The tail-elicited tail withdrawal reflex of Aplysia is mediated centrally at tail sensory-motor synapses and exhibits sensitization across multiple temporal domains

The defensive withdrawal reflexes of Aplysia californica have provided powerful behavioral systems for studying the cellular and molecular basis of memory formation. Among these reflexes the tail-elicited tail withdrawal reflex (T-TWR) has been especially useful. In vitro studies examining the monosynaptic circuit for the T-TWR, the tail sensory-motor (SN-MN) synapses, have identified the induction requirements and molecular basis of different temporal phases of synaptic facilitation that underlie sensitization in this system. They have also permitted more recent studies elucidating the role of synaptic and nuclear signaling during synaptic facilitation. Here we report the development of a novel, compartmentalized semi-intact T-TWR preparation that allows examination of the unique contributions of processing in the SN somatic compartment (the pleural ganglion) and the SN-MN synaptic compartment (the pedal ganglion) during the induction of sensitization. Using this preparation we find that the T-TWR is mediated entirely by central connections in the synaptic compartment. Moreover, the reflex is stably expressed for at least 24 h, and can be modified by tail shocks that induce sensitization across multiple temporal domains, as well as direct application of the modulatory neurotransmitter serotonin. This preparation now provides an experimentally powerful system in which to directly examine the unique and combined roles of synaptic and nuclear signaling in different temporal domains of memory formation

The impact of emergency department crowding measures on time to antibiotics for patients with community-acquired pneumonia

STUDY OBJECTIVE: We seek to determine the impact of emergency department (ED) crowding on delays in antibiotic administration for patients with community-acquired pneumonia. METHODS: We performed a retrospective cohort study of adult patients admitted with community-acquired pneumonia from January 1, 2003, to April 31, 2005, at a single, urban academic ED. The main outcome was a delay (\u3e4 hours from arrival) or nonreceipt of antibiotics in the ED. Eight ED crowding measures were assigned at triage. Multivariable regression and bootstrapping were used to test the adjusted impact of ED crowding measures of delayed (or no) antibiotics. Predicted probabilities were then calculated to assess the magnitude of the impact of ED crowding on the probability of delayed (or no) antibiotics. RESULTS: In 694 patients, 44% (95% confidence interval [CI] 40% to 48%) received antibiotics within 4 hours and 92% (95% CI 90% to 94%) received antibiotics in the ED. Increasing levels of ED crowding were associated with delayed (or no) antibiotics, including waiting room number (odds ratio [OR] 1.05 for each additional waiting room patient [95% CI 1.01 to 1.10]) and recent ED length of stay for admitted patients (OR 1.14 for each additional hour [95% CI 1.04 to 1.25]). When the waiting room and recent length of stay were both at the lowest quartiles (ie, not crowded), the predicted probability of delayed (or no) antibiotics within 4 hours was 31% (95% CI 21% to 42%); when both were at the highest quartiles, the predicted probability was 72% (95% CI 61% to 81%). CONCLUSION: ED crowding is associated with delayed and nonreceipt of antibiotics in the ED for patients admitted with community-acquired pneumonia

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

The NTPR maintains an ongoing database to study the outcomes of pregnancies in female transplant recipients as well as those pregnancies fathered by male transplant recipients. Recipients are entered into the database by completing. a single page questionnaire. There is steady follow-up of recipients and their offspring. While the majority of pregnancy outcomes have occurred in kidney recipients, data continue to accrue in the other types of organ recipients. KIDNEY: A small percentage of pregnancies in female kidney recipients are complicated by rejection with poorer outcomes with respect to both maternal graft function and their newborn. Other analyses this year focused on outcomes of recipients with systemic lupus erythematosus and those with multiple gestations. It was observed that recipients with systemic lupus erythematosus were able to maintain a pregnancy with outcomes that appear to be similar to other diagnoses. In an analysis of multiple gestations in female kidney recipients maintained on calcineurin inhibitors, no multiple gestations higher than triplets have been reported to the NTPR. Successful outcomes have been noted among these recipients. This does require continued surveillance, as there has been an increase in the number of multiple gestations in the general population with the use of adjunctive technologies. OTHER ORGANS: In analyzing outcomes in female liver recipients, no specific graft or newborn outcome differences have been noted when a comparison has been made between different caicineurin inhibitor regimens. Pregnancies in female pancreas-kidney recipients appear to be tolerated with respect to pancreas graft function with no diagnoses of gestational diabetes reported to the NTPR. Data continue to accrue among thoracic recipients. Poorer maternal survival postpartum in lung recipients may be related to higher risks inherent in this population and requires further experience and investigation. OTHER ISSUES: With the recent proliferation of newer immunosuppressive agents, a question that is raised is whether a regimen can be specifically designed with recipients of childbearing age in mind. Extensive data published on azathioprine and cyclosporine treated recipients suggests that while there is a pattern of prematurity among the newborn there has not been an increase in the incidence or pattern of specific malformations noted among the newborn. Less assurance can be given with newer agents such as sirolimus and MMF. Calcineurin inhibitor minimization or steroid withdrawal would require that other agents with less reproductive information be implemented. The unknown risk of teratogenicity must be balanced against the potential risk of rejection or graft dysfunction when deciding which agent to use during pregnancy. Through each of the organ recipient groups, there are sporadic cases of rejection, graft dysfunction, and graft deterioration. Birth defect patterns have not appeared to be specific to any specific regimen as yet. Two newborns with malformations have been noted among a limited series with MMF exposure, but other factors may also be at play. The use of MMF during pregnancy continues to be an unresolved issue in the transplant community. As yet, no one regimen has been identified as superior to another for use during pregnancy. Continued surveillance with the newer agents is necessary. Investigators have taken differing views regarding the safety of breastfeeding in the transplant recipient population, especially with regard to drug exposure to the infant. This issue remains unresolved and some transplant recipient mothers have chosen to breastfeed. Other factors for consideration are the potential long-term effects on offspring of transplant recipients. While there may not be specific structural defects noted at birth, more subtle effects on either immunologic or reproductive function may not manifest until later in life. Scott and his group in Utah have raised this issue with a case report and have initiated a study to focus on the next generation. The safety of pregnancy for parent and child remain the goals of the NTPR. Continued entries to the registry, especially in light of newer combinations of immunosuppressive agents, should assist in developing guidelines needed for management in this era of expanding immunosuppressive agents. All centers are encouraged to participate

Care of elderly patients: a prospective audit of the prevalence of hypotension and the use of BIS intraoperatively in 25 hospitals in London

Background: Anaesthesia is frequently complicated by intraoperative hypotension (IOH) in the elderly, and this is associated with adverse outcome. The definition of IOH is controversial, and although management guidelines for IOH in the elderly exist, the frequency of IOH and typical clinically applied treatment thresholds are largely unknown in the UK. Methods: We audited frequency of intraoperative blood pressure against national guidelines in elderly patients undergoing surgery. Depth of anaesthesia (DOA) monitoring was also audited due to the association between low DOA values and IOH with increased mortality (as part of "double" and "triple low" phenomena) and because it is a suggested management strategy to reduce IOH. Results: Twenty-five hospitals submitted data on 481 patients. Hypotension varied depending on the definition, but affected 400 patients (83.3 %) using the AAGBI standard. Furthermore, 2.9, 13.5, and 24.6 % had mean arterial blood pressures < 50, < 60, and < 70 mmHg for 20 min, respectively, and 136 (28.4 %) had systolic blood pressure decrease by 20 % for 20 min. DOA monitors were used for 45 (9.4 %) patients. Conclusions: IOH is common and use of DOA monitors is less than implied by guidelines. Improved management of IOH may be a simple intervention with real potential to reduce morbidity in this vulnerable group

Reasons for illicit drug use in people with schizophrenia: Qualitative study

<p>Abstract</p> <p>Background</p> <p>Drug misuse is an important clinical problem associated with a poorer outcome in patients who have a diagnosis of schizophrenia. Qualitative studies have rarely been used to elicit reasons for drug use in psychosis, but not in schizophrenia.</p> <p>Methods</p> <p>Seventeen people with a diagnosis of schizophrenia and who had used street drugs were interviewed and asked to describe, in narrative form, their street drug use from their early experiences to the present day. Grounded theory was used to analyse the transcripts.</p> <p>Results</p> <p>We identified five reasons for continuing street drug use. The reasons were: as an 'identity defining vocation', 'to belong to a peer group', due to 'hopelessness', because of 'beliefs about symptoms and how street drugs influence them' and viewing drugs as 'equivalent to taking psychotropic medication'. Street drugs were often used to reduce anxiety aroused by voice hearing. Some participants reported street drugs to focus their attention more on persecutory voices in the hope of outwitting their perceived persecutors.</p> <p>Conclusions</p> <p>It would be clinically useful to examine for the presence of the five factors in patients who have a diagnosis of schizophrenia and use street drugs, as this is likely to help the clinician to tailor management of substance misuse to the individual patient's beliefs.</p

A rare TP53 mutation predominant in ashkenazi jews confers risk of multiple cancers

Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li-Fraumeni syndrome (LFS). Here, we identified a rare TP53 tetramerization domain missense mutation, c.1000G\u3eC;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G\u3eC probands and one c.1000G\u3eA proband were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G\u3eC allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with TP53 normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3, and LCN15) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G\u3eC;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS