Pudendal Thigh Fasciocutaneous Flaps for Vaginal Reconstruction in Gynecologic Oncology

The pudendal thigh is a sensate fasciocutaneous flap supplied by the posterior labial artery. We report on the results of pudendal thigh flaps used for vaginal reconstruction in eight patients at the time of pelvic exenteration (6) and radical vaginectomy (2). Patients were interviewed and results were assessed 5 to 19 months after surgery. The flaps were raised in the thigh creases just lateral to the hair bearing area of the labia majora and included skin, subcutaneous tissues, deep fascia of the thigh, and the epimysium of the adductor muscles. Flap sizes varied from 9 × 4 cm to 15 × 6 cm. Bilateral flaps were used in seven patients. The flaps were technically easy to perform. Partial (apical) flap necrosis occurred in four patients. One patient developed complete necrosis of bilateral flaps, followed by an enterovaginal fistula. One patient whose flaps did not necrose developed a rectovaginal fistula at the site of rectal reanastomosis. The functional results are disappointing. The only patient having successful vaginal intercourse had a unilateral flap reconstruction following lower vaginectomy in a nonirradiated pelvis. No patient with bilateral flaps or prior pelvic irradiation has had successful coitus. Other long-term sequelae include vulvar pain (2), chronic vaginal discharge (2), hair growth (4), and protrusion of the flaps (2). These vulvovaginal symptoms discourage patients and their partners from genital contact. Breaching the integrity of the vulva to construct a neovagina that is likely to be unsuitable for sexual intercourse may deprive women of their only potential for normal genital sexual responsiveness. Techniques of vaginoplasty require continued assessment.     

Effect of budesonide on pulmonary hyperinflation in young asthmatic children.

In 19 asthmatic children, aged 2-6 years, the effect of six weeks' treatment with inhaled budesonide or placebo on functional residual capacity (FRC--helium dilution) and bronchodilator responsiveness was assessed in a double blind, randomised crossover trial. FRC was increased in most children at the start of treatment. Treatment with budesonide was associated with a reduction in FRC by comparison with placebo (median change 9% v 0%; p less than 0.05). There was a trend towards a greater response to a bronchodilator after budesonide. The results suggest that inhaled corticosteroids reduce hyperinflation in young asthmatic children.     

The physiological regulation of toll-like receptor expression and function in humans

Eleven mammalian toll-like receptors (TLRs 1–11) have been identified to date and are known to play a crucial role in the regulation of immune responses; however, the factors that regulate TLR expression and function in vivo are poorly understood. Therefore, in the present study, we investigated the physiological regulation of TLR expression and function in humans. To examine the influence of diurnal rhythmicity on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers ( n = 8) at time points coinciding with the peak and nadir in the endogenous circulating cortisol concentration. While no diurnal rhythmicity in the expression of TLRs 1, 2, 4 or 9 was observed, the upregulation of costimulatory (CD80 and CD86) and antigen-presenting (MHC class II) molecules on CD14⁺ monocytes following activation with specific TLR ligands was greater ( P < 0.05) in samples obtained in the evening compared with the morning. To examine the influence of physical stress on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers ( n = 11) at rest and following 1.5 h of strenuous exercise in the heat (34°C). Strenuous exercise resulted in a decrease ( P < 0.005) in the expression of TLRs 1, 2 and 4 on CD14⁺ monocytes. Furthermore, the upregulation of CD80, CD86, MHC class II and interleukin-6 by CD14⁺ monocytes following activation with specific TLR ligands was decreased ( P < 0.05) in samples obtained following exercise compared with at rest. These results demonstrate that TLR function is subject to modulation under physiological conditions in vivo and provide evidence for the role of immunomodulatory hormones in the regulation of TLR function.     

Further characterization of the discriminative stimulus effects of buspirone using monoamine agonists and antagonists in the pigeon

White Carneau pigeons were trained to discriminate 1.0 mg/kg buspirone from saline when key pecking was maintained under a fixed-ratio 30 schedule of food presentation. Buspirone (0.3-10.0 mg/kg), the serotonin 1A (5-HT(1A)) agonist 8-OH-DPAT (0.1-1mg/kg), the buspirone analog BMY 7378 (3.0-5.6mg/kg), the mixed 5-HT(1A/1B) agonist RU 24969 (3.0-10.0mg/kg) and the 5-HT(1A) agonist spiroxatrine (0.1-1.0mg/kg) occasioned at least 80% buspirone-appropriate responding in all subjects tested. Administration of the 5-HT(1B) agonist (TFMPP 0.1-10.0mg/kg) or the 5-HT(3) antagonist (MDL 72222 (3.0-17.0mg/kg) resulted in primarily saline-key responding. The dopamine receptor antagonist chlorpromazine (1.0-17.0mg/kg), the specific D-2 receptor antagonist eticlopride (0.03-0.56mg/kg), the noradrenergic alpha-2 antagonist yohimbine (0.1-1.0mg/kg), the alpha-2 agonist clonidine (0.003-0.10mg/kg) and (+/-) and (-) propranolol (3.0-30.0mg/kg) all produced primarily saline-appropriate responding. Coadministration of the beta-adrenergic agonist isoproterenol (1.0-5.6mg/kg) or the 5-HT(1A) partial agonist BMY 7378 (0.01-10.0mg/kg) with 1.0mg/kg buspirone did not block the discriminative stimulus effects of buspirone. However, 3.0-10.0mg/kg BMY 7378, in combination with a lower dose of buspirone (0.3mg/kg) decreased drug-key responding to approximately 50%. Results from the present study suggest that (1) the discriminative stimulus effects of buspirone, 8-OH-DPAT, BMY 7378, RU 24969 and spiroxatrine are mediated through the 5-HT(1A) receptor; (2) buspirone's discriminative stimulus effects do not interact with the noradrenergic or dopaminergic system; and 3) under this procedure BMY 7378 was a partial agonist at 5-HT(1A) receptors.     

Immunization with gastric H+/K(+)-ATPase induces a reversible autoimmune gastritis.

The gastric H+/K(+)-ATPase has been implicated as a major autoantigen in pernicious anaemia in humans and in thymectomy-induced autoimmune gastritis in mice. Here we have shown that autoimmune gastritis can be generated by direct immunization of non-thymectomized BALB/c mice with mouse gastric H+/K(+)-ATPase in complete Freund's adjuvant. The gastritis was characterized by infiltration of the gastric submucosa and mucosa with macrophages, CD4+ and CD8+ T cells, and B cells and by circulating autoantibodies to the H+/K(+)-ATPase. The mononuclear infiltrate within the gastric mucosa was accompanied by loss of parietal and zymogenic cells and accumulation of small immature epithelial cells. Splenocytes from gastritic mice adoptively transferred gastritis to naive recipients. Cessation of immunization resulted in decrease in autoantibody titre and regeneration of parietal and zymogenic cells. The results directly confirm that the gastric H+/K(+)-ATPase is the causative autoantigen in the genesis of autoimmune gastritis. Recovery of the lesion following cessation of immunization suggests that homeostatic mechanisms can reverse a destructive autoimmune process.     

Requirements for autoimmune responses to mouse gastric autoantigens

Autoimmune gastritis, in which the H+/K(+)-ATPase of parietal cells is the major antigen, is one of the most common autoimmune diseases. Here we examined if specific properties of the H+/K(+)-ATPase or parietal cells are involved in rendering them autoimmune targets. The model antigens beta-galactosidase and ovalbumin (OVA) were expressed in parietal cells of transgenic mice. On experimental induction of autoimmune gastritis by neonatal thymectomy, autoantibodies to beta-galactosidase developed in mice expressing beta-galactosidase in parietal cells, a response that was independent of either the response to the gastric H+/K(+)-ATPase or gastric inflammation. In contrast, mice that expressed OVA in parietal cells did not exhibit an antibody response to OVA after thymectomy. However, increasing the frequency of anti-OVA T lymphocytes in OVA-expressing mice resulted in autoantibodies to OVA and gastritis. These studies indicate that parietal cells can present a variety of antigens to the immune system. Factors such as the identity and expression level of the autoantigen and the frequency of autoreactive T cells play a role in determining the prevalence and outcome of the particular immune response. In addition, as not all mice of a particular genotype displayed autoimmunity, random events are involved in determining the target of autoimmune recognition.     

Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations

The nuclear-encoded Krebs cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDHB, -C and -D), act as tumour suppressors. Germline mutations in FH predispose individuals to leiomyomas and renal cell cancer (HLRCC), whereas mutations in SDH cause paragangliomas and phaeochromocytomas (HPGL). In this study, we have shown that FH-deficient cells and tumours accumulate fumarate and, to a lesser extent, succinate. SDH-deficient tumours principally accumulate succinate. In situ analyses showed that these tumours also have over-expression of hypoxia-inducible factor 1alpha (HIF1alpha), activation of HIF1alphatargets (such as vascular endothelial growth factor) and high microvessel density. We found no evidence of increased reactive oxygen species in our cells. Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate causes stabilization of HIF1alpha a plausible mechanism, inhibition of HIF prolyl hydroxylases, has previously been suggested by in vitro studies. The basic mechanism of tumorigenesis in HPGL and HLRCC is likely to be pseudo-hypoxic drive, just as it is in von Hippel-Lindau syndrome.     

Gallstones: advantages and disadvantages of five treatment alternatives

Cholecystectomy is the gold standard treatment for symptomatic gallstones. However, within the last decade peroral drug chemolysis, methyl-tert-butyl ether lavage, shock wave lithotripsy, and percutaneous cholecystolithotomy have been introduced. This article compares and contrasts the presently available therapeutic modalities for gallstones and highlights the limitations of each treatment option.