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Peroxisomal and mitochondrial fatty acid beta-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor alpha and peroxisomal fatty acyl-CoA oxidase. Genotype correlation with fatty liver phenotype.

Fatty acid β-oxidation occurs in both mitochondria and peroxisomes. Long chain fatty acids are also metabolized by the cytochrome P450 CYP4A ω-oxidation enzymes to toxic dicarboxylic acids (DCAs) that serve as substrates for peroxisomal β-oxidation. Synthetic peroxisome proliferators interact with peroxisome proliferator activated receptor α (PPARα) to transcriptionally activate genes that participate in peroxisomal, microsomal, and mitochondrial fatty acid oxidation. Mice lacking PPARα (PPARα−/−) fail to respond to the inductive effects of peroxisome proliferators, whereas those lacking fatty acyl-CoA oxidase (AOX−/−), the first enzyme of the peroxisomal β-oxidation system, exhibit extensive microvesicular steatohepatitis, leading to hepatocellular regeneration and massive peroxisome proliferation, implying sustained activation of PPARα by natural ligands. We now report that mice nullizygous for both PPARα and AOX (PPARα−/− AOX−/−) failed to exhibit spontaneous peroxisome proliferation and induction of PPARα-regulated genes by biological ligands unmetabolized in the absence of AOX. In AOX−/− mice, the hyperactivity of PPARα enhances the severity of steatosis by inducing CYP4A family proteins that generate DCAs and since they are not metabolized in the absence of peroxisomal β-oxidation, they damage mitochondria leading to steatosis. Blunting of microvesicular steatosis, which is restricted to few liver cells in periportal regions in PPARα−/−AOX−/− mice, suggests a role for PPARα-induced genes, especially members of CYP4A family, in determining the severity of steatosis in livers with defective peroxisomal β-oxidation. In age-matched PPARα−/− mice, a decrease in constitutive mitochondrial β-oxidation with intact constitutive peroxisomal β-oxidation system contributes to large droplet fatty change that is restricted to centrilobular hepatocytes. These data define a critical role for both PPARα and AOX in hepatic lipid metabolism and in the pathogenesis of specific fatty liver phenotype.

Molecular Detection of Prostate Epithelial Cells from the Surgical Field and Peripheral Circulation during Radical Prostatectomy

PURPOSE Prostate cancer progression despite organ confined pathological assessment has been reported in a variable number of men after radical retropubic prostatectomy. To study this phenomenon, we used the prostate specific antigen (PSA) reverse transcriptase-polymerase chain reaction assay. MATERIALS AND METHODS We prospectively assayed the peripheral venous blood before, during and after surgical manipulation as well as the intraoperative field blood for PSA reverse transcriptase-polymerase chain reaction-positive cells in 22 men undergoing radical retropubic prostatectomy. RESULTS PSA reverse transcriptase-polymerase chain reaction-positive cells were identified in 20 of the 22 operative field samples (91%) and 4 of 16 (25%) had evidence of intraoperative hematogenous dissemination (p = 0.046). No significant association was identified among Gleason score, pathological stage and the PSA reverse transcriptase-polymerase chain reaction result. CONCLUSIONS Our results suggest that tumor cell spillage and less frequently hematogenous dissemination may be associated with operative manipulation of the prostate during radical retropubic prostatectomy and may potentially represent mechanisms of failure after radical retropubic prostatectomy.

Insig-1 “brakes” lipogenesis in adipocytes and inhibits differentiation of preadipocytes

We have examined gene expression in the fat tissue of normal mice at the onset of diet-induced obesity. Insulin-induced gene 1 (insig-1) mRNA rose progressively with a high-fat diet and declined on a restricted diet. Because insig-1 binds sterol regulatory element-binding protein cleavage-activating protein in the endoplasmic reticulum, thereby blocking proteolytic processing required for sterol regulatory element-binding protein activation, we tested its influence on lipogenesis. In differentiating 3T3-L1 cells, insig-1 and -2 rose in parallel with aP2 mRNA during differentiation. The mRNA of the lipogenic transcription factor, carbohydrate response element-binding protein, was undetectable in undifferentiated 3T3-L1 preadipocytes but rose dramatically during differentiation in 25 mM, but not in 5 mM, glucose. Transfection of mouse or human insig-1 into 3T3-L1 preadipocytes completely prevented oil red O staining and blocked upregulation of aP2, peroxisome proliferator-activated receptor γ2, and carbohydrate response element-binding protein, while reducing down-regulation of preadipocyte factor 1. The results suggest that insig-1 expression restricts lipogenesis in mature adipocytes and blocks differentiation in preadipocytes.

Pyelovenous lymphatic migration of transitional cell carcinoma following flexible ureterorenoscopy

Ureterorenoscopy has enhanced the diagnosis and treatment of upper urinary tract disorders. However, the irrigation necessary for visualization and distention of the lumen may increase renal pelvic pressure, resulting in pyelovenous lymphatic backflow. We report a case of renal pelvic transitional cell carcinoma that may have migrated to submucosal venous and lymphatic spaces during flexible ureterorenoscopy.

Incident Dark-Field Illumination: a New Method for Microcirculatory Study

entery and lung have been studied by transillumination with light from a water cooled quartz rod and a standard microscopic lens system,.1-4 In the past several years some use has been made of incident light directed at an oblique angle to the subject.5 Both of these methods require careful alignment of the light source and the microscopic lens system. During the past decade the growing fields of metallurgy and petrology have stimulated the development of special microscopes which do not require transillumination of the subject for its visualization. More recently these optics have been widely employed for quality control in the production of electronic microcircuitry. In a casual conversation one of the authors (W.A.C.) was told of the use of these optics in plant biology. The possibility of their application to in vivo microcirculation of animal tissues suggested itself. The initial studies were directed at the semi-transparent lung and mesentery and subsequent studies included solid organs. We have now observed all major organs.

Surfactant in Chronic Smokers

ulmonary surfactant prevents progressive overdistention by increasing surface tension as the alveoli enlarge, and it prevents P progressive atelectasis by decreasing tension as the alveoli become smaller. Cigarette smoke applied directly to bronchial washings or to extracts from minced lung specimens has been found to reduce the effectiveness of pulmonary surfactant [I 9, 251. The present studies were done to evaluate the surfactant in bronchial washings taken from chronic cigarette smokers with and without overt pulmonary disease and from nonsmokers with pulmonary disease.

Voiding pattern abnormalities in children.

Forty-two children with voiding pattern abnormalities (wetting, incontinence, inappropriate voiding) were evaluated by urodynamic techniques. All patients were urologically evaluated and carefully appraised of the mechanics of the urodynamic testing procedure. All patients demonstrated good cooperation in an anxiety-free atmosphere. Twenty-three abnormal bladder types were identified and characterized. Specific pharmacologic and urologic modalities were applied to achieve improved or normal micturition.

Massive Retroperitoneal Hemorrhage Owing to a Ruptured Adrenal Cyst

We report a rare case of massive retroperitoneal hemorrhage owing to rupture of an adrenal cyst after blunt abdominal trauma. A large retroperitoneal hematoma was evacuated and subtotal adrenalectomy was performed. Convalescence was uneventful. Histology revealed an endothelial-lined adrenal cyst suggesting a vascular or lymphatic etiology.

Ultrasound-Guided Percutaneous Nephrostomy in the Pediatric Patient

Percutaneous nephrostomy drainage may be established rapidly using ultrasonic guidance in severely ill pediatric patients with obstructive uropathy. B-mode ultrasonography has proved to be rapid, accurate and free of irradiation hazards, making it applicable to children with little or no sedation.

Transthoracic Vertebral Surgery

Abstract Fifteen paraplegic patients are presented who were operated upon using a transthoracic anterior approach to the spinal cord. Compression was secondary to osteomyelitis, neoplasm, and trauma. The spinal cord was decompressed by complete removal of the destroyed vertebral bone and other tissue or evacuation of pus or both. The bony defect was bridged with struts of resected rib. Except for the 2 patients with irreversible traumatic paraplegia, all the patients had some neurological improvement and 7 of 12 had a complete or marked early neurological recovery. These 7 included 4 of the 10 patients with osteomyelitis and all 3 patients with neoplastic compression. Five additional patients with osteomyelitis had partial neurological recovery, and the remaining patient regained sphincter control. Early solid bone fusion and rehabilitation were achieved in the patients with fracture.