Cholinergic Stimulation by Pyridostigmine Bromide Before Myocardial Infarction Prevent Cardiac and Autonomic Dysfunction.

Inflammatory processes and cardiovascular autonomic imbalance are very relevant characteristic of the enormous dynamic process that is a myocardial infarction (MI). In this sense, some studies are investigating pharmacological therapies using acetylcholinesterase inhibitors, such as pyridostigmine bromide (PYR), aiming to increase parasympathetic tone after MI. Here we hypothesized that the use of PYR before the MI might bring an additional positive effect to the autonomic function, and consequently, in the inflammatory response and cardiac function. The present study aimed to evaluate left ventricular function, baroreflex sensitivity, autonomic modulation, and inflammatory profile in PYR-treated rats previously to MI. METHODS: Male Wistar rats (250-300 g) were treated for 60 days with PYR. After treatment, they were submitted to the MI. After the MI, the autonomic and ventricular function were evaluated, as well as the systemic, left ventricle, and adipose tissue inflammatory profile. RESULTS: PYR, performed before MI, prevented HR increase, systolic function impairment, baroreflex sensitivity drop, as well as pulse interval variance, RMSSD, blood pressure and parasympathetic modulation reduction in treated rats compared to untreated rats. Also, this positive functional changes may have been a result of the reduced inflammatory parameters in the left ventricle (IFN-γ, IL-6, and IL-1ß), as well as increased IL-10 expression and IL-10/TNF-α ratio in treated animals before MI. CONCLUSION: Prior treatment with PYR prevents impairment of the autonomic nervous system after MI, which may be associated with the attenuated expression of inflammatory factors and heart dysfunction.

Copy number variation in pediatric multiple sclerosis.

BACKGROUND: Pediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions. OBJECTIVES AND METHODS: The objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array. RESULTS AND DISCUSSION: We identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS. CONCLUSIONS: This is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient's disease course and prognosis.

Laparoscopic distal pancreatectomy: the Brisbane experience of forty-six cases.

BACKGROUND AND AIMS: Laparoscopic distal pancreatectomy (LDP) is a safe alternative to conventional open distal pancreatectomy, with advantages that include smaller incisions, less pain, and shorter postoperative recovery. Despite these apparent advantages, however, uptake of the procedure has been slow, with only a handful of series published. MATERIAL AND METHODS: All LDPs performed in Brisbane, Australia, over a 10-year period (May 1996 to June 2006) were retrospectively reviewed. RESULTS: Forty-six consecutive LDPs were performed. A variety of lesions were resected, including nine cancers. Twelve patients were converted for oncological (6) or technical reasons (6). The spleen was retained in 14/29 patients, either by main splenic vessel preservation (9) or solely supported by the short gastric vessels (5), resulting in inferior pole infarction in 2 patients. Overall morbidity was 39%, including 15% pancreatic fistula. All fistulas resolved after a median of 6 weeks without re-operation. A non-significant trend toward fewer fistulas with stapled rather than sutured stump closure was observed (13% vs 19%; p=0.43). Median operative duration and hospital stay were 157 min and 7 days, respectively. There was no mortality. CONCLUSION: LDP is a safe alternative to conventional resection for a wide range of lesions. As with open resection, pancreatic fistula is the dominant morbidity, but is generally indolent. While spleen preservation is often possible, care must be taken to avoid infarction of the inferior pole if the Warshaw technique is utilized.

Symptomatic and functional outcome after laparoscopic reoperation for failed antireflux surgery.

BACKGROUND: The aim was to determine symptomatic and functional outcome after reoperative antireflux surgery for recurrent reflux, persistent dysphagia and severe gas bloat, using a primarily laparoscopic surgical approach. METHODS: This was a retrospective analysis of prospectively collected data from 118 patients, of whom 70 had reoperative surgery for recurrent reflux, 35 for dysphagia and 13 for gas bloat. DeMeester scores before and 1 year after surgery, functional symptoms after surgery and overall patient satisfaction were analysed. RESULTS: Reoperation was completed laparoscopically in 101 patients (85.6 per cent), in 28 after previous open hiatal surgery. The operation was converted from an initial laparoscopic approach to open surgery in 17 patients. One-year follow-up data were available for 104 patients (88.1 per cent). After reoperation for recurrent reflux, 84 per cent had a DeMeester heartburn score of zero or one, and 87 per cent had a regurgitation score of zero or one. After reoperation for dysphagia, 21 of 32 patients had a dysphagia score of zero or one, with improvement observed in 25. All patients undergoing reoperation for severe gas bloat were satisfied with the outcome 1 year after operation. CONCLUSION: Revisional surgery for recurrent reflux using a laparoscopic approach offered high rates of success and patient satisfaction. Swallowing returned to normal in two-thirds of patients after reoperation.

The poor quality of information about laparoscopy on the World Wide Web as indexed by popular search engines.

BACKGROUND: This study was undertaken to determine the quality of information on the Internet regarding laparoscopy. METHODS: Four popular World Wide Web search engines were used with the key word "laparoscopy." Advertisements, patient- or physician-directed information, and controversial material were noted. RESULTS: A total of 14,030 Web pages were found, but only 104 were unique Web sites. The majority of the sites were duplicate pages, subpages within a main Web page, or dead links. Twenty-eight of the 104 pages had a medical product for sale, 26 were patient-directed, 23 were written by a physician or group of physicians, and six represented corporations. The remaining 21 were "miscellaneous." The 46 pages containing educational material were critically reviewed. At least one of the senior authors found that 32 of the pages contained controversial or misleading statements. All of the three senior authors (LKN, NAO, GAF) independently agreed that 17 of the 46 pages contained controversial information. CONCLUSION: The World Wide Web is not a reliable source for patient or physician information about laparoscopy. Authenticating medical information on the World Wide Web is a difficult task, and no government or surgical society has taken the lead in regulating what is presented as fact on the World Wide Web.

ECG Wave-Maven: a self-assessment program for students and clinicians.

Proficiency in the interpretation of electrocardiograms (ECGs) is an essential skill for medical students, house officers, and attending physicians. However, resources to develop and upgrade the necessary high level of "ECG literacy" are limited. A small number of centers have attempted to address this challenge by developing "ECG of the week" internet sites. These resources are difficult to maintain and update, and many of them quickly become stagnant. We present "ECG Wave-Maven," an innovative web-based tutorial that overcomes these obstacles via a direct link to the hospital's extensive and increasing clinical ECG repository. By interfacing our educational tool to live data, we can greatly decrease the time and effort required from the time a practitioner notes an interesting case to its inclusion in the program. Users can opt to encounter the test cases sequentially or randomly, or by reviewing a list of questions or diagnoses, making this not just a quiz, but a basic educational reference. This tool may be useful in meeting the challenge of reducing serious medical errors related to ECG misinterpretation.

Weaving the Web into legacy information systems.

For many years, client-server systems were developed as the backbone of clinical computing in leading hospitals around the country. Beth Israel Deaconess Medical Center now faces the challenge of bridging the technology gap between such systems and the Internet. While developing Web interfaces to legacy clinical systems gives a taste of the future, it is clear that complete institutional migration to the Web is not imminent. Asking clinicians to utilize two different systems, Web-based and legacy, in the interim phase is just one of the difficulties in such transition. This paper describes "Mbridge", a solution that allows legacy system users to exploit the benefits of the Internet in a fashion that does not interfere with their workflow and is both simple and affordable to implement. The service allows clinicians to work on the legacy platform while context-sensitive clinical content is streamed to the browser without their intervention. Using the system, we can gradually expose clinicians to new Web-based applications and resources without forcing them to operate two computing environments simultaneously. The service achieves these goals by means of linkage and coordination rather than by code-translation, data exchange or replication.

Chronic dysphagia following laparoscopic fundoplication.

BACKGROUND: Many surgeons practise tailored laparoscopic antireflux surgery in an attempt to prevent postoperative dysphagia. The aim of this study was to determine the effect of 360 degrees fundoplication (Nissen) or 270 degrees fundoplication (Toupet), and the influence of abnormal oesophageal peristalsis, upon postoperative dysphagia. METHODS: This was a cohort study from three tertiary referral centres, using dysphagia before laparoscopic fundoplication and 1 year after operation as the main outcome variable. Preoperative oesophageal manometry was performed on all patients. RESULTS: Some 761 patients underwent Nissen and 85 underwent Toupet fundoplication. Only 2 per cent reported severe postoperative dysphagia. There was a significant selection bias towards the Toupet operation for patients with abnormal oesophageal motility (P < 0.001). For patients whose oesophageal manometric findings were normal there was a significant improvement in dysphagia after Nissen fundoplication (P = 0.02), and no significant change following Toupet fundoplication. There was no significant change in the rate of dysphagia following either method of fundoplication amongst other subgroups in which oesophageal manometry was stratified as non-specific motor disorder, low-amplitude peristalsis, or aperistalsis. CONCLUSION: A tailored approach to the degree of fundoplication is unnecessary as patients with dysmotility suffer no more dysphagia after full laparoscopic Nissen fundoplication than those who have a partial Toupet wrap.

Effects of simvastatin on hepatic cholesterol metabolism, bile lithogenicity and bile acid hydrophobicity in patients with gallstones.

BACKGROUND AND AIMS: There is limited information available on the effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on hepatic and biliary cholesterol metabolism in patients with gallstones. The aims of this study were to determine the effect of simvastatin on the regulatory elements of cholesterol metabolism that determine the concentrations of cholesterol in plasma and bile. METHODS: Thirty-one gallstone patients were enrolled in the study; 17 were treated with 20 mg simvastatin daily for 3 weeks prior to cholecystectomy and 14 served as controls. Samples of blood, liver, gall-bladder bile and bile from the common bile duct (CBD) were collected and analysed. RESULTS: The plasma cholesterol (-30%), triacylglycerol (-23%) and low-density lipoprotein (LDL) cholesterol (-42%) concentrations were significantly lowered by simvastatin treatment, as was the plasma lathosterol: cholesterol (-70%), which reflects whole-body cholesterol synthesis. Despite these changes, the hepatic LDL receptor protein and LDL receptor activity in circulating mononuclear cells were similar in both groups. There were no differences in the plasma phytosterol: cholesterol, which reflects the intestinal cholesterol absorption capacity or in the activity of hepatic acyl-coenzyme A: cholesterol acyltransferase. There were however, lower cholesterol concentrations in CBD (-68%) and gall bladder (-41%) bile, and decreased lithogenic (-47%) and bile acid hydrophobicity (-22%) indices of CBD bile in the simvastatin group. CONCLUSIONS: These data indicate that simvastatin reduced plasma and biliary cholesterol levels primarily by reducing cholesterol synthesis. The reduction in CBD bile lithogenicity and bile acid hydrophobicity by simvastatin suggests that this agent may be useful for people who have early stages of cholesterol gallstone development and in whom a choleretic effect is required.

Active aminoacyl-tRNA synthetases are present in nuclei as a high molecular weight multienzyme complex.

Recent studies suggest that aminoacylation of tRNA may play an important role in the transport of these molecules from the nucleus to the cytoplasm. However, there is almost no information regarding the status of active aminoacyl-tRNA synthetases within the nuclei of eukaryotic cells. Here we show that at least 13 active aminoacyl-tRNA synthetases are present in purified nuclei of both Chinese hamster ovary and rabbit kidney cells, although their steady-state levels represent only a small percentage of those found in the cytoplasm. Most interestingly, all the nuclear aminoacyl-tRNA synthetases examined can be isolated as part of a multienzyme complex that is more stable, and consequently larger, than the comparable complex isolated from the cytoplasm. These data directly demonstrate the presence of active aminoacyl-tRNA synthetases in mammalian cell nuclei. Moreover, their unexpected structural organization raises important questions about the functional significance of these multienzyme complexes and whether they might play a more direct role in nuclear to cytoplasmic transport of tRNAs.

Mutations in the beta-subunit Thr(159) and Glu(184) of the Rhodospirillum rubrum F(0)F(1) ATP synthase reveal differences in ligands for the coupled Mg(2+)- and decoupled Ca(2+)-dependent F(0)F(1) activities.

In the crystal structure of the mitochondrial F(1)-ATPase, the beta-Thr(163) residue was identified as a ligand to Mg(2+) and the beta-Glu(188) as directly involved in catalysis. We replaced the equivalent beta-Thr(159) of the chromatophore F(0)F(1) ATP synthase of Rhodospirillum rubrum with Ser, Ala, or Val and the Glu(184) with Gln or Lys. The mutant beta subunits were isolated and tested for their capacity to assemble into a beta-less chromatophore F(0)F(1) and restore its lost activities. All of them were found to bind into the beta-less enzyme with the same efficiency as the wild type beta subunit, but only the beta-Thr(159) --> Ser mutant restored the activity of the assembled enzyme. These results indicate that both Thr(159) and Glu(184) are not required for assembly and that Glu(184) is indeed essential for all the membrane-bound chromatophore F(0)F(1) activities. A detailed comparison between the wild type and the beta-Thr(159) --> Ser mutant revealed a rather surprising difference. Although this mutant restored the wild type levels and all specific properties of this F(0)F(1) proton-coupled ATP synthesis as well as Mg- and Mn-dependent ATP hydrolysis, it did not restore at all the proton-decoupled CaATPase activity. This clear difference between the ligands for Mg(2+) and Mn(2+), where threonine can be replaced by serine, and Ca(2+), where only threonine is active, suggests that the beta-subunit catalytic site has different conformational states when occupied by Ca(2+) as compared with Mg(2+). These different states might result in different interactions between the beta and gamma subunits, which are involved in linking F(1) catalysis with F(0) proton-translocation and can thus explain the complete absence of Ca-dependent proton-coupled F(0)F(1) catalytic activity.

Spray of phospholipid powder reduces peritoneal adhesions in rabbits.

BACKGROUND: The possible effects of peritoneal dialysis and a combination of two exogenous phospholipids, dipalmitoylphosphatidylcholine (DPPC) and phosphatidylglycerol (PG), on experimentally induced intraperitoneal adhesion formation in rabbits were compared. METHODS: Fifty New Zealand rabbits equally divided in five groups underwent a midline laparotomy to create a right iliac fossa 5 x 1 cm parietal peritoneal defect and a matching defect over the adjacent large bowel. In 10 control rabbits (group I) the abdominal wound was closed without any further intervention. Twenty rabbits forming groups II and III underwent two sessions of peritoneal dialysis, one following abdominal closure and the second 24 h later, through a catheter placed at surgery. Rabbits in group III received an intraperitoneal injection of DPPC and PG after each session of dialysis. In 10 animals (group IV) a DPPC gel was applied to the defect over the large bowel and in 10 animals (group V) the peritoneal cavity was sprayed with a 'puff of DPPC:PG (7:3) powder prior to abdominal closure. All the animals were killed a week after the laparotomy to assess the extent of adhesion formation. RESULTS: The formation of adhesions was reduced in all the groups compared to the controls but a statistically significant difference was observed only in the group receiving the intraperitoneal 'puff' of DPPC:PG powder. CONCLUSION: A combination of DPPC and PG sprayed as a 'puff' intraperitoneally reduces experimentally induced peritoneal adhesions in rabbits.

Laparoscopic gastric banding for morbid obesity. Surgical outcome in 335 cases.

BACKGROUND: Morbid obesity occurs in 2-5% of the population of Europe, Australia, and the United States and is becoming more common. Open surgical techniques, such as vertical banded gastroplasty and other divisional procedures in the stomach, have led to long-term weight reduction as well as an amelioration of the attendant medical problems in approximately two-thirds of patients. MATERIALS AND METHODS: A total of 335 patients with a median age of 41 years underwent gastric banding. We emphasized the need for long-term maintenance and follow-up. The indications for surgery comprised a body mass index >35, a stated desire to undergo the procedure, and a full understanding of all possible complications. RESULTS: All patients have needed band adjustments of 1-4 ml over the course of their follow-up. No patient had increased his or her weight during the follow-up, and only three patients have not enjoyed sustained weight loss. CONCLUSIONS: Laparoscopic gastric banding has much to recommend it. Certainly in the short term, its results in terms of effectiveness of weight loss are at least as good as those of any open procedure. Longer follow-up will show whether this weight loss is maintainable. The procedure is technically demanding, and the major prerequisite of satisfactory performance of this surgery is laparoscopic experience.

Active specific immunotherapy with polyvalent melanoma cell vaccine for patients with in-transit melanoma metastases.

BACKGROUND: This study was conducted to document the rate, duration, and type of objective response to active specific immunotherapy with a polyvalent melanoma cell vaccine (PMCV) for patients with in-transit melanoma metastases and to identify any acute or chronic toxic effects of PMCV treatment. METHODS: An analysis was conducted of all in-transit melanoma patients seen at the John Wayne Cancer Institute in Santa Monica, California, during the period 1985-1997 who were enrolled in prospective PMCV protocols in the absence of other therapies with possible antitumor activity (n = 54). Clinical response to PMCV was assessed by standard criteria. Survival curves were estimated by the Kaplan-Meier method. Toxicity was graded according to the Eastern Cooperative Oncology Group standard. RESULTS: PMCV produced a 17% (9 of 54 patients) objective response rate with a 13% rate (7 of 54 patients) of complete remission (CR). The median duration of CR was >22 months. Complete response lasting more than 1 year was observed in 4 patients (7.2%); 1 patient remained in remission over 9 years. Median survival was >53 months (i.e., not reached) for responders, 42 months for nonresponders, and 53 months overall. Salvage interventions allowed reinduction with PMCV in 23 of 25 patients, who subsequently remained clinically free of disease for a median of 14 months. Overall toxicity was mild, easily tolerable, and did not significantly change the quality of life. There were no toxic deaths. CONCLUSIONS: PMCV can cause objective complete regression of measurable intransit metastatic melanoma with minimal toxicity, and may prolong patients' median survival.

Towards T-tube free laparoscopic bile duct exploration: a methodologic evolution during 300 consecutive procedures.

OBJECTIVE: To establish a simple, reproducible, and safe technique of laparoscopic common bile duct exploration (CBDE) with high clearance rates and low morbidity and mortality rates. SUMMARY BACKGROUND DATA: For most general surgeons, laparoscopic CBDE appears an unduly complex and demanding procedure. Since the introduction of laparoscopic cholecystectomy, many surgeons use endoscopic cholangiography (ERC) and endoscopic sphincterotomy as their only option in treating bile duct stones. ERC is more specific if used after surgery, but it carries an appreciable morbidity rate and has the disadvantage of requiring a second procedure to deal with bile duct stones. To this end, various methods of laparoscopic CBDE have been developed. METHODS: Between August 1991 and February 1997, 300 consecutive unselected patients underwent laparoscopic CBDE. RESULTS: Of 300 laparoscopic CBDE procedures, 173 (58%) were managed using a transcystic approach and 127 (42%) with choledochotomy. Successful laparoscopic stone clearance was achieved in 271 (90%). Of the 29 (10%) patients not cleared laparoscopically, 10 had an elective postsurgical ERC, 12 were converted to an open procedure early in the series, and 7 had unexpected retained stones. There was one death (mortality rate 0.3%) and major morbidity occurred in 22 patients (7%). The last 100 procedures were performed from July 1995 to February 1997, and stone clearance was unsuccessful in only two patients. CONCLUSIONS: Laparoscopic transcystic basket extraction of common duct stones under fluoroscopic guidance is a relatively quick, successful, and safe technique. Choledochotomy, when required, is associated with a higher morbidity rate, particularly with T-tube insertion, and the authors advocate primary bile duct closure with or without insertion of a biliary stent as a more satisfactory technique for both surgeon and patient. Most patients with gallbladder and common duct calculi should expect a curative one-stage laparoscopic procedure without the need for external biliary drainage or ERC.

Mutagenesis of beta-Glu-195 of the Rhodospirillum rubrum F1-ATPase and its role in divalent cation-dependent catalysis.

We introduced mutations at the fully conserved residue Glu-195 in subunit beta of Rhodospirillum rubrum F1-ATPase. The activities of the expressed wild type (WT) and mutant beta subunits were assayed by following their capacity to assemble into the earlier prepared beta-depleted, membrane-bound R. rubrum enzyme (Philosoph, S., Binder, A., and Gromet-Elhanan, Z. (1977) J. Biol. Chem. 252, 8742-8747) and to restore ATP synthesis and/or hydrolysis activity. All three mutations, beta-E195K, beta-E195Q, and beta-E195G, were found to bind as the WTbeta into the beta-depleted enzyme. They restored between 30 and 60% of the WT restored photophosphorylation activity and 16, 45, and 105%, respectively of the CaATPase activity. The mutants required, however, much higher concentrations of divalent cations and could not restore any significant MgATPase or MnATPase activities. Only beta-E195G could restore some of these activities when assayed in the presence of 100 mM sulfite and high MgCl2 or MnCl2 concentrations. These results suggest that the observed difference in restoration of ATP synthesis and CaATPase, as compared with MgATPase and MnATPase, can be due to the tight regulation of the last two activities, resulting in their inhibition at cation/ATP ratios above 0.5. The R. rubrum F1beta-E195 is equivalent to the mitochondrial F1beta-E199, which points into the tunnel leading to the F1 catalytic nucleotide binding sites (Abrahams, J. P., Leslie, A. G. W., Lutter, R., and Walker, J. E. (1994) Nature 370, 621-628). Our findings indicate that this residue, although not an integral part of the F1 catalytic sites, affects divalent cation binding and release of inhibitory MgADP, suggesting its participation in the interconversion of the F1 catalytic sites between different conformational states.

Laparoscopic underrunning of bleeding duodenal ulceration: a minimalist approach to therapy.

Surgical management of bleeding duodenal ulcer has traditionally included a procedure to reduce gastric acid production to enable ulcer healing and reduce the likelihood of rebleeding. The availability of intravenous proton pump inhibitors in the peri-operative period may promote rapid ulcer healing and as a component of anti-Helicobacter eradication therapy greatly reduces the incidence of ulcer recurrence. Using this approach, six patients with actively bleeding duodenal ulcer underwent laparoscopic duodenotomy and attempted suturing of the bleeding site. One patient required conversion to open surgery and subsequently re-bled at 60 h, necessitating a partial (Billroth II) gastrectomy. In the remaining five patients suture control of bleeding and luminal closure were completed laparoscopically without complications. Laparoscopic repair of acutely bleeding duodenal ulcers is technically feasible and had a low complication rate in this small series.

Laparoscopic management of acute small bowel obstruction.

BACKGROUND: Laparoscopic management of acute small bowel obstruction is hypothetically attractive but little is known of its clinical potential. METHODS: A retrospective study was undertaken of patients with acute small bowel obstruction requiring surgery, managed by a laparoscopic unit (LU; n = 69) and a general unit (GU; n = 70). RESULTS: Laparoscopy was performed in 55 patients (80 per cent) in the LU compared with ten (14 per cent) in the GU. Laparoscopic surgery completed treatment in 31 patients (45 per cent) in the LU and assisted in a further 15 (22 per cent). Patients treated laparoscopically were discharged earlier than those treated by laparotomy (median 3 (range 1-15) versus median 8 (range 1-46) days). Patients treated laparoscopically had a higher chance of early unplanned reoperation than those treated by laparotomy (five of 35 versus four of 88) (P < 0.05). CONCLUSION: Laparoscopy can be performed in a high percentage of patients requiring surgery for acute small bowel obstruction. Hospital stay was reduced but the risk of early unplanned reoperation was increased in patients managed laparoscopically.