Comparative effectiveness of interventions for cancer treatment-related cognitive impairment in adult cancer survivors: protocol for a systematic review.

BACKGROUND: Cancer treatment-related cognitive impairment (CTRCI) can substantially reduce the quality of life of cancer survivors. Many treatments of CTRCI have been evaluated in randomized controlled trials (RCTs), including psychological interventions, pharmacologic interventions, and other therapies. There is a pressing need to establish the benefits and harms of previously studied CTRCI treatments. The proposed systematic review and network meta-analyses will assess the relative efficacy and safety of competing interventions for the management of CTRCI. METHODS: In consultation with the review team, an experienced medical information specialist will draft electronic search strategies for MEDLINE®, Embase, CINAHL, PsycINFO, and the Cochrane Trials Registry. We will seek RCTs of interventions for the treatment of CTRCI in adults with any cancer, except cancers/metastases of the central nervous system. Due to the anticipated high search yields, dual independent screening of citations will be expedited by use of an artificial intelligence/machine learning tool. The co-primary outcomes of interest will be subjective and objective cognitive function. Secondary outcomes of interest will include measures of quality of life, mental and physical health symptoms, adherence to treatment, and harms (overall and treatment-related harms and harms associated with study withdrawal), where feasible, random-effects meta-analyses and network meta-analyses will be pursued. We will address the anticipated high clinical and methodological heterogeneity through meta-regressions, subgroup analyses, and/or sensitivity analyses. DISCUSSION: The proposed systematic review will deliver a robust comparative evaluation of the efficacy and safety of existing therapies for the management of CTRCI. These findings will inform clinical decisions, identify evidence gaps, and identify promising therapies for future evaluation in RCTs.

An evaluation of DistillerSR's machine learning-based prioritization tool for title/abstract screening - impact on reviewer-relevant outcomes.

BACKGROUND: Systematic reviews often require substantial resources, partially due to the large number of records identified during searching. Although artificial intelligence may not be ready to fully replace human reviewers, it may accelerate and reduce the screening burden. Using DistillerSR (May 2020 release), we evaluated the performance of the prioritization simulation tool to determine the reduction in screening burden and time savings. METHODS: Using a true recall @ 95%, response sets from 10 completed systematic reviews were used to evaluate: (i) the reduction of screening burden; (ii) the accuracy of the prioritization algorithm; and (iii) the hours saved when a modified screening approach was implemented. To account for variation in the simulations, and to introduce randomness (through shuffling the references), 10 simulations were run for each review. Means, standard deviations, medians and interquartile ranges (IQR) are presented. RESULTS: Among the 10 systematic reviews, using true recall @ 95% there was a median reduction in screening burden of 47.1% (IQR: 37.5 to 58.0%). A median of 41.2% (IQR: 33.4 to 46.9%) of the excluded records needed to be screened to achieve true recall @ 95%. The median title/abstract screening hours saved using a modified screening approach at a true recall @ 95% was 29.8 h (IQR: 28.1 to 74.7 h). This was increased to a median of 36 h (IQR: 32.2 to 79.7 h) when considering the time saved not retrieving and screening full texts of the remaining 5% of records not yet identified as included at title/abstract. Among the 100 simulations (10 simulations per review), none of these 5% of records were a final included study in the systematic review. The reduction in screening burden to achieve true recall @ 95% compared to @ 100% resulted in a reduced screening burden median of 40.6% (IQR: 38.3 to 54.2%). CONCLUSIONS: The prioritization tool in DistillerSR can reduce screening burden. A modified or stop screening approach once a true recall @ 95% is achieved appears to be a valid method for rapid reviews, and perhaps systematic reviews. This needs to be further evaluated in prospective reviews using the estimated recall.

[Thoracic endometriosis with aspecific manifestation]. / Thoracale endometriose met een aspecifieke uiting.

BACKGROUND: Endometriosis is a common disease, especially in subfertile women. The most common location is in the pelvis, but extragenital locations are also possible. This far less common condition has been described in almost all tissues in the body. Symptoms occurring cyclically are characteristic of endometriosis. CASE DESCRIPTION: A 37-year-old woman was discovered by chance to have ascites and pleural effusion. She had no symptoms of this. Thoracoscopy showed an image consistent with thoracic endometriosis. After initial drug therapy was unsuccessful, surgical intervention was performed. CONCLUSION: Thoracic endometriosis is a rare disease, in which the cyclical nature of the symptoms often leads to correct diagnosis. Drug therapy is the preferred treatment for patients.

[Hereditary optic neuropathies: from clinical signs to diagnosis]. / Les neuropathies optiques héréditaires: du signe clinique au diagnostic.

Inherited optic atrophy must be considered when working up any optic nerve involvement and any systemic disease with signs of optic atrophy, even with a negative family history. There are two classical forms: dominant optic atrophy, characterized by insidious, bilateral, slowly progressive visual loss and temporal disc pallor, and Leber's optic atrophy, characterized by acute loss of central vision followed by the same event in the fellow eye within a few weeks to months, with disc hyperemia in the acute phase. Family history is critical for diagnosis. In the absence of family history, the clinician must rule out an identifiable acquired cause, i.e. toxic, inflammatory, perinatal injury, traumatic or tumoral, with orbital and brain imaging (MRI). Recessive optic atrophies are more rare and more severe and occur as part of multisystemic disorders, particularly Wolfram syndrome (diabetes mellitus, diabetes insipidus, and hearing loss). Effective treatments are limited; alcohol and smoking should be avoided. A cyclosporine trial (taken immediately upon visual loss in the first eye) is in progress in Leber's optic atrophy to prevent involvement of the fellow eye.

[Course system of the Working Group for Gastro-intestinal Surgery Davos]. / Kurssystem der Arbeitsgemeinschaft für Gastrointestinale Chirurgie Davos.

Training in technical skills is essential for advanced surgical education. Training is moving more and more from the operating room to surgical training laboratories. A crucial impulse for this development came from Davos, where the first skills course was organized in 1984 after the formation of the Working Group for Gastro-intestinal (GI) Surgery (AGC Davos). Since this first course more than 5,000 residents have successfully completed the GI skills training course in Davos and many of the alumni are themselves teaching surgery today. The level and quality of this course has remained stable for 27 years on a high quality level although teaching has continuously been adjusted to modern techniques. The language of this international workshop is English. The number of applications exceeds the course capacity every year, which is an indication for the need of such training courses and should be principally included into the skills curriculum for surgeons.

Effect of bisacodyl on postoperative bowel motility in elective colorectal surgery: a prospective, randomized trial.

BACKGROUND: Postoperative ileus is a common condition after abdominal surgery. Many prokinetic drugs have been evaluated including osmotic laxatives. The data on colon-stimulating laxatives are scarce. This prospective, randomized, double-blind trial investigates the effect of the colon-stimulating laxative bisacodyl on postoperative ileus in elective colorectal resections. MATERIALS AND METHODS: Between November 2004 and February 2007, 200 consecutive patients were randomly assigned to receive either bisacodyl or placebo. Primary endpoint was time to gastrointestinal recovery (mean time to first flatus passed, first defecation, and first solid food tolerated; GI-3). Secondary endpoints were incidence and duration of nasogastric tube reinsertion, incidence of vomiting, length of hospital stay, and visual analogue scores for pain, cramps, and nausea. RESULTS: One hundred sixty-nine patients were analyzed, and 31 patients discontinued the study. Groups were comparable in baseline demographics. Time to GI-3 was significantly shorter in the bisacodyl group (3.0 versus 3.7 days, P = 0.007). Of the single parameters defining GI-3, there was a 1-day difference in time to defecation in favor to the bisacodyl group (3.0 versus 4.0 days, P = 0.001), whereas no significant difference in time to first flatus or tolerance of solid food was seen. No significant difference in the secondary endpoints was seen. Morbidity and mortality did not differ between groups. CONCLUSION: Bisacodyl accelerated gastrointestinal recovery and might be considered as part of multimodal recovery programs after colorectal surgery.

[Usher type I syndrome in children: genotype/phenotype correlation and cochlear implant benefits]. / Syndrome de Usher de type I chez l'enfant: corrlation génotype/phénotype et bénéfice de l'implant cochléaire.

OBJECTIVE: To assess the benefit of cochlear implant in children presenting an Usher type 1 syndrome (speech understanding, speech production intelligibility, academic performance) and to search any correlation between the phenotype and the genotype in this population. MATERIALS AND METHODS: Retrospective case series analysis about 13 implanted Usher type I children. Cochlear implantation was performed from 1995 to 2005. Our population was divided in three groups: group 1 (implantation between 1 and 3 years of age); group 2 (implantation between 4 and 7 years of age) and group 3 (implantation between 14 and 17 years of age). Postoperative speech perception, speech production intelligibility and education settings were evaluated. RESULTS: Molecular genetic analysis was performed in 11 patients and pathogenic mutations were identified in all cases: (mutation in myosin 7A gene in 5 cases; mutation in cadherin 23 gene in 6 cases). Four new mutations 2 in the MYO7A gene and 2 in the CDH23 gene never reported before were found. Walking delay and hearing level were not statistically correlated with the genotype abnormalities found. The speech discrimination skills, the speech production intelligibility and the academic performance were better in the group 1 children than the group 2 children after cochlear implantation. All the children of group 1 but one were in mainstreaming education. Specific language impairment was identified in two children of group 1. The group 3 children could not achieve open-set perceptive tasks after implantation--only closed-set word test can be done and their speech production remained unintelligible after cochlear implantation. CONCLUSION: Molecular analysis of Usher type I syndrome can ascertain the diagnosis in spite of the genetic heterogeneity. In this study, clinical symptoms weren't correlated with genotypic mutations. Speech discrimination skills, speech production quality, and academic performance were correlated with the age at implant.

Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium.

Previous studies have tested gene replacement therapy in RPE65-deficient dogs using recombinant adeno-associated virus 2/2 (rAAV2/2), -2/1 or -2/5 mediated delivery of the RPE65 gene. They all documented restoration of dark- and light-adapted electroretinography responses and improved psychophysical outcomes. Use of a specific RPE65 promoter and a rAAV vector that targets transgene expression specifically to the RPE may, however, provide a safer setting for the long-term therapeutic expression of RPE65. Subretinal injection of rAAV2 pseudotyped with serotype 4 (rAAV2/4) specifically targets the RPE. The purpose of our study was to evaluate a rAAV2/4 vector carrying a human RPE65cDNA driven by a human RPE65 promoter, for the ability to restore vision in RPE65-/- purebred Briard dogs and to assess the safety of gene transfer with respect to retinal morphology and function. rAAV2/4 and rAAV2/2 vectors containing similar human RPE65 promoter and cDNA cassettes were generated and administered subretinally in eight affected dogs, ages 8-30 months (n = 6 with rAAV2/4, n = 2 with rAAV2/2). Although fluorescein angiography and optical coherence tomography examinations displayed retinal abnormalities in treated retinas, electrophysiological analysis demonstrated that restoration of rod and cone photoreceptor function started as soon as 15 days post-injection, reaching maximal function at 3 months post-injection, and remaining stable thereafter in all animals treated at 8-11 months of age. As assessed by the ability of these animals to avoid obstacles in both dim and normal light, functional vision was restored in the treated eye, whereas the untreated contralateral eye served as an internal control. The dog treated at a later age (30 months) did not recover retinal function or vision, suggesting that there might be a therapeutic window for the successful treatment of RPE65-/- dogs by gene replacement therapy.

Randomized clinical trial of Lichtenstein's operation versus mesh plug for inguinal hernia repair.

BACKGROUND: Two of the most commonly used open prosthetic tension-free techniques for inguinal hernia repair are Lichtenstein's operation and the mesh plug repair. The technique of choice remains a subject of ongoing debate. The objective of the present investigation was to compare the two surgical procedures with respect to associated morbidity and recurrence rates. METHODS: Five hundred and ninety-five patients with 700 primary or recurrent inguinal hernias were randomized to undergo either Lichtenstein's operation or mesh plug repair. The primary endpoint of the investigation was the recurrence rate 1 year after surgery. Secondary endpoints were perioperative complications and reoperation rates. RESULTS: At 12-month follow-up, 597 hernia repairs (85.3 per cent) were evaluated. There were no significant differences regarding recurrence rates and perioperative complications. However, there was a significant difference in the overall reoperation rate between the two treatment groups, with 13 reoperations (4.2 per cent) in the Lichtenstein group and four (1.4 per cent) in the mesh plug group (P = 0.047). CONCLUSION: Lichtenstein's operation and the mesh plug repair are comparable with respect to perioperative complications and recurrence rates.

Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90%.

BACKGROUND: Usher syndrome, a devastating recessive disorder which combines hearing loss with retinitis pigmentosa, is clinically and genetically heterogeneous. Usher syndrome type 1 (USH1) is the most severe form, characterised by profound congenital hearing loss and vestibular dysfunction. OBJECTIVE: To describe an efficient protocol which has identified the mutated gene in more than 90% of a cohort of patients currently living in France. RESULTS: The five genes currently known to cause USH1 (MYO7A, USH1C, CDH23, PCDH15, and USH1G) were tested for. Disease causing mutations were identified in 31 of the 34 families referred: 17 in MYO7A, 6 in CDH23, 6 in PCDH15, and 2 in USH1C. As mutations in genes other than myosin VIIA form nearly 50% of the total, this shows that a comprehensive approach to sequencing is required. Twenty nine of the 46 identified mutations were novel. In view of the complexity of the genes involved, and to minimise sequencing, a protocol for efficient testing of samples was developed. This includes a preliminary linkage and haplotype analysis to indicate which genes to target. It proved very useful and demonstrated consanguinity in several unsuspected cases. In contrast to CDH23 and PCDH15, where most of the changes are truncating mutations, myosin VIIA has both nonsense and missense mutations. Methods for deciding whether a missense mutation is pathogenic are discussed. CONCLUSIONS: Diagnostic testing for USH1 is feasible with a high rate of detection and can be made more efficient by selecting a candidate gene by preliminary linkage and haplotype analysis.

Ileocecal reservoir reconstruction after total mesorectal excision: functional results of the long-term follow-up.

BACKGROUND: The aim of this study is to obtain functional results of the long-term follow-up after TME and ileocecal interposition as rectal replacement. METHODS: The study included patients operated on between March 1993 and August 1997 who received an ileocecal interposition as rectal replacement. Follow-up was carried out 3 and 5 years postoperatively. For statistical analysis, the paired t-test, rank test (Wilcoxon), and chi-square or Fisher's exact test were applied; level of significance, P<0.05. RESULTS: Forty-four patients were included in the studies. Of these, five were not available and four patients could not be evaluated (dementia 1, radiation proctitis 1, fistula 1, pouchitis 1). Seventeen patients died during the observation period; 12 died of the disease. Recurrence of the disorder occurred in 2 of 35 patients (5.7%); 26 and 18 patients, 3 and 5 years postoperatively, respectively remained in the study. At 5 years, 78% of the patients were continent; mean stool frequency was 2.5+/-1.6 per day. CONCLUSIONS: Functional results and subjective assessment of ileocecal interposition were constant at 3 and 5 years postoperatively. If construction of a colonic J-pouch is not possible due to lack of colonic length, especially after prior colonic resections, the ileocecal interpositional reservoir may offer an alternative to rectal replacement.

[Laparoscopic treatment for Crohn's disease]. / Trattamento laparoscopico del morbo di Crohn.

AIM: Several studies have demonstrated the feasibility and safety of laparoscopic surgery for Crohn's disease. A trend towards less morbidity as compared to laparotomy has been suggested. However, problems noted early in the experience may have prevented the optimal benefit from having been conferred. Accordingly, the aim of this study was to evaluate perioperatively those patients. METHODS: All 51 patients with Crohn's disease who underwent an intestinal resection at Cleveland Clinic Florida between January 1997 and December 1998 were analyzed. RESULTS: Seventeen patients underwent laparoscopic treatment: there were no significant differences between the 2 groups as to age, gender, incidences of comorbidity, prior laparotomy, or the use of anti-inflammatory and immunosuppressive agents. Similarly, there were no significant differences between the 2 groups as to either surgical indication, intraoperative findings, or procedure performed. Moreover, there were no significant differences concerning total anesthetic time or surgical operative time, the incidence of intraoperative morbidity or need for enterolysis or stoma construction, use of intraoperative endoscopy, or need for transfusion. Significant differences were noted in the duration of patient controlled analgesic usage (3.1 days in the laparoscopic group vs 3.9 days, respectively; p = 0.03), the incidence of postoperative morbidity (7/17 patients in the laparoscopic group vs 27/34 patients: p = 0.01), and length of hospital stay (6.4 days in the laparoscopic group vs 9.6 days, respectively; p = 0.05). CONCLUSIONS: In this retrospective cohort comparative study, laparoscopic intestinal resection for Crohn's disease, when compared to laparotomy, was associated with a short duration of patient controlled analgesic usage, a lower incidence of postoperative morbidity and a shorter hospital stay, without significantly increased operative time.

[Laparoscopic surgery for endoscopically irretrievable colonic polyps]. / Chirurgia laparoscopica dei polipi del colon non asportabili endoscopicamente.

AIM: The vast majority of benign colorectal neoplasms can be safely removed by colonoscopic polypectomy; while peduncolated polyps can be easily endoscopically excised, the removal of sessile polyps may be more difficult. METHODS: Between January 1997 and December 1998, 12 patients underwent laparoscopic or laparoscopic-assisted colonic resection for treatment of endoscopically irretrievable colonic polyps; this group was compared to 12 patients who underwent a laparotomic approach for polyps in the same period of time and to 23 patients who previously underwent similar laparoscopic resections. RESULTS: There were no significant differences between laparoscopic and laparotomic groups. CONCLUSION: Laparoscopic or laparoscopic-assisted colonic resection for treatment of endoscopically irretrievable colonic polyps remains our preferred method of treating these lesions.

Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437.

An increasing number of experimental chemotherapeutic agents induce apoptosis by directly triggering mitochondrial membrane permeabilization (MMP). Here we examined MMP induced by lonidamine, arsenite, and the retinoid derivative CD437. Cells overexpressing the cytomegalovirus-encoded protein vMIA, a protein which interacts with the adenine nucleotide translocator, were strongly protected against the MMP-inducing and apoptogenic effects of lonidamine, arsenite, and CD437. In a cell-free system, lonidamine, arsenite, and CD437 induced the permeabilization of ANT proteoliposomes, yet had no effect on protein-free liposomes. The ANT-dependent membrane permeabilization was inhibited by the two ANT ligands ATP and ADP, as well as by recombinant Bcl-2 protein. Lonidamine, arsenite, and CD437, added to synthetic planar lipid bilayers containing ANT, elicited ANT channel activities with clearly distinct conductance levels of 20+/-7, 100+/-30, and 47+/-7 pS, respectively. Altering the ATP/ADP gradient built up on the inner mitochondrial membrane by inhibition of glycolysis and/or oxidative phosphorylation differentially modulated the cytocidal potential of lonidamine, arsenite, and CD437. Inhibition of F(0)F(1)ATPase without glycolysis inhibition sensitized to lonidamine-induced cell death. In contrast, only the combined inhibition of glycolysis plus F(0)F(1)ATPase sensitized to arsenite-induced cell death. No sensitization to cell death induction by CD437 was achieved by glucose depletion and/or oligomycin addition. These results indicate that ANT is a target of lonidamine, arsenite, and CD437 and unravel an unexpected heterogeneity in the mode of action of these three compounds.

Laparoscopic surgery for inflammatory bowel disease.

BACKGROUND: Common laparoscopic colorectal procedures in patients with Crohn's disease include ileocolic resection and subtotal colectomy. The aim of this study was to compare and contrast the results of these two procedures. METHODS: Patients who underwent one of these procedures between June 1992 and January 1999 were identified and included in the study. Statistical analysis was performed using the Mann-Whitney test, Student's t-test, or Fisher's exact test. RESULTS: In all 109 patients (63 women and 46 men) with an average age of 36.7 years (range, 15-74) underwent ileocolic resection (ICR), while 21 patients (16 women and five men) with an average age of 36.5 years (range, 18-77) underwent subtotal colectomy (STC) (p = NS). There were 14 intraoperative complications, eight (7%) in the ICR group and six (29%) in the STC group (p = 0.01). Total operative time was 167 min (range, 90-285) in the ICR group and 231 min (range, 140-340) in the STC group (p < 0.01). Despite this difference in operating time, the hospital stays were very similar at 8.8 days (range, 3-27) and 8.8 days (range, 3-14) (p = NS). In 19 (17%) of the ICR patients and five (24%) of the STC patients, their procedure was converted to a laparotomy (p = NS). In the ICR group, 20 of the patients (18%) had surgery-related postoperative complications, including five anastomotic leaks. In the STC group, six of the patients (29%) had surgery-related complications, including two anastomotic leaks (p = NS). CONCLUSION: Although STC is a far more extensive procedure than ICR, the overall postoperative complication rate is not significantly different between the two groups; however, we found that there were more intraoperative complications associated with STC.

Restorative proctocolectomy with ileal pouch anal anastomosis in obese patients.

BACKGROUND: Obesity is a relative contraindication to performing restorative proctocolectomy. The aim of this study was to assess the morbidity and functional results after restorative proctocolectomy in obese patients as compared to a matched cohort of non-obese patients. METHODS: 334 patients who had restorative proctocolectomy were reviewed; obesity was defined as a body mass index (BMI) greater than or equal to 30 kg/m2. 31 obese patients were matched to 31 non-obese patients for age, gender, steroid use, and diagnosis. Operative time, length of hospitalization, and both perioperative (< 6 weeks) and long-term morbidity (> 6 weeks), especially sepsis, were evaluated. RESULTS: The BMI was significantly higher in the obese group (33.7 vs 23.2) (p < 0.0001), and no difference was found between the obese and non-obese groups relative to the matched parameters of age, gender, steroid use and diagnosis. There was no difference in the rate of mucosectomy performed between the obese and non-obese patients (9.6% vs 3.2%, p = NS). 16% of the obese patients underwent one stage restorative proctocolectomies as compared to 10% in the non-obese group. Operative time was longer in the obese group (229 min vs 196 min; p = 0.02), but overall hospital length of stay was similar (9.7 days vs 7.7 days; p = 0.13). Perioperative morbidity was higher in obese patients (32% vs 9.6%, p = 0.058). However, there was no statistical significance in long-term morbidity (23% vs 32%, p = 0.57) at a mean follow-up of 51 months in the obese group and 53 months in the non-obese group. Obese patients had more stomal complications (10 vs 0%) and incisional hernias (13 vs 3%) (p = NS). Overall the pelvic sepsis-rate was significantly higher in the obese group (16 vs 0%; p < 0.05). 60% of the obese patients who developed pelvic sepsis had pouch-anal anastomosis performed without proximal fecal diversion. Mean bowel movements/24 hours, pad use, nocturnal evacuation, accidents/24 hours and incontinence scores were not statistically significant between the groups. CONCLUSION: Obese patients have a higher rate of pelvic sepsis and peri-operative morbidity when compared to a matched non-obese cohort of patients; however, the functional outcome of restorative proctocolectomy in obese patients is not significantly different than in non-obese patients.

The adenine nucleotide translocator: a target of nitric oxide, peroxynitrite, and 4-hydroxynonenal.

Nitric oxide (NO), peroxynitrite, and 4-hydroxynonenal (HNE) may be involved in the pathological demise of cells via apoptosis. Apoptosis induced by these agents is inhibited by Bcl-2, suggesting the involvement of mitochondria in the death pathway. In vitro, NO, peroxynitrite and HNE can cause direct permeabilization of mitochondrial membranes, and this effect is inhibited by cyclosporin A, indicating involvement of the permeability transition pore complex (PTPC) in the permeabilization event. NO, peroxynitrite and HNE also permeabilize proteoliposomes containing the adenine nucleotide translocator (ANT), one of the key components of the PTPC, yet have no or little effects on protein-free control liposomes. ANT-dependent, NO-, peroxynitrite- or HNE-induced permeabilization is at least partially inhibited by recombinant Bcl-2 protein, as well as the antioxidants trolox and butylated hydroxytoluene. In vitro, none of the tested agents (NO, peroxynitrite, HNE, and tert-butylhydroperoxide) causes preferential carbonylation HNE adduction, or nitrotyrosylation of ANT. However, all these agents induced ANT to undergo thiol oxidation/derivatization. Peroxynitrite and HNE also caused significant lipid peroxidation, which was antagonized by butylated hydroxytoluene but not by recombinant Bcl-2. Transfection-enforced expression of vMIA, a viral apoptosis inhibitor specifically targeted to ANT, largely reduces the mitochondrial and nuclear signs of apoptosis induced by NO, peroxynitrite and HNE in intact cells. Taken together these data suggest that NO, peroxynitrite, and HNE may directly act on ANT to induce mitochondrial membrane permeabilization and apoptosis.

Control of mitochondrial membrane permeabilization by adenine nucleotide translocator interacting with HIV-1 viral protein rR and Bcl-2.

Viral protein R (Vpr), an apoptogenic accessory protein encoded by HIV-1, induces mitochondrial membrane permeabilization (MMP) via a specific interaction with the permeability transition pore complex, which comprises the voltage-dependent anion channel (VDAC) in the outer membrane (OM) and the adenine nucleotide translocator (ANT) in the inner membrane. Here, we demonstrate that a synthetic Vpr-derived peptide (Vpr52-96) specifically binds to the intermembrane face of the ANT with an affinity in the nanomolar range. Taking advantage of this specific interaction, we determined the role of ANT in the control of MMP. In planar lipid bilayers, Vpr52-96 and purified ANT cooperatively form large conductance channels. This cooperative channel formation relies on a direct protein-protein interaction since it is abolished by the addition of a peptide corresponding to the Vpr binding site of ANT. When added to isolated mitochondria, Vpr52-96 uncouples the respiratory chain and induces a rapid inner MMP to protons and NADH. This inner MMP precedes outer MMP to cytochrome c. Vpr52-96-induced matrix swelling and inner MMP both are prevented by preincubation of purified mitochondria with recombinant Bcl-2 protein. In contrast to König's polyanion (PA10), a specific inhibitor of the VDAC, Bcl-2 fails to prevent Vpr52-96 from crossing the mitochondrial OM. Rather, Bcl-2 reduces the ANT-Vpr interaction, as determined by affinity purification and plasmon resonance studies. Concomitantly, Bcl-2 suppresses channel formation by the ANT-Vpr complex in synthetic membranes. In conclusion, both Vpr and Bcl-2 modulate MMP through a direct interaction with ANT.

Effect of age on the functional outcome of total abdominal colectomy for colonic inertia.

OBJECTIVE: Colonic inertia (CI) usually presents in women in the third decade of life; however, elderly patients are at times diagnosed with the disease. Total abdominal colectomy (TAC) is considered the preferred surgical treatment for patients with well established CI refractory to conservative and medical management. Surgeons are reluctant to proceed with colectomy in aged patients because of anticipated high morbidity and poor functional outcome. MATERIALS AND METHODS: We retrospectively reviewed the outcome in 14 patients over the age of 65 years (range 65-80) (Group I) who underwent TAC for CI between 1988 and 1996. The functional and clinical outcome was compared with that of 41 patients under the age of 65 (range 21-61) (Group II) operated upon during the same time period. Functional outcome was assessed by postal and telephone questionnaires at least 12 months following surgery. RESULTS: There was no major postoperative morbidity in either group. Three (21%) patients in Group I developed small bowel obstruction postoperatively and, of them, 2 required surgical treatment. In Group II the rate of obstruction was 7% (3 patients), with one patient requiring surgery. One patient in Group I subsequently underwent completion proctectomy and creation of an end ileostomy due to continued panenteric hypomotility. Three patients in Group I died during follow-up from causes unrelated to surgery. The mean frequency of spontaneous bowel movements following surgery was 3.8 (range 1-10)/day in Group I and 2.9 (range 1-8)/day in Group II (P=NS). 'Excellent' outcome was reported by 7 patients (64%) in Group I and 39 patients (95%) in Group II (P=0.01). CONCLUSION: TAC can be performed in elderly patients with established CI with acceptable functional results and no increase in morbidity, resulting in lifestyle improvement. Complete physiological evaluation with increased emphasis on small bowel and gastric motility studies is required in this patient population.