A pilot study for presence of circulating tumour cells in adenoid cystic carcinoma.

Adenoid cystic carcinoma (ACC) is a rare salivary gland neoplasm with a poor long-term prognosis due to multiple recurrences and distant metastatic spread. Circulating tumour cells (CTCs) are tumour cells shed from a primary, recurrent, or metastatic cancer that are detectable in the blood or lymphatics. There is no literature to date confirming the presence of CTCs in ACC. The aim of this study was to determine whether CTCs are detectable in ACC. Blood samples were collected from eight patients with histologically confirmed ACC. The TNM stage of the tumour was recorded, as well as any prior treatment. CTCs were isolated by spiral microfluidics and detected by immunofluorescence staining. Three of the eight patients recruited (32.5%) had staining consistent with the presence of CTCs. Of these three patients with detectable CTCs, one had confirmed pulmonary metastasis, one had suspected pulmonary metastasis and was awaiting confirmation, and one had local recurrence confirmed on re-resection. One patient with known isolated pulmonary metastasis had previously undergone a lung metastasectomy and did not have CTCs detected. CTCs are detectable in ACC. In this small patient sample, CTCs were found to be present in those patients with recurrent local disease and known distant metastatic disease. CTCs in ACC should be investigated further for their potential use as an adjunct in staging, prognosis, and the detection of recurrence.

Functional dissociations between subregions of the medial prefrontal cortex on the rodent touchscreen continuous performance test (rCPT) of attention.

Converging evidence in humans, monkeys, and rodents suggests a functional dissociation of cognitive function along the dorso-ventral axis of the prefrontal cortex (PFC). Previous studies of attention suggest that the anterior cingulate cortex (ACC) plays a role in target detection, whereas the prelimbic (PL) cortex is important for tests requiring the combined detection and discrimination of signals. We investigated the effect of discrete, quinolinic acid-induced lesions of subregions of the rat medial PFC (mPFC)-ACC, PL cortex, and infralimbic (IL) cortex-on attentional performance on the recently developed rodent touchscreen continuous performance test (rCPT). Rats were tested under a range of behavioral conditions involving stimulus duration (SD), flanker distraction, temporal predictability, and event rate. Rats with lesions of the PL cortex demonstrated the most persistent attentional impairment under conditions of reduced and variable SD and high event rate (lower discrimination sensitivity [d'] and hit rate), and flanker distraction (lower hit rate). Rats with lesions of the ACC exhibited a profound but transient attentional impairment (lower d' and hit rate) in the early stages of behavioral testing, which ameliorated with repeated testing. Rats with lesions of the IL cortex showed no impairments on response control measures. The PL cortex plays a greater role than the ACC in the detection and discrimination of a complex visual stimulus among multiple nontarget stimuli in the rCPT. The findings support evidence for a functional dissociation of attentional performance along the dorso-ventral axis of the mPFC. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Pregnancy and childbirth after an iliac crest free flap.

We report two successful pregnancies and vaginal deliveries by patients who had previously had deep circumflex iliac artery free flaps that had been harvested for reconstruction in the head and neck.

Facilitation of spatial working memory performance following intra-prefrontal cortical administration of the adrenergic alpha1 agonist phenylephrine.

RATIONALE: Spatial working memory is dependent on the appropriate functioning of the prefrontal cortex (PFC). PFC activity can be modulated by noradrenaline (NA) released by afferent projections from the locus coeruleus. The coreuleo-cortical NA system could therefore be a target for cognitive enhancers of spatial working memory. Of the three classes of NA receptor potentially involved, the α2 and α1 classes seem most significant, though agents targeting these receptors have yielded mixed results. This may be partially due to the use of behavioural assays that do not translate effectively from the laboratory to the clinical setting. Use of a paradigm with improved translational potential may be essential to resolve these discrepancies. OBJECTIVES: The objective of this study was to assess the effects of PFC-infused α2 and α1 adrenergic receptor agonists on spatial working memory performance in the touchscreen continuous trial-unique non-matching to location (cTUNL) task in rats. METHODS: Young male rats were trained in the cTUNL paradigm. Cannulation of the mPFC allowed direct administration of GABA agonists for task validation, and phenylephrine and guanfacine to determine the effects of adrenergic agonists on task performance. RESULTS: Infusion of muscimol and baclofen resulted in a delay-dependent impairment. Administration of the α2 agonist guanfacine had no effect, whilst infusion of the α1 agonist phenylephrine significantly improved working memory performance. CONCLUSIONS: Spatial working memory as measured in the rat cTUNL task is dependent on the mPFC. Enhancement of noradrenergic signalling enhanced performance in this paradigm, suggesting a significant role for the α1 receptor in this facilitation.

Adopting seven-day working in practice: a report by the Royal College of Physicians and Surgeons of Glasgow.

Following the UK Academy of Medical Royal Colleges Report on seven day consultant present care, the Royal College of Physicians and Surgeons of Glasgow held a symposium to explore clinicians' views on the ways in which clinical care should best be enhanced outside 'normal' working hours. In addition, a survey of members and fellows was undertaken to identify the tests which would make the greatest impact on care out of hours. Key messages were: (a) that seven-day consultant delivered care would not achieve the desired benefit to patient care if introduced in isolation from other inter-relating factors. These include alternatives to hospital admission, enhanced nursing support, increased junior medical, pharmacy, social care and ambulance availability and greater access to selected diagnostic services; (b) that the care of hospital inpatients is a service which is one part of the totality of secondary care provision. Any significant change in the deployment of staff for inpatient care must be carefully managed so as not to result in a reduced quality of care provided by the rest of the system.

A multicenter cohort study of pregnancy outcomes among women with laboratory-confirmed H1N1 influenza.

OBJECTIVE: To evaluate associations between laboratory-confirmed 2009 H1N1 influenza infection and obstetric and neonatal outcomes. STUDY DESIGN: A multicenter cohort study was performed comparing laboratory-confirmed cases of 2009 H1N1 infection during pregnancy (N=142) with matched controls (N=710). Subanalysis was also performed comparing severely infected (hospitalized) women with controls. RESULT: No outcome differences were noted in comparing all women with H1N1 with controls. Women with severe infection had a higher incidence of delivering a small for gestational age (SGA) infant: 18.8% (6/32) versus 7.4% (52/707), adjusted odds ratio 2.35 (95% confidence interval 1.03, 5.36, P=0.02). Mean birth weight was 3013.0 g among severely infected women and 3223.3 g in controls (P=0.08), and incidence of preterm delivery was 25.0% (8/32) and 11.6% (82/710) (P=0.08), respectively. CONCLUSION: Pregnant women with mild clinical illness secondary to 2009 H1N1 were not at a greater risk of adverse pregnancy outcomes. However, severely infected women were more likely to deliver SGA infants.

Patterns of placental pathology in preterm premature rupture of membranes.

Inflammation is associated with preterm premature rupture of membranes (PPROM) and adverse neonatal outcomes. Subchorionic thrombi, with or without inflammation, may also be a significant pathological finding in PPROM. Patterns of inflammation and thrombosis may give insight into mechanisms of adverse neonatal outcomes associated with PPROM. To characterize histologic findings of placentas from pregnancies complicated by PPROM at altitude, 44 placentas were evaluated for gross and histological indicators of inflammation and thrombosis. Student's t-test (or Mann-Whitney U-test), χ 2 analysis (or Fisher's exact test), mean square contingency and logistic regression were used when appropriate. The prevalence of histologic acute chorioamnionitis (HCA) was 59%. Fetal-derived inflammation (funisitis and chorionic plate vasculitis) was seen at lower frequency (30% and 45%, respectively) and not always in association with HCA. There was a trend for Hispanic women to have higher odds of funisitis (OR = 5.9; P = 0.05). Subchorionic thrombi were seen in 34% of all placentas. The odds of subchorionic thrombi without HCA was 6.3 times greater that the odds of subchorionic thrombi with HCA (P = 0.02). There was no difference in gestational age or rupture-to-delivery interval, with the presence or absence of inflammatory or thrombotic lesions. These findings suggest that PPROM is caused by or can result in fetal inflammation, placental malperfusion, or both, independent of gestational age or rupture-to-delivery interval; maternal ethnicity and altitude may contribute to these findings. Future studies focused on this constellation of PPROM placental findings, genetic polymorphisms and neonatal outcomes are needed.

Insulin resistance in type 1 diabetes: what is 'double diabetes' and what are the risks?

In this review, we explore the concept of 'double diabetes', a combination of type 1 diabetes with features of insulin resistance and type 2 diabetes. After considering whether double diabetes is a useful concept, we discuss potential mechanisms of increased insulin resistance in type 1 diabetes before examining the extent to which double diabetes might increase the risk of cardiovascular disease (CVD). We then go on to consider the proposal that weight gain from intensive insulin regimens may be associated with increased CV risk factors in some patients with type 1 diabetes, and explore the complex relationships between weight gain, insulin resistance, glycaemic control and CV outcome. Important comparisons and contrasts between type 1 diabetes and type 2 diabetes are highlighted in terms of hepatic fat, fat partitioning and lipid profile, and how these may differ between type 1 diabetic patients with and without double diabetes. In so doing, we hope this work will stimulate much-needed research in this area and an improvement in clinical practice.

Cardiac troponin I concentrations in people presenting with diabetic ketoacidosis.

BACKGROUND: Elevated troponin concentrations may be observed in a wide spectrum of medical disorders in people without evidence of overt ischaemic heart disease. The prospective relationship between serum cardiac troponin I (cTnI) and diabetic ketoacidosis (DKA) has not been examined in adults. METHODS: Forty patients (14 male and 26 female) with type 1 diabetes were recruited. cTnI, creatine kinase (CK), cystatin C and beta-hydroxybutyrate were measured on admission and at 24, 48 and 72 h post-admission. Daily electrocardiographs were also performed. RESULTS: Four out of forty subjects presenting with DKA had an increase in cTnI (median (SD) 0.06 (0.31) microg/L). One of the subjects had multiple possible reasons for the elevated cTnI concentration. However, the other three subjects had no obvious precipitating factors. This cohort underwent echocardiography and thallium-201 scintigraphy, which revealed no abnormalities. CONCLUSIONS: Minor troponin elevations appear to occur in a small number of subjects with type 1 diabetes presenting with DKA. The clinical relevance of this at this stage remains unknown and further large-scale studies are suggested.

A comparison of glycaemic and metabolic control over time among South Asian and European patients with Type 2 diabetes: results from follow-up in a routine diabetes clinic.

AIMS: Although South Asians have a higher prevalence of diabetes which develops at a younger age, data on change in metabolic parameters post-diagnosis are relatively sparse. We therefore wished to determine whether South Asians with diabetes had similar or greater year-on-year deterioration in metabolic parameters compared with Europeans. METHODS: We analysed longitudinal change in metabolic parameters [glycated haemoglobin (HbA(1c)), blood pressure, body mass index (BMI), lipids] among South Asian (n = 210) and European (n = 1557) patients consecutively attending the same diabetes clinic over a mean period of 5.3 years. RESULTS: South Asians were younger than Europeans at first recorded diagnosis of diabetes (mean age 45.9 vs. 57.3 years, P < 0.001) and had significantly lower ( approximately 1.2 units) BMI and blood pressure. Mean HbA(1c) was not different across ethnic groups at first visit, but with time glycaemic control was worse in South Asians than Europeans, with average deterioration 1.31% (= 0.23%/year) in Asians vs. 0.82% (0.16%/year) in Europeans, P = 0.003. This ethnic difference in mean change in HbA(1c) persisted after adjustment for age, sex, baseline HbA(1c), and weight change in linear regression analysis (beta = 0.46, 95% CI 0.24-0.69, P < 0.001), and with additional adjustment for time to referral and duration of diabetes (P = 0.01). Moreover, South Asians had significantly smaller improvements in blood pressure (P < 0.001) and cholesterol (P = 0.044) over the follow-up period in keeping with fewer prescriptions of anti-hypertensive agents and lipid-lowering agents. CONCLUSIONS: These data suggest the need to be more aggressive in the management of diabetes and related risk factors in South Asians.

Proposed Measurement of the Beta-Neutrino Correlation in Neutron Decay.

Currently, the beta-neutrino asymmetry has the largest uncertainty (4 %) of the neutron decay angular correlations. Without requiring polarimetry this decay parameter can be used to measure λ (ga/gv ), test Cabibbo-Kobayashi-Maskawa (CKM) unitarity limit scalar and tensor currents, and search for Charged Vector Current (CVC) violation. We propose to measure the beta-neutrino asymmetry coeffcient, a, using time-of-flight for the recoil protons. We hope to achieve a systematic uncertainty of σa / a ≈ 1.0 %. After tests at Indiana University's Low Energy Neutron Source (LENS), the apparatus will be moved to the National Institute of Standards and Technology (NIST) where the measurement can achieve a statistical uncertainty of 1 % to 2 % in about 200 beam days.

Detecting the Radiative Decay Mode of the Neutron.

Beta decay of the neutron into a proton, electron, and electron antineutrino is occasionally accompanied by the emission of a photon. Despite decades of detailed experimental studies of neutron beta-decay, this rare branch of a fundamental weak decay has never been observed. An experiment to study the radiative beta-decay of the neutron is currently being developed for the NG-6 fundamental physics endstation at the National Institute of Standards and Technology (NIST) Center for Neutron Research (NCNR). The experiment will make use of the existing apparatus for the NIST proton-trap lifetime experiment, which can provide substantial background reduction by providing an electron-proton coincidence trigger. Tests and design of a detector for gamma-rays in the 10 keV to 200 keV range are under development. The need for a large solid-angle gamma-ray detector that can operate in a strong magnetic field and at low temperature has led us to consider scintillating crystals in conjunction with avalanche photodiodes. The motivation and experimental technique will be discussed.

A randomized, controlled trial to study the effect of exercise consultation on the promotion of physical activity in people with Type 2 diabetes: a pilot study.

AIM: To evaluate the effect of exercise consultation on promotion of physical activity in people with Type 2 diabetes. METHODS: Twenty-six sedentary people with Type 2 diabetes were randomly assigned to receive an exercise consultation and standard exercise information (experimental) or standard exercise information alone (control). Exercise consultation is a one-to-one discussion, based on the transtheoretical model, designed to educate, strengthen motivation and develop realistic strategies to promote physical activity. Changes from baseline at five weeks were assessed in (a) stage of exercise behaviour (b) physical activity levels (7-day recall questionnaire and an accelerometer) (c) quality of life (SF-36 Health Survey and 22-Item Well-Being Questionnaire). RESULTS: 82% (9/11) of participants receiving a consultation increased their stage of exercise behaviour compared to 33% (4/12) of controls (chi2 = 5.4, P = 0.02). Physical activity counts/week increased by 4% (1636 067/1696 191) in the experimental group and decreased by 9% (1560 960/1725 510) in controls. A significant difference was recorded for the change in activity counts per week from baseline to follow-up between the experimental and control group (98% CI = 60 673-710 827). The number of participants taking part in sport or leisure activity increased by 55% (6/11) in the experimental group and decreased by 6% (1/12) in controls. Positive changes were evident in the experimental group, compared to controls, in both quality of life questionnaires. CONCLUSION: Exercise consultation is more effective in stimulating exercise behaviour change in the short term than a standard exercise leaflet.

What is the relevance of the HOPE study in general practice?

The unique findings from the HOPE (Heart Outcomes Prevention Evaluation) study strongly support extending the use of the angiotensin-converting enzyme (ACE) inhibitor ramipril as a preventive agent for patients at high risk of cardiovascular events with normal left ventricular function. In addition, ramipril provides significant benefit in diabetic patients. These findings will impact on how ramipril is used in primary care, where ACE inhibitors are currently underprescribed. Patients reflecting the inclusion criteria of the HOPE study should be considered as suitable candidates for long-term ramipril therapy as an addition to their existing drug regimen. Screening should include control of kidney function (by serum creatinine), particularly within the first two weeks of treatment, in addition to regular monitoring of serum potassium. However, the HOPE study shows that ramipril is well tolerated at high doses and over a long treatment period. The effectiveness of therapy should also be regularly reviewed and dose adjustments made where necessary. If concern remains, referral to a specialist--a cardiologist or a diabetologist--may ultimately be necessary.

Consultants workload due to alcohol related conditions in acute medical receiving gastroenterology and endocrinology.

A four-week survey was performed into the incidence of alcohol related problems in the acute medical receiving unit, and the prevalence of alcohol related cases in a ward shared between two gastroenterologists and an endocrinologist. Alcohol related conditions were the commonest reason for acute admission (19%). Gastroenterologists, in contrast to their colleagues have a substantial workload related to alcohol, especially chronic liver disease. These patients have longer lengths of stay with higher morbidity and mortality than those without alcohol related conditions. The reason for these differences and the implications for service planning are discussed.

Coulombic effects of remote subsites on the active site of ribonuclease A.

The active-site cleft of bovine pancreatic ribonuclease A (RNase A) is lined with cationic residues that interact with a bound nucleic acid. Those residues interacting with the phosphoryl groups comprise the P0, P1, and P2 subsites, with the scissile P-O5' bond residing in the P1 subsite. Coulombic interactions between the P0 and P2 subsites and phosphoryl groups of the substrate were characterized previously [Fisher, B. M., Ha, J.-H., and Raines, R. T. (1998) Biochemistry 37, 12121-12132]. Here, the interactions between these subsites and the active-site residues His12 and His119 are described in detail. A protein variant in which the cationic residues in these subsites (Lys66 in the P0 subsite and Lys7 and Arg10 in the P2 subsite) were replaced with alanine was crystallized, both free and with bound 3'-uridine monophosphate (3'-UMP). Structures of K7A/R10A/K66A RNase A and the K7A/R10A/K66A RNase A.3'-UMP complex were determined by X-ray diffraction analysis to resolutions of 2.0 and 2.1 A, respectively. There is little observable change between these structures and that of wild-type RNase A, either free or with bound 3'-cytidine monophosphate. K7A/R10A/K66A RNase A was evaluated for its ability to cleave UpA, a dinucleotide substrate that does not span the P0 or the P2 subsites. In comparison to the wild-type enzyme, the value of kcat was decreased by 5-fold and that of kcat/Km was decreased 10-fold, suggesting that these remote subsites interact with the active site. These interactions were characterized by determining the pKa values of His12 and His119 at 0.018 and 0.142 M Na+, both in wild-type RNase A and the K7A/R10A/K66A variant. The side chains of Lys7, Arg10, and Lys66 depress the pKa values of these histidine residues, and this depression is sensitive to the salt concentration. In addition, the P0 and P2 subsites influence the interaction of His12 and His119 with each other, as demonstrated by changes in the cooperativity that gives rise to microscopic pKa values. Finally, the affinity of 3'-UMP for wild-type RNase A and the K7A/R10A/K66A variant at 0.018 and 0.142 M Na+ was determined by isothermal titration calorimetry. 3'-UMP binds to the variant protein with 5-fold weaker affinity at 0.018 M Na+ and 3-fold weaker affinity at 0.142 M Na+ than it binds to wild-type RNase A. Together these data demonstrate that long-range Coulombic interactions are an important feature in catalysis by RNase A.

A new remote subsite in ribonuclease A.

The interaction between bovine pancreatic ribonuclease A (RNase A) and its RNA substrate extends beyond the scissile bond. Enzymic subsites interact with the bases and the phosphoryl groups of a bound substrate. We evaluated the four cationic residues closest to known subsites for their abilities to interact with a bound nucleic acid. Lys-37, Arg-39, Arg-85, and Lys-104 were replaced individually by an alanine residue, and the resulting enzymes were assayed as catalysts of poly(cytidylic acid) (poly(C)) cleavage. The values of Km and kcat/Km for poly(C) cleavage were affected only by replacing Arg-85. Moreover, the contribution of Arg-85 to the binding of the ground state and the transition state was uniform---Km increased by 15-fold and kcat/Km decreased by 10-fold. The contribution of Arg-85 to binding was also apparent in the values of Kd for complexes with oligonucleotides of different length. This contribution was dependent on salt concentration, as expected from a coulombic interaction between a cationic side chain and an anionic phosphoryl group. Together, these data indicate that Arg-85 interacts with a particular phosphoryl group of a bound nucleic acid. We propose that Arg-85 comprises a new distal subsite in RNase A---the P(-1) subsite.

Coulombic forces in protein-RNA interactions: binding and cleavage by ribonuclease A and variants at Lys7, Arg10, and Lys66.

The interactions between bovine pancreatic ribonuclease A (RNase A) and its RNA substrate extend beyond the scissile P-O5' bond. Enzymic subsites interact with the bases and phosphoryl groups of the bound substrate. Those residues interacting with the phosphoryl group comprise the P0, P1, and P2 subsites, with the scissile bond residing in the P1 subsite. Here, the function of the P0 and P2 subsites of RNase A is characterized in detail. Lys66 (P0 subsite) and Lys7 and Arg10 (P2 subsite) were replaced with alanine residues. Wild-type RNase A and the K66A, K7A/R10A, and K7A/R10A/K66A variants were evaluated as catalysts for the cleavage of poly(cytidylic acid) [poly(C)] and for their abilities to bind to single-stranded DNA, a substrate analogue. The values of kcat and Km for poly(C) cleavage were affected by altering the P0 and P2 subsites. The kcat/Km values for poly(C) cleavage by the K66A, K7A/R10A, and K7A/R10A/K66A variants were 3-fold, 60-fold, and 300-fold lower, respectively, than that of wild-type RNase A. These values indicate that the P0 and P2 subsites contribute 0.70 and 2.46 kcal/mol, respectively, to transition-state binding. Binding experiments indicate that the P0 and P2 subsites contribute 0.92 and 1.21 kcal/mol, respectively, to ground-state binding. Thus, the P0 subsite makes a uniform contribution toward binding the ground state and the transition state, whereas the P2 subsite differentiates, binding more tightly to the transition state than to the ground state. In addition, nucleic acid binding to wild-type RNase A is strongly dependent on NaCl concentration, but this dependence is diminished upon alteration of the P0 or P2 subsite. The logarithm of Kd is a linear function of the logarithm of [Na+] over the range 0.018 M