Lipopolysaccharide does not affect acoustic startle reflex in mice

Bacterial endotoxin (lipopolysaccharide; LPS) evokes in rodents an adaptive sickness behavior. It also produces changes in stress hormones secretion and activity of brain serotonergic and noradrenergic systems that have been implicated in stress responses, fear, and anxiety. Acoustic startle reflex (ASR) is regarded as a protective behavioral response that is enhanced in threatening situations or following an aversive event, and it can be modulated by physiological and emotional state of an animal. Effects of intraperitoneal injections of LPS on ASR, prepulse inhibition (PPI), locomotor activity in open field, and blood plasma corticosterone concentration were studied in lines of mice that display high (HA line) or low (LA line) swim stress-induced analgesia and also differ in emotional behaviors, including the magnitude of ASR. In both lines LPS produced robust sickness behavior, as evidenced by a decrease in locomotion and body weight, and an increase in corticosterone concentration. However, in neither line LPS injections affected responses to acoustic stimuli as assessed by the ASR and PPI magnitudes. The findings suggest that in sickness behavior induced by LPS the protective responses to salient environmental stimuli are not impaired. The significance of this finding for the concept of sickness behavior is discussed.     

A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance

This study identifies macroautophagy as a key mechanism of cell survival in estrogen receptor-positive (ER+) breast cancer cells undergoing treatment with 4-hydroxytamoxifen (4-OHT). This selective ER modifier is an active metabolite of tamoxifen commonly used for the treatment of breast cancer. Our study provides the following key findings: (a) only 20% to 25% of breast cancer cells treated with 4-OHT in vitro die via caspase-dependent cell death; more typically, the antiestrogen-treated ER+ breast cancer cells express increased levels of macroautophagy and are viable; (b) 4-OHT-induced cell death, but not 4-OHT-induced macroautophagy, can be blocked by the pan-caspase inhibitor z-VAD-fmk, providing strong evidence that these two outcomes of antiestrogen treatment are not linked in an obligatory manner; (c) 4-OHT-resistant cells selected from ER+ breast cancer cells show an increased ability to undergo antiestrogen-induced macroautophagy without induction of caspase-dependent cell death; and (d) 4-OHT, when used in combination with inhibitors of autophagosome function, induces robust, caspase-dependent apoptosis of ER+, 4-OHT-resistant breast cancer cells. To our knowledge, these studies provide the first evidence that macroautophagy plays a critical role in the development of antiestrogen resistance. We propose that targeting autophagosome function will improve the efficacy of hormonal treatment of ER+ breast cancer.     

Elevated Blood Pressure in Urban Emergency Department Patients

Objectives: There has been little systematic study of emergency department (ED) patients with elevated blood pressure (BP) values. The authors sought to characterize ED patients with elevated BP values, assess presenting symptoms, and determine the prevalence of elevated BP after discharge. Methods: This was a cross‐sectional study performed in four academic EDs. Adults presenting with systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg were enrolled over a one‐week equivalent period. Demographics, medical history, and symptoms were obtained by chart abstraction and structured interview. A random patient subset underwent a three‐week follow‐up interview. BP measurements were staged, using Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC‐VI) criteria, according to the greatest value noted in the ED. Results: A total of 1,396 patients were enrolled. Stage 1 BP values were noted in 44.3%, stage 2 in 25.3%, and stage 3 in 30.3%. African American patients more frequently had stage 2 and 3 BP values than other ethnic groups. BP measurements were repeated in 61.1% of patients and were the same or greater in 51.3% of patients. Dyspnea was associated with greater BP values. Among the 63.9% of patients who were interviewed, 52.7% were not being treated for hypertension, and 42.1% of those with hypertension had recently missed a medication dose. Follow‐up was obtained in 74.7% of those targeted. A visit to a medical practitioner since discharge was reported by 63.2%; of these, 26.1% reported that their BP remained elevated. Conclusions: Elevated BP is common among ED patients. African American patients are more likely than those of other ethnic groups to have greater BP values. The ED visit may be a good opportunity to identify patients with unrecognized or poorly controlled hypertension.     

School-based adolescent health care. Review of a clinical service.

OBJECTIVE--To provide recommendations regarding the establishment and maintenance of school-based clinics, based on analysis of data from a clinic located in a New York City high school. DESIGN--Review of demographic, medical, and psychosocial data collected during student visits. SUBJECTS--During 2 1/2 years, 1283 students were seen. The students were 53% girls and 47% boys; 65% black and 25% Hispanic; and 65% grades 9-10 and 35% grades 11-12. RESULTS--There were 7920 visits. Visits were for acute or chronic medical problems (44%), physical examinations and immunizations (25%), gynecologic or sexuality-related issues (17%), and mental health concerns (14%). Psychosocial characteristics of the 378 students who enrolled during the 1989-1990 academic year indicated that only 27% lived with both natural parents, 55% were foreign-born, 37% had repeated a grade at least once, 44% were sexually active, 13% drank alcohol, and 14% had past or present suicidal ideation. CONCLUSIONS--These data demonstrate that a school-based clinic can be involved in the management of a wide range of health care needs for large numbers of at-risk youth. In addition, school-based clinics can serve as a major site for the teaching of medical students and residents, and as a valuable resource for clinical research.     

Melatonin Inhibits Prostaglandin E Release From the Medial Basal Hypothalamus of Pinealectomized Rats

The effects of pinealectomy and of melatonin administration on prostaglandin E synthesis in the medial basal hypothalamus were studied in male rats. Melatonin treatment significantly decreased prostaglandin E release from the medial basal hypothalamus in pinealectomized rats. The results of the present study suggest that melatonin modulates hypothalamo-hypophyseal function, at least in part, via inhibition of hypothalamic prostaglandin synthesis.     

Evaluation of a dosing regimen for continuous vancomycin infusion in critically ill patients: An observational study in intensive care unit patients

Purpose

We aimed to evaluate a dosing algorithm for continuous vancomycin administration in intensive care unit patients.

Materials and Methods

This observational study was conducted in a medical intensive care unit (German university hospital; June 2012-February 2013). Following a loading dose of 20 mg per kg actual body weight, vancomycin was administered continuously (20 or 30 mg of vancomycin per kg actual body weight over 24 hours depending on renal function). The vancomycin infusion rate was adjusted to achieve a target serum vancomycin concentration of 20-30 mg/L.

Results

Vancomycin was administered for a median (interquartile range) of 7 (5-9) days. The median vancomycin dose given as an initial bolus was 1750 (1400-2000) mg. The median daily vancomycin dose ranged from 480 (180–960) mg (day 6) to 3.120 (2596-3980) mg (day 1). Altogether, the achieved median serum vancomycin concentration was 29.0 (25.2-33.2) mg/L. On treatment days 1 to 7, we observed target serum vancomycin levels (20-30 mg/L) in 48%, 39%, 33%, 26%, 43%, 57%, and 69% of patients. Supra-therapeutic serum vancomycin concentrations (> 30 mg/L) were observed in 36%, 52%, 61%, 63%, 39%, 19%, and 15% of patients on treatment days 1 to 7.

Conclusions

The evaluated vancomycin dosing regimen for continuous infusion allowed rapid achievement of sufficient vancomycin serum levels. However, we frequently observed supra-therapeutic serum vancomycin concentrations in the first days of vancomycin treatment.     

A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients

Introduction

The Oncotype DX assay was recently reported to predict risk for distant recurrence among a clinical trial population of tamoxifen-treated patients with lymph node-negative, estrogen receptor (ER)-positive breast cancer. To confirm and extend these findings, we evaluated the performance of this 21-gene assay among node-negative patients from a community hospital setting.

Methods

A case-control study was conducted among 4,964 Kaiser Permanente patients diagnosed with node-negative invasive breast cancer from 1985 to 1994 and not treated with adjuvant chemotherapy. Cases (n = 220) were patients who died from breast cancer. Controls (n = 570) were breast cancer patients who were individually matched to cases with respect to age, race, adjuvant tamoxifen, medical facility and diagnosis year, and were alive at the date of death of their matched case. Using an RT-PCR assay, archived tumor tissues were analyzed for expression levels of 16 cancer-related and five reference genes, and a summary risk score (the Recurrence Score) was calculated for each patient. Conditional logistic regression methods were used to estimate the association between risk of breast cancer death and Recurrence Score.

Results

After adjusting for tumor size and grade, the Recurrence Score was associated with risk of breast cancer death in ER-positive, tamoxifen-treated and -untreated patients (P = 0.003 and P = 0.03, respectively). At 10 years, the risks for breast cancer death in ER-positive, tamoxifen-treated patients were 2.8% (95% confidence interval [CI] 1.7–3.9%), 10.7% (95% CI 6.3–14.9%), and 15.5% (95% CI 7.6–22.8%) for those in the low, intermediate and high risk Recurrence Score groups, respectively. They were 6.2% (95% CI 4.5–7.9%), 17.8% (95% CI 11.8–23.3%), and 19.9% (95% CI 14.2–25.2%) for ER-positive patients not treated with tamoxifen. In both the tamoxifen-treated and -untreated groups, approximately 50% of patients had low risk Recurrence Score values.

Conclusion

In this large, population-based study of lymph node-negative patients not treated with chemotherapy, the Recurrence Score was strongly associated with risk of breast cancer death among ER-positive, tamoxifen-treated and -untreated patients.