Mast Cell-Derived Histamine Mediates Cystitis Pain

Background: Mast cells trigger inflammation that is associated with local pain, but the mechanisms mediating pain are unclear. Interstitial cystitis (IC) is a bladder disease that causes debilitating pelvic pain of unknown origin and without consistent inflammation, but IC symptoms correlate with elevated bladder lamina propria mast cell counts. We hypothesized that mast cells mediate pelvic pain directly and examined pain behavior using a murine model that recapitulates key aspects of IC. Methods and Findings: Infection of mice with pseudorabies virus (PRV) induces a neurogenic cystitis associated with lamina propria mast cell accumulation dependent upon tumor necrosis factor alpha (TNF), TNF-mediated bladder barrier dysfunction, and pelvic pain behavior, but the molecular basis for pelvic pain is unknown. In this study, both PRV-induced pelvic pain and bladder pathophysiology were abrogated in mast cell-deficient mice but were restored by reconstitution with wild type bone marrow. Pelvic pain developed normally in TNF- and TNF receptor-deficient mice, while bladder pathophysiology was abrogated. Conversely, genetic or pharmacologic disruption of histamine receptor H1R or H2R attenuated pelvic pain without altering pathophysiology. Conclusions: These data demonstrate that mast cells promote cystitis pain and bladder pathophysiology through the separable actions of histamine and TNF, respectively. Therefore, pain is independent of pathology and inflammation, an

Blockade of NGF and trk receptors inhibits increased peripheral mechanical sensitivity accompanying cystitis in rats

Visceral inflammation, including that arising from bladder inflammation, reduces the threshold to sensation of innocuous or noxious stimuli applied to peripheral structures (referred hyperalgesia). Cystitis may induce transient or persistent plastic changes mediated by neurotrophins, particularly nerve growth factor (NGF), which contribute to increased nociceptive input. In this study, acute or subacute cystitis was induced in female rats by one or three (at 72-h intervals) 400-μl intravesical instillations of 1 mM acrolein. Sensitivity of the hindpaws to mechanical and thermal stimuli was determined before and 4, 24, 48, 72, and 96 h after treatment. Other groups of rats were treated with intravesical or intrathecal k252a [a nonspecific antagonist of tyrosine kinase (trk) receptors, including trkA, the high-affinity receptor for NGF] before the first or third acrolein instillation. Some rats were intraperitoneally injected with specific NGF-neutralizing antiserum or normal serum before acrolein instillation. Acute and subacute cystitis induced mechanical, but not thermal, referred hyperalgesia that was attenuated by intravesical pretreatment with k252a. Systemic treatment with NGF-neutralizing antiserum before instillation of acrolein suppressed subsequent mechanical referred hyperalgesia. Expression of NGF was increased within the bladder by acute or subacute cystitis and in L6/S1 dorsal root ganglia by subacute cystitis. These results suggest that the bladder-derived NGF acting via trk receptors at least partially mediates peripheral sensitization to mechanical stimuli associated with acute and subacute acrolein-induced cystitis

Delivery assistance in fetal macrosomia Assistência ao parto na macrossomia fetal

OBJECTIVES: to evaluate delivery assistance in fetal macrosomia. METHODS: this was a hospital-based cohort study of consecutive births at a tertiary perinatal center from January 1, 1996 to October 31, 1999. A total of 5261 pregnancies met the inclusion criteria which were singleton pregnancies with minimal birth weight of 1000 g. Fetal macrosomia was defined as birth weight of 4000 g or more. We studied the mode of delivery, the newborn condition at birth, considered low when the Apgar scored below seven in the first or fifth minute, and the presence of abnormalities that could indicate a Caesarian section (disproportion, uterine dysfunction, prolonged second period of birth and fetal distress). RESULTS: 296 (5,6%) of the babies were macrosomic. Macrosomia was a risk factor for Caesarian section (RR = 1,59, p <0,001) and for operative vaginal delivery RR = 1,12 (p <0,001). Newborn conditions was not worse in macrosomic babies. There was a positive correlation between fetal macrosomia and disproportion but not with uterine dysfunction, prolonged second period of birth or fetal distress. CONCLUSIONS: caesarian section was indicated more often for macrosomic babies, but our data did not suggest that a more extensive use of C-Sections was justified.<br>OBJETIVOS: avaliar a assistência ao parto na macrossomia fetal. MÉTODOS: Estudo do tipo coorte realizado em centro perinatal terciário no período de 1 de janeiro de 1996 a 31 de outubro de 1999. Foram selecionadas 5261 gestações de acordo com os critérios de inclusão, que foram: gestação única e peso mínimo ao nascimento de 1000 g. A macrossomia fetal foi definida como peso ao nascimento acima de 4000 g. Estudamos a via de parto, as condições ao nascimento, Apgar baixo quando inferior a sete no primeiro e quinto minutos e as anormalidades que serviram de indicação para cesariana (desproporção, distocia uterina, segundo período prolongado e sofrimento fetal). RESULTADOS: 296 (5,6%) dos conceptos eram macrossômicos. Macrossomia foi fator de risco para cesariana (RR = 1,59, p <0,001) e para parto operatório vaginal (RR = 1,12 p <0,001). As condições do recém-nascido não foram piores nos fetos macrossômicos. Houve correlação positiva entre macrossomia fetal e desproporção mas não para distocia uterina, prolongamento do segundo período ou sofrimento fetal. CONCLUSÕES: Houve maior número de indicações de cesariana para os fetos macrossômicos, mas os dados não sugerem que o uso mais generalizado da cesariana se justifique