Transcriptional targets of the schizophrenia risk gene MIR137.

Genome-wide association studies (GWAS) have strongly implicated MIR137 (the gene encoding the microRNA miR-137) in schizophrenia. A parsimonious hypothesis is that a pathway regulated by miR-137 is important in the etiology of schizophrenia. Full evaluation of this hypothesis requires more definitive knowledge about biological targets of miR-137, which is currently lacking. Our goals were to expand knowledge of the biology of miR-137 by identifying its empirical targets, and to test whether the resulting lists of direct and indirect targets were enriched for genes and pathways involved in risk for schizophrenia. We overexpressed miR-137 in a human neural stem cell line and analyzed gene expression changes at 24 and 48 h using RNA sequencing. Following miR-137 overexpression, 202 and 428 genes were differentially expressed after 24 and 48 h. Genes differentially expressed at 24 h were enriched for transcription factors and cell cycle genes, and differential expression at 48 h affected a wider variety of pathways. Pathways implicated in schizophrenia were upregulated in the 48 h findings (major histocompatibility complex, synapses, FMRP interacting RNAs and calcium channels). Critically, differentially expressed genes at 48 h were enriched for smaller association P-values in the largest published schizophrenia GWAS. This work provides empirical support for a role of miR-137 in the etiology of schizophrenia.

The cutaneous course of deep inferior epigastric perforators: implications for flap thinning.

BACKGROUND: The deep inferior epigastric artery (DIEA) perforator flap is frequently used for autologous breast reconstruction following mastectomy. Thinning of the flap is often performed to debulk the flap of excess fatty tissue, such as in partial mastectomy defects. Thinning may disrupt the blood supply to the flap and compromise viability, however adequate guidelines for thinning are lacking from the literature. METHODS: Clinical and anatomical studies were concurrently undertaken to explore the cutaneous course of perforators as a guide to flap thinning. Twenty consecutive patients undergoing DIEA perforator flap breast reconstruction underwent preoperative computerised tomography angiography (CTA), and a cadaveric study was also undertaken, in which six fresh, whole abdominal walls underwent CTA. All perforators greater than 2 mm were analysed for their cutaneous course. RESULTS: In all cases, perforators emerged from the anterior rectus sheath and traversed an oblique, but direct course through the deep layer of adipose tissue, before reaching Scarpa's fascia. Branching of perforators occurred in two planes of the superficial adipose layer: just superficial to Scarpa's fascia (the fascial plexus) and in the subdermal plexus. CONCLUSION: Thinning of DIEA perforator flaps can only be performed safely deep to Scarpa's fascia. Thinning performed superficial to Scarpa's fascia threatens the intrinsic blood supply to the flap.

The abductor digiti minimi flap: a case report and review.

The use of an abductor digiti minimi flap is reported here for coverage of a dorso-ulnar defect of the hand following excision of a tumour. This flap has not been widely used before. The abductor digiti minimi flap appears to have minimal donor site morbidity and a reliable vascular supply, and is straightforward to raise. The authors consider it would be a useful flap to provide cover on the ulnar side of the hand and wrist in patients who do not require highly dextrous use of the little finger.

Patient perspectives on smoking and peripheral vascular disease. A veteran population survey.

In keeping with the recent emphasis on smoking and health, we conducted a survey of patients with peripheral vascular disease in our institution. The objective of the survey was to examine the patient's perspective on a) the relative contribution of smoking to his disease, b) the value of alternative measures to encourage smoking cessation, and c) the smoker's role and responsibility in payment for future health care. One hundred sixty patients at the VAMC in Palo Alto, California, participated in the study. The participants were men who had visited the clinic with complaints related to vascular insufficiency. The "typical" smoker from our survey a) had smoked for more than 30 years, b) acknowledges the association between smoking and disease, and c) will not stop smoking until serious health problems intervene. The majority of respondents expected the same health care regardless of smoking history and did not endorse paying more for health services. Most patients identified serious heart and lung disease as potential sequelae of cigarette smoking, however only 44 per cent of active smokers attributed their peripheral vascular disease to smoking. Although the survey was conducted on patients with complaints related to vascular insufficiency, few respondents identified an association in smoking with gangrene of the lower extremity or leg amputations. It is unclear whether this represents a failure on the part of health professionals to stress this relationship or denial on the part of the smoker. Physicians should continue to advise against cigarette smoking. A strong relationship between continued smoking and lower extremity ischemia or amputation needs to be emphasized in the clinical setting and through public health information campaigns.

Semiclosed transfemoral iliac endarterectomy with an oscillating ring stripper.

The technique of endarterectomy for the removal of occlusive atherosclerotic lesions of the aorta and iliac arteries has been utilized successfully in the revascularization of ischemic limbs since its introduction in 1951. The oscillating loop endarterectomy device (Amsco-Hall arterial oscillator) has proven to be useful for endarterectomy of segmental occlusive disease as a substitute for bypass with prosthetic graft. For our elderly debilitated patients, we have adopted a new technique of semiclosed transfemoral iliac endarterectomy for management of occlusive external iliac disease with a patent common iliac artery. We report seven patients treated during May 1987 through May 1988 for external iliac artery occlusion by transfemoral oscillating loop endarterectomy. At 12 months for follow-up review, the cumulative limb salvage rate was 80% with no perioperative mortality. One patient required above-knee amputation eight months following endarterectomy to control forefoot sepsis. Two patients required subsequent leg bypass procedures to achieve full healing of foot level amputation. One patient required dilatation of residual stenosis at the iliac bifurcation by percutaneous balloon angioplasty. Semiclosed transfemoral endarterectomy with the Amsco-Hall oscillating loop device remains an attractive option to the vascular surgeon for recanalization of the iliac artery without the need for an extensive retroperitoneal dissection.

Digital manipulation of the thrombosed arterio-venous conduit.

The utility of a bedside technique for digital manipulation of the thrombosed arterio-venous conduit was retrospectively reviewed. During an 18 month period the records of all patients at this institution who were undergoing chronic hemodialysis, via a forearm modified arterial bovine heterograft, and who were successfully treated by digital manipulation for graft thrombosis were examined. Thirteen patients who underwent 30 successful graft manipulations constituted the study group. Bedside manipulation attempts were performed from one to 72 hours from the period of last known function. Complete response to the technique was indicated by the appearance of a pulse and panrhythmic bruit and thrill throughout the conduit. The average duration of restored flow was 58.6 days (range one to 430 days). No serious or life threatening complications (e.g. problems related to pulmonary thromboembolism) were observed. Conduit thrombosis secondary to faculty cannulation, prior hypotension, or extrinsic compression was amenable to the technique; however, when occlusion was secondary to an intrinsic problem in the graft (stenosis of the venous or arterial anastomosis), operative revision was required. If successful, the technique allows for immediate dialysis access without the need for additional measures. The procedure has negligible morbidity and can spare the patient considerable time and expense.

Transendoscopic balloon dilatation of complete colonic obstruction. An adjunct in the treatment of colorectal cancer: report of three cases.

Complete colonic obstruction secondary to colorectal cancer has traditionally been managed by a staged approach. Simple diversion or resection with colostomy is performed followed by reestablishment of intestinal continuity at a subsequent operation. The use of a transendoscopic technique of balloon dilatation for complete malignant obstruction in the management of three patients is discussed. Successful balloon dilatation allowed for complete bowel preparation and either elective single-stage resection or controlled Nd:YAG laser palliation in a clean field. Although not applicable to all clinical situations, balloon dilatation is a valuable adjunct in the management of obstructing colorectal cancer. Relief of obstruction by tumor dilatation allows 1) correction of fluid and electrolyte abnormalities, 2) administration of a complete bowel preparation, 3) single-stage resection and anastomosis, or 4) palliative laser photoablative therapy that avoids the need for colostomy.

Carotid endarterectomy in a general surgical training program.

Concern regarding the quality of surgical treatment performed within resident training programs and the need for direct, active involvement of the attending surgeon have been issues of interest to surgeons and the public. To provide specialized training in the diagnosis and treatment of vascular disease, vascular surgical fellowships have been established. In institutions with established vascular fellowships, one may question whether general surgical residents or vascular surgical fellows should perform carotid endarterectomies. The majority of carotid reconstructive procedures are performed at our institution by the chief general surgical resident under direct supervision. We elected to review our experience with surgical treatment of the carotid artery in an effort to examine the safety of this practice. The record of all patients who underwent carotid endarterectomy or reconstruction from April 1980 to July 1984 were reviewed. One hundred and twenty-nine patients who underwent 153 reconstructions of the carotid artery constituted the study group. The indication for operation was symptomatic carotid atheromatous disease in 96 and asymptomatic disease in 57. Ninety-three per cent of the procedures were performed by the chief general surgical resident under the supervision of one attending surgeon. Although the incidence of associated systemic problems (hypertension, diabetes and coronary artery disease) was significant in the study group, postoperative cardiovascular and cranial nerve and central neurologic deficits were 1.3 per cent, respectively, with no operative mortality. At our institution, the performance of carotid endarterectomy under close supervision provides an excellent context in which the resident in training may learn precise and careful dissection of the tissue and arterial repair. The need for formal vascular surgical fellowships to develop proficiency in judgment, technique and management of vascular disease is not questioned. However, as a learning experience for the general surgical resident, we believe this practice is both safe and effective, and a high standard of patient care is not compromised.

Endotoxin and pulmonary cell injury.

The physiopathologic similarity between adult respiratory distress syndrome (ARDS) secondary to sepsis and endotoxin-induced pulmonary abnormalities has provided extensive descriptive information confirming bacterial endotoxin as a factor initiating the heterogeneous pulmonary changes in ARDS. The present studies have used an established in vitro model for pulmonary cell injury to examine bacterial endotoxin 1, as a direct cytotoxic agent on the two major alveolar cell types, pulmonary endothelium and epithelium; 2, as a stimulant of neutrophil-mediated pulmonary cell injury, and 3, to examine effector mechanisms of cell-mediated damage by studying the potential effectiveness of antioxidants and antiproteolytic agents in the inhibition of this process. Endotoxin direct toxicity and stimulation of neutrophil-mediated pulmonary cell injury was observed in both pulmonary cell populations in systems free of activated serum complement. Endothelial cells were observed to be more susceptible to both the direct effect of endotoxin and to neutrophil-mediated injury when compared with epithelial cell derived monolayers. The addition of an antiprotease (soybean trypsin inhibitor [STI]) was superior to antioxidants (catalase, superoxide dismutase) in reducing the neutrophil-mediated endothelial toxicity (stimulated 51CR per cent release) observed. A 92 per cent degree of protection was observed with the highest dose of STI (5 milligrams per milliliter) used. Proteases released by activated neutrophils on endotoxin stimulation appear to be the predominant toxic species responsible for endothelial injury in this system.

Amputation level and distal bypass salvage of the limb.

The feasibility of revascularization of the lower extremity for salvage of the limb with grafts to the tibial and peroneal arteries has been well established. The results of prior reports have suggested that a failed distal bypass may convert a lower extremity amputation to a higher level than afforded by primary amputation. We reviewed all distal, tibial or peroneal artery bypasses performed at our institution during the period of March 1980 through October 1986. Fifty-three patients with 59 threatened lower extremities underwent distal bypass for salvage of the limb. No patient was excluded from review. Thirty-eight patients in the study group had diabetes, and 41 had a prior smoking history. In the postoperative period, six patients were lost to follow-up study, nine patients died, with follow-up data complete in 47 of the study group. The maximum length of follow-up study was 78 months, and the average length was 24 months. Data were examined by life table analysis with respect to cumulative salvage of the limb and graft patency. During the period of review, 12 major amputations were required (nine below-knee and three above-knee) for a cumulative salvage rate of 59 per cent. Of the distal grafts which failed (n = 27), three of 27 of the limbs required above-knee amputation. We conclude that a failed tibial or peroneal artery bypass does not preclude the possibility of salvage of the limb and does not predispose to a subsequent amputation.

Gastrointestinal manifestations of essential mixed cryoglobulinemia.

A patient with essential mixed cryoglobulinemia (EMC) presented initially with gastric ulcers and, six months later, with a lesion of the ileum, mild stricture of the transverse colon, and stricture of the sigmoid colon with deep ulceration. The initial diagnosis was Crohn's disease, but pathologic examination of the resected sigmoid lesion showed vasculitis secondary to EMC. Patients with EMC can present with gastrointestinal manifestations mimicking Crohn's disease. A review and classification of the gastrointestinal manifestations of EMC are presented.

A reappraisal of the Kock continent ileostomy in patients with Crohn's disease.

The diagnosis of Crohn's disease has been considered a contraindication to the construction of a Kock continent ileostomy. From 1975 to 1984, 95 Kock continent ileostomies were performed at the Stanford University Medical Center. The clinical course of seven patients with regional enteritis who were disease-free for five years was reviewed. All of the patients studied were women, with a mean disease-free interval of 7.7 years and a range of follow-up study of four to 50 months. To date, all of the patients are fully continent to gas and ileal effluent. The postoperative complication and revision rate (28 per cent) was comparable with the results cited in the literature for individuals with ulcerative colitis or familial polyposis. When revisions were necessary, patients elected to keep the Kock pouch rather than conversion to a conventional Brooke ileostomy. The authors agree that active regional enteritis is to be considered a contraindication to the construction of a continent ileostomy. However, the benefits afforded a patient with a continent ileal reservoir are substantial and warrant consideration in a select group of patients with Crohn's disease who are disease-free for a minimum of five years.

Quantitation of lipid profiles from isolated serum lipoproteins using small volumes of human serum.

Methodology is described that isolates the individual serum lipoproteins, VLDL, LDL and HDL and quantitates the free cholesterol, esterified cholesterol, triglycerides and phospholipid classes in each fraction using 2-3 mL of serum. The determination of the methyl esters of fatty acids from the various lipid classes is described. The lipoproteins are isolated by non-linear density ultracentrifugation using 1 mL of serum per swinging bucket. The lipids are obtained by solvent extraction. The cholesterol, cholesterol esters and triglycerides are separated by TLC using a petroleum ether:diethyl ether system and the phospholipids are separated using a chloroform:methanol system. All lipid classes are quantitatively determined and recovery data are presented. Analysis of the fatty acid profiles of the lipid classes using GLC is described. The methodology can be adapted to partial determination if in-depth studies are not required.