GGA1 acts as a spatial switch altering amyloid precursor protein trafficking and processing

The beta-amyloid (Abeta) precursor protein (APP) is cleaved sequentially by beta-site of APP-cleaving enzyme (BACE) and gamma-secretase to release the Abeta peptides that accumulate in plaques in Alzheimer's disease (AD). GGA1, a member of the Golgi-localized gamma-ear-containing ARF-binding (GGA) protein family, interacts with BACE and influences its subcellular distribution. We now report that overexpression of GGA1 in cells increased the APP C-terminal fragment resulting from beta-cleavage but surprisingly reduced Abeta. GGA1 confined APP to the Golgi, in which fluorescence resonance energy transfer analyses suggest that the proteins come into close proximity. GGA1 blunted only APP but not notch intracellular domain release. These results suggest that GGA1 prevented APP beta-cleavage products from becoming substrates for gamma-secretase. Direct binding of GGA1 to BACE was not required for these effects, but the integrity of the GAT (GGA1 and TOM) domain of GGA1 was. GGA1 may act as a specific spatial switch influencing APP trafficking and processing, so that APP-GGA1 interactions may have pathophysiological relevance in AD.     

Combined open and laparoscopic approach to chronic pain following open inguinal hernia repair

Introduction: Chronic groin pain is the most common long-term complication after open inguinal hernia repair. Traditional surgical management of the associated neuralgia consists of injection therapy followed by groin exploration, mesh removal, and nerve transection. The resultant hernia defect may be difficult to repair from an anterior approach. We evaluate the outcomes of a combined laparoscopic and open approach for the treatment of chronic groin pain following open inguinal herniorrhaphy. Methods: All patients who underwent groin exploration for chronic neuralgia after a prior open inguinal hernia repair were prospectively analyzed. Patient demographics, type of prior hernia repair, and prior nonoperative therapies were recorded. The operation consisted of a standard three trocar laparoscopic transabdominal preperitoneal hernia repair, followed by groin exploration, mesh removal, and nerve transection. Outcome measures included recurrent groin pain, numbness, hernia recurrence, and complications. Results: Twelve patients (11 male and 1 female) with a mean age of 41 years (range 29–51) underwent combined laparoscopic and open treatment for chronic groin pain. Ten patients complained of unilateral neuralgia, one patient had bilateral complaints, and one patient complained of orchalgia. All patients failed at least two attempted percutaneous nerve blocks. Prior repairs included Lichtenstein (n=9), McVay (n=1), plug and patch (n=1), and Shouldice (n=1). There were no intraoperative complications or wound infections. With a minimum of 6 weeks follow up, all patients were significantly improved. One patient complained of intermittent minor discomfort that required no further therapy. Two patients had persistent numbness in the ilioinguinal nerve distribution but remained satisfied with the procedure. Conclusions: A combined laparoscopic and open approach for postherniorrhaphy groin pain results in good to excellent patient satisfaction with no perioperative morbidity. It may be the preferred technique for the definitive management of chronic neuralgia after prior open hernia repair.     

Evaluation and audit in a paediatric disability service

Parental and professional responses to questionnaires evaluating a paediatric disability service are reported and the viability of auditing structural, process, and outcome aspects of clinical practice are discussed. Expectations of waiting time to first appointment (met for only 52% of consumers) illustrate structural issues. Process issues are reflected in consumer reactions to outreach work (for example, 94% of parents and 84% of professionals found this supportive). Outcome measures such as consumer satisfaction with the service (76% of consumers reported being 'very satisfied' and 20% 'fairly satisfied') suggest that service aims are being met. Good concurrence of service aims with consumer needs is indicated by parental reasons for referral (for example, 75% for diagnostic help, 73% for a better understanding of the disorder, 88% for practical help), referrers' reasons (for example, 55% for a second diagnostic opinion, 45% due to lack of local expertise), and reports from most other professionals involved with the case that a similar service was not provided locally.     

Passive immunization against tumor necrosis factor inhibits interleukin-2-induced microvascular alterations and reduces toxicity.

BACKGROUND. Antineoplastic therapy with interleukin-2 (IL-2) has been limited by dose-dependent systemic toxicities. Previous studies suggest that the hemodynamic instability and "vascular leak syndrome" that develop immediately after IL-2 administration occur secondary to neutrophil-mediated events in the microcirculation. Because IL-2 has limited direct effects on neutrophils and acutely induces the production of tumor necrosis factor-alpha (TNF), we hypothesized that the acute microvascular alterations and hemodynamic instability induced by IL-2 were mediated by TNF. METHODS. The cremaster muscles of anesthetized rats were prepared for intravital microscopy. All animals were injected with fluorescein isothiocyanate conjugated to bovine serum albumin, and relative interstitial fluorescence was quantitated as an index of macromolecular leakage. Vital signs, leukocyte-endothelial interactions, and interstitial fluorescence were quantitated every 30 minutes for 2 hours after intravenous injections of IL-2, TNF, and IL-2 with polyclonal antibody to TNF. RESULTS. Both IL-2 and TNF acutely induced hypotension, tachycardia, increased macromolecular leakage, and increased leukocyte-endothelial adherence. Polyclonal antibody to TNF effectively inhibited IL-2-induced leukocyte-endothelial adherence, macromolecular leakage, and hypotension. CONCLUSIONS. These data suggest that the acute microvascular alterations and hypotension induced by IL-2 are mediated by TNF.     

Behaviour and physiological responses during prone and supine sleep in early infancy

AIMS: To study the effect of prone and supine sleep on infant behaviour, peripheral skin temperature, and cardiorespiratory parameters to aid understanding of why prone sleeping is associated with an increased risk of sudden infant death syndrome. METHODS: Of 33 enrolled infants, 32 were studied at 2.5 and 28 at 5 months of age. A computer aided multichannel system was used for polysomnographic recordings. Behaviour was charted separately. RESULTS: Prone REM (active) sleep was associated with lower frequencies of short arousals, body movements and sighs, and a shorter duration of apnoeas than supine REM sleep at both ages. At 2.5 months there were less frequent episodes of periodic breathing during prone sleep in non-REM (quiet) and REM sleep. Heart rate and peripheral skin temperature were higher in the prone position during both sleep states at both ages. CONCLUSIONS: The observation of decreased variation in behaviour and respiratory pattern, increased heart rate, and increased peripheral skin temperature during prone compared with supine sleep may indicate that young infants are less able to maintain adequate respiratory and metabolic homoeostasis during prone sleep.     

Choledocholithiasis: evolving intraoperative strategies

In the era of open cholecystectomy, common bile duct stones were approached by traditional choledocholithotomy. Retained or recurrent stones discovered after cholecystectomy were approached by endoscopic extraction techniques or repeat surgery. With the advent of laparoscopic cholecystectomy, the approach to choledocholithiasis became more problematic as techniques for laparoscopic extraction were rudimentary. Preoperative endoscopic retrograde cholangiopancreatography rapidly became an adjunct to laparoscopic cholecystectomy when common duct stones were likely. Experience, however, revealed that many of these procedures were unnecessary. With developing sophistication of laparoscopic techniques, a variety of approaches to common duct stones developed. These included: transcystic extraction, direct laparoscopic choledocholithotomy, intraoperative endoscopic retrograde cholangiopancreatography, antegrade sphincterotomy, and transcystic placement of a common duct stent with subsequent endoscopic sphincterotomy and stone extraction. It is the purpose of this article to define the current role of each of these methods in the laparoscopic approach to choledocholithiasis.     

妥卡尼对豚鼠心室肌细胞钙电流和钾电流的抑制作用

利用酶分散的成年豚鼠心室肌细胞和全细胞电压钳技术,研究了妥卡尼(tocainide)对心室肌细胞钙电流(I_ca)、延迟整流钾电流(I_k)和ATP敏感性钾电流(Ik,ATP)的作用。结果表明,妥卡尼对I_ca和I_k均显示浓度相关的抑制作用,妥卡尼50umol·L^-1对I_ca和I_k的抑制率分别为16%和3%。这可能是妥卡尼有效抑制室上性心动过速和缩短心肌动作电位平台期的重要机制。     

回春液补肾助阳药效学的实验研究

回春液由人参、鹿茸、貂鞭等名贵中药组成。有补肾助阳,填精益气等功效。药效学研究证实,该药有促进幼鼠发育及增加去势大鼠前列腺——精液囊的重量,亦显著增加小鼠血红蛋白的含量,表明回春液有雄性激素样作用。