A transthalamic pathway crucial for perception.

Perception arises from activity between cortical areas, first primary cortex and then higher order cortices. This communication is served in part by transthalamic (cortico-thalamo-cortical) pathways, which ubiquitously parallel direct corticocortical pathways, but their role in sensory processing has largely remained unexplored. Here, we show that the transthalamic pathway linking somatosensory cortices propagates task-relevant information required for correct sensory decisions. Using optogenetics, we specifically inhibited the pathway at its synapse in higher order somatosensory thalamus of mice performing a texture-based discrimination task. We concurrently monitored the cellular effects of inhibition in primary or secondary cortex using two-photon calcium imaging. Inhibition severely impaired performance despite intact direct corticocortical projections, thus challenging the purely corticocentric map of perception. Interestingly, the inhibition did not reduce overall cell responsiveness to texture stimulation in somatosensory cortex, but rather disrupted the texture selectivity of cells, a discriminability that develops over task learning. This discriminability was more disrupted in the secondary than primary somatosensory cortex, emphasizing the feedforward influence of the transthalamic route. Transthalamic pathways thus appear critical in delivering performance-relevant information to higher order cortex and are critical hierarchical pathways in perceptual decision-making.

Accentuating effects of nicotine on ethanol response in mice with high genetic predisposition to ethanol-induced locomotor stimulation.

BACKGROUND: Co-morbid use of nicotine-containing tobacco products and alcohol is prevalent in alcohol dependent individuals. Common genetic factors could influence initial sensitivity to the independent or interactive effects of these drugs and play a role in their co-abuse. METHODS: Locomotor sensitivity to nicotine and ethanol, alone and in combination, was assessed in mice bred for high (FAST) and low (SLOW) sensitivity to the locomotor stimulant effects of ethanol and in an inbred strain of mouse (DBA/2J) that has been shown to have extreme sensitivity to ethanol-induced stimulation in comparison to other strains. RESULTS: The effects of nicotine and ethanol, alone and in combination, were dependent on genotype. In FAST and DBA/2J mice that show high sensitivity to ethanol-induced stimulation, nicotine accentuated the locomotor stimulant response to ethanol. This effect was not found in SLOW mice that are not stimulated by ethanol alone. CONCLUSIONS: These data indicate that genes underlying differential sensitivity to the stimulant effects of ethanol alone also influence sensitivity to nicotine in combination with ethanol. Sensitivity to the stimulant effects of nicotine alone does not appear to predict the response to the drug combination, as FAST mice are sensitive to nicotine-induced stimulation, whereas SLOW and DBA/2J mice are not. The combination of nicotine and ethanol may have genotype-dependent effects that could impact co-abuse liability.

The effects of police duty belt and seat design changes on lumbar spine posture, driver contact pressure and discomfort.

Police officers spend large amounts of time performing duties within a police cruiser and report a high prevalence of musculoskeletal problems. This study evaluated the effects of driver seat and duty belt design on posture, pressure and discomfort. Ten male and 10 female university students attended two sessions involving simulated driving in a standard police seat (CV) and an active lumbar support (ALS) seat. Participants wore a full duty belt (FDB) or reduced duty belt (RDB) in each seat. Lumbar postures, driver-seat and driver-duty belt pressures and perceived discomfort were measured. Gender × Seat interactions were found for pelvic (p = 0.0001) and lumbar postures (p = 0.003). Females had more lumbar flexion than males and were more extended in the ALS seat (-9.8 ± 11.3°) than CV seat (-19.8 ± 9.6°). The FDB had greater seat pressure than the RDB (p < 0.0001), which corresponded to increased pelvis discomfort. This study supports the use of an ALS seat and RDB to reduce injury risk associated with prolonged sitting in police officers. PRACTITIONER SUMMARY: Police officers report a high prevalence of musculoskeletal problems to the lower back, associated with prolonged driving and further investigation is needed to reduce injury risk. This simulated driving study investigated seat and duty belt configuration on biomechanical measures and discomfort. Seat design had the greatest impact, regardless of gender and males benefited more from a reduced belt configuration.

A feline anaesthetic death associated with equipment incompatibility.

BACKGROUND: A juvenile cat was anaesthetised for ovariohysterectomy. After intubation, the endotracheal tube was connected to an end-tidal CO2 (ETCO2) in-line adapter and then to a non-rebreathing anaesthetic system. Immediately on connection to the non-rebreathing system, the patient developed abdominal distension. The endotracheal tube was removed and found to be supplying a continuous flow of oxygen while connected to the ETCO2 monitor adapter and rebreathing system. The adapter was removed from the rebreathing line and the endotracheal tube re-inserted. Despite resuscitation attempts, the cat died. RESULTS: Necropsy revealed barotrauma to the lungs and separation of the diaphragm from the dorsal body wall, with retroperitoneal gas accumulation. Close inspection of the gas delivery system revealed the creation of a plastic-to-plastic seal between the internal fresh gas pipe of the non-rebreathing system and the ETCO2 adapter, preventing overflow of excess gas. CONCLUSION: Careful assessment of equipment compatibility before every anaesthetic event is essential.

Fine-mapping in African-American women confirms the importance of the 10p12 locus to sarcoidosis.

Sarcoidosis is a chronic granulomatous disease with a wide spectrum of symptoms. Genome-wide association studies in European populations have reported significant associations between sarcoidosis and single-nucleotide polymorphisms (SNPs) located in the intergenic region between the C10ORF67 and OTUD1 genes on chromosome 10p12, and the ANXA11 gene (chromosome 10q22). We carried out fine-mapping at 10p12 and 10q22 to assess associations of genetic variants in these regions with sarcoidosis risk in African-American women, based on 486 sarcoidosis cases and 943 age- and geography-matched controls in a nested case-control study within the Black Women's Health Study. There were no significant associations with variants of the ANXA11 gene (P=0.17). Haplotypic analyses of the C10ORF67-OTUD1 intergenic region revealed a strong inverse association of the variants rs1398024 and rs11013452 with sarcoidosis (odds ratio=0.52; P=0.01). Both SNPs are located inside an ∼300 kb low recombination region of chromosome 10p12, suggesting that both SNPs are tagging the same causal variant. Our top SNP (rs11013452) is located inside a smaller linkage disequilibrium block in HapMap YRI, further narrowing the position of the causal SNP to a region of ~8 kb on chromosome 10p12. The present findings confirm the potential importance of the 10p12 locus in the etiology of sarcoidosis.

Clinical evaluation of alfaxalone as an anaesthetic induction agent in cats less than 12 weeks of age.

OBJECTIVE: To assess the clinical suitability of alfaxalone as an anaesthetic induction and maintenance agent for kittens aged less than 12 weeks. MATERIALS AND METHODS: The study group comprised 34 kittens aged less than 12 weeks that were presented for surgical desexing. They were aged by dentition, examined and weighed prior to premedication with acepromazine, atropine and morphine. At 20-30 min after premedication, animals were anaesthetised with intravenous alfaxalone administered to effect, using a target maximum expected dose of 5 mg/kg. All cats were intubated: 25 were maintained with isoflurane in oxygen administered with a non-rebreathing circuit and 8 were maintained by supplemental intravenous administration of alfaxalone. Subjective measures of anaesthetic quality and vital signs were recorded from enrolment to recovery. Cats receiving supplemental alfaxalone for maintenance were evaluated for time to first supplemental dose and the total dose of supplemental alfaxalone (mg/kg/h). Descriptive and comparative statistics were used to analyse and present collected data. RESULTS: The mean (± SD) dose of alfaxalone for induction was 4.7 ± 0.5 mg/kg body weight. Subjective measures of anaesthetic quality indicated acceptable induction, maintenance and recovery standards. Measured cardiovascular and respiratory parameters were well maintained. CONCLUSION: Alfaxalone in 2-hydroxypropyl-beta-cyclodextrin (Alfaxan®) is a suitable injectable anaesthetic induction agent for juvenile cats aged less than 12 weeks requiring anaesthesia. Maintenance of anaesthesia with supplemental doses of alfaxalone may be a suitable alternative in kittens when the use of inhalant anaesthetic maintenance is not feasible.

Clinical evaluation of alfaxalone as an anaesthetic induction agent in dogs less than 12 weeks of age.

OBJECTIVE: To assess the efficacy of alfaxalone as an anaesthetic induction agent for dogs aged less than 12 weeks. MATERIALS AND METHODS: The study group comprised 25 juvenile dogs aged less than 12 weeks that were presented for surgical desexing. Dogs were aged by dentition, examined and weighed prior to premedication with acepromazine, atropine and morphine. At 20-30 min after premedication, animals were anaesthetised with intravenous alfaxalone administered to effect, using a target maximum expected dose of 2 mg/kg. Dogs were intubated and anaesthesia was maintained with isoflurane in oxygen administered with a non-rebreathing system. Subjective measures of anaesthetic quality and vital signs were recorded from enrollment to recovery. Descriptive and comparative statistics were used to analyse and present collected data. RESULTS: The mean (± SD) dose of alfaxalone for induction was 1.7 (± 0.3) mg/kg body weight. Subjective measures of anaesthetic quality indicated acceptable induction, maintenance and recovery standards. Measured cardiovascular and respiratory parameters were well maintained. CONCLUSION: Alfaxalone in 2-hydroxypropyl-beta-cyclodextrin (Alfaxan®) is a suitable injectable anaesthetic induction agent for dogs aged less than 12 weeks requiring anaesthesia.

Evaluation of the influence of mobile data terminal location on physical exposures during simulated police patrol activities.

Prolonged occupational police driving combined with use of an in-vehicle computer elicits awkward, sustained postures in a scenario that lacks the adjustability to accommodate many mobile officer anthropometries and job-specific components. Twenty participants performed simulated police patrol sessions at five mobile data terminal (MDT) locations and using two seats: standard police vehicle seat and modified seat designed for police use. An MDT location self-selected prior to the session reduced perceived discomfort by up to 50% in the low back (p < .0001) and 68% in the right shoulder (p < .0001) compared to other tested locations, including the most common currently used location recorded from a representative police force. Muscle activity was lowest at the self-selected and current MDT locations for all muscles, significantly so for posterior deltoid (p < .0001) and supraspinatus (p < .0001). The modified seat reduced low back discomfort from the standard seat by 28% (p < .0001). Combining a self-selected MDT location and modified driver seat generated lower discomfort and physical loading than the currently used configuration.

Sensitivity to rewarding or aversive effects of methamphetamine determines methamphetamine intake.

Amphetamines have rewarding and aversive effects. Relative sensitivity to these effects may be a better predictor of vulnerability to addiction than sensitivity to one of these effects alone. We tested this hypothesis in a dose-response study in a second replicate set of mouse lines selectively bred for high vs. low methamphetamine (MA) drinking (MADR). Replicate 2 high (MAHDR-2) and low (MALDR-2) MA drinking mice were bred based on MA consumption in a two-bottle choice procedure and examined for novel tastant drinking. Sensitivities to the rewarding and aversive effects of several doses of MA (0.5, 2 and 4 mg/kg) were measured using a place conditioning procedure. After conditioning, mice were tested in a drug-free and then drug-present state for time spent in the saline- and MA-paired contexts. Similar to the first set of MADR lines, by the end of selection, MAHDR-2 mice consumed about 6 mg MA/kg/18 h, compared to nearly no MA in MALDR-2 mice, but had similar taste preference ratios. MAHDR-2 mice exhibited place preference in both the drug-free and drug-present tests, and no significant place aversion. In contrast, MALDR-2 mice exhibited no place preference or aversion during the drug-free test, but robust place aversion in the drug-present test. These data extend our preliminary findings from the first set of MADR lines and support the hypothesis that the combination of greater sensitivity to the rewarding effects of MA and insensitivity to the aversive effects of MA is genetically associated with heightened risk for MA consumption.

The alpha 3 subunit gene of the nicotinic acetylcholine receptor is a candidate gene for ethanol stimulation.

Alcohol and nicotine are coabused, and preclinical and clinical data suggest that common genes may influence responses to both drugs. A gene in a region of mouse chromosome 9 that includes a cluster of three nicotinic acetylcholine receptor (nAChR) subunit genes influences the locomotor stimulant response to ethanol. The current studies first used congenic mice to confirm the influential gene on chromosome 9. Congenic F(2) mice were then used to more finely map the location. Gene expression of the three subunit genes was quantified in strains of mice that differ in response to ethanol. Finally, the locomotor response to ethanol was examined in mice heterozygous for a null mutation of the alpha 3 nAChR subunit gene (Chrna3). Congenic data indicate that a gene on chromosome 9, within a 46 cM region that contains the cluster of nAChR subunit genes, accounts for 41% of the genetic variation in the stimulant response to ethanol. Greater expression of Chrna3 was found in whole brain and dissected brain regions relevant to locomotor behavior in mice that were less sensitive to ethanol-induced stimulation compared to mice that were robustly stimulated; the other two nAChR subunit genes in the gene cluster (alpha 5 and beta 4) were not differentially expressed. Locomotor stimulation was not expressed on the genetic background of Chrna3 heterozygous (+/-) and wild-type (+/+) mice; +/- mice were more sensitive than +/+ mice to the locomotor depressant effects of ethanol. Chrna3 is a candidate gene for the acute locomotor stimulant response to ethanol that deserves further examination.

The atypical Rho GTPase RhoBTB2 is required for expression of the chemokine CXCL14 in normal and cancerous epithelial cells.

The Rho family of small GTPases control cell migration, cell invasion and cell cycle. Many of these processes are perturbed in cancer and several family members show altered expression in a number of tumor types. RhoBTB2/DBC2 is an atypical member of this family of signaling proteins, containing two BTB domains in addition to its conserved Rho GTPase domain. RhoBTB2 is mutated, deleted or silenced in a large percentage of breast and lung cancers; however, the functional consequences of this loss are unclear. Here we use RNA interference in primary human epithelial cells to mimic the loss of RhoBTB2 seen in cancer cells. Through microarray analysis of global gene expression, we show that loss of RhoBTB2 results in downregulation of CXCL14-a chemokine that controls leukocyte migration and angiogenesis, and whose expression is lost through unknown mechanisms in a wide range of epithelial cancers. Loss of RhoBTB2 expression correlates with loss of CXCL14 secretion by head and neck squamous cell carcinoma cell lines, whereas reintroduction of RhoBTB2 restores CXCL14 secretion. Our studies identify CXCL14 as a gene target of RhoBTB2 and support downregulation of CXCL14 as a functional outcome of RhoBTB2 loss in cancer.

Sensitivity to the locomotor-stimulant effects of ethanol and allopregnanolone: a quantitative trait locus study of common genetic influence.

Previous studies have suggested that common genetic mechanisms influence sensitivity to the locomotor-stimulant effects of ethanol and allopregnanolone. We conducted two quantitative trait locus (QTL) studies to identify chromosomal regions that harbor genes that influence locomotor response to ethanol (2 g/kg) and allopregnanolone (17 mg/kg) using F2 crosses between C57BL/6J and DBA/2J mice. Because our previous data from the BXD recombinant inbred strains had indicated that chromosome 2 contained QTL for sensitivity to the locomotor-stimulant effects of both ethanol and allopregnanolone, we also tested reciprocal chromosome 2 congenic strains for sensitivity to the locomotor-stimulant effects of both drugs. The F2 analysis for ethanol sensitivity identified significant QTL on chromosomes 1 and 2 and suggestive QTL on chromosomes 5 and 9. The analysis of the allopregnanolone F2 study identified suggestive QTL on chromosomes 3, 5 and 12. Suggestive evidence for a female-specific QTL on chromosome 2 was also found. The studies of congenic mouse strains indicated that both the congenic strains captured one or more QTL for sensitivity to the locomotor-stimulant effects of both ethanol (2 g/kg) and allopregnanolone (17 mg/kg). When Fisher's method was used to combine the P values for the RI, F2 and congenic studies of the chromosome 2 QTL, cumulative probability scores of 9.6 x 10(-15) for ethanol and 7.7 x 10(-7) for allopregnanolone were obtained. These results confirm the presence of QTL for ethanol and allopregnanolone sensitivity in a common region of chromosome 2 and suggest possible pleiotropic genetic influence on sensitivity to these drugs.

Sensitivity to psychostimulants in mice bred for high and low stimulation to methamphetamine.

Methamphetamine (MA) and cocaine induce behavioral effects primarily through modulation of dopamine neurotransmission. However, the genetic regulation of sensitivity to these two drugs may be similar or disparate. Using selective breeding, lines of mice were produced with extreme sensitivity (high MA activation; HMACT) and insensitivity (low MA activation; LMACT) to the locomotor stimulant effects of acute MA treatment. Studies were performed to determine whether there is pleiotropic genetic influence on sensitivity to the locomotor stimulant effect of MA and to other MA- and cocaine-related behaviors. The HMACT line exhibited more locomotor stimulation in response to several doses of MA and cocaine, compared to the LMACT line. Both lines exhibited locomotor sensitization to 2 mg/kg of MA and 10 mg/kg of cocaine; the magnitude of sensitization was similar in the two lines. However, the lines differed in the magnitude of sensitization to a 1 mg/kg dose of MA, a dose that did not produce a ceiling effect that may confound interpretation of studies using higher doses. The LMACT line consumed more MA and cocaine in a two-bottle choice drinking paradigm; the lines consumed similar amounts of saccharin and quinine, although the HMACT line exhibited slightly elevated preference for a low concentration of saccharin. These results suggest that some genes that influence sensitivity to the acute locomotor stimulant effect of MA have a pleiotropic influence on the magnitude of behavioral sensitization to MA and sensitivity to the stimulant effects of cocaine. Further, extreme sensitivity to MA may protect against MA and cocaine self-administration.

Behavioral sensitization to ethanol is modulated by environmental conditions, but is not associated with cross-sensitization to allopregnanolone or pentobarbital in DBA/2J mice.

RATIONALE: The ability of ethanol to facilitate GABA(A) receptor-mediated transmission may result in GABA(A) receptor alterations during repeated ethanol administration, and lead to dynamic behavioral changes, including sensitization to the locomotor stimulant effect of ethanol. Since alterations in GABA(A) receptors are likely to alter sensitivity to GABAergic drugs such as 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) and pentobarbital, we determined whether enhanced sensitivity to ethanol was associated with enhanced sensitivity (cross-sensitization) to these drugs. Two procedures that produced differences in the magnitude of expression of ethanol-induced locomotor sensitization were used. METHODS: After habituation to testing procedures for 2 days, female DBA/2J mice were injected with ethanol or saline for 12 days. On the following day, locomotion was recorded after a challenge injection of ethanol (2 g/kg), allopregnanolone (10 or 17 mg/kg), or pentobarbital (10 or 20 mg/kg). Due to evidence that exposure to the test chambers influenced sensitization, in some experiments, mice were exposed to the test apparatus on the day prior to challenge. RESULTS: Exposure to the test apparatus prior to drug challenge attenuated the expression of ethanol sensitization, compared with mice without this pre-exposure. Cross-sensitization was not observed to either allopregnanolone or pentobarbital under any condition; however, some groups of repeated ethanol-treated mice displayed tolerance to the initial stimulant effects of allopregnanolone and pentobarbital. CONCLUSIONS: These studies indicate that behavioral sensitization to ethanol is not associated with cross-sensitization to pentobarbital or allopregnanolone, and that the expression of ethanol sensitization is influenced by the relative novelty of the test chamber. In addition, these results do not support a mechanism in which alterations in the neurosteroid or barbiturate modulatory sites of the GABA(A) receptor are responsible for the expression of sensitization to the locomotor stimulant effects of ethanol.

Three days of pivmecillinam or norfloxacin for treatment of acute uncomplicated urinary infection in women.

Pivmecillinam is a unique beta-lactam antimicrobial that has been used for the treatment of acute uncomplicated urinary infection for > 20 y. Since this agent was introduced, the quinolone antimicrobials have become widely used for the same indication. This study compared the efficacy of a 3-d regimen of pivmecillinam 400 mg b.i.d. with norfloxacin 400 mg b.i.d. Women aged between 18 and 65 y presenting with symptoms of acute cystitis of < 7 d duration were eligible for enrollment; 483 were randomized to receive pivmecillinam and 471 to receive norfloxacin. In each group, 30% of women had negative urine cultures prior to therapy. Bacteriologic cure at early post-therapy follow-up was achieved in 222/298 (75%) pivmecillinam patients and 276/302 (91%) norfloxacin patients [p < 0.001; 95% confidence interval (CI) 12.0-21.8]. Clinical cure/improvement at Day 4 following initiation of therapy was observed in 434/457 (95%) women who received pivmecillinam and 425/442 (96%) who received norfloxacin (p = 0.39; 95% CI 1.5-3.9). Early post-therapy (11 +/- 2 d) clinical cure was achieved in 360/437 women (82%) who received pivmecillinam and 381/433 (88%) who received norfloxacin (p = 0.019; 95% CI 0.9-10.3). In women aged < or = 50 y, early clinical cure rates were 294/351 (84%) for pivmecillinam and 299/340 (88%) for norfloxacin (p = 0.11; 95% CI 1.0-9.4). Adverse effects were similar for both regimens, and there was no evidence of the emergence of organisms of increasing resistance with therapy. Short-course therapy with norfloxacin was superior to that with pivmecillinam in terms of bacteriologic outcome, although differences in clinical outcome were less marked. In conclusion, short-course therapy with pivmecillinam is an effective empirical treatment for pre-menopausal women.

Pancreatic duodenal homeobox-1, PDX-1, a major regulator of beta cell identity and function.

Pancreatic duodenal homeobox -1 is a transcription factor that is expressed in beta and delta cells of the islets of Langerhans and in dispersed endocrine cells of the duodenum. It is involved in regulating the expression of a number of key beta-cell genes as well as somatostatin. It also plays a pivotal part in the development of the pancreas and islet cell ontogeny. Thus homozygous disruption of the gene in mice and humans results in pancreatic agenesis. Heterozygous mutations in the gene result in impaired glucose tolerance and symptoms of diabetes as seen in MODY4 and late-onset Type II (non-insulin-dependent) diabetes mellitus. In adults pancreatic duodenal homeobox-1 expression is increased in duct cells of the pancreas that have been induced to proliferate and differentiate to form new islets. Defects in pancreatic duodenal homeobox-1 could therefore contribute to Type II diabetes by affecting compensatory mechanisms that increase the rate of beta-cell neogenesis to meet the increased insulin secretory demand. It could also be a pharmacological target for beta-cell defects in Type II diabetes, while its role as a regulator of islet stem cell activity is being exploited to produce a replenishable source of islet tissue for transplantation in Type I (insulin-dependent) diabetes mellitus.

A review of annual growth screening in Aboriginal schoolchildren in Australia.

OBJECTIVES: To determine if growth screening in school-age Aboriginal children detects new, treatable growth problems. METHODOLOGY: A retrospective review of health centre records of children identified as stunted or wasted from school screening from 11 remote Aboriginal communities in the Top End of the Northern Territory. The age of onset of growth faltering, the occurrence of new growth problems in school-age children and initiation of treatment in response to the school screening results were determined. RESULTS: Weight faltering had occurred in all children by 18 months. The average age of onset of weight faltering was 6.6 months (range 3.5-12 months) for stunted children and 8.9 months (range 7.5-18 months) for wasted children. Height faltering in stunted children commenced in all children with documented height measurements by 3 years. Staff did not report any new interventions for poor growth as a result of screening school-age children in 1993 although many children had previously been assessed by the local doctor or visiting paediatrician and were being monitored. CONCLUSIONS: All children that were found to be stunted or wasted were already known to have poor growth prior to school entry. A change in focus is needed from repeatedly weighing and measuring school-age children to developing community- based interventions to improve the nutritional status of all children. Annual measurement of weight and height beyond 5 years of age is not recommended unless it is used to help evaluate interventions aimed at improving nutritional status and educational achievement.