The effects of lead exposure on learning in a multiple repeated acquisition and performance schedule

This study sought to determine the selectivity of Pb-induced changes in learning, as distinct from non-specific or performance effects, and to explore the nature of the underlying error patterns contributing to any learning deficits. To accomplish this, rats were chronically exposed to 0, 50, or 250 ppm Pb acetate in drinking water from weaning and trained on a multiple repeated acquisition (RA) and performance (P) schedule beginning at 55 days of age. The RA component required the rat to learn a new 3-member sequence of responses during each experimental session (Center Right Left, RLC, CLR, RCL, and LRC), while the correct sequence of responses for the P component was constant across sessions (LCR). Significant decrements in accuracy on the RA component but not on the P component were found in Pb-exposed groups compared to control, effects that could not be attributed to differential rates of responding. Analyses of error patterns revealed that the effects of Pb exposure on RA accuracy levels derived from two sources. The first consisted of a perseveration of P-like sequence responding (LCR) even during the RA component. Secondly, Pb exposure increased perseverative responding on a single lever, even though the schedule itself never directly reinforced such repetitive responding. The increase in frequency of these two types of perseverative behavior was incompatible with acquisition of non P-like sequences during the RA component. Adding a 5 sec tone to the light stimuli signalling the transition between RA and P components of the multiple schedule failed to attenuate these effects of Pb, suggesting that deficits in stimulus control were not the sole behavioral mechanism of these impairments. Examination of individual data revealed the presence of both 'learners' and 'non-learners' in each group, with the prevalence of the latter being suggestively higher in Pb-exposed groups than in controls. These findings may be relevant to the classroom setting, where periods requiring learning may frequently be interspersed with periods of performance of learned skills.     

Vesicoureteral reflux and ureteropelvic junction obstruction: association, treatment options and outcome

PURPOSE: We investigated the association, treatment options and outcomes of patients with ureteropelvic junction obstruction and concomitant vesicoureteral reflux. MATERIALS AND METHODS: We analyzed 6,790 consecutive pediatric urology records at our university. Treatment options included observation, and primary pyeloplasty, ureteroneocystostomy and nephroureterectomy. Hydronephrosis, reflux and obstruction were judged as resolved, improved, unchanged or worse. RESULTS: A total of 1,140 patients had vesicoureteral reflux, 224 had ureteropelvic junction obstruction and 41 had both conditions (39 ipsilateral and 6 contralateral kidneys). There was no increased risk of obstruction in patients with reflux when all grades of reflux were grouped (odds ratio 1.26, confidence interval 0.91 to 1.71). In contrast, subgroup analysis of patients with high grade reflux demonstrated a 5-fold increased risk of obstruction (odds ratio 5.0, confidence interval 2.4 to 10.8). One patient was lost to followup. Observation of 6 kidneys led to resolution of reflux in 3 (50%), resolution of obstruction in 3 (50%) and resolution or improvement of hydronephrosis in 4 (67%). Primary pyeloplasty was done on 29 kidneys with 10 (35%) requiring subsequent ureteroneocystostomy. At latest followup hydronephrosis resolved or improved in 24 patients (83%), vesicoureteral reflux resolved or improved in 19 (66%) and ureteropelvic junction obstruction resolved in all. Primary ureteroneocystostomy was performed on 5 kidneys, all of which required subsequent pyeloplasty. Hydronephrosis resolved in 3 patients (60%), and reflux and obstruction resolved in all. Two patients treated with primary nephroureterectomy, and 1 who underwent concomitant pyeloplasty and ureteroneocystostomy have had no subsequent urological problems. One patient awaits primary pyeloplasty. CONCLUSIONS: High grade vesicoureteral reflux is associated with ureteropelvic junction obstruction. No association with low or intermediate grade reflux was demonstrated. While some patients may be monitored expectantly, in our series pyeloplasty or nephrectomy was required in 81% and ureteroneocystostomy was required in 36%. In no case did primary ureteroneocystostomy protect against the subsequent need for pyeloplasty.     

Identification of a gene that causes primary open angle glaucoma

Glaucoma is a major cause of blindness and is characterized by progressive degeneration of the optic nerve and is usually associated with elevated intraocular pressure. Analyses of sequence tagged site (STS) content and haplotype sharing between families affected with chromosome 1q-linked open angle glaucoma (GLC1A) were used to prioritize candidate genes for mutation screening. A gene encoding a trabecular meshwork protein (TIGR) mapped to the narrowest disease interval by STS content and radiation hybrid mapping. Thirteen glaucoma patients were found to have one of three mutations in this gene (3.9 percent of the population studied). One of these mutations was also found in a control individual (0.2 percent). Identification of these mutations will aid in early diagnosis, which is essential for optimal application of existing therapies.     

How the Listeria monocytogenes ActA protein converts actin polymerization into a motile force

The ActA protein is an essential determinant of pathogenicity that is responsible for the actin-based motility of Listeria monocytogenes in mammalian cells and cell-free extracts. ActA appears to control at least four functions that collectively lead to actin-based motility: (1) initiation of actin polymerization, (2) polarization of ActA function, (3) transformation of actin polymerization into a motile force and (4) acceleration of movement mediated by the host protein profilin.     

Should the same glucose values be targeted for type 1 as for type 2 diabetics in pregnancy?

OBJECTIVE: Our purpose was to determine whether the same maternal glycemic control is necessary to achieve similar perinatal outcomes for type 1 as for type 2 diabetics. STUDY DESIGN: The subjects were all women with pregestational diabetes mellitus delivered of live-born singletons. Glycemic control was achieved with diet and insulin. Self-monitoring of blood glucose was performed before meals and at bedtime. Target glucose values were 60 to 90 mg/dl fasting and 60 to 105 mg/dl at other times. RESULTS: Of 60,628 deliveries, 46 type 1 and 113 type 2 diabetic women met inclusion criteria. Respective differences were found between type 1 and type 2 diabetics in average daily glucose levels (112 mg/dl vs 97 mg/dl, p < 0.001), percent of values within target ranges (35% vs 57%, p < 0.001), and mean amplitude of glycemic excursion (48.1 mg/dl vs 24.9 mg/dl, p < 0.001). At least one daily glucose value was < 50 mg/dl during 19% of observation days for type 1 vs 2% of observation days for type 2 pregnancies (p < 0.001). There were no statistically significant differences between type 1 and type 2 diabetic pregnancies in neonatal macrosomia (30% vs 34%), proportion of cesarean deliveries during labor for arrest disorders (67% vs 69%), shoulder dystocia (2% vs 6%), and neonatal hypoglycemia (18% vs 26%). CONCLUSIONS: Less stringent maternal glycemic control may permit comparable maternal and neonatal outcomes for type 1 compared with type 2 diabetics. Higher target values for type 1 diabetics may decrease the frequency of maternal hypoglycemic episodes.     

Continuous assay of proteases using a microtiter plate fluorescence reader

The present study was designed to determine if spinal calcium channels, calmodulin, and calcium/calmodulin-dependent protein kinase II were involved in the production of antinociception induced by cold water swimming stress (CWSS). The effects of intrathecal (i.t.) injection of nimodipine, omega-conotoxin GVIA, calmidazolium, or (S)-5-isoquinolinesulfonic acid, 4-[2-[(5-isoquinolinyl-sulfonyl)methylamino]-3-oxo-3-(4-phenyl-1-piperaz inyl)-propyl]phenyl ester (KN-62) on CWSS-induced antinociception were studied in ICR mice. The antinociception was assessed by the tail-flick test. CWSS produced inhibition of the tail-flick response. Various doses of nimodipine (10-40 ng), omega-conotoxin GVIA (5-40 ng), calmidazolium (10-40 ng), or KN-62 (5-40 ng) injected i.t. alone did not show any antinociceptive effect in the tail-flick test. I.t. pretreatment with omega-conotoxin GVIA, calmidazolium, or KN-62 dose dependently attenuated the CWSS-induced inhibition of the tail-flick response. However, i.t. pretreatment with nimodipine did not affect the inhibition of the tail-flick response induced by CWSS. Our results suggest that spinal N-type calcium channel, calmodulin and calcium/calmodulin-dependent protein kinase II may be involved in the production of antinociception induced by CWSS. On the other hand, CWSS-induced antinociception appears not to be mediated via the spinal L-type calcium channel.     

Increased expression of peripheral benzodiazepine receptors in the facial nucleus following motor neuron axotomy

Peripheral benzodiazepine receptors (PBRs) are expressed in a variety of tissues but are normally found at low levels in the brain. Following various types of nerve injury, a reactive gliosis results that exhibits a high expression of this receptor. To further characterize the expression of PBRs following neuronal injury, we evaluated PBR expression in the facial nucleus following facial nerve axotomy (FNA). Injury to a peripheral nerve results in a complex series of metabolic and morphological changes around the injured neuron. Transections of the facial nerve results in a rapid activation of both astrocytes and microglia around axotomized motor neurons. FNA resulted in an increase in the staining for both astrocytes (glial fibrillary acidic protein) and activated microglia (OX42). There was also a reduction in synaptic contacts with the motor nucleus as evidenced by reduced staining for the synaptic marker, synaptophysin. In sections labeled with [3H]-PK11195, the subsequent autoradiograms displayed marked increases in the labeling for PBRs. This increase was observed at 5, 7 and 10 days after nerve transection. The increase was primarily in the level of expression (Bmax), with no change in the affinity of the ligand (Kd). The increase in PBR expression after FNA supports the hypothesis that PBRs can be used as a sensitive marker for CNS injury.     

Transplantation for end stage liver disease related to alpha 1 antitrypsin

Alpha 1 antitrypsin deficiency (AT) is an autosomal recessive disease associated with chronic liver disease in adults and children and emphysema in adults. The disease is one of the most common inherited disorders of the Caucasian population of North Europe and North America and is the most common genetic reason for pediatric orthotopic liver transplantation (OLTx), although it is a rare indication in adults. The natural history of the disease is unpredictable and the pathogenesis of the liver injury unclear. Thirty-five patients with histologically apparent alpha 1 AT accumulation in the liver (22 adults, 13 children) have been transplanted in this center. Clinical features were correlated with the pretransplant phenotype, serum alpha 1 antitrypsin levels and potential precipitating factors. All children were PiZZ homozygotes, most of whom had presented with neonatal hepatitis. The majority of adult patients were heterozygotes presenting with portal hypertension and liver cirrhosis. Current one-year posttransplant survival figures are 73% for adults and 87.5% for children. Replacement of the cirrhotic liver results in acquisition of the donor phenotype, a rise in serum levels of alpha 1 antitrypsin, and apparent prevention of associated disease.