Pharmacological characterization of 5-HT4 receptors mediating relaxation of canine isolated rectum circular smooth muscle.

This study aimed to characterize for the first time in vitro 5-HT4 receptors in the canine gastrointestinal tract. For this purpose, we used circular muscle strips of the canine isolated rectum. In the presence of methysergide (60 microM), 5-HT induced relaxation of methacholine (1 microM)-precontracted muscle strips, yielding a monophasic sigmoidal concentration-relaxation curve (pEC50 7.2+/-0.07). Tetrodotoxin (0.3 microM) did not affect the curve to 5-HT, suggesting the inhibitory 5-HT receptor is located on the smooth muscle. Granisetron (0.3 microM) did also not affect the curve to 5-HT, which excludes the 5-HT3 receptor mediating the relaxation to 5-HT. The presence of methysergide rules out the involvement of 5-HT1, 5-HT2 or 5-HT7 receptors. 5-HT, the selective 5-HT4 receptor agonists R076186, prucalopride (R093877) and SDZ HTF-919 and the 5-HT4 receptor agonists cisapride and 5-MeOT relaxed the muscle strips with a rank order of potency R076186 = 5-HT > cisapride > prucalopride > or = SDZ HTF-919 > 5-MeOT. The selective 5-HT4 receptor antagonists GR 125487, RS 39604 and GR 113808 competitively antagonized the relaxations to 5-HT, yielding pK(B) estimates of 9.7, 7.9 and 9.1, respectively. The selective 5-HT4 receptor antagonist SB 204070 shifted the curve to 5-HT rightward and depressed the maximal response (apparent pA2 10.6). GR 113808 (10 nM) produced a parallel rightward shift of the curve to the selective 5-HT4 receptor agonists R076186 (pA2 8.8). It is concluded that 5-HT induces relaxation of the canine rectum circular muscle through stimulation of a single population of smooth muscle 5-HT4 receptors. For the first time, a nonhuman species was shown to exhibit relaxant 5-HT4 receptors in the large intestine.     

Progressive biparietal atrophy: an atypical presentation of Alzheimer's disease.

OBJECTIVES: To define the clinical, neuropsychological, and radiological features of bilateral parietal lobe atrophy. METHODS: Four patients underwent a comprehensive longitudinal neuropsychological assessment, as well as MRI and HMPAO-SPECT. RESULTS: The consistent findings in the patients were early visuospatial problems, agraphia of a predominantly peripheral (or apraxic) type, and difficulty with bimanual tasks, all of which outweighted deficits in memory and language until later in the course of the illness. As the disease progressed, impairments in the phonological aspects of language and in auditory-verbal short term memory were often striking, perhaps reflecting spread from the parietal lobe to perisylvian language areas. Three patients went on to develop a global dementia and fulfilled the criteria for a clinical diagnosis of probable Alzheimer's disease; the fourth patient has only recently been identified. Neuroimaging disclosed bilateral parietal lobe atrophy (MRI) and hypoperfusion (SPECT), which was out of proportion to that seen elsewhere in the brain. One patient has died and had pathologically confirmed Alzheimer's disease with particular concentration in both superior parietal lobes. CONCLUSIONS: Bilateral biparietal atrophy is a recognisable clinical syndrome which can be the presenting feature of Alzheimer's disease. Although the label "posterior cortical atrophy" has been applied to such cases, review of the medical literature suggests that this broad rubric actually consists of two main clinical syndromes with features reflecting involvement of the occipitotemporal (ventral) and biparietal (dorsal) cortical areas respectively.     

Amyloid beta protein (Abeta) starts to deposit as plasma membrane-bound form in diffuse plaques of brains from hereditary cerebral hemorrhage with amyloidosis-Dutch type, Alzheimer disease and nondemented aged subjects

To clarify where and how beta-amyloid begins to deposit in senile plaques, we examined the ultrastructural localization of amyloid beta protein (Abeta) in diffuse plaques of brains with hereditary cerebral hemorrhage with amyloidosis-Dutch type. Alzheimer disease (AD), and from nondemented aged subjects. Serial ultrathin sections of osmium-plastic blocks were immunogold-labeled for Abetax-42 (Abeta42), and sections on grids were observed under the electron microscope (EM) after observing the exact localization of the diffuse plaques in sections on glass slides by the reflection contrast microscope. Abeta42 deposition, which was decollated with gold particles, appeared in 3 forms in all subjects under the EM: 1) Scattered small bundles of amyloid fibrils between cell processes, frequently seen in the densely stained area of diffuse plaques. 2) Scattered small foci of nonfibrillar materials between cell processes as a relatively minor form. 3) Abeta42 on a part of the cell surface plasma membrane of normal appearing cell processes, a major form in weakly immunostained areas. The last form was not associated with degenerative neurites or reactive glia. Abeta42 deposition on the cell surface plasma membrane appears to be an initial event in diffuse plaques, and then it develops into amorphous/fibrillar amyloid between cell processes.     

Follow-up of GFR estimated from plasma creatinine after cimetidine administration in patients with diabetes mellitus type 2

BACKGROUND: The glomerular filtration rate (GFR) can be estimated from plasma creatinine according to the formula of Cockcroft and Gault (CG). When tubular secretion of creatinine is inhibited by cimetidine the mean difference between the Cockcroft-Gault clearance (CG(Cim) and GFR approximates zero, but there is still some interindividual difference, especially in type-2-diabetic patients. We studied during longitudinal follow-up, whether the discrepancies between CG(Cim) and GFR per patient are consistent in time in type-2-diabetic patients. PATIENTS AND METHODS: In 1996 and 1998 (interval 20-26 months) GFR was measured in 21 patients as the urinary clearance of continuously infused 125I-iothalamate. Plasma creatinine was analyzed with an enzymatic assay before and after oral cimetidine 800 mg t.i.d. during 24 hours. GFR estimations were calculated with the Cockcroft-Gault formula before (CG) and after cimetidine (CG(Cim)) and expressed as means +/- SEM. RESULTS: GFR deteriorated from 89.7 +/- 5.7 to 81.3 + 5.8 ml/min/1.73 m2 and CG(Cim) from 85.3 +/- 5.7 to 81.1 +/- 6.6 ml/min/1.73 m2, whereas CG decreased from 102.4 +/- 6.8 to 98.4 +/- 7.0 ml/min/1.73 m2. Changes in GFR and changes in CG(Cim) were correlated (r = 0.72, p < 0.001) and were not significantly different from each other. The discrepancy between CG(Cim) and GFR per patient in 1996 also correlated with the discrepancy between CG(Cim) and GFR in 1998 (r = 0.85, p < 0.001 ). CONCLUSIONS: In individual patients the discrepancies between the CG(Cim) and GFR are consistent in time and the change in GFR is reflected by the change in CG(Cim). This small variability means that CG(Cim), based on an enzymatic plasma creatinine assay, would be suitable for follow-up of GFR in type-2-diabetic patients, independent of albuminuria.     

Thymic Function and Output of Recent Thymic Emigrant T Cells During Intracranial Glioma Progression

One of the hallmarks of patients with glioblastoma multiforme (GBM) is profound lymphopenia mostly confined to the T cell lineage. A deficiency in the production of naïve T cells from the thymus could contribute to the lymphopenia seen in GBM patients. In this study we asked whether thymic function and the production of recent thymic emigrant (RTE) T cells from the thymus was influenced by intracranial (i.c.) glioma progression. We found significant thymic involution in animals with progressive i.c. gliomas. Involuted thymi from animals with progressive i.c. T9.F gliomas showed dramatic losses of CD4⁺CD8⁺ (DP) thymocytes. Microscopic analysis complemented those findings by demonstrating a reversal of the typical cortico-medullary structure. Significant increases in apoptosis accompanied the rapid loss of viable thymocytes, which was prevented in part by adrenalectomy, suggesting a dominant role for endogenous glucocorticoids. This thymic involution was also associated with a significant decrease in peripheral RTE T cells, reflecting the diminished thymic function. Finally, we found that CD8⁺ RTE T cells were enriched in progressively growing T9 gliomas, which points to an immunological role for RTE's in anti-glioma immunity. Our findings may shed light on the significance of thymic function for anti-glioma immunity and the response to immunotherapeutic treatment paradigms.     

Risk factors for human herpesvirus 8 seropositivity and seroconversion in a cohort of homosexual men

Sexual and nonsexual modes of transmission of human herpesvirus 8 (HHV8) have been suggested, but specific routes remain unclear. Therefore, the objective of this study was to assess risk factors for HHV8 seropositivity and determine specific sexual practices associated with HHV8 seroconversion. Sera from 1,458 homosexual men (Amsterdam Cohort Study, 1984-1996) were tested for antibodies to HHV8 with a modified version of an enzyme immunoassay, using recombinant HHV8 lytic phase capsid (ORF65) and latent phase nuclear (ORF73) proteins. HHV8 seroprevalence at study entry was 20.9% (305/1,458); was highest among those with positive human immunodeficiency virus (HIV) status, no steady partner, and southern European or Latin American nationality; and increased with older age and higher number of sexual partners. During follow-up, 215 men seroconverted for HHV8 (incidence: 3.6/100 person-years). Both prevalence and incidence rates remained more or less stable during the study period. Orogenital insertive sex (odds ratio (OR) = 5.95; 95% confidence interval (CI): 2.88, 12.29) or orogenital receptive sex (OR = 4.29; 95% CI: 2.11, 8.71) with more than five partners in the past 6 months, older age (OR = 2.89; 95% CI: 1.13, 7.34, when older than 45 years), and preceding HIV infection (OR = 2.47; 95% CI: 1.53, 3.99) were independent predictors for HHV8 seroconversion. The authors found strong evidence for orogenital transmission of HHV8 among homosexual men.     

VASCULAR EMBOLOTHERAPY-HOW MUCH HAS BEEN ACHIEVED?

Emergency and elective embolotherapy of various systemic arteries in 64 patients was carried out at a tertiary centre of Armed Forces. Specific indications were haemoptysis (n=43), preoperative (n=18), haematuria (n=1), epistaxis (n=1) and chemoembolization (n=1). The procedures were performed with gelfoam pellets (n=46), gelfoam pellets and absolute alcohol (n=1), polyvinyl alcohol particles (PVA) (n=14), steel coils (n=2) and Adriamycin-in-oil emulsion (n=1). Embolotherapy resulted in complete haemostasis in 37 (82.2%) out of 45 cases of haemorrhage. In eight cases (17.8%), it resulted in significant improvement. Complete haemostasis was achieved in both cases of haematuria and epistaxis. Pre-operative embolotherapy resulted in considerable reduction of peroperative blood loss in all the cases. Chemoembolization of Hepatocellular carcinoma resulted in partial regression of the tumour. The purpose of this study was to assess the efficacy, safety and reliability of vascular embolotherapy for control of life threatening haemorrhage and preoperative reduction of lesions.KEY WORDS: Embolization, Embolotherapy, Haemorrhage     

Normal voiding patterns and determinants of increased diurnal and nocturnal voiding frequency in elderly men

PURPOSE: We determined the normal value of diurnal and nocturnal voiding frequency, and its determinants in a population based sample of elderly men. MATERIALS AND METHODS: We collected data on 1,688 men 50 to 78 years old recruited from the population of Krimpen, The Netherlands. Measurements consisted of self-administered questionnaires, including the International Prostate Symptom Score (I-PSS), a 3-day frequency-volume chart, transrectal prostatic ultrasound, uroflowmetry and post-void residual urine volume measurement. RESULTS: Diurnal voiding frequency is independent of age and more frequent in men with benign prostatic hyperplasia (BPH). Nocturia 2 or more times is present in 30% of men 50 to 54 and in 60% of those 70 to 78 years old, while nocturia 3 or more times is present in 4% and 20%, respectively. In addition, nocturia is strongly associated with BPH and nocturnal polyuria but apparently not with cardiovascular symptoms, hypertension or diabetes mellitus. We noted poor agreement of the responses on the frequency-volume charts and the I-PSS question on nocturia. Using the I-PSS leads to a higher prevalence of nocturia. CONCLUSIONS: Diurnal frequency is independent of age (median 5 voids, interquartile range 4 to 6) but higher in men with BPH. Nocturia increases with advancing age and is more frequent in men with nocturnal polyuria. BPH is an independent risk factor for nocturia and increased diurnal voiding frequency. In those with nocturia there is a great difference in subjective symptoms and objective data, indicating that the weight of the I-PSS question on nocturia for making treatment decisions should be reconsidered.     

Psychological Problems among Head and Neck Cancer Patients in Relation to Utilization of Healthcare and Informal Care and Costs in the First Two Years after Diagnosis

Background: To investigate associations between psychological problems and the use of healthcare and informal care and total costs among head and neck cancer (HNC) patients. Method: Data were used of the NETherlands QUality of Life and Biomedical Cohort study. Anxiety and depression disorder (diagnostic interview), distress, symptoms of anxiety and depression (HADS), and fear of cancer recurrence (FCR) and cancer worry scale (CWS) were measured at baseline and at 12-month follow-up. Care use and costs (questionnaire) were measured at baseline, 3-, 6-, 12-, and 24-month follow-up. Associations between psychological problems and care use/costs were investigated using logistic and multiple regression analyses. Results: Data of 558 patients were used. Distress, symptoms of anxiety or depression, FCR, and/or anxiety disorder at baseline were significantly associated with higher use of primary care, supportive care, and/or informal care (odds ratios (ORs) between 1.55 and 4.76). Symptoms of anxiety, FCR, and/or depression disorder at 12-month follow-up were significantly associated with use of primary care, supportive care, and/or informal care (ORs between 1.74 and 6.42). Distress, symptoms of anxiety, and FCR at baseline were associated with higher total costs. Discussion: HNC patients with psychological problems make more use of healthcare and informal care and have higher costs. This is not the result of worse clinical outcomes.