Golf-inhibiting gynecomastia associated with atorvastatin therapy.
Gynecomastia can have a significant emotional and social impact on men. Although numerous drug therapies may cause this condition, we found no documented cases of gynecomastia associated with atorvastatin. We describe the development of breast enlargement and tenderness in a 52-year-old Caucasian man 6 months after his simvastatin therapy had been switched to atorvastatin. His symptoms ultimately interfered with his ability to play golf and participate in other activities. These problems resolved after atorvastatin discontinuation and did not recur despite resumption of simvastatin therapy. The gynecomastia in this patient represented a possible adverse effect of atorvastatin according to the Naranjo adverse drug reaction probability scale. The mechanism may be atorvastatin's theoretical suppression of adrenal or gonadal steroid production through effects on cholesterol synthesis. Based on this and other case reports, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) should be considered as a potential cause when evaluating otherwise unexplainable cases of gynecomastia in patients taking these drugs.


Autism-related deficits via dysregulated eIF4E-dependent translational control.
Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is thought to cause autism spectrum disorders (ASDs). The mammalian target of rapamycin (mTOR) is strongly implicated in ASDs by means of upstream signalling; however, downstream regulatory mechanisms are ill-defined. Here we show that knockout of the eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2)-an eIF4E repressor downstream of mTOR-or eIF4E overexpression leads to increased translation of neuroligins, which are postsynaptic proteins that are causally linked to ASDs. Mice that have the gene encoding 4E-BP2 (Eif4ebp2) knocked out exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviours (that is, social interaction deficits, altered communication and repetitive/stereotyped behaviours). Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, but not neuroligin 2, protein levels restores the normal excitation/inhibition ratio and rectifies the social behaviour deficits. Thus, translational control by eIF4E regulates the synthesis of neuroligins, maintaining the excitation-to-inhibition balance, and its dysregulation engenders ASD-like phenotypes.


A risk management audit: are we complying with the national guidelines for sedation by non-anaesthetists?
To assess the effect of a preprinted form in ensuring an improved and sustained quality of documentation of clinical data in compliance with the national guidelines for sedation by non-anaesthetists. The process of retrospective case note audit was used to identify areas of poor performance, reiterate national guidelines, introduce a post-sedation advice sheet, and demonstrate improvement. Emergency Department, Musgrove Park Hospital, Taunton. Forty seven patients requiring sedation for relocation of a dislocated shoulder or manipulation of a Colles' fracture between July and October 1996 and July and October 1997. Evidence that the following items had been documented: consent for procedure, risk assessment, monitored observations, prophylactic use of supplementary oxygen, and discharging patients with printed advice. Case note review was performed before (n = 23) and after (n = 24) the introduction of a sedation audit form. Notes were analysed for the above outcome measures. The monitored observations analysed included: pulse oximetry, respiratory rate, pulse rate, blood pressure, electrocardiography, and conscious level. Use of the form significantly improved documentation of most parameters measured. Introduction of the form, together with staff education, resulted in enhanced documentation of data and improved conformity with national guidelines. A risk management approach to preempting critical incidents following sedation, can be adopted in this area of emergency medicine.


The nature of communication throughout diagnosis and management planning in initial audiologic rehabilitation consultations.
Effective practitioner-patient communication throughout diagnosis and management planning positively influences patient outcomes. A patient-centered approach whereby patient involvement in decision making is facilitated, a therapeutic relationship is developed, and information is bilaterally exchanged in an appropriate manner, leads to improved patient satisfaction, adherence to treatment, and self-management. Despite this knowledge, little is known about the nature of audiologist-patient communication throughout diagnosis and management planning. This research aimed to explore verbal communication between audiologists and patients/companions throughout diagnosis and management planning in initial audiology consultations. Specifically, this study aimed to describe the nature and dynamics of communication by examining the number, proportion, and type of verbal utterances by all speakers (audiologist, patient, and companion when present). In addition, this study aimed to investigate the influence of audiologist, patient, and consultation factors, such as verbal dominance, content balance, and communication control, on the dynamics of communication. A total of 62 initial audiological rehabilitation consultations (involving 26 different audiologists) were filmed and analyzed using the Roter Interaction Analysis System. All patients were older than 55 yr, and a companion was present in 17 consultations. This study focused solely on the communication relating to diagnosis and management planning (referred to as the "counseling phase"). Diagnosis, recommendations, rehabilitation options, and patient decisions were recorded along with the communication profiles and communication dynamics measured using the Roter Interaction Analysis System. Associations between communication dynamics (content balance, communication control, and verbal dominance) and eight variables were evaluated with Linear Mixed Model methods. The mean length of time for diagnosis and management planning was 29.0 min (range, 2.2-78.5 min). Communication profiles revealed that patient-centered communication was infrequently observed. First, opportunities to build a relationship were missed, such that patients' psychosocial concerns were rarely addressed and patients/companions showed little involvement in management planning. Second, the amount of talk was asymmetrical and the majority of audiologists' education and counseling utterances related to hearing aids; yet, only 56% of patients decided to obtain hearing aids at the conclusion of the consultation. Hearing aids were recommended in 83% of consultations where a hearing loss was diagnosed and alternative options were rarely provided. Thus, shared decision making rarely occurred, and audiologists often diagnosed a hearing loss and recommended hearing aids without patient involvement. In addition, when a greater proportion of time was dedicated to diagnosis and management planning, patients had greater input and control by asking more questions and requesting further information. Patient-centered communication was rarely observed in the 62 consultations. Thus, although not measured in this study, patient outcomes are likely to be affected. Future research should examine the influence of audiologist communication on outcomes and encourage a shift toward patient-centered audiological rehabilitation.


Transgenerational Transmission of the Effect of Gestational Ethanol Exposure on Ethanol Use-Related Behavior.
Prenatal alcohol exposure (PAE) enhances the risk for alcoholism by increasing the propensity to consume alcohol and altering neurophysiological response to alcohol challenge. Trans-generationally transmittable genetic alterations have been implicated in these behavioral changes. To date, transgenerational transmission of PAE-induced behavioral responses to alcohol has never been experimentally investigated. Therefore, we explored the transgenerational transmission of PAE-induced behavioral effects across 3 generations. Pregnant Sprague Dawley dams received 1 g/kg ethanol (EtOH) or water daily on gestational days 17 through 20 via gavage, or remained untreated in their home cages. To produce second filial (F2) or F3 generations, similarly treated adult F1 or F2 offspring were mated and left undisturbed through gestation. On postnatal day (PND) 14, male and female F1, F2, and F3 offspring were tested for consumption of 5% (w/v) EtOH (in water), or water. Using the loss of righting reflex (LORR) paradigm on PND 42, F1 and F2 adolescent male offspring were tested for sensitivity to acute EtOH-induced sedation-hypnosis at 3.5 or 4.5 g/kg dose. F3 male adolescents were similarly tested at 3.5 g/kg dose. Blood EtOH concentration (BEC) was measured at waking. EtOH exposure increased EtOH consumption compared to both water and untreated control groups in all generations. EtOH-treated group F1 and F2 adolescents displayed attenuated LORR duration compared to the water group. No attenuated LORR was observed in the F3 generation. BEC at waking corroborated with the significant LORR duration differences while also revealing differences between untreated control and water groups in F1 and F2 generations. Our results provide novel behavioral evidence attesting that late gestational moderate EtOH exposure increases EtOH intake across 3 generations and may alter sensitivity to EtOH-induced sedation-hypnosis across 2 generations.


Acute and adaptive responses in humans to exercise in a warm, humid environment.
Acute and repeated exposure for 8-13 consecutive days to exercise in humid heat was studied. Twelve fit subjects exercised at 150 W [45% of maximum O2 uptake (V.O2,max)] in ambient conditions of 35 degrees C and 87% relative humidity which resulted in exhaustion after 45 min. Average core temperature reached 39.9 +/- 0.1 degrees C, mean skin temperature (T-sk) was 37.9 +/- 0.1 degrees C and heart rate (HR) 152 +/- 6 beats min-1 at this stage. No effect of the increasing core temperature was seen on cardiac output and leg blood flow (LBF) during acute heat stress. LBF was 5.2 +/- 0.3 l min-1 at 10 min and 5.3 +/- 0.4 l min-1 at exhaustion (n = 6). After acclimation the subjects reached exhaustion after 52 min with a core temperature of 39.9 +/- 0.1 degrees C, T-sk 37.7 +/- 0.2 degrees C, HR 146 +/- 4 beats min-1. Acclimation induced physiological adaptations, as shown by an increased resting plasma volume (3918 +/- 168 to 4256 +/- 270 ml), the lower exercise heart rate at exhaustion, a 26% increase in sweating rate, lower sweat sodium concentration and a 6% reduction in exercise V.O2. Neither in acute exposure nor after acclimation did the rise of core temperature to near 40 degrees C affect metabolism and substrate utilization. The physiological adaptations were similar to those induced by dry heat acclimation. However, in humid heat the effect of acclimation on performance was small due to physical limitations for evaporative heat loss.


Low anthropometric measures and mortality--results from the Malmö Diet and Cancer Study.
To study the association between anthropometric measures: body mass index (BMI), percent body fat, waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), waist-to-hip-to-height ratio (WHHR), and A Body Shape Index (ABSI); to see if individuals in the lowest 5 percentiles for these measures have an increased risk of mortality. A population-based prospective cohort study (10,304 men and 16,549 women), the Malmö Diet and Cancer study (MDC), aged 45-73 years. During a mean follow-up of 14 ± 3 years, 2,224 men and 1,983 women died. There was a significant increased mortality risk after adjustments for potential confounders in the group with the 5% lowest BMI (referent 25%-75%); hazard ratios (HR) with 95% confidence intervals were 1.33 (1.10-1.61) for women and 1.27 (1.07-1.52) for men. A similar significant increased mortality risk was seen with the 5% lowest percent body fat, HR 1.31 (1.07-1.60) for women and 1.25 (1.04-1.50) for men. Women with an ABSI in the lowest 5 percentiles had a lower mortality risk HR 0.64 (0.48-0.85). These results imply that BMI or percent body fat could be used to identify lean individuals at increased mortality risk.


Measurement of volumetric (OUR) and determination of specific (qO2) oxygen uptake rates in animal cell cultures.
Oxygen is a key substrate in animal cell metabolism. It has been reported that the oxygen uptake rate (OUR) is a good indicator of cellular activity, and even under some conditions, a good indicator of the number of viable cells. The measurement of OUR is difficult due to many different reasons. In particular, the very low specific consumption rate (0.2 x 10(-12) mol cell h-1), the sensitivity of the cells to variations in dissolved oxygen concentration and the difficulty to provide oxygen without damaging the cells are problems which must be taken into account for the development of OUR measurement methods. Different solutions based on an oxygen balance on either the liquid phase or around the entire reactor, and with a variable or stable concentration of dissolved oxygen have been reported. The accuracy of the OUR measurements and the required analytical devices are very different from method to method.


Overexpression of Bcl-2 in bladder cancer cells inhibits apoptosis induced by cisplatin and adenoviral-mediated p53 gene transfer.
To investigate the effects of the expression of Bcl-2 protein in bladder cancer on the apoptosis induced by cisplatin or adenoviral-mediated p53 gene (Ad5CMV-p53) transfer, we transfected the bcl-2 gene into KoTCC-1, a human bladder cancer cell line that does not express the Bcl-2 protein. The Bcl-2-transfected KoTCC-1 (KoTCC-1/B) exhibited significantly higher resistance to both cisplatin and Ad5CMV-p53 transfer than did either the parental KoTCC-1 (KoTCC-1/P) or the vector-only transfected cell line (KoTCC-1/C). The flow cytometric analysis of the propidium iodide-stained nuclei and DNA fragmentation analysis after cisplatin or Ad5CMV-p53 treatment revealed DNA degradation in both KoTCC-1/P and KoTCC-1/C, whereas KoTCC1/B showed a marked inhibition of DNA degradation. Following the treatment with cisplatin or Ad5CMV-p53, the accumulation of p53 protein was highly detectable for a long period in KoTCC-1/B compared to that in KoTTC-1/P and KoTCC-1/C. Furthermore, the cisplatin and Ad5CMV-p53 treatments each reduced the volume of the subcutaneous tumors established in nude mice formed by KoTCC-1/P or KoTCC-1/C; in contrast, their reductive effects on the tumors formed by KoTCC-1/B were significantly suppressed. The intraperitoneal tumor cell implantation model revealed that the prognoses of mice injected with KoTCC-1/B were significantly inferior to those of the mice injected with either KoTCC-1/P or KoTCC-1/C after treatment with cisplatin or Ad5CMV-p53. These findings suggest that the expression of Bcl-2 in bladder cancer cells interferes with the therapeutic effects of cisplatin and Ad5CMV-p53 through the inhibition of the apoptotic pathway.


Development of the outflow tracts with reference to aortopulmonary windows and aortoventricular tunnels.
Although malformations involving the ventricular outflow tracts are often described as conotruncal malformations, there is no consensus as to the lesions included in, or excluded from, this category, reflecting, in part, the current lack of precise definitions of the embryonic truncus and conus. Analysis of development of the outflow tract in terms of proximal, intermediate, and distal components greatly facilitates understanding of the morphology of the aortopulmonary window and aortoventricular tunnels. The aortopulmonary windows reflect failure to close the embryonic aortopulmonary foramen, the space between the distal end of the cushions that divide the lumen of the outflow tract itself and the dorsal wall of the aortic sac. The aortopulmonary tunnels are produced subsequent to abnormal development of the cushions themselves. The distal ends of these cushions excavate to produce the sinuses and leaflets of the arterial valves. The proximal parts of the cushions muscularise to form the subpulmonary infundibulum. The middle part of the cushion mass disappears to provide a tissue plane between the infundibulum and the aortic root. Abnormal formation of this area accounts for the various types of aortoventricular tunnel. In our brief review, we show how the anatomy of these lesions correlates with development of the outflow tract.


The effects of a two-year randomized, controlled trial of whey protein supplementation on bone structure, IGF-1, and urinary calcium excretion in older postmenopausal women.
The effects of dietary protein on bone structure and metabolism have been controversial, with evidence for and against beneficial effects. Because no long-term randomized, controlled studies have been performed, a two-year study of protein supplementation in 219 healthy ambulant women aged 70 to 80 years was undertaken. Participants were randomized to either a high-protein drink containing 30 g of whey protein (n = 109) or a placebo drink identical in energy content, appearance, and taste containing 2.1 g of protein (n = 110). Both drinks provided 600 mg of calcium. Dual-energy X-ray absorptiometric (DXA) hip areal bone mineral density (aBMD), 24-hour urinary calcium excretion, and serum insulin-like growth factor 1 (IGF-1) were measured at baseline and at 1 and 2 years. Quantitative computed tomographic (QCT) hip volumetric bone mineral density (vBMD) and a femoral neck engineering strength analysis were undertaken at baseline and at 2 years. Baseline average protein intake was 1.1 g/kg of body weight per day. There was a significant decrease in hip DXA aBMD and QCT vBMD over 2 years with no between-group differences. Femoral neck strength was unchanged in either group over time. The 24-hour urinary calcium excretion increased significantly from baseline in both groups at 1 year but returned to baseline in the placebo group at 2 years, at which time the protein group had a marginally higher value. Compared with the placebo group, the protein group had significantly higher serum IGF-1 level at 1 and 2 years (7.3% to 8.0%, p < .05). Our study showed that in protein-replete healthy ambulant women, 30 g of extra protein increased IGF-1 but did not have beneficial or deleterious effects on bone mass or strength. The effect of protein supplementation in populations with low dietary protein intake requires urgent attention.


Clinical Use of Quantitative Computed Tomography-Based Advanced Techniques in the Management of Osteoporosis in Adults: the 2015 ISCD Official Positions-Part III.
The International Society for Clinical Densitometry (ISCD) has developed new official positions for the clinical use of computed tomography (CT) scans acquired without a calibration phantom, for example, CT scans obtained for other diagnosis such as colonography. This also addresses techniques suggested for opportunistic screening of osteoporosis. The ISCD task force for quantitative CT reviewed the evidence for clinical applications of these new techniques and presented a report with recommendations at the 2015 ISCD Position Development Conference. Here we discuss the agreed upon ISCD official positions with supporting medical evidence, rationale, controversy, and suggestions for further study. Advanced techniques summarized as statistical parameter mapping methods were also reviewed. Their future use is promising but the clinical application is premature. The clinical use of QCT of the hip is addressed in part I and of finite element analysis of the hip and spine in part II.


Self-similarity and points of interest.
In this work, we present a new approach to interest point detection. Different types of features in images are detected by using a common computational concept. The proposed approach considers the total variability of local regions. The total sum of squares computed on the intensity values of a local circular region is divided into three components: between-circumferences sum of squares, between-radii sum of squares, and the remainder. These three components normalized by the total sum of squares represent three new saliency measures, namely, radial, tangential, and residual. The saliency measures are computed for regions with different radii and scale spaces are built in this way. Local extrema in scale space of each of the saliency measures are located. They represent features with complementary image properties: blob-like features, corner-like features, and highly textured points. Results obtained on image sets of different object classes and image sets under different types of photometric and geometric transformations show high robustness of the method to intraclass variations as well as to different photometric transformations and moderate geometric transformations and compare favorably with the results obtained by the leading interest point detectors from the literature. The proposed approach gives a rich set of highly distinctive local regions that can be used for object recognition and image matching.


The depletion attraction: an underappreciated force driving cellular organization.
Cellular structures are shaped by hydrogen and ionic bonds, plus van der Waals and hydrophobic forces. In cells crowded with macromolecules, a little-known and distinct force-the "depletion attraction"-also acts. We review evidence that this force assists in the assembly of a wide range of cellular structures, ranging from the cytoskeleton to chromatin loops and whole chromosomes.


Improving primary care in British Columbia, Canada: evaluation of a peer-to-peer continuing education program for family physicians.
An innovative program, the Practice Support Program (PSP), for full-service family physicians and their medical office assistants in primary care practices was recently introduced in British Columbia, Canada. The PSP was jointly approved by both government and physician groups, and is a dynamic, interactive, educational and supportive program that offers peer-to-peer training to physicians and their office staff. Topic areas range from clinical tools/skills to office management relevant to General Practitioner (GP) practices and "doable in real GP time". PSP learning modules consist of three half-day learning sessions interspersed with 6-8 week action periods. At the end of the third learning session, all participants were asked to complete a pen-and-paper survey that asked them to rate (a) their satisfaction with the learning module components, including the content and (b) the perceived impact the learning has had on their practices and patients. A total of 887 GPs (response rates ranging from 26.0% to 60.2% across three years) and 405 MOAs (response rates from 21.3% to 49.8%) provided responses on a pen-and-paper survey administered at the last learning session of the learning module. The survey asked respondents to rate (a) their satisfaction with the learning module components, including the content and (b) the perceived impact the learning has had on their practices and patients. The psychometric properties (Chronbach's alphas) of the satisfaction and impact scales ranged from .82 to .94. Evaluation findings from the first three years of the PSP indicated consistently high satisfaction ratings and perceived impact on GP practices and patients, regardless of physician characteristics (gender, age group) or work-related variables (e.g., time worked in family practice). The Advanced Access Learning Module, which offers tools to improve office efficiencies, decreased wait times for urgent, regular and third next available appointments by an average of 1.2, 3.3, and by 3.4 days across all physicians. For the Chronic Disease Management module, over 87% of all GP respondents developed a CDM patient registry and reported being able to take better care of their patients. After attending the Adult Mental Health module: 94.1% of GPs agreed that they felt more comfortable helping patients who required mental health care; over 82% agreed that their skills and their confidence in diagnosing and treating mental health conditions had improved; and 41.0% agreed that their frequency of prescribing medications, if appropriate, had decreased. Additionally for the Adult Mental Health module, a 3-6 month follow-up survey of the GPs indicated that the implemented changes were sustained over time. GP and medical office assistant participant ratings show that the PSP learning modules were consistently successful in providing GPs and their staff with new learning that was relevant and could be implemented and used in "real-GP-time".


Comparison of various repetitive DNA elements as genetic markers for strain differentiation and epidemiology of Mycobacterium tuberculosis.
Five different genetic elements have been found to be associated with genetic rearrangements in Mycobacterium tuberculosis complex strains. Of these elements, the insertion sequence IS6110 is presently the most frequently used genetic marker for strain differentiation of M. tuberculosis. In the present study we compared five genetic elements for their potentials to differentiate a given cluster of M. tuberculosis strains. Because of the presence of only a single copy of IS6110 or two IS6110 copies at the same chromosomal locus, a large number of strains could not be differentiated by IS6110 fingerprinting. Most strains, including the low-copy-number IS6110 strains, could be differentiated by fingerprinting with the 36-bp direct repeat or the polymorphic GC-rich repetitive DNA element. Less discriminative power was obtained with the major polymorphic tandem repeat and the insertion element IS1081. One strain which did not contain IS6110 DNA was encountered. Until now, this element has invariantly been found to be present in all M. tuberculosis complex strains. On the basis of classical taxonomic criteria and sequencing of the 16S rRNA gene, this strain was shown to be a genuine M. tuberculosis strain. Therefore, the use of this element as a target for polymerase chain reaction-facilitated detection of M. tuberculosis should be reconsidered.


A systematic approach to mapping recessive disease genes in individuals from outbred populations.
The identification of recessive disease-causing genes by homozygosity mapping is often restricted by lack of suitable consanguineous families. To overcome these limitations, we apply homozygosity mapping to single affected individuals from outbred populations. In 72 individuals of 54 kindred ascertained worldwide with known homozygous mutations in 13 different recessive disease genes, we performed total genome homozygosity mapping using 250,000 SNP arrays. Likelihood ratio Z-scores (ZLR) were plotted across the genome to detect ZLR peaks that reflect segments of homozygosity by descent, which may harbor the mutated gene. In 93% of cases, the causative gene was positioned within a consistent ZLR peak of homozygosity. The number of peaks reflected the degree of inbreeding. We demonstrate that disease-causing homozygous mutations can be detected in single cases from outbred populations within a single ZLR peak of homozygosity as short as 2 Mb, containing an average of only 16 candidate genes. As many specialty clinics have access to cohorts of individuals from outbred populations, and as our approach will result in smaller genetic candidate regions, the new strategy of homozygosity mapping in single outbred individuals will strongly accelerate the discovery of novel recessive disease genes.


Longitudinal Myelitis of a Neuro-Behçet Patient.
Behçet's disease is a chronic, relapsing inflammatory disorder of unknown etiology. Neuro-Behçet's disease (NBD) occurs in approximately 5 to 49% of patients with Behçet's disease. Spinal cord involvement is very rare in NBD. In this article, we report a 22-year-old male patient of NBD with longitudinal myelitis involving the entire spinal cord. Patient was admitted with one-week of headache, vomiting, and urinary incontinence. Before admission, he felt motor weakness for two years and had noticed recurrent genital and oral ulcers with a frequency of more than three episodes per year for five years. T2-weighted spinal magnetic resonance images showed hyperintensities within the entire spinal cord. He was diagnosed as NBD with longitudinal myelitis. Intravenous methylprednisolone (120 mg/day) was administered for three days, followed by an oral administration of prednisolone (45 mg/day). In conjunction with the steroid therapy, intravenous cyclophosphamide (0.4 g/week) was administered twice. Rapid improvements were detected after receiving treatments for half a month. NBD associated longitudinal myelitis is really rare. This case provided important implications for the diagnosis and treatment of longitudinal myelitis in NBD patients.


The role of subscapularis muscle denervation in the pathogenesis of shoulder internal rotation contracture after neonatal brachial plexus palsy: a study in a rat model.
We assessed the role of subscapularis muscle denervation in the development of shoulder internal rotation contracture in neonatal brachial plexus injury. Seventeen newborn rats underwent selective denervation of the subscapular muscle. The rats were evaluated at weekly intervals to measure passive shoulder external rotation. After 4 weeks, the animals were euthanized. The subscapularis thickness was measured using 7.2T MRI axial images. The subscapularis muscle was then studied grossly, and its mass was registered. The fiber area and the area of fibrosis were measured using collagen-I inmunostained muscle sections. Significant progressive decrease in passive shoulder external rotation was noted with a mean loss of 58° at four weeks. A significant decrease in thickness and mass of the subscapularis muscles in the involved shoulders was also found with a mean loss of 69%. Subscapularis muscle fiber size decreased significantly, while the area of fibrosis remained unchanged. Our study shows that subscapularis denervation, per se, could explain shoulder contracture after neonatal brachial plexus injury, though its relevance compared to other pathogenic factors needs further investigation.


Optical imaging and electrophysiology of rat barrel cortex. I. Responses to small single-vibrissa deflections.
A study was undertaken to investigate the response of the rodent somatosensory barrel cortex to single-whisker, near-threshold vibrissal stimuli. Cortical responses to controlled whisker deflections were recorded by (i) conventional multi-unit extracellular recording within the cytochrome oxidase rich barrels centers and the interbarrel septa, and (ii) intrinsic signal optical imaging, a technique that provides a spatial view of cortical activation thought to be related to the deoxygenation of hemoglobin in activated areas. Barrel cortex neurons responded weakly to whisker deflections of 0.04 degrees. Their response to a series of small stimuli of increasing amplitude was well-fitted by a logarithmic function. Responses to larger stimuli declined monotonically with distance from the center of the barrel column, and were characterized by greater onset and offset firing rates, by greater post-excitatory reduction of firing to below spontaneous levels, and by shorter response latency. In comparison to measurements taken previously from primary vibrissal afferent fibers, we conclude that cortical cells can respond to activity in a very small fraction of first-order sensory neurons.


A review of the handling of missing longitudinal outcome data in clinical trials.
The aim of this review was to establish the frequency with which trials take into account missingness, and to discover what methods trialists use for adjustment in randomised controlled trials with longitudinal measurements. Failing to address the problems that can arise from missing outcome data can result in misleading conclusions. Missing data should be addressed as a means of a sensitivity analysis of the complete case analysis results. One hundred publications of randomised controlled trials with longitudinal measurements were selected randomly from trial publications from the years 2005 to 2012. Information was extracted from these trials, including whether reasons for dropout were reported, what methods were used for handing the missing data, whether there was any explanation of the methods for missing data handling, and whether a statistician was involved in the analysis. The main focus of the review was on missing data post dropout rather than missing interim data. Of all the papers in the study, 9 (9%) had no missing data. More than half of the papers included in the study failed to make any attempt to explain the reasons for their choice of missing data handling method. Of the papers with clear missing data handling methods, 44 papers (50%) used adequate methods of missing data handling, whereas 30 (34%) of the papers used missing data methods which may not have been appropriate. In the remaining 17 papers (19%), it was difficult to assess the validity of the methods used. An imputation method was used in 18 papers (20%). Multiple imputation methods were introduced in 1987 and are an efficient way of accounting for missing data in general, and yet only 4 papers used these methods. Out of the 18 papers which used imputation, only 7 displayed the results as a sensitivity analysis of the complete case analysis results. 61% of the papers that used an imputation explained the reasons for their chosen method. Just under a third of the papers made no reference to reasons for missing outcome data. There was little consistency in reporting of missing data within longitudinal trials.


Mapping loci for pentylenetetrazol-induced seizure susceptibility in mice.
DBA/2J (D2) and C57BL/6J (B6) mice exhibit differential sensitivity to seizures induced by various chemical and physical methods, with D2 mice being relatively sensitive and B6 mice relatively resistant. We conducted studies in mature D2, B6, F1, and F2 intercross mice to investigate behavioral seizure responses to pentylenetetrazol (PTZ) and to map the location of genes that influence this trait. Mice were injected with PTZ and observed for 45 min. Seizure parameters included latencies to focal clonus, generalized clonus, and maximal seizure. Latencies were used to calculate a seizure score that was used for quantitative mapping. F2 mice (n = 511) exhibited a wide range of latencies with two-thirds of the group expressing maximal seizure. Complementary statistical analyses identified loci on proximal (near D1Mit11) and distal chromosome 1 (near D1Mit17) as having the strongest and most significant effects in this model. Another locus of significant effect was detected on chromosome 5 (near D5Mit398). Suggestive evidence for additional PTZ seizure-related loci was detected on chromosomes 3, 4, and 6. Of the seizure-related loci identified in this study, those on chromosomes 1 (distal), 4, and 5 map close to loci previously identified in a similar F2 population tested with kainic acid. Results document that the complex genetic influences controlling seizure response in B6 and D2 mice are partially independent of the nature of the chemoconvulsant stimulus with a locus on distal chromosome 1 being of fundamental importance.


Anti-GP2 IgA autoantibodies are associated with poor survival and cholangiocarcinoma in primary sclerosing cholangitis.
Pancreatic autoantibodies (PABs), comprising antibodies against glycoprotein 2 (anti-GP2), are typically associated with complicated phenotypes in Crohn's disease, but have also been observed with variable frequencies in patients with UC. In a previous study, we observed a high frequency of primary sclerosing cholangitis (PSC) in patients with anti-GP2-positive UC. We therefore aimed to characterise the role of anti-GP2 in PSC. In an evaluation phase, sera from 138 well-characterised Norwegian patients with PSC were compared with healthy controls (n=52), and patients with UC without PSC (n=62) for the presence of PABs by indirect immunofluorescence. Further, 180 German patients with PSC served as a validation cohort together with 56 cases of cholangiocarcinoma without PSC, 20 of secondary sclerosing cholangitis (SSC) and 18 of autoimmune hepatitis. Anti-GP2 IgA specifically occurred at considerable rates in large bile duct diseases (cholangiocarcinoma=36%, PSC and SSC about 50%). In PSC, anti-GP2 IgA consistently identified patients with poor survival during follow-up (Norwegian/German cohort: p Log Rank=0.016/0.018). Anti-GP2 IgA was associated with the development of cholangiocarcinoma in both PSC cohorts, yielding an overall OR of cholangiocarcinoma in patients with anti-GP2 IgA-positive PSC of 5.0 (p=0.001). Importantly, this association remained independent of disease duration, bilirubin level and age. Anti-GP2 IgA can be hypothesised as a novel marker in large bile duct diseases. In particular, in PSC, anti-GP2 IgA identified a subgroup of patients with severe phenotype and poor survival due to cholangiocarcinoma. Anti-GP2 IgA may therefore be a clinically valuable tool for risk stratification in PSC.


CRISPR-Cas Adaptive Immune Systems of the Sulfolobales: Unravelling Their Complexity and Diversity.
The Sulfolobales have provided good model organisms for studying CRISPR-Cas systems of the crenarchaeal kingdom of the archaea. These organisms are infected by a wide range of exceptional archaea-specific viruses and conjugative plasmids, and their CRISPR-Cas systems generally exhibit extensive structural and functional diversity. They carry large and multiple CRISPR loci and often multiple copies of diverse Type I and Type III interference modules as well as more homogeneous adaptation modules. These acidothermophilic organisms have recently provided seminal insights into both the adaptation process, the diverse modes of interference, and their modes of regulation. The functions of the adaptation and interference modules tend to be loosely coupled and the stringency of the crRNA-DNA sequence matching during DNA interference is relatively low, in contrast to some more streamlined CRISPR-Cas systems of bacteria. Despite this, there is evidence for a complex and differential regulation of expression of the diverse functional modules in response to viral infection. Recent work also supports critical roles for non-core Cas proteins, especially during Type III-directed interference, and this is consistent with these proteins tending to coevolve with core Cas proteins. Various novel aspects of CRISPR-Cas systems of the Sulfolobales are considered including an alternative spacer acquisition mechanism, reversible spacer acquisition, the formation and significance of antisense CRISPR RNAs, and a novel mechanism for avoidance of CRISPR-Cas defense. Finally, questions regarding the basis for the complexity, diversity, and apparent redundancy, of the intracellular CRISPR-Cas systems are discussed.


Protection against HIV-1 gp120-induced brain damage by neuronal expression of human amyloid precursor protein.
Expression of the HIV-1 envelope protein gp120 in brains of transgenic (tg) mice induces extensive neurodegeneration (Toggas, S. M., E. Masliah, E. M. Rockenstein, G. F. Rall, C. R. Abraham, and L. Mucke. 1994. Nature [Lond.]. 367:188-193.). To further analyze the pathogenesis of gp120-induced neurotoxicity and to assess the neuroprotective potential of human amyloid precursor proteins (hAPPs) in vivo, different hAPP isoforms were expressed in neurons of gp120/hAPP-bigenic mice: hAPP751, which contains a Kunitz-type protease inhibitor domain, or hAPP695, which lacks this domain. Bigenic mice overexpressing hAPP751 at moderate levels showed significantly less neuronal loss, synapto-dendritic degeneration, and gliosis than singly tg mice expressing gp120 alone. In contrast, higher levels of hAPP695 expression in bigenic mice failed to prevent gp120-induced brain damage. These data indicate that hAPP can exert important neuroprotective functions in vivo and that the efficiency of this protection may depend on the hAPP isoform expressed and/or on the level of neuronal hAPP expression. Hence, molecules that mimic beneficial APP activities may be useful in the prevention/treatment of HIV-1-associated nervous system damage and, perhaps, also of other types of neural injury.


Associations of genetic polymorphisms in the renin-angiotensin system with central aortic and ambulatory blood pressure in type 2 diabetic patients.
Patients with type 2 diabetes (T2D) are at high risk of developing hypertension and related cardiovascular disease. The renin-angiotensin system (RAS) plays a central role in regulation of blood pressure (BP). Accordingly, each component of this system represents a potential candidate in the etiology of hypertension. This study investigated the impact of polymorphisms within the RAS on ambulatory and central BP in T2D subjects. A cohort of 761 subjects (55-65 years) with T2D was studied. Ambulatory and central BP were measured, and ACE I/D genotype, angiotensinogen M235T, renin rs6693954 and ATR1-A1166C polymorphisms were analyzed. Women carrying the AA-genotype had lower 24-hour and day-time systolic and diastolic BP (p<0.05), and lower night-time and central diastolic BP (p<0.05), compared to T allele carriers. In men, the AA-genotype was instead associated with higher central diastolic BP (p=0.018) and higher augmentation index (p=0.016). Further, the associations between the renin rs6693954 SNP and diastolic BP were strongly gender dependent (p≤0.001). In T2D patients, there is a gender-dependent association of the renin rs6693954 SNP with central and ambulatory BP. Women carrying the renin rs6693954 AA-genotype may be protected against the higher BP seen in men with the same genotype.


Urinary Neutrophil Gelatinase-Associated Lipocalin as Predictor of Short- or Long-Term Outcomes in Cardiac Surgery Patients.
To determine the ability of urinary neutrophil gelatinase-associated lipocalin (uNGAL) to predict cardiac surgery-associated acute kidney injury (CSA-AKI), continuous renal replacement therapy (CRRT), mortality, and a composite outcome of major adverse kidney events at 365 days (MAKE365), and to investigate the influence of cardiopulmonary bypass (CPB) on NGAL release. A prospective observational study. A single-center university hospital. A cohort of 288 adult cardiac surgery patients. uNGAL was measured at baseline, immediately after surgery, and on days 1 and 2 postoperatively. The authors used the recent Kidney Disease Improving Global Outcomes consensus criteria to define CSA-AKI. CSA-AKI occurred in 36.1% of patients. uNGAL rapidly became significantly higher in patients who developed AKI, with peak value immediately after surgery (349.9 [76.6-1446.6] v 90.1 [20.8-328] ng/mg creatinine; p<0.001). No measure of uNGAL (peak, postsurgery, day 1 or 2 postsurgery) accurately predicted CSA-AKI, CRRT, mortality, or MAKE365. However, immediately after surgery, CPB induced greater uNGAL release compared with off-pump surgery (265.5 µmol/L [71-989.6] v 48.7 ng/mg creatinine [17-129.8]; p<0.001). Moreover, such early uNGAL release correlated with CPB duration (r = 0.505; p<0.001) but not with peak serum creatinine values on day 3 or 7 after surgery. uNGAL had a limited predictive ability for CSA-AKI or other relevant clinical outcomes after cardiac surgery and appeared to be more closely related to the use and duration of CPB. Thus, its levels may represent the aggregate effect of an inflammatory response to CPB as well as a renal response to cardiac surgery and inflammation.


Cleavage of 3',5'-pyrophosphate-linked dinucleotides by ribonuclease A and angiogenin.
Recently, 3',5'-pyrophosphate-linked 2'-deoxyribodinucleotides were shown to be >100-fold more effective inhibitors of RNase A superfamily enzymes than were the corresponding monophosphate-linked (i.e., standard) dinucleotides. Here, we have investigated two ribo analogues of these compounds, cytidine 3'-pyrophosphate (P'-->5') adenosine (CppA) and uridine 3'-pyrophosphate (P'-->5') adenosine (UppA), as potential substrates for RNase A and angiogenin. CppA and UppA are cleaved efficiently by RNase A, yielding as products 5'-AMP and cytidine or uridine cyclic 2',3'-phosphate. The k(cat)/K(m) values are only 4-fold smaller than for the standard dinucleotides CpA and UpA, and the K(m) values (10-16 microM) are lower than those reported for any earlier small substrates (e.g., 500-700 microM for CpA and UpA). The k(cat)/K(m) value for CppA with angiogenin is also only severalfold smaller than for CpA, but the effect of lengthening the internucleotide linkage on K(m) is more modest. Ribonucleotide 3',5'-pyrophosphate linkages were proposed previously to exist in nature as chemically labile intermediates in the pathway for the generation of cyclic 2',3'-phosphate termini in various RNAs. We demonstrate that in fact they are relatively stable (t(1/2) > 15 days for uncatalyzed degradation of UppA at pH 6 and 25 degrees C) and that cleavage in vivo is most likely enzymatic. Replacements of the RNase A catalytic residues His12 and His119 by alanine reduce activity toward UppA by approximately 10(5)-and 10(3.3)-fold, respectively. Thus, both residues play important roles. His12 probably acts as a base catalyst in cleavage of UppA (as with RNA). However, the major function of His119 in RNA cleavage, protonation of the 5'-O leaving group, is not required for UppA cleavage because the pK(a) of the leaving group is much lower than that for RNA substrates. A crystal structure of the complex of RNase A with 2'-deoxyuridine 3'-pyrophosphate (P'-->5') adenosine (dUppA), determined at 1.7 A resolution, together with models of the UppA complex based on this structure suggest that His119 contributes to UppA cleavage through a hydrogen bond with a nonbridging oxygen atom in the pyrophosphate and through pi-pi stacking with the six-membered ring of adenine.


The New Runner's High? Examining Relationships Between Cannabis Use and Exercise Behavior in States With Legalized Cannabis.
Scientific literature examining cannabis use in the context of health behaviors, such as exercise engagement, is extremely sparse and has yielded inconsistent findings. This issue is becoming increasingly relevant as cannabis legalization continues, a situation that has been associated with increased initiation of use among adults, and increased potency of available products in legalized states. Physical activity is among the most important health behaviors, but many Americans do not meet minimum exercise recommendations for healthy living. Common issues surrounding low exercise rates include inadequate enjoyment of and motivation to exercise, and poor recovery from exercise. It is unclear whether cannabis use shortly before and/or after exercise impacts these issues, and whether this co-use affects exercise performance. The present online survey study examines attitudes and behaviors regarding cannabis use with exercise among adult cannabis users living in states with full legal access (N = 605). Results indicated that the majority (81.7%) of participants endorsed using cannabis concurrently with exercise, and those who did tended to be younger and more likely to be males (p < 0.0005 for both). Even after controlling for these differences, co-users reported engaging in more minutes of aerobic and anaerobic exercise per week (p < 0.01 and p < 0.05, respectively). In addition, the majority of participants who endorsed using cannabis shortly before/after exercise reported that doing so enhances their enjoyment of and recovery from exercise, and approximately half reported that it increases their motivation to exercise. This study represents an important step in clarifying cannabis use with exercise among adult users in states with legal cannabis markets, and provides guidance for future research directions.


Fractional curve progression with maintenance of fusion mass in congenital scoliosis: An 18-year follow-up of a case report.
The management of congenital scoliosis concentrates on early diagnosis and proper surgical treatment before the development of severe deformities. Decision making regarding the appropriate fusion levels, proper surgical treatment, and reduction amount of kyphoscoliosis is very important but difficult in the treatment of congenital scoliosis, especially in young children. We report an 11-year follow-up of revision surgery for fractional curve progression after combined anterior and posterior fusion without hemivertebra resection using pedicle screw fixation (PSF) in congenital kyphoscoliosis at age 4 years (a total 18-year follow-up). A T12 hemivertebra was documented in a 4-year-old girl and was treated by combined anterior and posterior fusion in two stages with PSF. The fusion mass was maintained but the distal compensatory curve progressed during the follow-up period. The patient underwent a posterior vertebral column resection (PVCR) with extended posterior fusion at the age of 11, 7 years after initial surgery. Eleven years after the revision surgery with PVCR, the patient showed satisfactory results and her spine was well balanced. The cause of revision surgery for the curve progression may include inappropriate fusion level, incomplete hemivertebra resection, or failure of anterior and posterior fusion. Especially, inappropriate fusion level may result in deterioration of the compensatory curve even without progression of the fusion mass. Appropriate selection of fusion levels, complete resection of hemivertebra, and satisfactory reduction of scoliosis and kyphosis are important factors for deformity correction and prevention of progression of both main and compensatory curves (adding-on of structural curve or progression of compensatory curve) as well as reducing the influence of adjacent vertebral growth using as short a fusion as possible.


Nonverbal synchrony of head- and body-movement in psychotherapy: different signals have different associations with outcome.
The coordination of patient's and therapist's bodily movement - nonverbal synchrony - has been empirically shown to be associated with psychotherapy outcome. This finding was based on dynamic movement patterns of the whole body. The present paper is a new analysis of an existing dataset (Ramseyer and Tschacher, 2011), which extends previous findings by differentiating movements pertaining to head and upper-body regions. In a sample of 70 patients (37 female, 33 male) treated at an outpatient psychotherapy clinic, we quantified nonverbal synchrony with an automated objective video-analysis algorithm (motion energy analysis). Head- and body-synchrony was quantified during the initial 15 min of video-recorded therapy sessions. Micro-outcome was assessed with self-report post-session questionnaires provided by patients and their therapists. Macro-outcome was measured with questionnaires that quantified attainment of treatment goals and changes in experiencing and behavior at the end of therapy. The differentiation of head- and body-synchrony showed that these two facets of motor coordination were differentially associated with outcome. Head-synchrony predicted global outcome of therapy, while body-synchrony did not, and body-synchrony predicted session outcome, while head-synchrony did not. The results pose an important amendment to previous findings, which showed that nonverbal synchrony embodied both outcome and interpersonal variables of psychotherapy dyads. The separation of head- and body-synchrony suggested that distinct mechanisms may operate in these two regions: Head-synchrony embodied phenomena with a long temporal extension (overall therapy success), while body-synchrony embodied phenomena of a more immediate nature (session-level success). More explorations with fine-grained analyses of synchronized phenomena in nonverbal behavior may shed additional light on the embodiment of psychotherapy process.


Community participation of families of children with profound intellectual and multiple disabilities in South Africa.
Families struggle to support family members with profound intellectual and multiple disabilities (PIMD), especially in low resourced settings where formal services may not be available. The adapted Family Community Participation survey, measuring perceptions of community participation, was administered to 67 primary caregivers of children with PIMD in Cape Town by community-based rehabilitation workers. Families were most satisfied going to religious activities and getting together with family and friends. They were most dissatisfied with doing activities together in public and working or volunteering outside the home. Barriers to participation included negative attitudes, insufficient money and unavailability of community activities. Transportation, safety and security were additional challenges. Participants advocate awareness raising, community support and provision of services to address barriers to community participation. Families should be consulted on community issues to integrate their specific family needs into the overall needs of the community.


The psychiatric status schedule as a measure of dimensions of psychopathology in the general population.
The Psychiatric Status Schedule (PSS) is a widely used interview that was designed to improve the research value of clinical judgments. Although it was developed with psychiatric patients, its authors hoped it could be used to evaluate nonpatients, a capability that would make it a much needed tool for epidemiologic research. The present study tests the internal consistency reliability of scales drawn from the PSS in both a general population sample (n. = 133) and a patient sample (n. = 100). Like the PSS's authors, we found a wide variety of clinically meaningful scales reliable for use with patients. In striking contrast, however, most of these proved unreliable in the general population sample. Speculative explanations are offered for the failure of most of the PSS scales in the general population sample and for the success of a few.


Transgenic Expression of the Anti-parasitic Factor TEP1 in the Malaria Mosquito Anopheles gambiae.
Mosquitoes genetically engineered to be resistant to Plasmodium parasites represent a promising novel approach in the fight against malaria. The insect immune system itself is a source of anti-parasitic genes potentially exploitable for transgenic designs. The Anopheles gambiae thioester containing protein 1 (TEP1) is a potent anti-parasitic protein. TEP1 is secreted and circulates in the mosquito hemolymph, where its activated cleaved form binds and eliminates malaria parasites. Here we investigated whether TEP1 can be used to create malaria resistant mosquitoes. Using a GFP reporter transgene, we determined that the fat body is the main site of TEP1 expression. We generated transgenic mosquitoes that express TEP1r, a potent refractory allele of TEP1, in the fat body and examined the activity of the transgenic protein in wild-type or TEP1 mutant genetic backgrounds. Transgenic TEP1r rescued loss-of-function mutations, but did not increase parasite resistance in the presence of a wild-type susceptible allele. Consistent with previous reports, TEP1 protein expressed from the transgene in the fat body was taken up by hemocytes upon a challenge with injected bacteria. Furthermore, although maturation of transgenic TEP1 into the cleaved form was impaired in one of the TEP1 mutant lines, it was still sufficient to reduce parasite numbers and induce parasite melanization. We also report here the first use of Transcription Activator Like Effectors (TALEs) in Anopheles gambiae to stimulate expression of endogenous TEP1. We found that artificial elevation of TEP1 expression remains moderate in vivo and that enhancement of endogenous TEP1 expression did not result in increased resistance to Plasmodium. Taken together, our results reveal the difficulty of artificially influencing TEP1-mediated Plasmodium resistance, and contribute to further our understanding of the molecular mechanisms underlying mosquito resistance to Plasmodium parasites.


Invasive Haemophilus influenzae Disease in Adults ≥65 Years, United States, 2011.
Since the introduction of the Haemophilus influenzae serotype b vaccine, H influenzae epidemiology has shifted. In the United States, the largest burden of disease is now in adults aged ≥65 years. However, few data exist on risk factors for disease severity and outcome in this age group. A retrospective case-series review of invasive H influenzae infections in patients aged ≥65 years was conducted for hospitalized cases reported to Active Bacterial Core surveillance in 2011. There were 299 hospitalized cases included in the analysis. The majority of cases were caused by nontypeable H influenzae, and the overall case fatality ratio (CFR) was 19.5%. Three or more underlying conditions were present in 63% of cases; 94% of cases had at least 1. Patients with chronic heart conditions (congestive heart failure, coronary artery disease, and/or atrial fibrillation) (odds ratio [OR], 3.27; 95% confidence interval [CI], 1.65-6.46), patients from private residences (OR, 8.75; 95% CI, 2.13-35.95), and patients who were not resuscitate status (OR, 2.72; 95% CI, 1.31-5.66) were more likely to be admitted to the intensive care unit (ICU). Intensive care unit admission (OR, 3.75; 95% CI, 1.71-8.22) and do not resuscitate status (OR, 12.94; 95% CI, 4.84-34.55) were significantly associated with death. Within this age group, burden of disease and CFR both increased significantly as age increased. Using ICU admission as a proxy for disease severity, our findings suggest several conditions increased risk of disease severity and patients with severe disease were more likely to die. Further research is needed to determine the most effective approach to prevent H influenzae disease and mortality in older adults.


Influence of spinal reflexes on the locomotor pattern after spinal cord injury.
In complete spinal cord injured (cSCI) subjects a shift from dominant early (60-120ms latency) to dominant late (120-450ms latency) spinal reflex (SR) components occurs over time after injury. This shift is assumed to reflect a spinal neuronal dysfunction below the level of a spinal lesion. The neuronal pathways of SR are suggested to be closely connected with spinal locomotor circuits. The aim of this study was to explore the influence of the two SR components on the electromyographic (EMG) pattern induced by assisted locomotion in cSCI subjects. Leg muscle EMG activity was analysed during assisted locomotion in both healthy and motor cSCI subjects. SR were evoked by non-noxious tibial nerve stimulation during mid-stance phase of the gait cycle. Early and late SR components had a differential influence on the locomotor pattern. In healthy and cSCI subjects with a dominant early SR component the locomotor EMG pattern was modulated in the form of a short increase in leg flexors activity in the stance phase (tibialis anterior, biceps femoris). In contrast, in chronic cSCI subjects with a dominant late SR component no activation in biceps femoris but a long-lasting activation of tibialis anterior and rectus femoris muscles during the stance phase was evoked. It is concluded that the same tibial nerve stimuli activated two different neuronal pathways, resulting in divergent interactions with spinal locomotor circuitries. It is proposed that the two SR components have different physiological roles during locomotion.


Role of luminal nutrients and endogenous GLP-2 in intestinal adaptation to mid-small bowel resection.
To elucidate the role of luminal nutrients and glucagon-like peptide-2 (GLP-2) in intestinal adaptation, rats were subjected to 70% midjejunoileal resection or ileal transection and were maintained with total parenteral nutrition (TPN) or oral feeding. TPN rats showed small bowel mucosal hyperplasia at 8 h through 7 days after resection, demonstrating that exogenous luminal nutrients are not essential for resection-induced adaptation when residual ileum and colon are present. Increased enterocyte proliferation was a stronger determinant of resection-induced mucosal growth in orally fed animals, whereas decreased apoptosis showed a greater effect in TPN animals. Resection induced significant transient increases in plasma bioactive GLP-2 during TPN, whereas resection induced sustained increases in plasma GLP-2 during oral feeding. Resection-induced adaptive growth in TPN and orally fed rats was associated with a significant positive correlation between increases in plasma bioactive GLP-2 and proglucagon mRNA expression in the colon of TPN rats and ileum of orally fed rats. These data support a significant role for endogenous GLP-2 in the adaptive response to mid-small bowel resection in both TPN and orally fed rats.


Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer.
The majority of estrogen receptor (ER)-positive breast cancers are treated with endocrine therapy. While this is effective, acquired resistance to therapies targeted against ER is a major clinical challenge. Here, model systems of ER-positive breast cancers with differential susceptibility to endocrine therapy were employed to define common nodes for new therapeutic interventions. These analyses revealed that cell cycle progression is effectively uncoupled from the activity and functional state of ER in these models. In this context, cyclin D1 expression and retinoblastoma tumor suppressor protein (RB) phosphorylation are maintained even with efficient ablation of ER with pure antagonists. These therapy-resistant models recapitulate a key feature of deregulated RB/E2F transcriptional control. Correspondingly, a gene expression signature of RB-dysfunction is associated with luminal B breast cancer, which exhibits a relatively poor response to endocrine therapy. These collective findings suggest that suppression of cyclin D-supported kinase activity and restoration of RB-mediated transcriptional repression could represent a viable therapeutic option in tumors that fail to respond to hormone-based therapies. Consistent with this hypothesis, a highly selective CDK4/6 inhibitor, PD-0332991, was effective at suppressing the proliferation of all hormone refractory models analyzed. Importantly, PD-0332991 led to a stable cell cycle arrest that was fundamentally distinct from those elicited by ER antagonists, and was capable of inducing aspects of cellular senescence in hormone therapy refractory cell populations. These findings underscore the clinical utility of downstream cytostatic therapies in treating tumors that have experienced failure of endocrine therapy.


Identification and functional analysis of CITED2 mutations in patients with congenital heart defects.
Recent reports have demonstrated that mice lacking the transcription factor Cited2 die in utero showing various cardiac malformations. We present for the first time functionally relevant mutations of CITED2 in patients with congenital heart defects (CHDs). CITED2 encodes a CREBBP/EP300 interacting transcriptional modulator of HIF1A and TFAP2. To study the potential impact of sequence variations in CITED2 for CHDs in humans, we screened a cohort of 392 well-characterized patients and 192 control individuals using DHPLC, sequencing, and Amplifluor genotyping techniques. We identified 15 CITED2 nucleotide alterations. Seven of these alterations were found only in CHD patients and were not detected in controls, including three mutations leading to alterations of the amino acid sequence (p.Ser170_Gly178del, p.Gly178_Ser179ins9, and p.Ser198_Gly199del). All three of these amino acid changing mutations cluster in the serine-glycine-rich junction of the protein, to which no functionality had heretofore been assigned. Here we show that these mutations significantly reduce the capacity of CITED2 to transrepress HIF1A, and that the p.Ser170_Gly178del mutation significantly diminishes TFAP2C coactivation. This reveals a modifying role for the serine-glycine-rich region in CITED2 function. In summary, the observation of these mutations in patients with septal defects indicates that CITED2 has a causative impact in the development of CHD in humans.


Radiofrequency polarization effects in low-field electron paramagnetic resonance.
Low-field optically detected EPR spectra of photochemically formed transient radical ion pairs are reported for weak circularly and linearly polarized radiofrequency (RF) fields. The spectra are found to be strongly dependent on the polarization and frequency of the RF field and on the angle between the static magnetic field and the plane containing the RF field. The spectra are discussed in terms of resonances arising from Zeeman and hyperfine interactions; the conditions for validity of the rotating frame approximation are determined. Knowledge of the latter is important when using low-field EPR as a diagnostic test for the operation of the radical pair mechanism.


aDolescents gEnder surVey, rEsponsible coupLes evaluatiOn, and capacity building Project in India (DEVELOP): a study protocol.
Gender-based violence against women is a serious concern in India. This affects the health and wellbeing of victims and their dependents. Published evidence has documented a variety of reasons for such violence in Indian societies, paving a pathway to design, implement, and evaluate intervention models to address this issue. DEVELOP is a research study designed by UK and Indian research teams to plan future projects to address gender-based discrimination and violence against women and girls in India. This study protocol provides detailed information on the objectives, research methods, data collection, storage, analysis, and dissemination plans of the DEVELOP. The first component is a survey of adolescent boys and girls from rural areas of Maharashtra state of India to understand their gender equality related knowledge and beliefs. The insight gathered will be used to design interventions targeted at adolescent populations through future research and development programmes. Secondly, an evaluation of the 'Responsible Couples' project will be conducted to assess its success and challenges, and to design suitable programme activities and models. The 'Responsible Couples' project is implemented in 40 villages of Maharashtra state to improve relationships in married couples, prevent violence against women, intervene during violence, and to provide support services for women and their family members. Research findings will be disseminated though public engagement events in India, international conferences, and peer reviewed publications. This will impact on the policy and work models of Indian partners to plan future project investments. Research findings will be also useful for local government authorities and non-government agencies striving to advance gender equality.


Narrative reports to monitor and evaluate the integration of pharmacists into family practice settings.
Narratives can capture unfolding events and negotiation of roles and thus can help to evaluate interventions in interdisciplinary health care teams. We describe a practical qualitative method, the narrative report, and its role in evaluating implementation research. We used narrative reports as a means to evaluate an intervention to integrate pharmacists into group family practices. The pharmacists submitted 63 written narrative reports during a 1-year period. Our interdisciplinary research team analyzed these reports to monitor the progress of the implementation, to identify pharmacists' needs, and to capture elements of the integration process. The monthly narrative reports allowed the research team to document early learning and calibrate the program in terms of clinical support, adapting roles, and realigning expectations. The reports helped the research team stay in tune with practice-related implementation challenges, and the preliminary summary of narrative findings provided a forum for sharing innovations among the integrating pharmacists. The narrative report can be a successful qualitative tool to track and evaluate the early stages of an intervention in the context of evolving primary health care teams.


Whole transcriptome analysis of the silicon response of the diatom Thalassiosira pseudonana.
Silicon plays important biological roles, but the mechanisms of cellular responses to silicon are poorly understood. We report the first analysis of cell cycle arrest and recovery from silicon starvation in the diatom Thalassiosira pseudonana using whole genome microarrays. Three known responses to silicon were examined, 1) silicified cell wall synthesis, 2) recovery from silicon starvation, and 3) co-regulation with silicon transporter (SIT) genes. In terms of diatom cell wall formation, thus far only cell surface proteins and proteins tightly associated with silica have been characterized. Our analysis has identified new genes potentially involved in silica formation, and other genes potentially involved in signaling, trafficking, protein degradation, glycosylation and transport, which provides a larger-scale picture of the processes involved. During silicon starvation, an overrepresentation of transcription and translation related genes were up-regulated, indicating that T. pseudonana is poised to rapidly recover from silicon starvation and resume cell cycle progression upon silicon replenishment. This is in contrast to other types of limitation, and provides the first molecular data explaining the well-established environmental response of diatoms to grow as blooms and to out-compete other classes of microalgae for growth. Comparison of our data with a previous diatom cell cycle analysis indicates that assignment of the cell cycle specific stage of particular cyclins and cyclin dependent kinases should be re-evaluated. Finally, genes co-varying in expression with the SITs enabled identification of a new class of diatom-specific proteins containing a unique domain, and a putative silicon efflux protein. Analysis of the T. pseudonana microarray data has provided a wealth of new genes to investigate previously uncharacterized cellular phenomenon related to silicon metabolism, silicon's interaction with cellular components, and environmental responses to silicon.


"Am I cut out for this?" Understanding the experience of doubt among first-year medical students.
Existing research shows that medical students experience high levels of distress. The purpose of this study was to understand how medical students experience doubt, and how doubt relates to distress. A mixed-methods study was conducted among first-year students at the Johns Hopkins University School of Medicine in June 2012. Students answered survey questions and participated in focus groups about doubt and other forms of distress. Ninety-four percent (112) of students responded to the survey, with 49% reporting a moderate or high degree of doubt. Compared to those reporting no or low doubt, students with moderate/high doubt were significantly more likely to question their purpose and identity, struggle to cope with doubt, and experience depression and emotional hardening. Twenty-eight percent of students (34/112) participated in focus groups to explore their doubt, and three themes emerged: types of doubt, ways of coping with doubt, and impact of doubt. Doubt is highly prevalent among first-year medical students, affects their identity and purpose, and has positive and negative consequences. Doubt among medical students merits awareness and further study, as it may be an important mediator of students' emerging identity and sense of well-being.


Occupational differences in COVID-19 incidence, severity, and mortality in the United Kingdom: Available data and framework for analyses.
There are important differences in the risk of SARS-CoV-2 infection and death depending on occupation. Infections in healthcare workers have received the most attention, and there are clearly increased risks for intensive care unit workers who are caring for COVID-19 patients. However, a number of other occupations may also be at an increased risk, particularly those which involve social care or contact with the public. A large number of data sets are available with the potential to assess occupational risks of COVID-19 incidence, severity, or mortality. We are reviewing these data sets as part of the Partnership for Research in Occupational, Transport, Environmental COVID Transmission (PROTECT) initiative, which is part of the National COVID-19 Core Studies. In this report, we review the data sets available (including the key variables on occupation and potential confounders) for examining occupational differences in SARS-CoV-2 infection and COVID-19 incidence, severity and mortality. We also discuss the possible types of analyses of these data sets and the definitions of (occupational) exposure and outcomes. We conclude that none of these data sets are ideal, and all have various strengths and weaknesses. For example, mortality data suffer from problems of coding of COVID-19 deaths, and the deaths (in England and Wales) that have been referred to the coroner are unavailable. On the other hand, testing data is heavily biased in some periods (particularly the first wave) because some occupations (e.g. healthcare workers) were tested more often than the general population. Random population surveys are, in principle, ideal for estimating population prevalence and incidence, but are also affected by non-response. Thus, any analysis of the risks in a particular occupation or sector (e.g. transport), will require a careful analysis and triangulation of findings across the various available data sets.


Informal Support, Health, and Burden Among Parents of Adult Children With Autism.
Many adults with autism spectrum disorders require lifelong reliance on caregiver support. As these caregivers age and experience health challenges, social support can be critical. This study seeks to understand if caregiver health moderates the relationship between informal social support and caregiver burden. A total of 320 parents (age 50+ years) of adult children diagnosed with ASD were recruited from autism organizations and support groups and completed a web-based survey. Separate moderation analyses were used to determine if caregiver health was moderating the relationship between informal social support and composite caregiver burden, as well as the separate domains of developmental, time dependence, emotional burden, and impact of caregiving on finances. For each analysis, perceptions of available informal social support were the independent variable, composite and domains of caregiver burden were dependent variables, and parents' self-reported general health was the moderating variable. Caregiver health had a statistically significant moderating effect when predicting the relationships between informal social support and composite caregiver burden, as well as time dependence burden and impact of caregiving on finances. Increased attention should be focused on supporting the current and future needs of both aging caregivers and their adult children with ASD. Future research on the dynamics of social support, health, and burden is also urgently needed to address the growing number of aging caregivers of adults diagnosed with ASD.


A novel role of the budding yeast separin Esp1 in anaphase spindle elongation: evidence that proper spindle association of Esp1 is regulated by Pds1.
In Saccharomyces cerevisiae, the metaphase-anaphase transition is initiated by the anaphase-promoting complex-dependent degradation of Pds1, whereby Esp1 is activated to promote sister chromatid separation. Although this is a fundamental step in the cell cycle, little is known about the regulation of Esp1 and how loss of cohesion is coordinated with movement of the anaphase spindle. Here, we show that Esp1 has a novel role in promoting anaphase spindle elongation. The localization of Esp1 to the spindle apparatus, analyzed by live cell imaging, is regulated in a manner consistent with a function during anaphase B. The protein accumulates in the nucleus in G2 and is mobilized onto the spindle pole bodies and spindle midzone at anaphase onset, where it persists into midanaphase. Association with Pds1 occurs during S phase and is required for efficient nuclear targeting of Esp1. Spindle association is not fully restored in pds1 mutants expressing an Esp1-nuclear localization sequence fusion protein, suggesting that Pds1 is also required to promote Esp1 spindle binding. In agreement, Pds1 interacts with the spindle at the metaphase-anaphase transition and a fraction remains at the spindle pole bodies and the spindle midzone in anaphase cells. Finally, mutational analysis reveals that the conserved COOH-terminal region of Esp1 is important for spindle interaction.


Effect of Gravity on Periapical Extrusion of Irrigating Solution With Different Irrigation Protocols in Immature Anterior Teeth.
Periapical extrusion is frequently observed during endodontic therapy. It can lead to acute injury of periapical tissues, resulting in interappointment pain or swelling. The effect is pronounced in teeth with immature teeth which are more susceptible to the extrusion of irrigant. The aim of this study was to evaluate the effect of gravity on apical extrusion of irrigating solution with different irrigation protocols in immature anterior teeth. An extracted maxillary central incisor was modified to simulate an open apex with an apical diameter of 1.3 mm and parallel canal walls. The tooth was subjected to a cone-beam computed tomographic scan, and the image data set was utilized to prepare 30 resin tooth models with a 3D printer. These resin teeth were used to form an open-ended Myers and Montgomery extrusion models. These were then randomly divided into two groups to simulate their orientation in the jaw during endodontic therapy, i.e., group I (maxillary arch, n=15) models fixed at 45° inclined plane and group II (mandibular arch, n=15) models placed at a plane parallel to the floor. Five models from each group (n=5) were tested by three different irrigation protocols: positive pressure (PP) Irrigation, passive ultrasonic irrigation (PUI), and negative pressure (NP) irrigation. The extruded irrigating solution was collected in glass vials, and the volume was measured. The volume of extruded irrigating solution in groups I and II was compared using Mann-Whitney U-test. The median values for PP, PUI, and NP irrigation protocols were 0.6, 1, and 0 ml and 10, 10, and 0.5 ml for groups I and II, respectively. PP and PUI protocols were associated with significantly less extrusion in group I when compared to group II (P=0.004). There was no statistically significant difference in the volume of irrigating solution extruded in groups I and II (P=0.007) for NP irrigation protocol. Gravitation force has an influence on periapical extrusion of irrigant in immature permanent teeth irrespective of the irrigant system used. NP performed better when compared to PP or PUI irrigation protocol irrespective of the tooth orientation.


Hybrid cardiac imaging: SPECT/CT and PET/CT. A joint position statement by the European Association of Nuclear Medicine (EANM), the European Society of Cardiac Radiology (ESCR) and the European Council of Nuclear Cardiology (ECNC).
Improvements in software and hardware have enabled the integration of dual imaging modalities into hybrid systems, which allow combined acquisition of the different data sets. Integration of positron emission tomography (PET) and computed tomography (CT) scanners into PET/CT systems has shown improvement in the management of patients with cancer over stand-alone acquired CT and PET images. Hybrid cardiac imaging either with single photon emission computed tomography (SPECT) or PET combined with CT depicts cardiac and vascular anatomical abnormalities and their physiologic consequences in a single setting and appears to offer superior information compared with either stand-alone or side-by-side interpretation of the data sets in patients with known or suspected coronary artery disease (CAD). Hybrid systems are also advantageous for the patient because of the single short dual data acquisition. However, hybrid cardiac imaging has also generated controversy with regard to which patients should undergo such integrated examination for clinical effectiveness and minimization of costs and radiation dose, and if software-based fusion of images obtained separately would be a useful alternative. The European Association of Nuclear Medicine (EANM), the European Society of Cardiac Radiology (ESCR) and the European Council of Nuclear Cardiology (ECNC) in this paper want to present a position statement of the institutions on the current roles of SPECT/CT and PET/CT hybrid cardiac imaging in patients with known or suspected CAD.


Distinct retrieval and retention mechanisms are required for the quality control of endoplasmic reticulum protein folding.
Proteins destined for the secretory pathway must first fold and assemble in the lumen of endoplasmic reticulum (ER). The pathway maintains a quality control mechanism to assure that aberrantly processed proteins are not delivered to their sites of function. As part of this mechanism, misfolded proteins are returned to the cytosol via the ER protein translocation pore where they are ubiquitinated and degraded by the 26S proteasome. Previously, little was known regarding the recognition and targeting of proteins before degradation. By tracking the fate of several mutant proteins subject to quality control, we demonstrate the existence of two distinct sorting mechanisms. In the ER, substrates are either sorted for retention in the ER or are transported to the Golgi apparatus via COPII-coated vesicles. Proteins transported to the Golgi are retrieved to the ER via the retrograde transport system. Ultimately, both retained and retrieved proteins converge at a common machinery at the ER for degradation. Furthermore, we report the identification of a gene playing a novel role specific to the retrieval pathway. The gene, BST1, is required for the transport of misfolded proteins to the Golgi, although dispensable for the transport of many normal cargo proteins.


Innate lymphoid cells regulate intestinal epithelial cell glycosylation.
Fucosylation of intestinal epithelial cells, catalyzed by fucosyltransferase 2 (Fut2), is a major glycosylation mechanism of host-microbiota symbiosis. Commensal bacteria induce epithelial fucosylation, and epithelial fucose is used as a dietary carbohydrate by many of these bacteria. However, the molecular and cellular mechanisms that regulate the induction of epithelial fucosylation are unknown. Here, we show that type 3 innate lymphoid cells (ILC3) induced intestinal epithelial Fut2 expression and fucosylation in mice. This induction required the cytokines interleukin-22 and lymphotoxin in a commensal bacteria-dependent and -independent manner, respectively. Disruption of intestinal fucosylation led to increased susceptibility to infection by Salmonella typhimurium. Our data reveal a role for ILC3 in shaping the gut microenvironment through the regulation of epithelial glycosylation.


Transcriptional profiling of Arabidopsis root hairs and pollen defines an apical cell growth signature.
Current views on the control of cell development are anchored on the notion that phenotypes are defined by networks of transcriptional activity. The large amounts of information brought about by transcriptomics should allow the definition of these networks through the analysis of cell-specific transcriptional signatures. Here we test this principle by applying an analogue to comparative anatomy at the cellular level, searching for conserved transcriptional signatures, or conserved small gene-regulatory networks (GRNs) on root hairs (RH) and pollen tubes (PT), two filamentous apical growing cells that are a striking example of conservation of structure and function in plants. We developed a new method for isolation of growing and mature root hair cells, analysed their transcriptome by microarray analysis, and further compared it with pollen and other single cell transcriptomics data. Principal component analysis shows a statistical relation between the datasets of RHs and PTs which is suggestive of a common transcriptional profile pattern for the apical growing cells in a plant, with overlapping profiles and clear similarities at the level of small GTPases, vesicle-mediated transport and various specific metabolic responses. Furthermore, cis-regulatory element analysis of co-regulated genes between RHs and PTs revealed conserved binding sequences that are likely required for the expression of genes comprising the apical signature. This included a significant occurrence of motifs associated to a defined transcriptional response upon anaerobiosis. Our results suggest that maintaining apical growth mechanisms synchronized with energy yielding might require a combinatorial network of transcriptional regulation. We propose that this study should constitute the foundation for further genetic and physiological dissection of the mechanisms underlying apical growth of plant cells.


The Relationship Between Insurance Coverage and Use of Prescription Contraception by Race and Ethnicity: Lessons From the Affordable Care Act.
We describe contraception use by race and ethnicity before and after the Affordable Care Act (ACA) and assess the relationship between insurance coverage and prescription contraception use in both periods. Using data for women ages 15 to 45 at risk of unintended pregnancy from the 2006-2010 and 2015-2017 National Surveys of Family Growth, we examined changes in patterns of contraception use over time by race and ethnicity. We also examined changes in insurance coverage over the same period and considered how the relationship between insurance coverage and prescription contraception use has changed over time within each racial and ethnic group using both descriptive and multivariate regression methods. Before the ACA, Black and Hispanic women were less likely than White women to use prescription contraception by 13.2 and 9.9 percentage points, respectively. After the ACA Medicaid and Marketplace coverage expansions, all groups experienced a decrease in uninsurance, but only Black women experienced a significant increase in prescription contraception use. As a result, the post-ACA Black-White difference in prescription contraception use narrowed to 3.9 percentage points, and the Hispanic-White gap remained unchanged. Our results suggest that, despite significant declines in uninsurance under the ACA, there was no increase in use of prescription contraception for White or Hispanic women. Moreover, the decrease in uninsurance among Black women did not fully explain the large increase in use of prescription contraception for this population.


Albumin modulation of capillary permeability: role of endothelial cell [Ca2+]i.
Albumin is required in vascular perfusates to maintain the normal permeability of microvessel walls. The most common mechanism proposed for action of albumin involves binding to the endothelial cell surface to increase the resistance to water and solute flows through hydraulic pathways across the capillary wall. The results of the present experiments do not conform to this simple adsorption model. Ringer perfusion increased the hydraulic conductivity (Lp) of the wall of single perfused frog mesenteric microvessels by 4.0 +/- 0.5-fold. The increase in Lp was associated with an increase of cytoplasmic calcium concentration ([Ca2+]i) from 59 +/- 5 nM when albumin was in the perfusate to a transient peak of 181 +/- 13 nM, 1-2 min after Ringer perfusion. [Ca2+]i then fell back to close to 100 nM. Processes that reduced Ca2+ influx into endothelial cells (removal of extracellular Ca2+, membrane depolarization) reduced Ca2+ influx and attenuated the increase in [Ca2+]i. The same processes abolished the increase in Lp after Ringer perfusion and restored Lp to close to control values during Ringer perfusion. Thus Ca2+ entry into endothelial cells is required to initiate and maintain the increased permeability during Ringer perfusion.


Curcumin inhibits tyrosine kinase activity of p185neu and also depletes p185neu.
Curcumin, a natural compound present in turmeric, possessing both anti-inflammatory and antioxidant effects, has been studied vigorously as a chemopreventative in several cancer models. The erbB2/neu gene-encoded p185neu tyrosine kinase is a potent oncoprotein. Overexpression of p185neu in breast cancer is known to be a poor prognostic factor. We investigated the effect of curcumin on p185neu tyrosine kinase and on the growth of breast cancer cell lines. Curcumin dose-dependently inhibited p185neu autophosphorylation and transphosphorylation in vitro and depleted p185neu protein in vivo. It dissociated the binding of p185neu with GRP94 (glucose-regulated protein), a molecular chaperone, and enhanced the depletion of p185neu. The amount of p185neu protein on the cell membrane was drastically decreased after curcumin treatment. These data demonstrated a new mechanism of the anti-tyrosine kinase activity of curcumin. The growth of several breast cancer cell lines was inhibited; the IC50 ranged from 7 to 18 microM, which, however, did not correlate with the expression level of p185neu. Colony formation in the soft agar assay, a hallmark of the transformation phenotype, was preferentially suppressed in p185neu-overexpressing cell lines by 5 microM curcumin (% of control, basal level versus overexpression: 59.3 versus 16.7%; P < 0.001 by Student's t test). Because curcumin effectively inhibited p185neu tyrosine kinase activity by depleting p185neu and potently suppressed the growth of multiple breast cancer cell lines, its therapeutic potential in advanced breast cancer is worthy of further investigation.


Role of acupuncture in the management of diabetic painful neuropathy (DPN): a pilot RCT.
To examine the role of acupuncture in the treatment of diabetic painful neuropathy (DPN) using a single-blind, placebo-controlled RCT and to collect data that would be required in a future definitive study of the efficacy of acupuncture in DPN. 45 patients were allocated to receive a 10-week course either of real (53%) or sham (47%) acupuncture. Five standardised acupuncture points on the lower limb of each leg were used in the study: LR3, KI3, SP6, SP10 and ST36. Outcome measures included the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale, lower limb pain (Visual Analogue Scale, VAS); Sleep Problem Scale (SPS); Measure Yourself Medical Outcome Profile (MYMOP); 36-item Short Form 36 Health Survey and resting blood pressure (BP). Over the 10-week treatment period, small improvements were seen in VAS -15 (-26 to -3.5), MYMOP -0.89 (-1.4 to -0.3), SPS -2.5 (-4.2 to -0.82) and resting diastolic BP -5.2 (-10.4 to -0.14) in the true acupuncture group. In contrast, there was little change in those receiving sham acupuncture. A moderate treatment effect in favour of active acupuncture was detected in MYMOP scores -0.66 (-0.96 to -0.35) but non-significant effect sizes in LANSS Pain Scale -0.37 (-2.2 to 1.4), resting diastolic BP -0.50 (-3.0 to 1.99) and the SPS -0.51 (-2.2 to 1.16). We have demonstrated the practicality and feasibility of acupuncture as an additional treatment for people with DPN. The treatment was well tolerated with no appreciable side effects. Larger randomised trials are needed to confirm the clinical and cost-effectiveness of acupuncture in the treatment of DPN. ISRCTN number: 39740785.


Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis - United States.
Tickborne rickettsial diseases continue to cause severe illness and death in otherwise healthy adults and children, despite the availability of low-cost, effective antibacterial therapy. Recognition early in the clinical course is critical because this is the period when antibacterial therapy is most effective. Early signs and symptoms of these illnesses are nonspecific or mimic other illnesses, which can make diagnosis challenging. Previously undescribed tickborne rickettsial diseases continue to be recognized, and since 2004, three additional agents have been described as causes of human disease in the United States: Rickettsia parkeri, Ehrlichia muris-like agent, and Rickettsia species 364D. This report updates the 2006 CDC recommendations on the diagnosis and management of tickborne rickettsial diseases in the United States and includes information on the practical aspects of epidemiology, clinical assessment, treatment, laboratory diagnosis, and prevention of tickborne rickettsial diseases. The CDC Rickettsial Zoonoses Branch, in consultation with external clinical and academic specialists and public health professionals, developed this report to assist health care providers and public health professionals to 1) recognize key epidemiologic features and clinical manifestations of tickborne rickettsial diseases, 2) recognize that doxycycline is the treatment of choice for suspected tickborne rickettsial diseases in adults and children, 3) understand that early empiric antibacterial therapy can prevent severe disease and death, 4) request the appropriate confirmatory diagnostic tests and understand their usefulness and limitations, and 5) report probable and confirmed cases of tickborne rickettsial diseases to public health authorities.


Triangular relationship between sleep spindle activity, general cognitive ability and the efficiency of declarative learning.
EEG sleep spindle activity (SpA) during non-rapid eye movement (NREM) sleep has been reported to be associated with measures of intelligence and overnight performance improvements. The reticular nucleus of the thalamus is generating sleep spindles in interaction with thalamocortical connections. The same system enables efficient encoding and processing during wakefulness. Thus, we examined if the triangular relationship between SpA, measures of intelligence and declarative learning reflect the efficiency of the thalamocortical system. As expected, SpA was associated with general cognitive ability, e.g. information processing speed. SpA was also associated with learning efficiency, however, not with overnight performance improvement in a declarative memory task. SpA might therefore reflect the efficiency of the thalamocortical network and can be seen as a marker for learning during encoding in wakefulness, i.e. learning efficiency.


Postoperative imaging in femoroacetabular impingement.
Femoroacetabular impingement (FAI) has been recognized as a common cause of pain, limited range of motion, and development of early osteoarthritis of the hip in adolescents and adults. Current surgical approaches include femoral osteochondroplasty, acetabular rim resection, and reattachment of torn labrum as either open surgical or arthroscopic techniques as well as periacetabular osteotomy. Conventional radiographs are routinely obtained in the postoperative setting. In addition, MRI serves for work-up in patients with persistent or recurrent groin pain after surgery. Inappropriate correction of the underlying femoral or acetabular osseous abnormality, insufficiency fractures of the femoral neck due to bone resection, intra-articular adhesions, ongoing joint degeneration including advanced cartilage damage, iatrogenic cartilage injury, retear of the labrum, rarely avascular necrosis of the femoral head, defects of the hip joint capsule, or heterotopic ossification might be observed after surgery for FAI.


Enhanced induction of anti-tumor CTLs in vitro by a lentivirus-transduced dendritic cell vaccine expressing secondary lymphoid tissue chemokine and mucin 1.
Dendritic cell (DC)-based cancer immunotherapy requires an immunogenic tumor associated antigen (TAA) and an effective strategy for its presentation to lymphocytes. Here, we explored whether transduction of DCs with lentiviruses (LVs) expressing a fusion protein of secondary lymphoid tissue chemokine (SLC) and mucin 1 (MUC1) could stimulate antigen-specific cytotoxic T cells (CTLs) to human cancer cells in vitro. HLA-A2+ peripheral blood monocyte-derived DCs were transduced with recombinant lentiviruses LV at different multiplicities of infection (MOI), and MUC1, SLC or SLC-MUC1 mRNA and protein were detected by RT-PCR and Western blotting, respectively. Transduction efficiencies and phenotypes of DCs were evaluated by flow cytometry. Induction of T lymphocyte proliferation by DCs was examined with a Cell Count Kit-8 (CCK-8). CTL activities against tumor cells were analyzed by lactate dehydrogenase (LDH) cytotoxicity and enzyme-linked immunospot (ELISPOT) assays. Stable expression of MUC1, SLC and SLC-MUC1 was obtained in DCs transduced with recombinant LVs, and the transduction efficiencies were dose-dependent. Transduction with LVs did not appreciably change the DC phenotype. CTL induced by LV MUC1 DCs potently and specifically lysed the HLA-A2+, MUC1+colon cancer cell line HCT-116. Moreover, this cytolytic activity against HCT-116 was enhanced with CTL stimulated by LV SLC-MUC1 DCs. DCs transduced with MUC1 could induce effective cytolytic activity against tumor cells in an antigen-specific and HLA-restricted fashion in vitro, and SLC promoted MUC1-specific anti-tumor activity. The transduction of DCs with LV SLC- MUC1 may be a promising strategy in DC-based cancer immunotherapy.