Exome Sequence Data From Multigenerational Families Implicate AMPA Receptor Trafficking in Neurocognitive Impairment and Schizophrenia Risk

Schizophrenia is a mental disorder characterized by impairments in behavior, thought, and neurocognitive performance. We searched for susceptibility loci at a quantitative trait locus (QTL) previously reported for abstraction and mental flexibility (ABF), a cognitive function often compromised in schizophrenia patients and their unaffected relatives. Exome sequences were determined for 134 samples in 8 European American families from the original linkage study, including 25 individuals with schizophrenia or schizoaffective disorder. At chromosome 5q32–35.3, we analyzed 407 protein-altering variants for association with ABF and schizophrenia status. For replication, significant, Bonferroni-corrected findings were tested against cognitive traits in Mexican American families (n = 959), as well as interrogated for schizophrenia risk using GWAS results from the Psychiatric Genomics Consortium (PGC). From the gene SYNPO, rs6579797 (MAF = 0.032) shows significant associations with ABF (P = .015) and schizophrenia (P = .040), as well as jointly (P = .0027). In the Mexican American pedigrees, rs6579797 exhibits significant associations with IQ (P = .011), indicating more global effects on neurocognition. From the PGC results, other SYNPO variants were identified with near significant effects on schizophrenia risk, with a local linkage disequilibrium block displaying signatures of positive selection. A second missense variant within the QTL, rs17551608 (MAF = 0.19) in the gene WWC1, also displays a significant effect on schizophrenia in our exome sequences (P = .038). Remarkably, the protein products of SYNPO and WWC1 are interaction partners involved in AMPA receptor trafficking, a brain process implicated in synaptic plasticity. Our study reveals variants in these genes with significant effects on neurocognition and schizophrenia risk, identifying a potential pathogenic mechanism for schizophrenia spectrum disorders.Key words: schizophrenia, cognition, SYNPO, WWC1, synaptic plasticity     

Pilot double-blind, randomized controlled trial of short-term atorvastatin for prevention of acute kidney injury after cardiac surgery

Aim: To test whether short‐term perioperative administration of oral atorvastatin could reduce incidence of postoperative acute kidney injury (AKI) in cardiac surgical patients. Methods: We conducted a double‐blind, randomized controlled trial in 100 cardiac surgical patients at increased risk of postoperative AKI. Patients were randomized to atorvastatin (40 mg once daily for 4 days starting preoperatively) or identical placebo capsule. Primary outcome was to detect a smaller absolute rise in postoperative creatinine with statin therapy. Secondary outcomes included AKI defined by the creatinine criteria of RIFLE consensus classification (RIFLE R, I or F), change in urinary neutrophil gelatinase‐associated lipocalin (NGAL) concentration, requirement for renal replacement therapy, length of stay in intensive care, length of stay in hospital and hospital mortality. Results: Study groups were well matched. For each patient maximal increase in creatinine during the 5 days after surgery was assessed; median maximal increase was 28 µmol/L in the atorvastatin group and 29.5 µmol/L in the placebo group (P = 0.62). RIFLE R or greater occurred in 26% of patients with atorvastatin and 32% with placebo (P = 0.65). Postoperatively urine NGAL changes were similar (median NGAL : creatinine ratio at intensive care unit admission: atorvastatin group 1503 ng/mg, placebo group 1101 ng/mg; P = 0.22). Treatment was well tolerated and adverse events were similar between groups. Conclusion: Short‐term perioperative atorvastatin use was not associated with a reduced incidence of postoperative AKI or smaller increases in urinary NGAL. (ClinicalTrials.gov NCT00910221).     

Evolution of Treatment of Fistula in Ano

Background  

Fistula-in-ano is a common medical problem affecting thousands of patients annually. In the past, the options for treatment of fistula-in-ano were limited to fistulotomy and/or seton placement. Current treatment options also include muscle-sparing techniques such as a dermal island flap, endorectal advancement flap, fibrin sealent injection, anal fistula plug, and most recently ligation of the intersphincteric fistula tract (procedure). This study seeks to evaluate types and time trends for treatment of fistula-in-ano.     

Propeller DICAP flap for a large defect on the back—Case report and review of the literature

Reconstruction of large soft tissue defects of the back is a challenging problem. Large defects of the back were reconstructed with multiple random pattern or local pedicled muscle (and skin graft) or musculocutaneous flaps. The clinical use of perforator flaps has demonstrated that harvesting of flaps on a single perforator is possible for reconstruction of large defects. We present a 71‐year‐old male with a lesion on his left mid back that measured 10 × 10 × 4 cm³. Biopsy of the lesion was consistent with dermatofibrosarcoma protruberans. Wide local excision of the lesion with 4 cm margin was performed. The soft tissue defect, ～20 cm in diameter, was reconstructed with a large propeller dorsal intercostal artery perforator (DICAP) flap. The DICAP flap measured 40 × 15 cm² based on a single perforator—lateral branch of dorsal rami of the seventh posterior intercostal artery on the right side. The perforator flap was elevated at the subfascial level and transposed 180° into the defect. The donor site on the right side of the back was closed directly. This case illustrates the size of the propeller DICAP flap that could be safely harvested on a single perforator from the dorsal rami of the posterior intercostal artery. To our knowledge this is the largest reported pedicled perforator flap harvested on a single perforator on the posterior trunk. © 2012 Wiley Periodicals, Inc. Microsurgery, 2012.     

Two in one: Double free flap from a single free fibula osteocutaneous unit

In the past two decades, the advancement in the microsurgical techniques has revolutionised the reconstruction of post-oncological head and neck defects. Free fibula osteocutaneous flap (FFOCF) has been considered as the treatment of choice by many for mandible reconstruction. The improvement in the surgical resection and adjuvant treatment has improved the survival rates even in patients with advanced cancer. Simultaneously the reconstruction is addressed towards more functional and aesthetic aspects to improve the quality of life in these patients. In this respect, a double free flap is advocated in certain cases of extensive composite oromandibular defects (COMDs). But in our institute, we have managed two such cases of extensive COMD with a single FFOCF unit – fibula bone with a skin paddle for inner lining and a perforator-based skin paddle from the proximal part of the FFOCF unit, anastomosed separately for outer cover. Compared to two separate free flaps, this method has the advantage of single donor site and reduction in reconstruction time. Though the technique of divided paddle, deepithelisation and supercharging has been mentioned for FFOCF, no such clinical cases of two free flaps from a single FFOCF unit have been mentioned in the literature.KEY WORDS: Composite oromandibular defect, double free flap, free fibula osteocutaneous flap     

Trends in reporting Gleason score 1991 to 2001: changes in the pathologist's practice

OBJECTIVE: The prostate specific antigen (PSA) era has been associated with a grade migration towards moderately-differentiated (Gleason 5-7) prostate cancer. We investigated whether changes in interpretation of the Gleason system could be a contributing factor by reviewing the Gleason scores for prostate cancer in our region. PATIENTS AND METHODS: Records of patients with prostate cancer assigned a Gleason score between 1991-2001 were retrospectively reviewed. We analysed trends in Gleason score, method of diagnosis and age at diagnosis. Following this, 50 cases from the dataset were randomly selected (stratified to contain half Gleason 2-4 reports) and reviewed in a blinded manner by an uropathologist and given a new Gleason score. RESULTS: 2737 patients were diagnosed and given a Gleason score; 1484 by prostate biopsy (PB) and 1172 by transurethral resection of prostate (TURP). 273 radical prostatectomy (RP) specimens were received, although the results of pre-operative biopsies were available in only 192 of these patients. Over time, there was an increase in the proportion of patients with Gleason 5-7, and a significant decrease in reporting of Gleason 2-4 cancer (r2 = 0.81, p < 0.0001). In 1991, 24% of cancers were Gleason 2-4; in 2001 this had decreased to 2.4%. TURP was associated with more Gleason 2-4 reports (23%) compared with PB (13.2%) and RP (9.2%). On blinded review, all Gleason 2-4 reports were upgraded to Gleason 5-7 cancer (p < 0.001). CONCLUSION: Over time, the proportion of Gleason 2-4 prostate cancer reported has significantly decreased. Our study suggests that a change in practice by the pathologist is a significant factor in this grade migration.     

The effect of traction on compartment pressures during intramedullary nailing of tibial-shaft fractures. A prospective randomised trial

Our aim was to study the effect of traction on the compartment pressures during intramedullary nailing of closed tibial-shaft fractures. Thirty consecutive patients with Tscherne C1 fractures were randomised into two groups. Sixteen patients underwent intramedullary nailing of the tibia with traction and 14 patients without traction. Compartment pressures were measured before the application of traction or commencement of the procedure and at the end of the procedure. The data collected was analysed using Students t test. There was no statistically significant difference (p>0.05) in the pre-operative mean compartment pressures for both groups. The mean post-operative measurements were higher in all four compartments in the traction group (p<0.05). None of the pressures reached the critical level. These results show that traction as an aid unnecessarily increases compartment pressures.

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Résumé Notre but était détudier leffet de la traction sur la tension compartimentale pendant lenclouage centromédullaire des fractures tibiales fermées. Trente malades consécutifs avec des fractures Tscherne C1 ont été randomisés dans deux groupes. Seize malades ont subi un enclouage centromédullaire tibial avec traction et quatorze malades sans traction. Les pressions compartimentales ont été mesurées avant la mise en traction ou au commencement de lopération et à la fin de lopération. Les données ont été analysées avec le Student t-test. Il ny avait aucune différence statistiquement significative (p>0.05) dans les pressions moyennes préopératoires des compartiments pour les deux groupes. Les mesures postopératoires moyennes étaient plus élevées dans les quatre compartiments dans le groupe avec traction (p<0.05). Aucune des pressions nest arrivée au niveau critique. Ces résultats montrent que la traction augmente les pressions des compartiments.

     

Permanent induction of morphological abnormalities in the penis and penile skeletal muscles in adult rats treated neonatally with diethylstilbestrol or estradiol valerate: a dose-response study

This study evaluated the effects of neonatal exposure to different doses of diethylstilbestrol (DES) or estradiol valerate (EV) on penile morphology, penile skeletal muscles, and fertility. Male pups received DES or EV at a dose of 10 microg, 1 microg, 100 ng, 10 ng, or 1 ng per rat on alternate days from postnatal days 2-12. Fertility was tested at 120 days, and tissues were examined at 150 days. Generally, DES and EV induced similar effects within the 10- and 1-microg groups. Fertility was reduced to 0; the weight, length, and diameter of the penis and the weight of penile skeletal muscles, especially bulbocavernosus muscle, were decreased (P <.05) in a dose-dependent manner; the preputial sheath was partially released or its release was delayed; testicular descent was delayed; and the cavernous spaces and smooth muscle cells in the corpora cavernosa penis were replaced by fat cells. Conversely, all of the above parameters were similar in controls and the lower dose groups, except in the 100-ng DES group, in which 4 of 7 males did not sire pups (compared with 1 of 7 in controls and 2 of 6 in the 100-ng EV group). The loss of fertility in these 4 males of the DES group and 1 male of the EV group was associated with partial release of the preputial sheath and abnormal penile morphology. Plasma testosterone was reduced (P <.05) in the 100-ng and higher dose groups for DES and EV. Hence, neonatal exposure to DES or EV at a cumulative dose of 600 ng per rat or more lowers fertility, which is associated with permanent alterations in penile morphology and penile skeletal muscles and decreased testosterone.     

Clinical results of Keller's arthroplasty

Fifty cases of hallux valgus treated by Keller's arthroplasty were reviewed over an average period of 91 months. This revealed radiographic changes in the first metatarsal head suggestive of avascular necrosis (AVN) in as many as eight feet. The blood supply to the first metatarsal head and probable cause of these AVN changes are discussed.     

Recrudescent Tobacco Exposure Following Heart Transplantation: Clinical Profiles and Relationship with Athero-Thrombosis Risk Markers

To identify tobacco recidivism among 86 heart transplant recipients who were smokers but demonstrated compliance with a smoking cessation program pre-transplant, we used a questionnaire and randomly tested urine for nicotine and its by-products. In 36 patients, we also evaluated circulating levels of HS-CRP, homocysteine and MPV. Twenty-eight (32.5%) of 86 patients met our definition for tobacco exposure. In this cohort, 28 (32.5%) of 86 patients met our definition for tobacco exposure. Of these 28, 12 patients self-reported tobacco use and demonstrated biochemical verification; 14 patients demonstrated only biochemical evidence of significant tobacco exposure; 2 patients self-reported tobacco use but did not demonstrate biochemical positivity. Smoking cessation within 6 months of transplantation (r = 0.52) and time post-transplantation (r = 0.43) were independent predictors for recidivism of tobacco use, p < 0.01. No differences in HS-CRP, homocysteine and MPV levels were noted among the groups. Our investigation demonstrates a high rate of tobacco recidivism among heart transplant recipients, yet few admit to it. The adverse effects of tobacco do not appear to be directly modulated by an effect on athero-thrombotic risk markers.