Epithelial cell proliferation in the rat urinary system induced by parenteral injection of lead salts.

In Wistar rats a single intravascular injection of lead nitrate causes substantial cellular proliferation in the proximal tubules of the kidneys and in the epithelium of the renal pelvis, ureters and urinary bladder. The tritiated thymidine labelling index (LI) reaches a peak 18 to 24 h after injection and the mitotic index (MI) increases to a comparable extent 6 to 10 h later. The proliferation is most prominent in the bladder and proximal tubules and is virtually complete at 48 h. After a single intraperitoneal injection the proliferative changes are confined to the ureteric and bladder epithelium. In all affected tissues the proliferation develops without preceding necrosis and appears to be a hyperplastic phenomenon. After intravascular administration the volume of urine and its total protein content are significantly increased and certain proteins were detected which were not present in the urine of saline controls.     

Seizure Disorders: The Changes With Age

Summary: Age has a profound influence on our approach to the convulsive disorders. Age is a variable which is an important determinant for risk factors for epilepsy. Age, as a surrogate of brain maturation, is a determinant of the specific characteristics of the seizure disorder in those with epilepsy, and age-related changes in these manifestations can be identified. Age is a determinant for the occurrence of acute symptomatic seizures in several types of metabolic or central nervous system insults. Age is a determinant for prognosis, whether one considers remission, medication withdrawal in those entering remission, relapse following prolonged remission, or mortality. Last, age per se seems to be a risk factor for epilepsy independent of other factors. This seems particularly true for partial seizures.     

Effects of the 5-HT1A partial agonists gepirone,ipsapirone and buspirone on local cerebral glucose utilization in the conscious rat

The azospirones gepirone (10 mg/kg), ipsapirone (10 mg/kg) and buspirone (10 mg/kg) were examined for their effect on regional cerebral glucose utilization in conscious rats using quantitative 2-deoxyglucose autoradiography. All three 5-HT_1A partial agonists reduced glucose utilization in the hippocampus and dentate gyrus by 20–25% and increased glucose utilization by 38–65% in the lateral habenular nucleus; an important relay between striatal/limbic areas and the mid-brain raphe nuclei. The findings emphasize the potential importance of the hippocampus as a site of action for 5-HT_1A receptor active drugs in vivo and also suggest that functional activity in the striatal/limbichabenular-raphe pathway may be influenced by gepirone, ipsapirone and buspirone.     

Translational crossroads for biomarkers.

A group of investigators met at a Specialized Programs of Research Excellence Workshop to discuss key issues in the translation of biomarker discovery to the development of useful laboratory tests for cancer care. Development and approval of several new markers and technologies have provided informative examples that include more specific markers for prostate cancer, more sensitive tests for ovarian cancer, more objective analysis of tissue architecture and an earlier indication of response to treatment in breast cancer. Although there is no clear paradigm for biomarker development, several principles are clear. Marker development should be driven by clinical needs, including early cancer detection, accurate pretreatment staging, and prediction of response to treatment, as well as monitoring disease progression and response to therapy. Development of a national repository that uses carefully preserved, well-annotated tissue specimens will facilitate new marker development. Reference standards will be an essential component of this process. Both hospital-based and commercial laboratories can play a role in developing biomarkers from discovery to test validation. Partnering of academe and industry should occur throughout the process of biomarker development. The National Cancer Institute is in a unique position to bring together academe, industry, and the Food and Drug Administration to (a) define clinical needs for biomarkers by tumor type, (b) establish analytic and clinical paradigms for biomarker development, (c) discuss ways in which markers from different companies might be evaluated in combination, (d) establish computational methods to combine data from multiple biomarkers, (e) share information regarding promising markers developed in National Cancer Institute-supported programs, and (f) exchange data regarding new platforms and techniques that can accelerate marker development.     

Synthetic and computer-assisted analyses of the pharmacophore for the benzodiazepine receptor inverse agonist site

The structural requirements for ligand binding to the benzodiazepine receptor (BzR) inverse agonist site were probed through the synthesis and in vitro evaluation of 3-substituted beta-carbolines 6, 7, 11, 12, gamma-carboline 13, and diindoles 18-21, 23-25, 27, 28, and 34. On the basis of the apparent binding affinities of these and other analogues, a hydrogen bond acceptor site (A2) on the receptor is proposed to interact with the N(9) hydrogen atom of the beta-carbolines or the N(7) hydrogen nuclei of the diindoles. Likewise, a proposed hydrogen bond donating site (H1) interacts with the N(2) nitrogen atom of the beta-carbolines or the N(5) nitrogen atom of the diindoles. It appears that interaction with both sites is a prerequisite for high affinity since analogues which have either one or both of these positions blocked exhibit substantial reduction in affinity. Moreover, H1 appears to be capable of engaging in a three-centered hydrogen bond with appropriately functionalized ligands, which explains the increase in potency observed in the following series of 3-substituted beta-carbolines: the n-butyl (12, IC50 = 245 nM), n-propoxy (9, IC50 = 11 nM), and propyl ketone (11, IC50 = 2.8 nM) congeners. In addition to H1 and A2, there appears to be a relatively narrow hydrophobic pocket in the binding cleft that can accommodate substituents at the 3-position of the beta-carbolines which have chain lengths less than or equal to C5. There is a 1 order of magnitude decrease in affinity between n-propoxy analogue 9 (IC50 = 11 nM, chain length = 4) and n-butoxy derivative 7 (IC50 = 98 nM, chain length = 5). Furthermore, alpha- and gamma-branching [e.g. ethoxycarbonyl (2), IC50 = 5 nM and tert-butoxycarbonyl (31) IC50 = 10 nM] but not beta- and delta-branching [e.g. isopropoxy (6), IC50 = 500 nM and (neopentyloxy) carbonyl (48), IC50 = 750 nM] at position 3 are tolerated. Occupation of this hydrophobic pocket is clearly important for high affinity as evidenced by the relatively low affinity of 30, a beta-carboline which possesses a hydrogen atom at the 3-position. This same hydrophobic pocket is partially filled by the D and E rings of the diindoles, which accounts for the high affinity of several members of this series. An excluded volume analysis using selected 3-substituted beta-carbolines and ring-E substituted pyridodiindoles is consistent with the presence of this hydrophobic pocket (see Figure 1).(ABSTRACT TRUNCATED AT 400 WORDS)     

Causes of blindness in children attending four schools for the blind in Thailand and the Philippines

Using WHO definitions of visual loss and a standardised methodology, 256 children were examined in schools for the blind in Thailand (1 school) and the Philippines (3 schools). 244 (95%) were blind (BL) or severely visually impaired (SVI). Causes of SVI and blindness were classified anatomically and aetiologically, and avoidable causes identified. Causes of visual loss in Khon Kaen, Thailand (n = 65) and Manila, Philippines, (n = 113) were similar, with conditions of the whole globe accounting for 27.7 and 27.4% of SVI/BL; retinal disease 29.2 and 23.0%; cataract 16.9 and 16.8%; corneal disease 12.3 and 13.4%; and optic nerve disease and glaucoma 6.2 and 8.8%. Perinatal factors accounted for 20.0 and 23.0% of SVI/BL; hereditary disease 13.8 and 17.7%; and 12.3 and 15.0% was due to events occurring during childhood. The underlying aetiology could not be determined in 50.8 and 41.6% of cases, respectively. In the two schools together twenty six children (15%) were blind from retinopathy of prematurity (ROP) and 16 (9%) from corneal scarring attributed to Vitamin A deficiency. 103 of 178 (58%) children had avoidable causes of visual loss. In the Filipino towns of Baguio and Davao (n = 66), the causes of visual loss were different from those in Khon Kaen and Manila, with 54.8 and 42.9% of SVI/BL being due to corneal disease, and only 3.2 and 8.5% to retinal disease. Childhood factors were more important (61.3 and 57.1%) than hereditary (9.7 and 17.1%) or perinatal factors (0 and 2.9%). Thirty one children (47%) had SVI/BL attributed to Vitamin A deficiency. No child was blind from ROP. 42 of 66 (64%) of children had avoidable causes of blindness. Overall 60% of children with SVI/BL had avoidable causes of visual loss in these 4 schools. Approximately half could have been prevented by primary health and eye care services and half could have been managed by surgical ophthalmological procedures. The causes of blindness identified in this blind school study suggest that the major causes are different for schools serving rural populations compared to those serving urban communities. Different control strategies are required for the different situations.     

Family physicians' perceptions of academic detailing: a quantitative and qualitative study

Background  

The efficacy of academic detailing in changing physicians' knowledge and practice has been the subject of many primary research publications and systematic reviews. However, there is little written about the features of academic detailing that physicians find valuable or that affect their use of it. The goal of our project was to explore family physicians' (FPs) perceptions of academic detailing and the factors that affect their use of it.