Insulin, glucose, insulin resistance, and incident colorectal cancer in male smokers.

BACKGROUND & AIMS: Hyperinsulinemia is a putative colorectal cancer (CRC) risk factor. Insulin resistance (IR) commonly precedes hyperinsulinemia and can be quantitatively measured by using the homeostasis model assessment-insulin resistance (HOMA-IR) index. To date, few studies have directly examined serum insulin as an indicator of CRC risk, and none have reported associations on the basis of HOMA-IR. METHODS: We performed a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (n=29,133). Baseline exposure and fasting serum biomarker data were available for 134 incident CRC case and 399 non-case subjects. HOMA-IR was derived as fasting insulin x fasting glucose/22.5. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by using age-adjusted and multivariable-adjusted Cox proportional hazards regression models. RESULTS: Median (interquartile range) values for serum insulin, glucose, and HOMA-IR were 4.1 (2.9-7.2) mIU/L, 101 (94-108) mg/dL, and 0.99 (0.69-1.98) for case subjects and 4.1 (2.7-6.1) mIU/L, 99 (93-107) mg/dL, and 1.02 (0.69-1.53) for non-case subjects, respectively. On the basis of comparison of the highest versus lowest quartiles for each biomarker, insulin (HR, 1.84; 95% CI, 1.03-3.30) and HOMA-IR (HR, 1.85; 95% CI, 1.06-3.24) were significantly associated with incident CRC, whereas glucose was marginally associated with incident CRC (HR, 1.70; 95% CI, 0.92-3.13) in age-adjusted risk models. However, trends across biomarker quartiles were somewhat inconsistent (P trend=.12, .04, and .12, respectively), and multivariable adjustment generally attenuated the observed risk estimates. CONCLUSIONS: Data from this prospective study of male smokers provide limited support for hyperinsulinemia, hyperglycemia, and/or insulin resistance as CRC risk factors.     

Serotonin 5-HT2C receptor-mediated phosphoinositide hydrolysis in rat choroid plexus after fluoxetine and citalopram treatments.

Selective serotonin reuptake inhibitors (SSRIs) bind directly to various neurotransmitter receptors. The clinical effects of SSRIs appear gradually during weeks of treatment, suggesting a role for adaptive changes in neurotransmitter receptors. Most clinically used antidepressants, e.g. fluoxetine, bind to 5-HT2C receptors. When administered chronically, many antidepressants elicit adaptive regulation of 5-HT2C receptors. The present study was conducted in order to determine the effects of acute and chronic fluoxetine and citalopram treatments on the density and function of 5-HT2C receptors in the rat choroid plexus. Acute and chronic treatments followed by phosphoinositide (PI) hydrolysis assays and quantitative receptor autoradiography were performed. Acute (single-dose) treatment with neither drug significantly affected basal or 5-HT-stimulated PI hydrolysis, but acute citalopram (20 mg/kg) treatment increased both agonist and antagonist binding to 5-HT(2C) receptors. Chronic (14 days) citalopram treatment (20 mg/kg) increased the maximal PI hydrolysis response by 40%, but fluoxetine lacked this effect. The present data suggest that sensitisation of 5-HT2C receptor-mediated intracellular signal transduction may play a role in the effects of citalopram. In contrast, fluoxetine treatment does not functionally sensitise 5-HT2C receptors. Thus, functional 5-HT2C receptor sensitisation is not a common effect of antidepressants, but the differential effects may explain some of the pharmacodynamic differences seen with these drugs, especially upon repeated administration.     

TK-GFP fusion gene virus vectors as tools for studying the features of HSV-TK/ganciclovir cancer gene therapy in vivo

The fusion gene of herpes simplex virus thymidine kinase and green fluorescent protein (TK-GFP) was shown to be a versatile tool for examining the features of thymidine kinase/ganciclovir gene therapy in vitro. In this study, we used viral vectors carrying the fusion gene to characterize the aspects of this gene therapy form in rodent tumor models. Growth of subcutaneous 9L rat tumors transduced ex vivo with TK-GFP gene was prevented when ganciclovir (GCV) treatment was initiated immediately after tumor inoculation. Established tumors (>100 mm(3)), however, were untreatable despite the initial 55% proportion of TK-GFP positive cells. This was due to a rapid clearance of TK-GFP positive cells, but not GFP positive cells. Propidium iodide staining revealed that TK-GFP lentivirus vector was able to induce apoptosis/necrosis in 9L cells, as opposed to the respective GFP vector. Furthermore, when a subcutaneous nude mouse tumor model was used, the percentage of TK-GFP positive cells in vivo was maintained similarly as in cultured cells, suggesting contribution of a fully functional immune response to the disappearance of fusion gene positive cells. In vivo gene transfer studies: adenovirus TK-GFP vector injections resulted in about 25% gene transfer efficiency to 9L tumors and showed that their growth could be significantly reduced even when the tumor volumes were already >120 mm(3). Part of the effect was shown to be due to cytotoxicity of the vector. In summary, our results demonstrate the utility of TK-GFP fusion gene-carrying viral vectors in animal studies and show that readily detectable therapeutic genes can help us to understand the complicated nature of in vivo cancer gene therapy experiments.     

Rupture of splanchnic artery aneurysms

The results of surgical therapy for acute ruptured splanchnic artery aneurysms in 6 patients treated at Helsinki University Central Hospital from 1964 to 1984 were analyzed. There were 3 patients with ruptured splenic, 2 with ruptured hepatic and 1 with ruptured superior mesenteric artery aneurysms. The condition remained undiagnosed in all patients preoperatively, and the diagnosis was obtained only at emergency laparotomy performed for severe shock, abdominal pain, and distension. Five of the 6 patients survived, including a pregnant woman, who gave birth to a living baby by ceserean section. The results indicate that immediate, aggressive surgical approach dictated by the clinical condition of the patient affords good survival in patients suffering from acute rupture of splanchnic artery aneurysms.

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Resumen Se analizan los resultados del tratamiento quirúrgico de la ruptura aguda de aneurismas de arterias esplnicas en 6 pacientes manejados en el Hospital Central de la Universidad de Helsinki en el periodo 1964–1984. Se presentaron 3 pacientes con ruptura de aneurismas de la arteria esplénica, 2 de la hepática y 1 de la mesentérica superior. La condición clínica se mantuvo sin diagnóstico durante la fase preoperatoria, y el diagnóstico sólo fue hecho en el curso de la laparotomía, procedimiento que fue realizado por shock severo, dolor abdominal y distensión. Cinco de los 6 pacientes sobrevivieron, incluyendo una mujer embarazada, quien dio a luz un niño vivo mediante sección cesárea. Los resultados indican que el enfoque quirúrgico inicial agresivo indicado por la condición clínica del paciente ofrece una buena oportunidad de supervivencia en pacientes que presentan ruptura de aneurismas de las arterias esplácnicas.

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Résumé Les résultats du traitement chirurgical de 6 ruptures d'anévrysmes des artères splanchniques traités à l'Hôpital Central Universitaire d'Helsinki de 1964 à 1984 sont étudiés par les auteurs. Ils concernent la rupture anévrysmale de 3 artères spléniques, de 2 artères hépatiques, de 1 artère mésentérique. Le diagnostic ne fut porté qu'au moment de l'intervention d'urgence pratiquée en présence d'un état de choc sévère s'accompagnant de douleur et de distension abdominales. Cinq des 6 opérés ont survécu, dont une femme enceinte chez qui une césarienne fut pratiquée avec succès. Ces résultats plaident en faveur de l'action chirurgicale d'urgence.

     

Up-regulation of β1-adrenergic receptors in rat brain after chronic citalopram and fluoxetine treatments

Quantitative receptor autoradiography was used to study the effects of the selective serotonin reuptake inhibitors citalopram and fluoxetine and the tricyclic antidepressant imipramine on the regulation of ₁-adrenergic receptors in the rat brain. Rats were treated with saline, citalopram (10 mg kg^–1), fluoxetine (10 mg kg^–1), or imipramine (15 mg kg^–1) SC once daily for 14 days. [¹²⁵I]Iodocyanopindolol binding to ₁-adrenergic receptors was found to increase significantly in the caudate-putamen and the somatosensory areas of the frontal cortex after both citalopram and fluoxetine treatments. Imipramine treatment elicited a marked decrease in ₁ binding in the outer laminae of the cingulate cortex, as well as in the motor and somatosensory areas of the frontal cortex. In a separate experiment, rats were treated with saline, citalopram (2.5, 10 and 20 mg kg^–1) or fluoxetine (2.5, 10 and 20 mg kg^–1) SC once daily for 14 days. The effects of citalopram and fluoxetine on ₁ receptors in the somatosensory cortex and caudate-putamen were replicated. These results demonstrate that chronic administration of selective serotonin reuptake inhibitors, in contrast to imipramine, can cause a regional up-regulation of ₁-adrenergic receptors in the rat brain.     

Alphacalcidol oral pulses normalize uremic hyperparathyroidism prior to dialysis

Alphacalcidol oral pulse therapy was given for secondary hyperparathyroidism to 22 children (mean age of 5.6 years) with renal insufficiency. At the beginning of the study, the glomerular filtration rate was <50% of normal, serum intact parathyroid hormone (PTH) was >100 ng/l and the serum phosphate and calcium concentrations were within the normal range. Alphacalcidol (0.5–3.0 g) was given orally thrice weekly in the evening and adjusted according to PTH, ionized calcium and phosphate concentrations. Serum PTH (mean ± SEM) decreased significantly from a pre-treatment level of 393±81 ng/l to 122±34 ng/l after 12 months, and stabilized at this level. Mean vitamin D metabolite concentrations were within the normal range. 1,25-Dihydroxyvitamin D did not increase during therapy, while PTH decreased. The estimated creatinine clearance remained almost unchanged (20±3 and 21±6 ml/min per 1.73 m²). Growth remained low normal (height standard deviation score –1.8±0.3 initially and –1.7±0.4 12 months later) and bone mineral density did not decrease. We concluded that feedback regulation of PTH with oral alphacalcidol pulse therapy is effective in the treatment of hyperparathyroidism in children with renal failure prior to dialysis.     

Dietary carotenoids and risk of lung cancer in a pooled analysis of seven cohort studies.

Intervention trials with supplemental beta-carotene have observed either no effect or a harmful effect on lung cancer risk. Because food composition databases for specific carotenoids have only become available recently, epidemiological evidence relating usual dietary levels of these carotenoids with lung cancer risk is limited. We analyzed the association between lung cancer risk and intakes of specific carotenoids using the primary data from seven cohort studies in North America and Europe. Carotenoid intakes were estimated from dietary questionnaires administered at baseline in each study. We calculated study-specific multivariate relative risks (RRs) and combined these using a random-effects model. The multivariate models included smoking history and other potential risk factors. During follow-up of up to 7-16 years across studies, 3,155 incident lung cancer cases were diagnosed among 399,765 participants. beta-Carotene intake was not associated with lung cancer risk (pooled multivariate RR = 0.98; 95% confidence interval, 0.87-1.11; highest versus lowest quintile). The RRs for alpha-carotene, lutein/zeaxanthin, and lycopene were also close to unity. beta-Cryptoxanthin intake was inversely associated with lung cancer risk (RR = 0.76; 95% confidence interval, 0.67-0.86; highest versus lowest quintile). These results did not change after adjustment for intakes of vitamin C (with or without supplements), folate (with or without supplements), and other carotenoids and multivitamin use. The associations generally were similar among never, past, or current smokers and by histological type. Although smoking is the strongest risk factor for lung cancer, greater intake of foods high in beta-cryptoxanthin, such as citrus fruit, may modestly lower the risk.