treatment which consisted of combined irradiation and surgery or, in some instances, primary irradiation alone. The second study utilized cisplatin and 5-fluorouracil in three cycles prior to standard treatment. An objective tumor response to chemotherapy was observed in 68% in the first study and 85% in the second. The patient survival in both studies (at 24 months in the first; at 19 in the second) was better in the control than that in the experimental groups (43% to 31%; 69% to 46%). In the second study, the average length of delay of standard treatment was longer than in the first study (95 days vs. 66 days; P less than .02). Results combining the P-values of both studies indicate that the relative risk of having persistent disease was 2.9 times greater for patients who received chemotherapy. While toxicity to chemotherapy was not a factor in survival, the number of patients who withdrew from the studies and those who did not comply with treatment were greater in the chemotherapy groups. Except for new drug regimens of exceptional promise, it is recommended that future studies be designed so that chemotherapy is given concurrent with, or following the completion of standard treatment.

Cisplatin and fluorouracil as neoadjuvant therapy in head and neck cancer. A preliminary report.

A randomized, prospective trial utilizing cisplatin and fluorouracil as neoadjuvant chemotherapy in the treatment of advanced squamous cell carcinomas of the upper aerodigestive tract was initiated in January 1983. Sixty patients were stratified by site (oral cavity, 19; larynx, 14; hypopharynx, 14; oropharynx, 11; nasopharynx, one; and paranasal sinuses, one) and by stage (III, 19; IV, 41), and then randomized to receive either standard treatment (defined as preoperative irradiation followed by radical excision or irradiation alone) or adjuvant chemotherapy followed by standard treatment. An additional three patients were entered into the study, but withdrew. Chemotherapy consisted of three cycles for those patients in whom an objective tumor response was observed; nonresponders received standard treatment. Response to chemotherapy was complete in five and partial (greater than 50%) in 18 patients, for an overall response rate of 85%. The follow-up for surviving patients was a minimum of 24 months and a maximum of 44 months. Survival was compared for patients in both treatment groups according to the method of Lee and Desu. Despite excellent tumor response, actuarial survival was 70% in the standard treatment group as opposed to 56% in the experimental group. It was therefore evident that the high response rates reported in previous pilot studies do not necessarily result in improved survival in these cancers.

Bupropion in breast milk: an exposure assessment for potential treatment to prevent post-partum tobacco use.

OBJECTIVES: To assess potential infant exposure to bupropion and its active metabolites in breast milk such as would occur during treatment to prevent post-partum relapse to tobacco use, and to compare the concentrations of bupropion in urine and saliva with plasma and breast milk. DESIGN AND SETTING: Cohort study, outpatient clinical research centre. SUBJECTS: Ten healthy post-partum volunteers who agreed to take bupropion for seven days, pump and discard their breast milk, and have samples of breast milk, plasma, saliva, and urine analysed. INTERVENTION: Bupropion 150 mg a day for three days and then 300 mg a day for four days. MAIN OUTCOME MEASURES: Concentrations of bupropion and its active metabolites (hydroxybupropion, erythrohydrobupropion, threohydrobupropion) in breast milk, plasma, saliva, and urine. Determination of average infant exposure. RESULTS: The calculated average dosage of bupropion in breast milk was 6.75 microg/kg/day. Therefore, the average infant exposure is 0.14% of the standard adult dose of bupropion, corrected for the difference in body weight. Considering the sum of bupropion and its active metabolites, the average infant exposure is expected to be 2% of the standard maternal dose on a molar basis. The concentration of bupropion and its active metabolites in breast milk was not associated with age, body mass index, use of oral contraceptive pills, age of infant, or the frequency of breast feeding at the time the study was initiated. The coefficient of determination (r2) between the concentration of bupropion in breast milk and in urine was 0.77 (p < 0.01). CONCLUSIONS: Bupropion and its active metabolites are present in the breast milk of lactating women. The concentrations of bupropion in breast milk and urine were highly correlated. These results indicate that the daily dose of bupropion and metabolites that would be delivered to an infant of a woman taking a therapeutic dose of bupropion is small. These results suggest that the effectiveness of bupropion to prevent post-partum relapse to tobacco use should be evaluated without excluding women who plan to breast feed.

A possible chemical explanation for the events associated with the death of Gloria Ramirez at Riverside General Hospital.

The events associated with the death of Gloria Ramirez at Riverside General Hospital on 19 February 1994 have been portrayed as a major medical mystery. A potential chemical explanation for this incident has been developed. The hypothetical scenario depends upon the oxidation of a common solvent, dimethyl sulfoxide, through dimethyl sulfone to dimethyl sulfate. The latter compound is a volatile and highly toxic agent that can be quite hazardous to humans in small amounts. It is also environmentally nonpersistent. Much of the mystery surrounding the circumstances at the hospital may be explainable if this postulated metabolic pathway took place at the time of the emergency room incident. Although dimethyl sulfate was not detected in any analyses pertinent to this event, there are plausible scientific explanations to account for that fact. The sulfate anion, a hydrolysis product of dimethyl sulfate, was measured at an appreciably elevated concentration in Ramirez' blood. The descriptions of the symptoms of the hospital-staff victims appear quite consistent with dimethyl sulfate exposures. This paper attempts to make some sense of the reported data and eyewitness accounts, and perhaps provide new insight for any future research that could further explain this reported occurrence of toxic exposure.

Chemical and elemental comparison of two formulations of oleoresin capsicum.

In-custody deaths following the application of pepper spray weaponry by law enforcement personnel have increased in California over the last few years. Oleoresin capsicum (OC), an oily extract of hot peppers, is the active ingredient in the spray, but little detailed information on product mixtures is available. Since OC extracts contain a multitude of natural compounds at irregular concentrations, there could be considerable, variation in overall chemical composition among the different formulations of both 'natural' and 'synthetic' OC preparations. This was confirmed by organic and inorganic analyses performed on OC sprays produced by two manufacturers licensed for distribution within the state of California. The results indicated that the differences could lead to considerable inconsistency in weapon effectiveness, and suggested that more comprehensive studies are warranted.

Inhibitory synaptic plasticity: spike timing-dependence and putative network function.

While the plasticity of excitatory synaptic connections in the brain has been widely studied, the plasticity of inhibitory connections is much less understood. Here, we present recent experimental and theoretical findings concerning the rules of spike timing-dependent inhibitory plasticity and their putative network function. This is a summary of a workshop at the COSYNE conference 2012.