Cytotoxicity of streptozotocin on neuroendocrine cells of the pancreas and the gut

Streptozotocin has been used to induce diabetes mellitus in experimental animals and has been thought to have a selective cytotoxic effect on the -cells in the islets of Langerhans. The aim of the present study was to determine whether streptozotocin has any cytotoxic effect on other neuroendocrine cells of the gastrointestinal tract. Eight female Sprague-Dawley rats received intraperitoneal injections of 100 mg/kg streptozotocin in citric acid buffer; the concentration of streptozotocin was adjusted to 25 mg/ml buffer. Seven rats, serving as controls, received an equivalent volume of the vehicle. The rats were killed after three days and the fundus, antrum, small intestine and pancreas were examined for neuroendocrine cells. Our study confirms that streptozotocin is cytotoxic towards -cells. In addition, it is cytotoxic towards neuroendocrine cells of the oxyntic mucosa of the stomach. This finding may have clinical significance and suggests that streptozotocin may be used in the treatment of gastric neuroendocrine tumors as well as insulinomas.     

Neuroendocrine expression in node positive prostate cancer: correlation with systemic progression and patient survival

PURPOSE: Neuroendocrine cells are ubiquitous but uncommon in benign and neoplastic prostate epithelium, and they are considered important for regulating cell growth and differentiation. The predictive value of neuroendocrine immunoreactivity for patient outcome after radical prostatectomy is uncertain. In this study we determined the expression of 2 important neuroendocrine markers, chromogranin and serotonin, in benign epithelium, primary prostate cancer and lymph node metastases, and correlated cellular expression with patient outcome. MATERIALS AND METHODS: We studied 196 patients with node positive prostate adenocarcinoma who underwent bilateral pelvic lymphadenectomy and radical prostatectomy at Mayo Clinic between 1987 and 1992. Mean followup was 6.8 years (range 0.3 to 11). The cellular expression of chromogranin and serotonin in matched samples of benign tissue, primary prostate cancer and lymph node metastases from the same patients was evaluated by immunohistochemical staining using commercially available monoclonal antibodies. Results were correlated with patient age, pathological findings (Gleason score, DNA ploidy and cancer volume) and patient outcome, including clinical progression, cancer specific and all cause survival. RESULTS: Chromogranin immunoreactivity was greater in benign prostatic epithelium and primary cancer cases (99% each) than in those of lymph node metastases (37.5%) (pairwise comparisons with metastases p <0.001). The mean incidence of immunoreactive cells in benign epithelium, primary cancer and metastases was 6% (median 5%), 6% (median 3%) and 2.2% (median 0%), respectively. Serotonin immunoreactivity was greatest in benign prostate epithelium cases (98.5%) with less in primary cancer (95%) and lymph node metastases (21.5%) (pairwise comparisons p <0.001). The mean incidence of immunoreactive cells in benign epithelium, primary cancer and metastases was 2.2% (median 3%), 2.4% (median 2%) and 0.4% (median 0%), respectively. Chromogranin expression was invariably greater than that of serotonin for all 3 diagnostic categories (p <0.0001). There was a marginally significant positive trend in the level of chromogranin expression in benign prostatic epithelium and systemic progression (p = 0.05) but no significant association with cancer specific or all cause survival (p >0.1). No significant association was observed of chromogranin expression in primary cancer or lymph node metastases with any patient outcomes (p >0.1). There was a significant association of the level of serotonin expression in benign prostatic epithelium with cancer specific survival (p = 0.03) but no significant association with systemic progression or all cause survival (p > 0.1). There were positive trends in the association of serotonin immunoreactivity in primary cancer with systemic progression (p = 0.09) and cancer specific survival (p = 0.05) but not with all cause survival (p >0.1). No significant association was observed of serotonin expression in lymph node metastases with any patient outcomes (p >0.1). CONCLUSIONS: Benign prostatic epithelium and primary prostate cancer express a significantly greater number of chromogranin and serotonin immunoreactive cells than lymph node metastases, suggesting that decreased expression of neuroendocrine markers is involved in cancer progression. However, neuroendocrine expression was marginally useful for predicting the outcome in patients with node positive prostate cancer treated with radical prostatectomy.     

Vocal-acoustic circuitry and descending vocal pathways in teleost fish: convergence with terrestrial vertebrates reveals conserved traits

Vocal behavior is multifaceted and requires that vocal-motor patterning be integrated at multiple brain levels with auditory, neuroendocrine, and other social behavior processes (e.g., courtship and aggression). We now provide anatomical evidence for an extensive vocal network in teleost fishes (Batrachoididae: Porichthys notatus; Opsanus beta) that is strongly integrated with neuroendocrine and auditory pathways and that exhibits striking similarities to the vocal-acoustic circuitry known for mammals. Biotin compound injections into neurophysiologically identified vocal regions of the forebrain (preoptic area and anterior hypothalamus) and of the midbrain (periaqueductal gray and paralemniscal tegmentum) reveal extensive connectivity within and between these regions, as well as reciprocal relationships with the auditory thalamus and/or auditory midbrain (torus semicircularis). Thus, specific components of the basal forebrain and midbrain are here designated as the forebrain vocal-acoustic complex (fVAC) and midbrain vocal-acoustic complex (mVAC), respectively. Biotin injections into the mVAC and a previously identified hindbrain vocal pattern generator likewise provide anatomical evidence for a distributed network of descending projections to the vocal pacemaker-motoneuron circuitry. Together, the present experiments establish a vocal-auditory-neuroendocrine network in teleost fish that links the forebrain and midbrain to the hindbrain vocal pattern generator (i.e., fVAC --> mVAC --> pattern generator) and provides an anatomical framework for the previously identified neuropeptide modulation of vocal activity elicited from the forebrain and midbrain, which contributes to the expression of sex- and male morph-specific behavior. We conclude with a broad comparison of these findings with those for other vertebrate taxa and suggest that the present findings provide novel insights into the structure of conserved behavioral regulatory circuits that have led to evolutionary convergence in vocal-acoustic systems.     

Postoperative Pain Management and Proinflammatory Cytokines: Animal and Human Studies

The postoperative period is associated with neuroendocrine, metabolic, and immune alterations, which are the combined result of tissue damage, anesthesia, postoperative pain, and psychological stress. Limited evidence indicates that pain management in the postoperative period can affect the outcome of the surgery, reducing cardiac, pulmonary, and metabolic complications. Recent evidence indicates that pain and immune factors, especially proinflammatory cytokines, mutually interact and influence each other. A series of animal studies demonstrates that effective preemptive analgesia improved postoperative recovery, and this effect was enhanced by coadministration of IL-1ra together with the preemptive analgesics. Furthermore, preemptive analgesia attenuated surgery-induced PGE₂ production in the amygdala and the activation of the HPA axis. IL-1 signaling is required for the production of amygdala PGE₂ in response to surgical stress, and may thus affect the physiological and psychological aspects of surgical stress. These reports suggest that short-term effective analgesia can have long-lasting beneficial effects on surgery recovery. They further suggest that IL-1 blockade should be considered in the clinical management of pain associated with peripheral or nerve injury. Another series of human studies describes an interaction between the effectiveness of postoperative pain relief and surgery-associated immune alterations: In three separate studies, the more effective pain management technique was associated with diminished surgery-induced immune alterations, especially diminished elevation of IL-1. Reduced elevation of postoperative IL-1 and effective pain relief may both contribute to an attenuated illness response and a better surgery outcome.Presented at the 12th SNIP Conference, Santa Fe, New Mexico, April 5–9, 2006.     

Primary undifferentiated carcinoma arising from the retroperitoneum: a case report

A 35-year-old woman, gravida 1, para 1, underwent cesarean section in her 39th week of pregnancy. At the time of operation, multiple retroperitoneal tumors were found. Postoperative computed tomography and magnetic resonance imaging showed multiple solid tumors, each approximately 3-5 cm, in the right pelvic retroperitoneal space. Total resection of the tumors was performed without any macroscopic residual. A systematic workup for the primary tumor from which the retroperitoneal tumors may have metastasized failed to demonstrate any responsible tumor. We therefore assumed it to be a primary retroperitoneal tumor. The histopathologic features of the tumors were consistent with small-cell carcinoma. Two months postoperatively, recurrent tumors in the right inguinal and common iliac regions were detected. Since chemotherapy with irinotecan hydrochloride or paclitaxel did not produce any beneficial effect, a second tumor reduction surgery was performed 8 months after the initial operation. Four months after the second operation, a third operation including total hysterectomy, bilateral salpingo-oophorectomy, and tumor resection in the contralateral iliac region were done. Afterward, a new recurrent tumor appeared along the aorta up to the left supraclavicular node. The patient died 19 months after the first operation.     

胃肠道类癌中激素蛋白的表达及意义

目的:探讨消化道类癌激素蛋白的表达及其临床意义。方法:应用免疫组化SP法对36例消化道类癌组织中6种蛋白进行检测。结果:36例类癌组织中,生长抑素在典型、非典型和低分化3组类癌中阳性表达率分别是71·4%(10/14)66·7%(8/12)和20·0%(2/10),3组比较差异有统计学意义,P=0·028。生长抑素阳性标记率在进展期类癌和有淋巴结转移类癌分别为25·0%(4/16)、25·0%(3/12),显著低于早期类癌和无淋巴结转移类癌,其阳性表达率分别随组织分化降低而上升典型、非典型和低分化3组类癌比较胃泌素阳性率分别是57·1%(8/14)、83·3%(10/12)和100·0%(10/10),P=0·038,降钙素阳性率分别是0(0/14)、8·3%(1/12)和50·0%(5/10),P=0·003,差异有统计学意义。早期和进展期类癌比较,胃泌素和降钙素阳性表达率分别为65·0%(13/20)93·8%(15/16)和10%(2/20)、37·5%(6/16),P值分别为0·039和0·049。有无淋巴结转移比较,胃泌素和降钙素阳性表达率分别为100%(12/12)、66·7%(16/24)和41·7%(5/12)、12·5%(3/24),P值分别为0·023和0·047,差异均有统计学意义结论:在类癌组织中胃泌素和降钙素高表达,生长抑素的低表达可能与肿瘤的组织分化、侵袭和浸润有关,它们的异常表达可预测肿瘤的生物学行为。     

Localization of agmatine in vasopressin and oxytocin neurons of the rat hypothalamic paraventricular and supraoptic nuclei

Agmatine (decarboxylated l-arginine), an endogenous ligand of imidazoline and alpha(2) adrenoreceptors, is particularly enriched in the rat hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. The present study utilized light and electron microscopic immunocytochemical methods to determine the distribution and extent of colocalization of agmatine relative to subpopulations of vasopressin- (VP) and oxytocin- (OT) producing neurons in PVN and SON nuclei. By light microscopy, agmatine-immunoreactive perikarya were found in both the magnocellular and the parvocellular neuronal subdivisions of PVN and SON. Confocal and electron microscopy revealed that agmatine-immunoreactivity (I) within neuronal perikarya was associated with the nuclear membrane as well as mitochondria, Golgi complexes, endoplasmic reticula, and plasmalemma. Additionally, agmatine-I was identified in both axons and axonal terminals, which were enriched in large dense-core vesicles. Dual and triple immunocytochemical labeling experiments also demonstrated that agmatine coexists with VP or OT in most PVN and SON magnocellular neurons. Combinations of iontophoretic injections of Fluorogold into the dorsomedullary complex with immunocytochemical labeling revealed that many retrogradely labeled neurons in the parvocellular region of the PVN contained agmatine-I and either VP or OT. These findings provide evidence that agmatine may function as a modulator of both hypothalamically mediated neuroendocrine and autonomic responses.