Lutetium-labelled peptides for therapy of neuroendocrine tumours

Treatment with radiolabelled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumours. Symptomatic improvement may occur with 177Lu-labelled somatostatin analogues that have been used for peptide receptor radionuclide therapy (PRRT). The results obtained with 177Lu-[DOTA0,Tyr3]octreotate (DOTATATE) are very encouraging in terms of tumour regression. Dosimetry studies with 177Lu-DOTATATE as well as the limited side effects with additional cycles of 177Lu-DOTATATE suggest that more cycles of 177Lu-DOTATATE can be safely given. Also, if kidney-protective agents are used, the side effects of this therapy are few and mild and less than those from the use of 90Y-[DOTA0,Tyr3]octreotide (DOTATOC). Besides objective tumour responses, the median progression-free survival is more than 40 months. The patients' self-assessed quality of life increases significantly after treatment with 177Lu-DOTATATE. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with 177Lu-DOTATATE. These findings compare favourably with the limited number of alternative therapeutic approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable neuroendocrine tumours

Why medical students choose psychiatry - a 20 country cross-sectional survey

BACKGROUND: Recruitment to psychiatry is insufficient to meet projected mental health service needs world-wide. We report on the career plans of final year medical students from 20 countries, investigating factors identified from the literature which influence psychiatric career choice. METHODS: Cross sectional electronic or paper survey. Subjects were final year medical students at 46 medical schools in participating countries. We assessed students' career intentions, motivations, medical school teaching and exposure to psychiatry. We assessed students' attitudes and personality factors. The main outcome measure was likelihood of specializing in psychiatry. Multilevel logistic regression was used to examine the joint effect of factors upon the main outcome. RESULTS: 2198 of 9135 (24%) of students responded (range 4 to 91%) across the countries. Internationally 4.5% of students definitely considered psychiatry as a career (range 1 to 12%). 19% of students (range 0 to 33%) were "quite likely", and 25% were "definitely not" considering psychiatry. Female gender, experience of mental/physical illness, media portrayal of doctors, and positive attitudes to psychiatry, but not personality factors, were associated with choosing psychiatry. Quality of psychiatric placement (correlation coefficient = 0.22, p < 0.001) and number of placements (correlation coefficient =0.21, p < 0.001) were associated with higher ATP scores. During medical school, experience of psychiatric enrichment activities (special studies modules and university psychiatry clubs), experience of acutely unwell patients and perceived clinical responsibility were all associated with choice of psychiatry.Multilevel logistic regression revealed six factors associated with students choosing psychiatry: importance of own vocation, odds ratio (OR) 3.01, 95% CI 1.61 to 5.91, p < 0.001); interest in psychiatry before medical school, OR 10.8 (5.38 to 21.8, p < 0.001); undertaking a psychiatry special study module, OR 1.45 (1.05 to 2.01, p = 0.03) or elective OR 4.28 (2.87- 6.38, p < 0.001); membership of a university psychiatry club, OR 3.25 (2.87 to 6.38, p < 0.001); and exposure to didactic teaching, OR 0.54 (0.40 to 0.72, p < 0.001). CONCLUSIONS: We report factors relevant to medical student selection and psychiatry teaching which affect career choice. Addressing these factors may improve recruitment to psychiatry internationally

Inhibition of Nitric Oxide Synthase by l-NAME Speeds Phase II Pulmonary V̇O2 Kinetics in the Transition to Moderate-Intensity Exercise in Man

There is evidence that the rate at which oxygen uptake (V̇O2) rises at the transition to higher metabolic rates within the moderate exercise intensity domain is modulated by oxidative enzyme inertia, and also that nitric oxide regulates mitochondrial function through competitive inhibition of cytochrome c oxidase in the electron transport chain. We therefore hypothesised that inhibition of nitric oxide synthase (NOS) by nitro-L-arginine methyl ester (l-NAME) would alleviate the inhibition of mitochondrial V̇O2 by nitric oxide and result in a speeding of V̇O2 kinetics at the onset of moderate-intensity exercise. Seven males performed square-wave transitions from unloaded cycling to a work rate requiring 90 % of predetermined gas exchange threshold with and without prior intravenous infusion of l-NAME (4 mg kg−1 in 50 ml saline over 60 min). Pulmonary gas exchange was measured breath-by-breath and V̇O2 kinetics were determined from the averaged response to four exercise bouts performed in each condition using a mono-exponential function following elimination of the phase I response. There were no significant differences between the control and l-NAME conditions for baseline V̇O2 (means ± s.e.m. 797 ± 32 vs. 794 ± 29), the duration of phase I (15.4 ± 0.8 vs. 17.2 ± 0.6), or the steady-state increment in V̇O2 above baseline (1000 ± 83 vs. 990 ± 85 ml min−1), respectively. However, the phase II time constant of the V̇O2 response was significantly smaller following l-NAME infusion (22.1 ± 2.4 vs. 17.9 ± 2.3; P < 0.05). These data indicate that inhibition of NOS by l-NAME results in a significant (19 %) speeding of pulmonary V̇O2 kinetics in the transition to moderate-intensity cycle exercise in man. At least part of the intrinsic inertia to oxidative metabolism at the onset of moderate-intensity exercise may result from competitive inhibition of mitochondrial V̇O2 by nitric oxide at cytochrome c oxidase, although other mechanisms for the effect of l-NAME on V̇O2 kinetics remain to be explored

5`-aminoimidazole-4-carboxyamide-ribonucleoside- activated glucose transport is not prevented by nitric oxide synthase inhibition in rat isolated skeletal muscle

1. The nucleoside intermediate 5\u27-aminoimidazole-4-carboxyamide-ribonucleoside (AICAR) activates skeletal muscle AMP-activated protein kinase (AMPK) and increases glucose uptake. The AMPK phosphorylates neuronal nitric oxide synthase (nNOS)&micro; in skeletal muscle fibres. There is evidence that both AMPK and nNOS&micro; may be involved in the regulation of contraction-stimulated glucose uptake.2. We examined whether both AICAR- and contraction-stimulated glucose uptake were mediated by NOS in rat skeletal muscle.3. Rat isolated epitrochlearis muscles were subjected in vitro to electrically stimulated contractions for 10 min and/or incubated in the presence or absence of AICAR (2 mmol/L) or the NOS inhibitor NG-monomethyl-l-arginine (l-NMMA; 100 &micro;mol/L).4. Muscle contraction significantly (P &lt; 0.05) altered the metabolic profile of the muscle. In contrast, AICAR and l-NMMA had no effect on the metabolic profile of the muscle, except that AICAR increased muscle 5\u27-aminoimidazole-4-carboxyamide-ribonucleotide (ZMP) and AICAR content. Nitric oxide synthase inhibition caused a small but significant (P &lt; 0.05) reduction in basal 3-O-methylglucose transport, which was observed in all treatments. 5\u27-Aminoimidazole-4-carboxyamide-ribonucleoside significantly increased (P &lt; 0.05) glucose transport above basal, with NOS inhibition decreasing this slightly (increased by 209% above basal compared with 184% above basal with NOS inhibition). Contraction significantly increased glucose transport above basal, with NOS inhibition substantially reducing this (107% increase vs 31% increase). 5\u27-Aminoimidazole-4-carboxyamide-ribonucleoside plus contraction in combination were not additive on glucose transport.5. These results suggest that NO plays a role in basal glucose uptake and may regulate contraction-stimulated glucose uptake. However, NOS/nitric oxide do not appear to be signalling intermediates in AICAR-stimulated skeletal muscle glucose uptake.<br /