Synthesis of thymosin α1 by fragment condensation using tert.-butyl side chain protection

A novel synthesis of thymosin α₁ by classical methods using seven tert. -butyl side chain protected fragments is described. Optimum conditions were found for the final DCC/HOBt coupling of the two key intermediates; decapeptide and octadecapeptide. Thymosin α₁ was purified by two stages of preparative HPLC (partial purification with C₈ and final purification with C₁₈ reverse phase silica gel) to give a 30% overall yield for the final four stages of synthesis (including catalytic hydrogenation of octadecapeptide, coupling, deprotection and purification). The product was shown to be homogeneous by thin-layer and paper high voltage electrophoresis, isoelectric focusing analysis, thin-layer chromatography and high performance liquid chromatography. Amino acid analysis, optical rotation, ¹ H-n.m.r. spectroscopy, FAB mass spectroscopy and peptide mapping after tryptic digestion confirmed the structure of thymosin α₁. Three minor stereoisomer contaminants were isolated by HPLC and characterized as [D-Lys¹⁴]-thymosin α₁, [D-Lys¹⁷]-thymosin α₁ and [D-Ala³]-thymosin α₁ resulting from racemization at Lys¹⁴, Lys¹⁷ and Ala³ during the coupling of the fragments. A final contaminant, isolated by HPLC, was characterized as N^α-isobutyloxycarbonyl-thymosin α₁ (15–28), which results from “wrong way opening” of an activated mixed anhydride.     

MODIFICATION OF THE CIRCULATORY EFFECTS OF EXTRADURAL BLOCK COMBINED WITH GENERAL ANAESTHESIA BY THE ADDITION OF ADRENALINE TO LIGNOCAINE SOLUTIONS

The cardiovascular changes associated with extradural blockwere measured in two groups of patients who were also receivinglight general anaesthesia. In the first group (five patients)2% plain lignocaine 20 ml was used and decreases occurred inmean arterial pressure, cardiac output, stroke volume and peripheralresistance. In the second group (10 patients) 2% lignocaine20 ml to which adrenaline 1: 200 000 had been added was used.Decreases in arterial pressure and peripheral resistance occurredin all patients, but the responses of the cardiac output andheart rate were variable, decreasing in three patients and remainingstable or increasing in seven patients. A high segmental blockwas presumed to have occurred in those patients who developedbradycardia and a decreased cardiac output. The differencesbetween these studies in anaesthetized patients and those previouslyreported in conscious volunteers are discussed.     

Impaired macrophage leishmanicidal activity at cutaneous temperature

Summary Temperature is one of the primary influences upon the pathogenesis of cutaneous leishmaniasis. In this study, we measured the temperature of murine leishmanial lesions and determined the ability of lymphokine (LK) activated macrophages to kill Leishmania major at these temperatures. The temperature of leishmanial lesions in BALB/c and C3H/HeN mice ranged from 27°C to 32°C. We found that LK activated resident or inflammatory macrophages exhibited significantly less leishmanicidal activity in vitro at temperatures closer to those measured in vivo . The decrease in microbicidal activity was not due to the enhanced growth of the parasites at lower temperatures, since impaired killing was also observed against non-replicating radiation attenuated amastigotes. Finally, the tumoricidal activity of macrophages was found to be significantly depressed at temperatures below 37°C, indicating a generalized impairment of macrophage function at these temperatures. These findings suggest that impaired macrophage microbicidal activity at cutaneous temperatures may contribute to parasite survival, and imply that healing of leishmanial lesions, as well as other cutaneous infections, may require an exceptionally potent local LK response.     

The long-term learning effect of training in stage of change for smoking cessation: a three-year follow up of community pharmacy staff's knowledge and attitudes

Objective — A randomised controlled trial has already demonstrated that a training workshop on smoking cessation counselling for pharmacists and their assistants, based on the stage of change model, had a positive effect on the knowledge and attitudes of pharmacy personnel for at least a year, and was associated with increased and more useful counselling, and higher smoking cessation rates. An extension of the study aimed to monitor the duration of the training effect and so help to determine the optimum time span for refresher training. This paper reports the results of two further annual follow-ups. Method — A previously developed and validated self-completion questionnaire assessing knowledge and attitudes was re-administered to intervention and control personnel at 24 and 36 months. One hundred and thirty-four questionnaires were completed at 24 months (85 per cent response rate) and 124 (83 per cent) at 36 months. Setting — Community pharmacies in Grampian, Scotland, United Kingdom. Key findings — The training had a significant effect on knowledge for at least three years, since at both 24 and 36 months the intervention pharmacy teams had a significantly greater knowledge and understanding of the model than the controls (24 months, P=0.0001; 36 months, P=0.031). At 24 months, the intervention pharmacy teams were significantly more confident in their ability to counsel smokers (P=0.021) and were more positive about the outcome of smoking cessation counselling provided in community pharmacies (P=0.043). These attitudinal differences were no longer statistically significant at 36 months. Conclusion — This study has demonstrated the long-term benefit of the stage of change training over a three-year period, for both community pharmacists and their staff, on knowledge and attitudes.     

Long-Term Pacing in Heart Transplant Recipients is Usually Unnecessary

The indications for and timing of permanent pacing were reviewed in all 17 of 154 adult heart transplant recipients at this center who have had permanent pacemakers implanted. Resting 12-lead ECGs recorded during routine follow-up were examined. A prospective study of pacing requirement was then undertaken. Holter monitoring was performed before and after reprogramming the pacemakers to VVI mode at 50 beats/min. Exercise responses in various pacing modes were then assessed in seven patients with rate responsive pacemakers using a standard Bruce protocol treadmill test. The indication for pacing was sinus node dysfunction in 59% (10/17) and atrioventricular (AV) block in 41% (7/17). The majority of pacemakers were implanted between seven and 21 days after transplantation. There was a progressive reduction in the frequency of pacing on 12-Jead ECGs with time after transplantation. Eight of 14 patients with empirically selected programming paced during Holter monitoring. After reprogramming to 50 beats/ min VVI mode only three of 14 patients, all with sinus node dysfunction, paced. Rate responsive pacing made no difference to exercise time. The requirement for long-term pacing in cardiac transplant recipients is small (3/154) and is limited lo patients with sinus node dysfunction. Rate responsive pacing did not increase exercise tolerance.     

Outcome analysis of the transglabellar/subcranial approach for lesions of the anterior cranial fossa: A comparison with the classic craniotomy approach

The classic approach to anterior skull base lesions uses bifrontal craniotomies together with lateral rhinotomies. This approach requires frontal lobe retraction and is associated with postoperative anosmia and the development of frontal lobe encephalomalacia. The transglabellar/subcranial approach permits removal of anterior skull base lesions without frontal lobe retraction and avoids facial scars. No studies to date, however, have directly compared the two approaches in terms of patient morbidity. The present retrospective study compares the two approaches when used for the removal of anterior skull base lesions in terms of estimated blood loss, number of transfusions, number of days in the hospital and intensive care unit, and postoperative complications. Twenty patients with anterior skull base lesions were examined. The classic approach was used on 10, and the transglabellar/subcranial route was used on 10. When compared with the classic approach, the transglabellar/subcranial approach resulted in a lower estimated blood loss and subsequent transfusion rate, fewer days in the hospital and intensive care unit, and lower numbers and less severe types of complications. Furthermore, visualization of the tumors before resection with the transglabellar/subcranial approach allowed preservation of olfaction in virtually all of these patients. Although this study represents a small sample population, the results are sufficiently impressive to favor the transglabellar/subcranial approach for the removal of a variety of anterior skull base lesions. (Otolaryngol Head Neck Surg 1997;116:642-6.)     

Non–response bias in alcohol and drug population surveys

Introduction and Aims. This proposed study was to assess non‐response bias in the 2004 Canadian Addictions Survey (CAS). Design and Methods. Two approaches were used to assess non‐response bias in the CAS which had a response rate of only 47%. First, the CAS sample characteristics were compared with the 2002 Canadian Community Health Survey (CCHS, response rate 77%) and the 2001 Canada Census data. Second, characteristics of early and late respondents were compared. Results. People with lowest income and less than high‐school education and those who never married were under‐represented in the CAS compared with the Census, but similar to the CCHS. Substance use was more prevalent in the CAS than the CCHS sample, but most of the CAS and CCHS estimates did not exceed±3% points. Late respondents were also significantly more likely to be male, young adult, highly educated, used, have high income, live in different provinces and report substance use. Multivariate logistic regression found significant non‐response bias for lifetime, past 12 months, chronic risky, acute risky and heavy monthly alcohol use, lifetime and past year cannabis use, lifetime hallucinogen use, any illicit drug uses of lifetime and past year. Adjustment for non‐response bias substantially increased prevalence estimates. For example, the estimates for lifetime and past 12 month illicit drug use increased by 5.22% and 10.34%. Discussion and Conclusions. It is concluded that non‐response bias is a significant problem in substance use surveys with low response rates but that some adjustments can be made to compensate.[Zhao J, Stockwell T, Macdonald S. Non‐response bias in alcohol and drug population surveys. Drug Alcohol Rev 2009]