Synthesis of analogs of L-valacyclovir and determination of their substrate activity for the oligopeptide transporter in Caco-2 cells.

L-Valacyclovir, a prodrug of acyclovir, is a substrate for the peptide transporter (PepT1) in the intestinal mucosa, which accounts for its higher than expected oral bioavailability. The substrate activity of L-valacyclovir for PepT1 is surprising, particularly when one considers that the molecule has the structural features of a nucleoside rather than a peptide. In an attempt to better understand the structure-transport relationships (STR) for the interactions of L-valacyclovir with PepT1, analogs of this molecule with structural changes in the guanine moiety were synthesized and their substrate activity for PepT1 in Caco-2 cell monolayers was determined. The analogs synthesized include those that had the guanine moiety of L-valacyclovir substituted with purine, benzimidazole, and 7-azaindole. All three analogs (purine, benzimidazole, and 7-azaindole) exhibited affinity for PepT1 in binding studies, but only the purine analog (as the L-valine ester) showed PepT1-associated transcellular transport across Caco-2 cell monolayers. The benzimidazole and 7-azaindole analogs (as their L-valine esters) were rapidly metabolized by esterase when applied to the apical surface of Caco-2 cells, which probably explains their low penetration as the intact prodrugs via PepT1.     

Quartz-dust-induced production of reactive oxygen metabolites by human granulocytes

We studied the effect of quartz on the production of reactive oxygen species by human polymorphonuclear leukocytes (PMN) in vitro by a chemiluminescence (CL) assay. Quartz caused a rapid dose-dependent CL response in the cells. Diamond dust used as an inert control did not stimulate the production of reactive oxygen metabolites by PMN. The quartz-induced activation of oxygen metabolism was also demonstrated by measuring oxygen consumption, nitroblue tetrazolium reduction, and superoxide and hydrogen peroxide production by PMN. Poly-vinyl-pyridine N-oxide (a quartz surface modifying agent) completely abolished the quartz-induced response, but had no effect on opsonized zymosan-induced CL response of PMN. The effect of N-acetylcysteine (a known antioxidant) was inhibitory to the CL formation induced by both quartz and opsonized zymosan. Our results are in agreement with the hypothesis that quartz-induced production of reactive oxygen metabolites is a possible mechanism by which quartz dust produces chronic inflammation and tissue injury of the lung. Agents interfering with the generation of reactive oxygen metabolites may provide a rationale for treatment of mineral-dust-induced pulmonary disease.     

Neonatal resuscitation after severe asphyxia - a critical evaluation of 177 Swedish cases.

AIM: To evaluate neonatal resuscitation of infants born with severe asphyxia. METHOD: All case records of the 472 claims for financial compensation due to suspected medical malpractice in conjunction with childbirth in Sweden between 1990 and 2005 were scrutinized. Inclusion criteria were: gestational age > or =33 completed weeks, planned vaginal onset of delivery, a reactive CTG at onset of labour, neonatal asphyxia (defined as metabolic acidosis [pH of < 7.05 and/or a base excess of < -12]), or an Apgar score <7 at 5 min. It was assessed that 177 infants suffered from cerebral palsy or early death due to severe asphyxia presumably caused by malpractice around labour. RESULTS: Median Apgar score at 5 min was 3, indicating that all infants needed immediate and extensive resuscitation. There was insufficient adherence to guidelines concerning neonatal resuscitation, including delayed initiation of excessive resuscitation in 19 infants, lack of satisfactory ventilation in 79 infants, and untimely interruption of resuscitation in 38 infants. CONCLUSIONS: Compliance with guidelines for resuscitation of severely asphyctic newborn may be improved, especially concerning ventilation and prompt paging for skilled personnel in cases of imminent asphyxia. Documentation of neonatal resuscitation must be improved to enable reliable evaluation.     

The effect of a multidimensional exercise programme on symptoms and side-effects in cancer patients undergoing chemotherapy--the use of semi-structured diaries.

The aim of this study was to evaluate the effects of a 6-week intervention with structured physical activity, relaxation, body-awareness techniques and massage on the symptoms/side-effects of cancer patients undergoing chemotherapy. The study was prospective and exploratory, and 54 patients completed assessments for all 6 weeks of the intervention. In order to obtain a continuous record of side-effects, a diary was developed for the patients' use throughout the intervention. The patients scored their symptoms/side-effects on a scale from 0 to 4, using the Common Toxicity Criteria and reported these scores in questionnaires. Twelve possible symptoms/side-effects were registered daily: lack of appetite, nausea, vomiting, diarrhea, paraesthesia, constipation, physical fatigue, mental fatigue, treatment-related fatigue, muscle pain, arthralgia and other pain. During the intervention a decrease in the scoring for 10 out of the 12 side-effects was found. Statistical significance was observed in the pain score (P=0.046) and the arbitrary-derived sum of the scores for symptoms and side-effects (P=0.036) respectively. Patients with evidence of disease (n=26) had significantly higher levels of symptoms/side-effects than patients with no evidence of disease (n=28) (P=0.027). The results indicate that a six weeks multidimensional exercise intervention undertaken by cancer patients with or without residual disease while undergoing chemotherapy can lead to a reduction in treatment-related symptoms.     

Firing properties of sudomotor neurones in hyperhidrosis and thermal sweating

Objectives  Idiopathic palmar-plantar hyperhidrosis is characterized by excessive sweating of the palms and feet, and is commonly treated by transthoracic regional sympathicotomy. As the condition is believed to be due to a high sudomotor drive, we wanted to assess the firing properties of individual sudomotor neurones in this state of sympathoexcitation, extending our recent work on other pathologies associated with high sympathetic nerve activity. Methods  Single-unit recordings were made from eight sudomotor neurones supplying the fingers via tungsten microelectrodes inserted percutaneously into the median nerve at the wrist or upper arm. Results  Typical of sudomotor, muscle vasoconstrictor and cutaneous vasoconstrictor neurones recorded in healthy individuals in states of high sympathetic drive, all units had low firing probabilities (active in only 30.0 ± 6.7 (SE) % of cardiac intervals) and primarily fired only once per heart beat. The percentage of cardiac intervals in which the neurones generated 1, 2, 3 or 4 spikes was 60.4 ± 6.3, 22.9 ± 3.9, 9.7 ± 2.1 and 3.4 ± 1.3%, respectively. For comparison, these values were 77.6 ± 7.7, 15.0 ± 4.1, 4.6 ± 2.3 and 1.8 ± 1.3% for eight sudomotor neurones innervating the hairy skin of the foot during thermally-induced sweating in normal subjects. Interpretation  We conclude that the firing properties of spontaneously active sudomotor neurones in subjects with hyperhidrosis are similar to those of sudomotor neurones active during thermal sweating, reflecting an increase in central sympathetic drive to the sweat glands in hyperhidrosis.     

乳腺X线筛查及其他方法检出的乳腺癌发生远期复发的危险

背景：对确诊患乳腺癌的妇女行全身辅助治疗是基于其肿瘤复发的危险。进行危险评估时，通过乳腺X线筛查发现的肿瘤发生复发的危险与其他方法发现的大小相似的肿瘤相同。目的：对乳腺X线筛查或其他方法发现的女性乳腺癌患者的复发危险和生存率进行比较。设计、地点及患者：对乳腺X线筛查出的肿瘤和其他方法发现的肿瘤进行回顾性研究，比较其临床、组织病理学和生物学特性。从芬兰肿瘤登记处（Finnish Cancer Registry）检出1991年或1992年诊断患有乳腺癌的妇女（n=2842）。中位随访时间为9．5年。应用免疫组织化学或原位杂交法对肿瘤的生物学特性进行肿瘤组织微矩阵分析，包括ERBB2、TP53、MK167表达和ERBB2扩增数据。主要观察指标：影响乳腺癌远期复发和10年生存率的潜在危险因素的单变量分析和多变量分析。结果：在1983例患单侧浸润性乳腺癌的妇女中，1918例有肿瘤直径数据。通过乳腺X线筛查发现的肿瘤患者与其他方法发现的肿瘤患者比较，前者10年远期无病生存率更高（肿瘤≤10mm[n=386]：92％比85％[P=0．04]；肿瘤11～20mm[n=808]：88％比76％[P〈0．001]；肿瘤21～30mm[n=409]：86％比63％[P=0．008]；肿瘤〉30mm[n=315]：68％比50％[P=0．12]）。在包括各种肿瘤生物学因素的Cox多变量模型中，其他方法发现的肿瘤患者发生远期复发的相对风险比（hazard ratio[HR]，1．90；95％可信区间，1．15—3．11）显著高于乳腺X线筛查发现的肿瘤患者（P=0．01）。通过乳腺X线筛查确诊乳腺癌是降低远期复发相对HR的独立预后变量。这种作用相当于甚至超过肿瘤直径缩少1cm的作用（HR，1．20；95％可信区间，1．10～1．31）。结论：通过乳腺X线筛查发现的肿瘤与其他方法发现的大小相似的肿瘤比较，前者预后更好。在评估远期转移危险时必须考虑肿瘤检测方法，否则就会高估经乳腺X线筛查确诊的肿瘤患者发生远期转移的危险。     

Long-term Mortality after Acute Myocardial Infarction in Relation to Prescribed Dosages of a Beta-Blocker at Hospital Discharge

This study was designed to describe the 5-year mortality rate in relation to the dose of metoprolol prescribed at hospital discharge after hospitalisation for acute myocardial infarction (AMI). All patients discharged alive after being hospitalized for AMI at Sahlgrenska Hospital (covering half of the community of Göteborg, with 500,000 inhabitants) during 1986–1987 (period I) and all patients discharged alive after hospitalization for AMI at Sahlgrenska Hospital and östra Hospital (covering the whole area of the community of Göteborg) in 1990–1991 (period II) were included. Overall mortality was retrospectively evaluated over 5 years of follow-up. In all there were 2161 patients who were discharged after AMI. Seventy-three percent of these patients were prescribed a beta-blocker and 59% were prescribed metoprolol. Of the patients prescribed metoprolol, 34% were on 200 mg, 46% on 100 mg, and 20% on 50 mg or less. Information on 5-year mortality was available for 2142 of the 2161 patients (99.1%). The 5-year mortality was 24% among patients prescribed 200 mg, 33% among patients prescribed 100 mg, and 43% among patients prescribed 50 mg (P < 0.0001). Patients prescribed another beta-blocker had a 5-year mortality of 39%, and patients prescribed no beta-blocker at all had a 5-year mortality of 61%. When correcting for dissimilarities at baseline, patients who were prescribed 100 mg had an adjusted risk ratio for death of 0.79 (95% confidence limit 0.64–0.96; P = 0.021) as compared with patients not prescribed a beta blocker. The corresponding figure for patients prescribed >100 mg was 0.63 (95% confidence limit 0.48–0.84; P = 0.001). Both patients prescribed high and low doses of metoprolol after AMI appeared to benefit from treatment. There was a trend indicating more benefit when larger doses were prescribed.