Choosing to take cocaine in the human laboratory: effects of cocaine dose,inter-choice interval,and magnitude of alternative reinforcement

Cocaine abuse involves a variety of behaviors including the initiation of cocaine-seeking, the self-selected patterning of cocaine administrations, and the cessation of cocaine-taking. To date, most human laboratory models of cocaine self-administration have only assessed the amount of cocaine consumed under a fixed set of conditions. This double-blind, randomized, within-subject, inpatient study evaluated a novel model of human cocaine self-administration that aimed to quantify the reinforcing value of cocaine after cocaine-taking was initiated. Cocaine-dependent volunteers (n=8) sampled cocaine (12.5, 25 or 50 mg per 70 kg i.v.) or placebo and were subsequently allowed to choose between another injection of the same dose or money over six trials during 12 experimental sessions. The value of the monetary alternative increased with each trial from US dollars 1 to 16. Each cocaine dose was assessed under three inter-choice intervals: 15 min, 30 min, and an interval selected by the volunteer. Injection choices increased dose dependently; however, there was little relationship between the value of the alternative reinforcer and the choice to take cocaine. Most volunteers exclusively chose injections when active cocaine was available and money when placebo was available. Inter-choice interval did not affect cocaine choices. These results illustrate the persistence of cocaine self-administration once cocaine-taking has been initiated.     

Effect of operative volume on morbidity, mortality, and hospital use after esophagectomy for cancer

OBJECTIVE: We sought to evaluate the effect of operative volume, hospital size, and cancer specialization on morbidity, mortality, and hospital use after esophagectomy for cancer. METHODS: Data derived from the Health Care Utilization Project was used to evaluate all Medicare-reimbursed esophagectomies for treatment of cancer from 1994 to 1996 in 13 national cancer institutions and 88 community hospitals. The complications of care, length of stay, hospital charges, and mortality were assessed according to hospital size (>/=600 beds vs <600 beds), cancer specialization (national cancer institution vs community hospital), and operative volume (esophageal [>/=5 Medicare esophagectomies per year vs <5 Medicare esophagectomies per year] and nonesophageal operations [>/=3333 cases per year vs <3333 cases per year]). RESULTS: Mortality was lower in national cancer institution hospitals (4.2% [confidence interval, 2.0%-6.4%] vs 13.3% [confidence interval, 4.2%-26.2%], P =. 05) and in hospitals performing a large number of esophagectomies (3. 0% [confidence interval, 0.09%-5.1%] vs 12.2% [confidence interval, 4.5%-19.8%], P <.05). Multivariate analysis revealed that the independent risk factor for operative mortality was the volume of esophagectomies performed (odds ratio, 3.97; P =.03) and not the number of nonesophageal operations, hospital size, or cancer specialization. Hospitals performing a large number of esophagectomies also showed a tendency toward decreased complications (55% vs 68%, P =.06), decreased length of stay (14.7 days vs 17.7 days, P =.006), and decreased charges ($39,867 vs $62, 094, P <.005). CONCLUSIONS: These results demonstrate improved outcomes and decreased hospital use in hospitals that perform a large number of esophagectomies and support the concept of tertiary referral centers for such complex oncologic procedures as esophagectomies.     

Cardiac myocyte follistatin-like 1 functions to attenuate hypertrophy following pressure overload

Factors secreted by the heart, referred to as "cardiokines," have diverse actions in the maintenance of cardiac homeostasis and remodeling. Follistatin-like 1 (Fstl1) is a secreted glycoprotein expressed in the adult heart and is induced in response to injurious conditions that promote myocardial hypertrophy and heart failure. The aim of this study was to investigate the role of cardiac Fstl1 in the remodeling response to pressure overload. Cardiac myocyte-specific Fstl1-KO mice were constructed and subjected to pressure overload induced by transverse aortic constriction (TAC). Although Fstl1-KO mice displayed no detectable baseline phenotype, TAC led to enhanced cardiac hypertrophic growth and a pronounced loss in ventricular performance by 4 wk compared with control mice. Conversely, mice that acutely or chronically overexpressed Fstl1 were resistant to pressure overload-induced hypertrophy and cardiac failure. Fstl1-deficient mice displayed a reduction in TAC-induced AMP-activated protein kinase (AMPK) activation in heart, whereas Fstl1 overexpression led to increased myocardial AMPK activation under these conditions. In cultured neonatal cardiomyocytes, administration of Fstl1 promoted AMPK activation and antagonized phenylephrine-induced hypertrophy. Inhibition of AMPK attenuated the antihypertrophic effect of Fstl1 treatment. These results document that cardiac Fstl1 functions as an autocrine/paracrine regulatory factor that antagonizes myocyte hypertrophic growth and the loss of ventricular performance in response to pressure overload, possibly through a mechanism involving the activation of the AMPK signaling axis.     

Inhibition of voltage-gated Ca2+ channels by antazoline

We showed recently that imidazolines exert neuroprotection against hypoxia and NMDA toxicity in cerebellar and striatal neuronal cultures, through a voltage-dependent blockade of glutamatergic NMDA receptors. Here, we report that in striatal neuronal cultures from mouse embryos the imidazoline compound, antazoline, inhibits voltage-gated Ca2+ channels by acting at a phencyclidine-like site. This effect was fast, fully reversible, voltage-dependent and predominant on P/Q- and N-type Ca2+ channels. Taken together, these results suggest that imidazolines may elicit neuroprotective effects also by decreasing the release of glutamate through inhibition of presynaptic Ca2+ channels.     

Molecular Epidemiology of Carbapenem-Resistant Acinetobacter baumannii Isolates in the Gulf Cooperation Council States: Dominance of OXA-23-Type Producers

The molecular epidemiology and mechanisms of resistance of carbapenem-resistant Acinetobacter baumannii (CRAB) were determined in hospitals in the states of the Cooperation Council for the Arab States of the Gulf (Gulf Cooperation Council [GCC]), namely, Saudi Arabia, United Arab Emirates, Oman, Qatar, Bahrain, and Kuwait. Isolates were subjected to PCR-based detection of antibiotic resistance genes and repetitive sequence-based PCR (rep-PCR) assessments of clonality. Selected isolates were subjected to multilocus sequence typing (MLST). We investigated 117 isolates resistant to carbapenem antibiotics (either imipenem or meropenem). All isolates were positive for OXA-51. The most common carbapenemases were the OXA-23-type, found in 107 isolates, followed by OXA-40-type (OXA-24-type), found in 5 isolates; 3 isolates carried the ISAba1 element upstream of bla_OXA-51-type. No OXA-58-type, NDM-type, VIM-type, or IMP-type producers were detected. Multiple clones were detected with 16 clusters of clonally related CRAB. Some clusters involved hospitals in different states. MLST analysis of 15 representative isolates from different clusters identified seven different sequence types (ST195, ST208, ST229, ST436, ST450, ST452, and ST499), as well as three novel STs. The vast majority (84%) of the isolates in this study were associated with health care exposure. Awareness of multidrug-resistant organisms in GCC states has important implications for optimizing infection control practices; establishing antimicrobial stewardship programs within hospital, community, and agricultural settings; and emphasizing the need for establishing regional active surveillance systems. This will help to control the spread of CRAB in the Middle East and in hospitals accommodating transferred patients from this region.     

Attitudes toward psychiatry among Irish final year medical students

This study investigated the attitudes of medical students towards psychiatry, both as a subject on the medical curriculum and as a career choice. Three separate questionnaires previously validated on medical student populations were administered prior to and immediately following an 8-week clinical training programme. The results indicate that the perception of psychiatry was positive prior to clerkship and became even more so on completion of training. On completion of the clerkship, there was a rise in the proportion of students who indicated that they might choose a career in psychiatry. Attitudes toward psychiatry correlated positively with the psychiatry examination results. Those that intended to specialise in psychiatry achieved significantly higher examination scores in the psychiatry examination.     

Curcumin causes superoxide anion production and p53-independent apoptosis in human colon cancer cells

Curcumin from the rhizome of the Curcuma longa plant has chemopreventative activity and inhibits the growth of neoplastic cells. Since p53 has been suggested to be important for anticancer activity by curcumin, we investigated curcumin-induced cytotoxicity in cultures of p53^+/+ and p53^−/− HCT-116 colon cancer cells, as well as mutant p53 HT-29 colon cancer cells. Curcumin killed wild-type p53 HCT-116 cells and mutant p53 HT-29 cells in a dose- and time-dependent manner. In addition, curcumin-treated p53^+/+ HCT-116 cells and mutant p53 HT-29 cells showed upregulation of total and activated p53, as well as increased expression of p53-regulated p21, PUMA (p53 upregulated modulator of apoptosis), and Bax; however, an equivalent cytotoxic effect by curcumin was observed in p53^+/+ and p53^−/− HCT-116 cells, demonstrating that curcumin-induced cytotoxicity was independent of p53 status. Similar results were obtained when the cytotoxic effect of curcumin was assessed in wild-type p53 HCT-116 cells after siRNA-mediated p53 knockdown. Chromatin condensation, poly (ADP-ribose) polymerase-1 cleavage and reduced pro-caspase-3 levels in curcumin-treated p53^+/+ and p53^−/− HCT-116 cells suggested that curcumin caused apoptosis. In addition, exposure to curcumin resulted in superoxide anion production and phosphorylation of oxidative stress proteins in p53^+/+ and p53^−/− HCT-116 cells. Collectively, our results indicate that, despite p53 upregulation and activation, curcumin-induced apoptosis in colon cancer cells was independent of p53 status and involved oxidative stress. Curcumin may therefore have therapeutic potential in the management of colon cancer, especially in tumors that are resistant to conventional chemotherapy due to defects in p53 expression or function.     

Benign breast papilloma: Is surgical excision necessary?

In many centers internationally, current standard of care is to excise all papillomas of the breast, despite recently reported low rates of upgrade to malignancy on final excision. The objective of this study was to determine the upgrade rate to malignancy in patients with papilloma without atypia. A retrospective review of a prospectively maintained database of all cases of benign intraductal papilloma in a tertiary referral symptomatic breast unit between July 2008 and July 2018 was performed. Patients with evidence of malignancy or atypia on core biopsy and those with a history of breast cancer or genetic mutations predisposing to breast cancer were excluded. One hundred and seventy‐three cases of benign papilloma diagnosed on core biopsy were identified. Following exclusions, the final cohort comprised of 138 patients. Mean age at presentation was 51. Mean follow‐up time was 9.6 months. The most common symptom was a lump (40%). Of the 124 patients who underwent excision, three had ductal carcinoma in situ and there were no cases of invasive disease, giving an upgrade rate to malignancy of 2.4%. Upgrade to other high‐risk lesions (atypical lobular and ductal hyperplasia and lobular carcinoma in situ) was demonstrated in 15 cases (12.1%). Benign papilloma was confirmed in 100 cases (81.5%), and 6 (4.8%) had no residual papilloma found on final excision. Twelve patients (8.7%) were managed conservatively. Of those, one later went on to develop malignancy. Patients with a diagnosis of benign papilloma without atypia on core biopsy have a low risk of upgrade to malignancy on final pathology, suggesting that observation may be a safe alternative to surgical excision. Further research is warranted to determine which patients can be safely managed conservatively.     

Effect of a tailored physical activity intervention delivered in general practice settings: results of a randomized controlled trial

OBJECTIVES: We evaluated the effectiveness of a minimal intervention physical activity strategy (physician-based assessment and counseling for exercise [PACE]) applied in general practice settings in the Netherlands. METHODS: Randomization took place at the general practice level. Participants were patients aged 18-70 years of age who had been diagnosed with hypertension, hypercholesterolemia, or non-insulin-dependent diabetes and had not been regularly physically active in the past 6 months. Outcome measures were assessed at baseline and at 8-week, 6-month, and 1-year follow-ups. RESULTS: No significant intervention effect over time was observed on physical activity level or stage of change for regular physical activity, and an inverse intervention effect was observed for waist circumference. However, the study population as a whole exhibited a significant increase in physical activity and a borderline significant decrease in body weight at the 1-year follow-up. CONCLUSIONS: Positive effects on physical activity level and body weight were observed, but the PACE intervention was not more effective than the standard physical activity advice.