Neutron spectrum measurements near KAMINI reactor south beam vault door using nested neutron spectrometer.

KAlpakkam MINI reactor (KAMINI) is a 233U fuelled research reactor has various neutron irradiation locations for experimental purposes. The pit at the south beam end of KAMINI reactor is being extensively utilised for neutron attenuation experiments in prospective shielding materials as well as for neutron radiography. During reactor operation, it will be closed by a movable shield. A vault door is located above the shield and the movable shield is used to attenuate streaming neutrons and gamma-rays during reactor operation. Even with the shield, there exists significant dose because of streaming neutrons and gamma rays. Its variation depends on the power of the reactor. The neutron and gamma dose rates close to the south beam vault door have recently been found to be 275-300 µSv/h and 175-200 µSv/h, respectively, when the reactor is operating at 10 kW. In order to characterise the streaming neutron spectra of vault door place for the first time, measurements are done using the Nested Neutron Spectrometer. Along with the neutron flux, neutron mean energy and ambient dose-equivalent rate are also measured and compared with earlier measurements carried out inside the south beam pit. It is observed that the presence of paraffin shield reduces the neutron average energy from 370 to 178 keV. Apart from energy reduction, 10 kW normalised neutron flux of south beam pit is also attenuated by the shield by 25 000 times and it is found that the neutron spectrum of the measured location is also more thermalized. Neutron reference data of the location are generated.

Ventral hernia repair in India: a Delphi consensus.

PURPOSE: While research on inguinal hernias is well-documented, ventral/incisional hernias still require investigation. In India, opinions on laparoscopic ventral hernia repair (LVHR) techniques are contested. The current consensus aims to standardize LVHR practice and identify gaps and unfulfilled demands that compromise patient safety and therapeutic outcomes. METHODS: Using the modified Delphi technique, panel of 14 experts (general surgeons) came to a consensus. Two rounds of consensus were conducted online. An advisory board meeting was held for the third round, wherein survey results were discussed and the final statements were decided with supporting clinical evidence. RESULTS: Experts recommended intraperitoneal onlay mesh (IPOM) plus/trans-abdominal retromuscular/extended totally extraperitoneal/mini- or less-open sublay operation/transabdominal preperitoneal/trans-abdominal partial extra-peritoneal/subcutaneous onlay laparoscopic approach/laparoscopic intracorporeal rectus aponeuroplasty as valid minimal access surgery (MAS) options for ventral hernia (VH). Intraperitoneal repair technique is the preferred MAS procedure for primary umbilical hernia < 4 cm without diastasis; incisional hernia in the presence of a vertical single midline incision; symptomatic hernia, BMI > 40 kg/m2, and defect up to 4 cm; and for MAS VH surgery with grade 3/4 American Society of Anaesthesiologists. IPOM plus is the preferred MAS procedure for midline incisional hernia of width < 4 cm in patients with a previous laparotomy. Extraperitoneal repair technique is the preferred MAS procedure for L3 hernia < 4 cm; midline hernias < 4 cm with diastasis; and M5 hernia. CONCLUSION: The consensus statements will help standardize LVHR practices, improve decision-making, and provide guidance on MAS in VHR in the Indian scenario.

APOE Genotype Influences Postprandial Blood Pressure after High Fat Feeding in Older Adults.

OBJECTIVE: Postprandial hypotension (PPH) is a common phenomenon among older adults. The degree to which individuals experience PPH is related to cerebrovascular risk factors and the presence of neurodegenerative diseases such as Alzheimer's disease (AD). Carrier status of the E4 allele of the apolipoprotein E (APOE) gene is a risk factor for AD and influences a variety of responses to metabolic and dietary interventions. However, it is unknown whether APOE genotype influences the risk of PPH and whether type of meal can mediate that response. DESIGN: Acute meal study with a crossover design. PARTICIPANTS: 32 cognitively healthy older adults with (n=18) and without (n=14) E4+ carrier status. INTERVENTION: As a part of an ongoing meal study we examined the postprandial blood pressure response after ingestion of a high carbohydrate (HCM) and high fat meal (HFM). MEASUREMENTS: Blood pressure measurements were taken at 7 time points and change scores, area under the curve (AUC) scores were calculated. Data were analyzed by repeated measures ANOVA as well as Pearson correlation. RESULTS: Both meals produced a sustained drop in systolic (SBP) and diastolic (DBP) blood pressure, with 37.5% of participants meeting criteria for PPH. Participants carrying the E4+ risk gene experienced a larger decrease in SBP than E4- participants, and this was significantly different after the HFM (E4+ AUC = -30.8 ± 7.6, E4- AUC = -0.2 ± 8.7, p=0.015). Increasing age was associated with a larger drop in postprandial blood pressure but only for the E4+ group after the HFM (p=0.002). CONCLUSIONS: These data suggest that E4+ individuals experience a greater postprandial blood pressure response particularly following high fat feeding, and this effect becomes more pronounced with age. The prevalence of PPH may play a role in the development of AD and may be mediated by diet.

Gamma oscillatory activity in vitro: a model system to assess pathophysiological mechanisms of comorbidity between autism and epilepsy.

Autism spectrum disorder (ASD) and temporal lobe epilepsy exhibit remarkable comorbidity, but for reasons not clearly understood. To reveal a common pathophysiological mechanism, we here describe and characterize an in vitro epileptiform activity in the rat hippocampus that exhibits common features with in vivo activity in rodent ASD models. We discovered the development of this activity in the CA1 region of horizontal slices after prolonged interictal-like epileptiform activity in the CA3 region that was provoked by incubation in high potassium artificial cerebrospinal fluid. The CA1 epileptiform bursts were insensitive to blockers of glutamatergic transmission, and were carried by synaptic as well as extrasynaptic, tonically activated gamma-aminobutyric acid type A (GABA(A)) receptors. The bursts bear resemblance to in vivo gamma-oscillatory activity found in rat ASD models with respect to their gamma frequency spectrum, their origin (in the CA1), and their sensitivity to blockers of cation-chloride pumps (NKCC1 and KCC2), as well as to oxytocin. Considering this bursting activity as an in vitro model for studying comorbidity between epilepsy and ASD may help to disentangle the intricate interactions that underlie the comorbidity between both diseases and suggests that extrasynaptic tonic GABAergic transmission could represent a potential target for ASD.

Pregnancy after diabetes obesity surgery (PADOS): Qualitative study of pre-pregnancy care.

Half of all bariatric surgical procedures are in women of childbearing age. Surgery may improve fertility yet exacerbate nutritional deficiencies, that may be disadvantageous to the fetus. A frequently encountered subgroup of obese women have type 2 diabetes. The health risks, to both mother and child, of diabetes in pregnancy are well described including 4.7× risk of stillbirth and 2× risk of congenital abnormality. What is not clear is whether bariatric surgery mitigates or complicates the health consequences of women with obesity and diabetes in pregnancy. In addition the influence of the type of surgery, the optimal interval between surgery and conception and evidence based preconception recommendations are unknown. This study complements wider research aiming to inform optimal management of this patient population. Obese diabetic women require clear guidance regarding pregnancy planning after surgery. This study will develop an understanding of the barriers and facilitators (psychological, behavioural, attitudinal and nutritional) to achieving effective pre-pregnancy health and care in women with type 2 diabetes who have undergone metabolic surgery. Currently women's perception of fertility issues and risks after bariatric surgery is unknown and thus a qualitative interpretive paradigm was chosen. Interviews with the target population will explore decision-making processes; experience regarding metabolic surgery and perceived pregnancy risk. Interviews with a broad range of health professionals involved in bariatric care will include rationale for selected surgical procedure and post surgery referral processes e.g. contraceptive care. This will advance understanding of how to provide targeted support and monitoring.

Pregnancy after diabetes obesity surgery (PADOS): Incidence and outcomes.

Half of all bariatric surgical procedures are in women of childbearing age but it remains unclear whether surgery is suitable for women who subsequently conceive: specifically the relative risks and benefits of potential nutrient deficiencies versus weight reduction. We will present data collected from Clinical Practice Research Databases on the maternal and fetal outcomes of pregnancies complicated either by obesity or previous bariatric surgery (BS). Two groups, matched to obese controls for BMI pre-BS and post-BS (at the time of ante-natal booking) will be compared. In this way, the effect of BS on pregnancy outcomes may be examined, independent of its effect on weight. A sub-group of women with antecedent Type 2 diabetes (T2DM) will allow for investigation of the additional impact and persistence of this co-morbidity. This builds upon pilot data collected from a retrospective cohort of women (18-45years) undergoing laparoscopic roux-en-Y (RYGB) surgery over a 24-month period (n=218). After exclusions and loss to follow up, data from 111 patients were analysed; 81 (73%) had conceived prior to RYGB, 20 (18%) became pregnant post RYGB and a further 22 patients (20%) were trying to conceive at the time of data collection. Three women had T2DM which resolved post BS. A suggestion of greater miscarriage risk prior to surgery in this sub-group will be confirmed as more women are recruited. Pregnancy is a frequent desire/occurrence after BS. This database study will advance understanding of the maternal and fetal outcomes of such pregnancies and inform antenatal care.

Modeling the role of basal ganglia in saccade generation: is the indirect pathway the explorer?

We model the role played by the Basal Ganglia (BG) in the generation of voluntary saccadic eye movements. The BG model explicitly represents key nuclei like the striatum (caudate), Substantia Nigra pars reticulata (SNr) and compata (SNc), the Subthalamic Nucleus (STN), the two pallidal nuclei and Superior Colliculus. The model is cast within the Reinforcement Learning (RL) framework, with the dopamine representing the temporal difference error, the striatum serving as the critic, and the indirect pathway playing the role of the explorer. Performance of the model is evaluated on a set of tasks such as feature and conjunction searches, directional selectivity and a successive saccade task. Behavioral phenomena such as independence of search time on number of distractors in feature search and linear increase in search time with number of distractors in conjunction search are observed. It is also seen that saccadic reaction times are longer and search efficiency is impaired on diminished BG contribution, which corroborates with reported data obtained from Parkinson's Disease (PD) patients.

Persistence and adherence in the treatment of overactive bladder syndrome with anticholinergic therapy: a systematic review of the literature.

Overactive bladder syndrome (OAB) is a chronic condition that has an impact on patients' daily activities and health-related quality of life (HRQL). Anticholinergic therapy is often prescribed following insufficient results with behaviour modification alone; however, rates of treatment discontinuation are consistently high. This study systematically reviewed persistence and adherence data in patients with OAB treated with anticholinergic therapy. A search focused on the intersection of OAB, persistence/adherence, and anticholinergic therapy was conducted in MEDLINE and EMBASE. Articles published after 1998 were reviewed and selected for inclusion based on prespecified criteria. A total of 147 articles and two abstracts were included in the review. Results from 12-week clinical trials showed high rates of discontinuation, ranging from 4% to 31% and 5% to 20% in treatment and placebo groups, respectively. Unsurprisingly, rates of discontinuation found in medical claims studies were substantially higher, with 43% to 83% of patients discontinuing medication within the first 30 days and rates continuing to rise over time. Findings from medical claims studies also suggest that over half of patients never refill their initial prescription and that adherence levels tend to be low, with mean/median medication possession ratio (MPR) values ranging from 0.30 to 0.83. The low levels of persistence and adherence documented in this review reveal cause for concern about the balance between the efficacy and tolerability of anticholinergic agents. Strategies should be identified to increase persistence and adherence. New agents and non-pharmacologic alternatives with good efficacy and minimal side effects should be explored.

Modeling basal ganglia for understanding Parkinsonian reaching movements.

We present a computational model that highlights the role of basal ganglia (BG) in generating simple reaching movements. The model is cast within the reinforcement learning (RL) framework with correspondence between RL components and neuroanatomy as follows: dopamine signal of substantia nigra pars compacta as the temporal difference error, striatum as the substrate for the critic, and the motor cortex as the actor. A key feature of this neurobiological interpretation is our hypothesis that the indirect pathway is the explorer. Chaotic activity, originating from the indirect pathway part of the model, drives the wandering, exploratory movements of the arm. Thus, the direct pathway subserves exploitation, while the indirect pathway subserves exploration. The motor cortex becomes more and more independent of the corrective influence of BG as training progresses. Reaching trajectories show diminishing variability with training. Reaching movements associated with Parkinson's disease (PD) are simulated by reducing dopamine and degrading the complexity of indirect pathway dynamics by switching it from chaotic to periodic behavior. Under the simulated PD conditions, the arm exhibits PD motor symptoms like tremor, bradykinesia and undershooting. The model echoes the notion that PD is a dynamical disease.

A computational model of Parkinsonian handwriting that highlights the role of the indirect pathway in the basal ganglia.

Parkinsonian handwriting is typically characterized by micrographia, jagged line contour, and unusual fluctuations in pen velocity. In this paper we present a computational model of handwriting generation that highlights the role of the basal ganglia, particularly the indirect pathway. Whereas reduced dopamine levels resulted in reduced letter size, transition of STN-GPe dynamics from desynchronized (normal) to synchronized (PD) condition resulted in increased fluctuations in velocity in the model. We also present handwriting data from PD patients (n=34) who are at various stages of disease and had taken medication various lengths of time before the handwriting sessions. The patient data are compared with those of age-matched controls. PD handwriting statistically exhibited smaller size and larger velocity fluctuation compared to normal handwriting.

Performance of CURB-65 and CURB-age in community-acquired pneumonia.

BACKGROUND: Community-acquired pneumonia (CAP) is common and associated with significant mortality. In this study, we validated a newly proposed severity assessment rule for CAP, CURB-age, and also compared with to the currently recommended criteria in UK, CURB-65. METHODS: We conducted a prospective study in three hospitals in Norfolk and Suffolk, UK. One hundred and ninety patients were included and followed up for 6 weeks. RESULTS: Of 190 patients, 100 were men (53%). The age range was 18-101 years (median 76 years). Sixty-five (34%) had severe pneumonia by CURB-65 and 54 (28%) had severe pneumonia by CURB-age. There were 54 deaths during follow-up. There were 32 deaths (50%) in severe and 22 deaths (18%) in non-severe group by CURB-65. There were 27 deaths each in both the groups by CURB-age (50% of severe cases and 20% of non-severe cases). For CURB-65, sensitivity, specificity, and positive and negative predictive values were 59.3% (45.0-72.4), 75.7% (67.6-82.7), 49.2% (36.6-61.9) and 82.4% (74.6-88.6), respectively. For CURB-age, the respective values were 50.0% (31.1-63.9), 80.1% (72.4-86.5), 50.0% (36.1-63.9) and 80.1% (72.4-86.5). Exclusion of patients aged < 65 years did not alter the results. CONCLUSIONS: Despite better specificity in correctly identifying 6-week mortality for CAP, CURB-age appears to be less sensitive than CURB-65. Our findings further assure the usefulness of CURB-65 for predicting mortality in CAP.

Predicting altered pathways using extendable scaffolds.

Many diseases, especially solid tumors, involve the disruption or deregulation of cellular processes. Most current work using gene expression and other high-throughput data, simply list a set of differentially expressed genes. We propose a new method, PAPES (predicting altered pathways using extendable scaffolds), to computationally reverse-engineer models of biological systems. We use sets of genes that occur in a known biological pathway to construct component process models. We then compose these models to build larger scale networks that capture interactions among pathways. We show that we can learn process modifications in two coupled metabolic pathways in prostate cancer cells.

Rapid spread of penicillin-resistant Streptococcus pneumoniae among high-risk hospital inpatients and the role of molecular typing in outbreak confirmation.

This study describes an outbreak of penicillin-resistant Streptococcus pneumoniae among patients on an ear, nose and throat (ENT) ward. Over a period of 10 days, S. pneumoniae [penicillin minimum inhibitory concentration (MIC) 0.75] was isolated from a total of seven patients with symptoms and signs of lower respiratory tract infection. Standard source isolation was implemented and the ward was closed to admissions and discharges. Screening of nasopharyngeal secretions was undertaken on all patients and staff contacts. Three patients (of eight possible contacts) and none of the staff (47 screened) were identified as colonized with the same strain. Nasal mupirocin and oral rifampicin were administered to carriers. Confirmation of the outbreak was achieved rapidly using a contemporary molecular typing method (pulsed-field gel electrophoresis) and timely introduction of infection control measures successfully contained the outbreak. Implications for pneumococcal vaccination are discussed.

Mechanism of topology simplification by type II DNA topoisomerases.

Type II DNA topoisomerases actively reduce the fractions of knotted and catenated circular DNA below thermodynamic equilibrium values. To explain this surprising finding, we designed a model in which topoisomerases introduce a sharp bend in DNA. Because the enzymes have a specific orientation relative to the bend, they act like Maxwell's demon, providing unidirectional strand passage. Quantitative analysis of the model by computer simulations proved that it can explain much of the experimental data. The required sharp DNA bend was demonstrated by a greatly increased cyclization of short DNA fragments from topoisomerase binding and by direct visualization with electron microscopy.

Analysis of the binding of p53 to DNAs containing mismatched and bulged bases.

The tumor suppressor protein p53 modulates cellular response to DNA damage by a variety of mechanisms that may include direct recognition of some forms of primary DNA damage. Linear 49-base pair duplex DNAs were constructed containing all possible single-base mismatches as well as a 3-cytosine bulge. Filter binding and gel retardation assays revealed that the affinity of p53 for a number of these lesions was equal to or greater than that of the human mismatch repair complex, hMSH2-hMSH6, under the same binding conditions. However, other mismatches including G/T, which is bound strongly by hMSH2-hMSH6, were poorly recognized by p53. The general order of affinity of p53 was greatest for a 3-cytosine bulge followed by A/G and C/C mismatches, then C/T and G/T mismatches, and finally all the other mismatches.

Statistical methods for the objective design of screening procedures for macromolecular crystallization.

The crystallization of a new macromolecule is still very much a trial-and-error process. As is well known, it requires the search of a large parameter space of experimental settings to find the relatively few idiosyncratic conditions that lead to diffraction-quality crystals. Crystallographers have developed a variety of screens to help identify initial crystallization conditions, including those based on systematic grids, incomplete factorial and sparse-matrix approaches. These are somewhat subjectively formulated based on accumulated data from past crystallization experiments. Ideally, one would prefer as objective a procedure as possible; however, that requires objective methods that incorporate a broad source of crystallization data. The Biological Macromolecular Crystallization Database (BMCD), a repository of all published crystallization conditions, is an obvious source of this data. This database has been augmented with a hierarchical classification of the macromolecules contained in the BMCD as well as extensive data on the additives used with them. A statistical analysis of the augmented BMCD shows the existence of significant correlations between families of macromolecules and the experimental conditions under which they crystallize. This in turn leads to a Bayesian technique for determining the probability of success of a set of experimental conditions based on the data in the BMCD as well as facts about a macromolecule known prior to crystallization. This has been incorporated into software that enables users to rank experimental conditions for new macromolecules generated by a dense partial factorial design. Finally, an additional advantage of the software described here is that it also facilitates the accumulation of the data required for improving the accuracy of estimation of the probabilities of success - knowledge of the conditions which lead to failure of crystallization.

hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA.

Mismatch recognition by the human MutS homologs hMSH2-hMSH6 is regulated by adenosine nucleotide binding, supporting the hypothesis that it functions as a molecular switch. Here we show that ATP-induced release of hMSH2-hMSH6 from mismatched DNA is prevented if the ends are blocked or if the DNA is circular. We demonstrate that mismmatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts hMSH2-hMSH6 into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. Our results support a model for bidirectional mismatch repair in which stochastic loading of multiple ATP-bound hMSH2-hMSH6 sliding clamps onto mismatch-containing DNA leads to activation of the repair machinery and/or other signaling effectors similar to G protein switches.

Ultraviolet-induced DNA damage stimulates topoisomerase I-DNA complex formation in vivo: possible relationship with DNA repair.

An antibody-based method was used to examine genomic DNA cleavage by endogenous topoisomerases in living cells. The method quantifies cleavable (covalent) complex formation in vivo after exposure to topoisomerase poisons, as reported previously (D. Subramanian et al., Cancer Res., 55: 2097-2103, 1995). Unexpectedly, exposing cells to UVB irradiation stimulated endogenous topoisomerase I-DNA covalent complex formation by as much as 8-fold, even in the absence of drugs that stabilize the cleavable complex. Covalent complexes are not a result of nonspecific UV protein-DNA cross-linking; rather, they result from the enzymatic activity of topoisomerase I on genomic DNA. Because the action of topoisomerase II on genomic DNA was not affected by UVB exposure, the observation appears to be specific for type I. Topoisomerase I is rapidly mobilized onto the genome (within 12 min after UVB exposure); however, topoisomerase I polypeptide levels did not show a corresponding increase, suggesting that preexisting enzyme is being recruited to sites of DNA damage. Complexes persist up to 5 h post-UV exposure (concurrent with the period of active DNA repair), and their formation is independent of S phase. These findings can be partially explained by the fact that in vitro topoisomerase I activity on UV-damaged DNA tends to favor formation of cleavage complexes; thus, a higher yield of covalent complexes are detected at or near cyclopyrimidine dimer lesions. Because repair-deficient cells are additionally compromised in their ability to recruit topoisomerase I, a direct role for the enzyme in DNA excision repair process in vivo is proposed that may be related to the activity of the xeroderma pigmentosum complementation group D helicase. Finally, these results collectively demonstrate that topoisomerase I is a repair-proficient topoisomerase in vivo.