One-Stage Anterior Urethroplasty

Purpose

A deficient urethral segment was replaced with penile skin during a 1-stage procedure in patients with a long, tight urethral stricture, multiple attempts at hypospadias repair or severe hypospadias and circumcision.

Materials and Methods

In 29 patients a pedicled circumferential strip of distal penile skin was used to construct a neourethral floor. The roof was formed by regeneration of the epithelium from the edges of the floor over Buck's fascia. In our series the urethra was reconstructed because of an anterior urethral stricture in 11 patients, multiple failed hypospadias repairs in 6 and severe hypospadias with circumcision in 12.

Results

A neourethra of sufficient caliber and length was constructed with minimal postoperative complications in all patients. There were 2 cases of urethrocutaneous fistula at the subcoronal region, 1 meatal stenosis, 1 persistent chordee and 1 small distal penile skin patch slough that required only prolonged dressings. Mean followup was 19 months.

Conclusion

Our urethroplasty technique can be used to correct various types of anterior urethral stricture or hypospadias associated with insufficient penile or preputial skin.     

Enhanced response of human head and neck cancer xenograft tumors to cisplatin combined with 2-deoxy-D-glucose correlates with increased 18F-FDG uptake as determined by PET imaging

PURPOSE: To determine whether the response of human head and neck cancer xenografts to cisplatin (CIS) could be enhanced with 2-deoxy-D-glucose (2DG); whether 2-[(18)F]-fluoro-2-deoxy-D-glucose (FDG) uptake correlated with responses to this drug combination; and whether 2DG would enhance CIS-induced radiosensitization. METHODS AND MATERIALS: Clonogenic survival responses to CIS + 2DG were determined in FaDu and Cal-27 cells and reduced/oxidized glutathione levels were monitored as parameters indicative of oxidative stress. The efficacy of CIS + 2DG was determined in FaDu and Cal-27 xenografts, and FDG uptake was determined by using positron emission tomography. RESULTS: Use of CIS + 2DG enhanced cell killing of FaDu and Cal-27 cells compared with either drug alone while increasing the percentage of oxidized glutathione in vitro. Use of CIS + 2DG inhibited FaDu and Cal-27 tumor growth and increased disease-free survival compared with either drug alone. The Cal-27 tumors showed greater pretreatment FDG uptake and increased disease-free survival when treated with 2DG + CIS relative to FaDu tumors. Treatment with 2DG enhanced CIS-induced radiosensitization in FaDu tumor cells grown in vitro and in vivo and resulted in apparent cures in 50% of tumors. CONCLUSIONS: These results show the enhanced therapeutic efficacy of CIS + 2DG in human head and neck cancer cells in vitro and in vivo compared with either drug alone, as well as the potential for FDG uptake to predict tumor sensitivity to 2DG + CIS. These findings provide a strong rationale for evaluating 2DG + CIS in combined-modality head and neck cancer therapy with radiation in a clinical setting.     

Severe pancreatico-duodenal injuries: the effectiveness of pyloric exclusion with vagotomy.

The operative management and clinical course of 17 patients treated for severe pancreatico-duodenal injuries from 1983 to 1990 was reviewed. The etiology of these injuries was gunshot wound in 15 patients; stab wound in 1 patient; and a motor vehicle accident in 1 patient. Seven patients presented in shock with a systolic blood pressure of less than 80. At exploration, 57 associated injuries were found in the 17 patients including 16 major vascular injuries. All patients were treated with pyloric exclusion and drainage. Vagotomy was performed in eight patients. None of these 17 patients were felt to have extensive enough damage to require pancreatico-duodenectomy. Two patients died in the immediate postoperative period of severe coagulopathy and two patients died of sepsis. Seven patients had complications related to the pancreatico-duodenal injury. All seven developed pancreatic fistulas; three also had pancreatitis and two developed multiple enterocutaneous fistulas. Systemic complications included pulmonary complications in eight patients and sepsis in five patients, including two patients with abdominal abscesses. Six patients bled in the immediate postoperative period secondary to coagulopathy. Three patients had complications related to pyloric exclusion. One developed afferent loop syndrome necessitating reoperation. The other two had marginal ulcers, which either perforated or bled and required reoperation. Of interest, neither of these two patients had vagotomy initially. The results of this series confirm the effectiveness of pyloric exclusion with vagotomy for severe pancreatico-duodenal injury.     

Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is a heterogeneous genetic disorder characterized by many features, including obesity and cardiovascular disease. We previously developed knockout mouse models of 3 BBS genes: BBS2, BBS4, and BBS6. To dissect the mechanisms involved in the metabolic disorders associated with BBS, we assessed the development of obesity in these mouse models and found that BBS-null mice were hyperphagic, had low locomotor activity, and had elevated circulating levels of the hormone leptin. The effect of exogenous leptin on body weight and food intake was attenuated in BBS mice, which suggests that leptin resistance may contribute to hyperleptinemia. In other mouse models of obesity, leptin resistance may be selective rather than systemic; although mice became resistant to leptin's anorectic effects, the ability to increase renal sympathetic nerve activity (SNA) was preserved. Although all 3 of the BBS mouse models were similarly resistant to leptin, the sensitivity of renal SNA to leptin was maintained in Bbs4 -/- and Bbs6 -/- mice, but not in Bbs2 -/- mice. Consequently, Bbs4 -/- and Bbs6 -/- mice had higher baseline renal SNA and arterial pressure and a greater reduction in arterial pressure in response to ganglionic blockade. Furthermore, we found that BBS mice had a decreased hypothalamic expression of proopiomelanocortin, which suggests that BBS genes play an important role in maintaining leptin sensitivity in proopiomelanocortin neurons.     

A Caenorhabditis elegans model of tau hyperphosphorylation: induction of developmental defects by transgenic overexpression of Alzheimer's disease-like modified tau

The microtubule-associated tau proteins become functionally and structurally altered in Alzheimer's disease (AD). To analyze tau modification and its role in a non-vertebrate animal model, we produced transgenic Caenorhabditis elegans strains with a panneuronal expression of human tau and a pseudohyperphosphorylated (PHP) tau construct that mimics AD-relevant tau modification. We show that human tau in C. elegans becomes highly phosphorylated and exhibits conformational changes similar to PHP tau and human PHF tau. Both, wt tau and PHP tau induced a progressive age-dependent development of a phenotype of uncoordinated locomotion (unc) in the absence of neuronal degeneration. However, only PHP tau induced a defective pattern of motor neuron development as indicated by the presence of gaps in the dorsal cord, commissures on the wrong side and local broadening of axons. The data indicate that C. elegans is capable of highly phosphorylating human tau to an AD-like state whereas only stable disease-like tau modification induce developmental defects suggesting a specific interference of pathologic tau with intracellular mechanisms of axonal outgrowth and pathfinding.     

IL‐10 polymorphisms and T‐cell subsets could affect the clinical presentation and outcome of childhood immune thrombocytopenia in Egyptian population

The aim is to study IL‐10 polymorphisms and IL‐10 level and assess their relation to T‐cell subsets in childhood immune thrombocytopenia (ITP). In all, 40 (25 acute, 15 chronic) ITP child patients were investigated at time of presentation, compared to 15 healthy, age‐ and gender‐matched controls and followed up for 1 year to determine chronic cases. Studying the effect of IL‐10 promoter polymorphism was done by PCR‐RFLP, IL‐10 level was determined by ELISA, natural killer cells and T‐cell subsets were evaluated by flow cytometry. Subjects with IL‐10 promoter (1082 AA and 592 AA) genotypes had lower IL‐10 levels and had lower CD4%, higher CD8%, lower CD4/CD8 ratio and lower T‐reg%. IL‐10 polymorphisms had no effect on NK%. IL‐10 serum levels and IL‐10 promoter polymorphic genotype frequencies are not different between ITP cases and controls; however, in ITP patients, IL‐10 promoter (1082 AA and 592 AA) genotypes and associated lower CD4, higher CD8, lower CD4/CD8 ratio is associated with more severe thrombocytopenia at presentation and had a poorer response to first‐line treatment. Patients with lower T‐reg cells had a higher tendency to develop chronic ITP. IL‐10 level and polymorphisms as well as disturbed T‐cell subsets percentages are demonstrable effectors of immune dysfunction in ITP and can affect the presentation and outcome of childhood ITP.