Involvement of serotonin and dopamine in the mechanism of action of novel antidepressant drugs: a review

BACKGROUND: By the time patients are diagnosed with ovarian carcinoma, peritoneal dissemination of the tumor often has occurred. The progressive growth and spread of ovarian carcinoma depend, in part, on the formation of an adequate blood supply. We determined whether the expression of genes that regulate distinct steps in angiogenesis (i.e., the formation of new blood vessels) was associated with the pattern and progressive growth of human ovarian carcinomas implanted in the peritoneal cavity of nude mice. METHODS: Five different human ovarian carcinomas were injected individually into the peritoneal cavity of female NCr-nu/nu nude mice. The expression of basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), interleukin 8 (IL-8), and collagenase type IV (MMP-2 [matrix metalloproteinase-2] and MMP-9) was determined by northern blot analysis, in situ hybridization of messenger RNA, and immunohistochemical analysis. Blood vessel distribution and density, macrophage infiltration pattern, and stromal reaction were determined by immunohistochemical analysis with specific antibodies. RESULTS: Three of the carcinomas produced both solid lesions and ascitic tumors, whereas the remaining two produced only solid lesions. Two of the carcinomas produced rapidly progressive disease, two produced slow disease, and one produced intermediate disease. The formation of ascites was directly associated with expression of VEGF/ VPF, and survival was inversely associated with expression of IL-8. In rapidly growing tumors, the number of blood vessels was high throughout the lesion; in contrast, in slow-growing tumors, most vessels (and infiltrating macrophages) were located at the periphery. CONCLUSIONS: The expression of various genes that regulate angiogenesis in human ovarian carcinomas is associated with the pattern of the disease and its progression. Therefore, targeting specific genes that regulate angiogenesis could offer new approaches to the treatment of ovarian cancer.     

Resistance to endotoxin shock in spontaneously hypertensive rats

Septic shock involves systemic vasodilation mediated by proinflammatory cytokines. In essential hypertension, vascular and immune dysfunctions are closely associated. The response of hypertensive animals compared with normotensive controls to endotoxin (lipopolysaccharide; LPS) challenge is not known. Age-matched (12 weeks) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were exposed to intravenous injection of 10 mg/kg LPS. Survival rate at 24 hours was markedly higher in SHR than in WKY (12 of 15 and 3 of 15, respectively; P<0.01). Survival of LPS-injected SHR was not related to their hypertension because hydralazine-treated SHR with normalized pressure had similar survival rates, and WKY made hypertensive by clipping of one renal artery showed fatality similar to that of normotensive WKY. Continuous arterial pressure and sequential plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) were measured in LPS-treated SHR and WKY. Both the duration of the delayed hypotensive phase and the systemic release of IL-6 were much lower in SHR than WKY, whereas both acute hypotension and plasma TNF peak were equivalent. We further explored in vitro the inflammatory response and showed that LPS-activated whole blood from SHR produced less TNF and IL-6 than WKY LPS-activated whole blood. Our results indicate that SHR have a greater ability to resist endotoxic shock than WKY. This is not related to their hypertension but is associated with an attenuated inflammatory response to LPS.     

Sequence specificity of viral end DNA binding by HIV-1 integrase reveals critical regions for protein-DNA interaction

HIV-1 integrase specifically recognizes and cleaves viral end DNA during the initial step of retroviral integration. The protein and DNA determinants of the specificity of viral end DNA binding have not been clearly identified. We have used mutational analysis of the viral end LTR sequence, in vitro selection of optimal viral end sequences, and specific photocrosslinking to identify regions of integrase that interact with specific bases in the LTR termini. The results highlight the involvement of the disordered loop of the integrase core domain, specifically residues Q148 and Y143, in binding to the terminal portion of the viral DNA ends. Additionally, we have identified positions upstream in the LTR termini which interact with the C-terminal domain of integrase, providing evidence for the role of that domain in stabilization of viral DNA binding. Finally, we have located a region centered 12 bases from the viral DNA terminus which appears essential for viral end DNA binding in the presence of magnesium, but not in the presence of manganese, suggesting a differential effect of divalent cations on sequence-specific binding. These results help to define important regions of contact between integrase and viral DNA, and assist in the formulation of a molecular model of this vital interaction.     

Differential expression of the retinoblastoma gene family members pRb/p105, p107, and pRb2/p130 in lung cancer

The Rb (retinoblastoma) gene family is composed of three members: the RB gene (one of the best-studied tumor suppressor genes) and two related genes, p107 and pRb2/p130. These three proteins share many structural and functional features and play a fundamental role in growth control. Using immunocytochemical techniques, we evaluated a variety of lung tumor specimens for the expression of this family of proteins and compared protein expression with the histological grading of the tumors and with the expression of the proliferating cell nuclear antigen. These Rb family members displayed distinctive patterns when compared and contrasted using different parameters. The highest percentage of undetectable levels in all of the specimens examined and the tightest inverse correlation (P) with the histological grading and with proliferating cell nuclear antigen expression in the most aggressive tumor types were found for pRb2/p130, which may suggest an important role for this protein in the pathogenesis and progression of lung cancer.     

Ambulatory anesthesia practice in a University Hospital Center: what is done; what could be done. Ambulatory Anesthesia Study Group

OBJECTIVES: To estimate the number and type of patients, who could be managed on a day-care basis in a University Hospital. Cases of ambulatory anaesthesia (AA) which could be managed in optimal conditions and current AA practice. To assess patients' opinion on inpatient or outpatient practices. STUDY DESIGN: Prospective survey over 8 weeks in 21 medical units potentially concerned by ambulatory practice. PATIENTS: Series of 1,396 patients undergoing an operation included in a previously established list of outpatient procedures. METHOD: A questionnaire was completed for each patient, from preoperative anaesthesia consultation until discharge. Thereafter patients were contacted after home discharge by telephone or mail. RESULTS: In the group of the 1,396 selected patients, 301 (22%) were contra-indicated for AA. In optimal conditions AA was indicated in 20% of all patients treated in these units. At the time of the survey there were 285 outpatients (26% of potential AA, 5% of all patients). Complications were uncommon. Ninety-eight percent of them would choose day surgery again. Among the 810 inpatients, 279 responded: 53% would prefer to be an ambulatory patient. CONCLUSION: At the time of this survey only one fourth of the possible oupatients for AA had in fact been treated on a day-case basis. Its development requires an improvement of the structures, team organisation and patients' information.     

Effect of blood gas derangement on QTc dispersion in severe chronic obstructive pulmonary disease: evidence of an electropathy?

Mature myocardium utilizes calcium released by the sarcoplasmic reticulum (SR) for cell contraction. Transient exposure of mature myocytes to caffeine is known to directly trigger Ca2+ release from the SR. In contrast, neonatal rabbit heart cells rely on transsarcolemmal Ca2+ influx for tension generation. SR function is decreased in immature heart and appears to play a minimal role as a calcium source. Accordingly, we hypothesized that neonatal rabbit myocytes would not respond to a caffeine pulse. Isolated neonatal and adult myocytes were paced to load the SR with calcium and then exposed to a 1-s pulse of 10 mM caffeine. As previously described, adult myocytes exhibited a brisk contraction in response to caffeine. Unexpectedly, neonatal myocytes also exhibited a similar, brisk response. These caffeine-induced contractions were not dependent on extracellular Ca2+ but were dependent upon the loading of SR Ca2+ stores. When SR Ca2+ stores were depleted by exposure to caffeine, mature myocytes exhibited only small, slow contractions in response to electrical field stimulation. Replenishing the SR Ca2+ stores resulted in normal, brisk contractions. In contrast, electrically stimulated contractions in immature myocytes were largely unaffected by caffeine-induced SR depletion. Thus, although neonatal myocytes are capable of loading and releasing calcium from the SR, such SR calcium release is not normally required for contraction in the developing heart. The minor role of SR Ca2+ release in immature rabbit heart may not result from immaturity of the SR, but rather from an inadequate mechanism to trigger SR calcium release.     

Fecal incontinence and rectal prolapse. Clinico-functional assessment

Rectal Prolapse is a rare and distressing condition, with a multifactorial etiopathogenesis. Often, this pathology is associated with fecal incontinence. The recommended approach to the patient with rectal prolapse and fecal incontinence is to repair the prolapse first, then deal particularly with fecal incontinence at a second operation. A retrospective, clinical and manometric study has varying degrees of fecal incontinence. Clinically five of their operation, and a further three patients improved, in two patients the degree of fecal incontinence remained invariable. One patient was worsened after surgery. Manometrically resting and pressure (RAP) was significantly higher in continent patients than in voluntary contraction pressure (MVCP) (p < 0.05) in preoperative testing. Postoperatively, there was a significant increase in the resting anal pressure as well as in maximum voluntary contraction pressure. Patients who remained incontinent had a significantly lower RAP and MVCP than patients who improved our regained continence. In conclusion this study shows an alteration of internal and external sphincteric function in patients with rectal prolapse. The surgical treatment of this disease improves sphincteric function. Incontinent patients with RAP < 10 mmHg and MCVP < 20 mmHg, probably they would be better treated simultaneously either for rectal prolapsus and incontinence. In this kind of patients the perianal proctectomy with total sphincteroplasty could be the elective treatment.