Benefits of dual chamber pacing in sick sinus syndrome.
The effects of DDD (fully automatic) and VVI (ventricular demand) pacing modes on exercise tolerance, symptom diary cards, and Holter monitoring were investigated in a randomised double blind crossover study of 16 patients who had had DDD pacemakers implanted because of frequent syncope. Eight patients presented with sick sinus syndrome and, with one exception, retrograde atrioventricular conduction and eight age and sex matched patients presented with 2:1 or complete atrioventricular block. Maximal symptom limited exercise in those with atrioventricular block was significantly higher after one month of DDD pacing than after VVI pacing. In those with sick sinus syndrome, however, maximal effort tolerance was not significantly different for the two pacing modes. In all but one patient with sick sinus syndrome sinus rhythm developed during exercise in VVI pacing. For both VVI and DDD modes maximal atrial rates were significantly lower in those with sick sinus syndrome. Palpitation and general wellbeing were significantly improved during DDD pacing in the eight patients with sick sinus syndrome. Shortness of breath was improved by DDD pacing in the eight patients with atrioventricular block but not in those with sick sinus syndrome. Holter monitoring showed that sick sinus syndrome patients remained in paced rhythm, either DDD or VVI, for most of the 24 hour period. DDD pacing was better than VVI pacing in sick sinus syndrome with retrograde atrioventricular conduction. Despite their ability to show sinus rhythm and inhibit their pacemakers on exercise patients with sick sinus syndrome are just as likely to have symptomatic benefit from DDD pacing as patients with atrioventricular block.


Preparing a neuropediatric upper limb exergame rehabilitation system for home-use: a feasibility study.
Home-based, computer-enhanced therapy of hand and arm function can complement conventional interventions and increase the amount and intensity of training, without interfering too much with family routines. The objective of the present study was to investigate the feasibility and usability of the new portable version of the YouGrabber® system (YouRehab AG, Zurich, Switzerland) in the home setting. Fifteen families of children (7 girls, mean age: 11.3y) with neuromotor disorders and affected upper limbs participated. They received instructions and took the system home to train for 2 weeks. After returning it, they answered questions about usability, motivation, and their general opinion of the system (Visual Analogue Scale; 0 indicating worst score, 100 indicating best score; ≤30 not satisfied, 31-69 average, ≥70 satisfied). Furthermore, total pure playtime and number of training sessions were quantified. To prove the usability of the system, number and sort of support requests were logged. The usability of the system was considered average to satisfying (mean 60.1-93.1). The lowest score was given for the occurrence of technical errors. Parents had to motivate their children to start (mean 66.5) and continue (mean 68.5) with the training. But in general, parents estimated the therapeutic benefit as high (mean 73.1) and the whole system as very good (mean 87.4). Children played on average 7 times during the 2 weeks; total pure playtime was 185 ± 45 min. Especially at the beginning of the trial, systems were very error-prone. Fortunately, we, or the company, solved most problems before the patients took the systems home. Nevertheless, 10 of 15 families contacted us at least once because of technical problems. Despite that the YouGrabber® is a promising and highly accepted training tool for home-use, currently, it is still error-prone, and the requested support exceeds the support that can be provided by clinical therapists. A technically more robust system, combined with additional attractive games, likely results in higher patient motivation and better compliance. This would reduce the need for parents to motivate their children extrinsically and allow for clinical trials to investigate the effectiveness of the system. ClinicalTrials.gov NCT02368223.


OARSI/OMERACT initiative to define states of severity and indication for joint replacement in hip and knee osteoarthritis. An OMERACT 10 Special Interest Group.
To define pain and physical function cutpoints that would, coupled with structural severity, define a surrogate measure of "need for joint replacement surgery," for use as an outcome measure for potential structure-modifying interventions for osteoarthritis (OA). New scores were developed for pain and physical function in knee and hip OA. A cross-sectional international study in 1909 patients was conducted to define data-driven cutpoints corresponding to the orthopedic surgeons' indication for joint replacement. A post hoc analysis of 8 randomized clinical trials (1379 patients) evaluated the prevalence and validity of cutpoints, among patients with symptomatic hip/knee OA. In the international cross-sectional study, there was substantial overlap in symptom levels between patients with and patients without indication for joint replacement; indeed, it was not possible to determine cutpoints for pain and function defining this indication. The post hoc analysis of trial data showed that the prevalence of cases that combined radiological progression, high level of pain, and high degree of function impairment was low (2%-12%). The most discriminatory cutpoint to define an indication for joint replacement was found to be [pain (0-100) + physical function (0-100) > 80]. These results do not support a specific level of pain or function that defines an indication for joint replacement. However, a tentative cutpoint for pain and physical function levels is proposed for further evaluation. Potentially, this symptom level, coupled with radiographic progression, could be used to define "nonresponders" to disease-modifying drugs in OA clinical trials.


The incidence of coronary anomalies on routine coronary computed tomography scans.
This study aimed to assess the incidence of coronary anomalies using 64-multi-slice coronary computed tomography (MSCT). The diagnostic MSCT scans of 745 consecutive patients were reviewed. The incidence of coronary anomalies was 4.96%. The detected coronary anomalies included the conus artery originating separately from the right coronary sinus (RCS) (n = 8, 1.07%), absence of the left main artery (n = 7, 0.93%), a superior right coronary artery (RCA) (n = 7, 0.93%), the circumflex artery (CFX) arising from the RCS (n = 4, 0.53%), the CFX originating from the RCA (n = 2, 0.26%), a posterior RCA (n = 1, 0.13%), a coronary fistula from the left anterior descending artery and RCA to the pulmonary artery (n = 1, 0.13%), and a coronary aneurysm (n = 1, 0.13%). This study indicated that MSCT can be used to detect common coronary anomalies, and shows it has the potential to aid cardiologists and cardiac surgeons by revealing the origin and course of the coronary vessels.


The role of correlations in direction and contrast coding in the primary visual cortex.
The spiking activity of nearby cortical neurons is not independent. Numerous studies have explored the importance of this correlated responsivity for visual coding and perception, often by comparing the information conveyed by pairs of simultaneously recorded neurons with the sum of information provided by the respective individual cells. Pairwise responses typically provide slightly more information so that encoding is weakly synergistic. The simple comparison between pairwise and summed individual responses conflates several forms of correlation, however, making it impossible to judge the relative importance of synchronous spiking, basic tuning properties, and stimulus-independent and stimulus-dependent correlation. We have applied an information theoretic approach to this question, using the responses of pairs of neurons to drifting sinusoidal gratings of different directions and contrasts that have been recorded in the primary visual cortex of anesthetized macaque monkeys. Our approach allows us to break down the information provided by pairs of neurons into a number of components. This analysis reveals that, although synchrony is prevalent and informative, the additional information it provides frequently is offset by the redundancy arising from the similar tuning properties of the two cells. Thus coding is approximately independent with weak synergy or redundancy arising, depending on the similarity in tuning and the temporal precision of the analysis. We suggest that this would allow cortical circuits to enjoy the stability provided by having similarly tuned neurons without suffering the penalty of redundancy, because the associated information transmission deficit is compensated for by stimulus-dependent synchrony.


Long-term responses of women to indole-3-carbinol or a high fiber diet.
We test the hypothesis that the estrogen metabolite ratio 2-OH-estrone:estriol can be raised via dietary indole-3-carbinol (I3C) and that this higher ratio can be sustained over a 3-month test period. We also explore the possible role of pure fiber on estradiol metabolism. Using a randomized clinical trial with three arms, each containing 20 subjects, arm 1 received 400 mg/day of I3C daily for 3 months, arm 2 received 20 g of alpha-cellulose daily for the same time period as a source of added fiber, and arm 3 received a placebo dose. Blood levels of a variety of biochemical parameters were measured. The urinary 2-OH-estrone:estriol estrogen metabolite ratio was measured monthly at the same time of the menstrual cycle. While no changes were observed in the control and alpha-cellulose-treated arms, a substantial mean increase in the ratio was observed in the I3C-treated arm at month 1; that increase was maintained over the 3-month time period. Three of the 20 subjects in this I3C-treated group differed from the others in that no significant change in the metabolite ratio was observed at any time point. The results suggest that I3C can serve to increase the 2-OH-estrone:estriol metabolite ratio in a sustained manner without detectable side effects and that some individuals may be resistant to such change.


Quantum Dot Infrared Photodetectors: Photoresponse Enhancement Due to Potential Barriers.
Potential barriers around quantum dots (QDs) play a key role in kinetics of photoelectrons. These barriers are always created, when electrons from dopants outside QDs fill the dots. Potential barriers suppress the capture processes of photoelectrons and increase the photoresponse. To directly investigate the effect of potential barriers on photoelectron kinetics, we fabricated several QD structures with different positions of dopants and various levels of doping. The potential barriers as a function of doping and dopant positions have been determined using nextnano(3) software. We experimentally investigated the photoresponse to IR radiation as a function of the radiation frequency and voltage bias. We also measured the dark current in these QD structures. Our investigations show that the photoresponse increases ~30 times as the height of potential barriers changes from 30 to 130 meV.


Targeting low HDL-cholesterol to decrease residual cardiovascular risk in the managed care setting.
Most clinicians recognize the importance of reducing low-density lipoprotein cholesterol (LDL-C) and, therefore, address this therapeutic need to decrease cardiovascular disease risk. In addition to the critical role that LDL-C plays, recent studies have shown the contribution of other lipid fractions, such as high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG), to overall cardiovascular health. Managed care initiatives to reduce cardiovascular risk typically focus on highly effective statin therapies, which are primarily LDL-C-lowering agents and have lesser TG-lowering and HDL-C-raising effects. However, clinical and epidemiologic data illustrate the need to expand the scope of therapies to reduce the residual cardiovascular risk associated with low HDL-C levels and elevated TG levels, even when LDL-C is managed successfully. To address the value of treating beyond LDL-C level to improve patient health outcomes and reduce health care-related costs. Several large trials and meta-analyses have investigated the effects of lipid-lowering statin therapy and have consistently demonstrated that statin therapy significantly reduces LDL-C levels and incidence of cardiovascular events. In spite of the efficacy of statin therapy in these studies, statins did not eliminate cardiovascular risk. Rather, significant residual cardiovascular risk remains after treatment with statins, especially in high-risk patients such as those with diabetes. Residual cardiovascular risk stems, at least partially, from low HDL-C and elevated TG. Low HDL-C levels have been identified as a significant, independent predictor of cardiovascular risk, and increases in HDL-C are associated with reductions in cardiovascular events. High TG levels are a significant risk factor for cardiovascular disease and are a marker for atherogenic remnant lipo-proteins, such as very low-density lipoprotein cholesterol (VLDL-C). Additionally, with elevated TG levels, a combination of LDL-C with VLDL-C in the measure of non-HDL-C may be a better predictor of cardiovascular risk than LDL-C alone. Recent national treatment guidelines suggest that combination therapy may be necessary to address multiple lipid targets (i.e., LDL-C, non-HDL-C, HDL-C, and TG); adding niacin or a fibrate to a statin is a therapeutic option that should be considered. As monotherapy agents, fibrates and niacin have been demonstrated to alter several lipid parameters and reduce cardiovascular events. Niacin appears to exert the greatest beneficial effects on the widest range of lipoprotein abnormalities, in addition to possessing an established safety profile. Moreover, niacin/statin combination therapy may provide greater benefits, as manifested through a correction of atherogenic lipid abnormalities, a slowing of atherosclerosis progression in coronary heart disease (CHD) patients, and a reduction of residual cardiovascular risk. Pharmacoeconomic modeling studies have been used to describe the potential effects on both cardiovascular events and health care costs by the achievement of, or failure to achieve, combined optimal lipid values (OLVs). Achievement of OLVs is predicted to be associated with a reduced risk of cardiovascular events, in which greater magnitudes of risk reduction accompany the achievement of a greater number of lipid goals. Based on patient baseline lipid values and product labeling information, mathematical models estimate that OLVs are achieved more frequently with extended-release niacin (niacin ER)/simvastatin combination therapy than with other high-potency agents. These modeling estimates were maintained in different patient groups, including those with diabetes or the metabolic syndrome. Finally, these modeling studies estimated that a fixed-dose niacin ER/simvastatin combination therapy would reduce direct medical costs of CHD events more effectively than would high-dose simvastatin monotherapy. Statins are highly effective for lowering LDL-C levels and, consequently, cardiovascular event rates. However, statins do not eliminate cardiovascular risk. Even in the presence of tightly controlled LDL-C levels, evidence indicates that high TG and low HDL-C levels are independent cardiovascular risk factors. Treating lipid parameters beyond LDL-C may require the addition of niacin or a fibrate to statin therapy. Niacin is the most effective agent for raising HDL-C levels, and pharmacoeconomic modeling suggests that niacin ER/statin combination therapy may promote the cost-effective achievement of OLVs in several at-risk patient populations.


Adding in vivo quantitative 1H MR spectroscopy to improve diagnostic accuracy of breast MR imaging: preliminary results of observer performance study at 4.0 T.
To determine whether the addition of in vivo quantitative hydrogen 1 (1H) magnetic resonance (MR) spectroscopy can improve the radiologist's diagnostic accuracy in interpreting breast MR images to distinguish benign from malignant lesions. The study was approved by the institutional review board and, where appropriate, was compliant with the Health Insurance Portability and Accountability Act. All patients provided written informed consent. Fifty-five breast MR imaging cases-one lesion each in 55 patients aged 24-66 years with biopsy-confirmed findings-were retrospectively evaluated by four radiologists. Patients were examined with contrast material-enhanced fat-suppressed T1-weighted 4.0-T MR imaging. The concentration of total choline-containing compounds (tCho) was quantified by using single-voxel 1H MR spectroscopy. For each case, the radiologists were asked to give the percentage probability of malignancy, the Breast Imaging and Reporting Data System category, and a recommendation for patient treatment. Two interpretations were performed for each case: The initial interpretation was based on the lesion's morphologic features and time-signal intensity curve, and the second interpretation was based on the lesion's morphologic features, time-signal intensity curve, and tCho concentration. Receiver operating characteristic (ROC), Wilcoxon signed rank, kappa statistic, and accuracy (based on the area under the ROC curve) analyses were performed. Of the 55 lesions evaluated, 35 were invasive carcinomas and 20 were benign. The addition of 1H MR spectroscopy resulted in higher sensitivity, specificity, accuracy, and interobserver agreement for all four radiologists. More specifically, two of the four radiologists achieved a significant improvement in sensitivity (P=.03, P=.03), and all four radiologists achieved a significant improvement in accuracy (P = .01, P = .05, P = .009, P < .001). Current study results suggest that the addition of quantitative 1H MR spectroscopy to the breast MR imaging examination may help to improve the radiologist's ability to distinguish benign from malignant breast lesions.


Clinical Guidelines for Management of Bone Health in Rett Syndrome Based on Expert Consensus and Available Evidence.
We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians. An initial guidelines draft was created which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions. Agreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended. A clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.


Resuscitation regimens for hemorrhagic shock must contain blood.
Endothelial cell dysfunction occurs during hemorrhagic shock (HS) and persists despite adequate resuscitation (RES) that restores and maintains hemodynamics. We hypothesize that RES from HS with crystalloid solutions alone aggravate the endothelial cell dysfunction. To test this hypothesis, anesthetized nonheparinized rats were monitored for hemodynamics, and the terminal ileum was studied with intravital video microscopy. HS was 50% of mean arterial pressure (MAP) for 60 min. Four hemorrhaged groups (10 animals in each group) were randomized for RES: group I with shed blood returned + equal volume of normal saline (NS); group II with shed blood returned + 2x NS; group III with 2x NS only; and group IV with 4x NS only. Two hours post-RES, endothelial cell function was assessed with the endothelial-dependent agonist acetylcholine (ACh, 10(-9)-10(-4) M). Maximum arteriolar diameter was elicited by the endothelial-independent agonist sodium nitroprusside (NTP, 10(-4) M). HS caused a selective vasoconstriction associated with low blood flow in inflow A1 arterioles in all hemorrhaged groups. Post-RES vasoconstriction developed in A1 and premucosal arterioles (pA3 and dA3) In all hemorrhaged groups regardless of the RES regimen. However, A1 vasoconstriction and flow were significantly worst in the animals RES with NS alone (-43% and -75%, respectively) compared with those resuscitated with blood and NS (-27% and -57%). Impaired dilation response to ACh was noted in all hemorrhaged animals. However, a significant shift to the right of the dose-response curve (decreased sensitivity) was observed in the animals resuscitated with NS alone irrespective of the RES volume. These animals required at least two orders of magnitude greater ACh concentration to produce a 20% dilation response. For all vessel types, Group II had the best preservation of endothelial cell function. In conclusion, HS causes a selective vasoconstriction of A1 arterioles, which was not observed in A3 vessels. RES from HS results in progressive vasoconstriction in all intestinal arterioles irrespective of the RES regimen. Crystalloid RES after HS does not restore hemodynamics to baseline and is associated with a marked endothelial cell dysfunction. Blood-containing RES regimens preserve and maintain hemodynamics and are associated with the least microvascular dysfunction. Therefore, regimens for RES from HS must contain blood. Endothelial cell dysfunction is not the sole etiologic factor of post-RES microvascular impairment.


Is there a relation between Chlamydia infection and primary biliary cirrhosis?
Over the past two decades, a number of studies have failed to provide direct evidence of specific microbial chronic infection in primary biliary cirrhosis (PBC). However, a recent report suggests that there is a specific association of Chlamydia pneumoniae in patients with PBC and that C. pneumoniae or similar antigens might play a role in the pathogenesis of disease. To determine if Chlamydia infection is associated with PBC, we applied a combination of immunological and molecular approaches to investigate (a) the serological reactivity against two common Chlamydia human pathogens, C. pneumoniae and C. trachomatis, by immunoblotting, (b) the presence of Chlamydia in liver samples of patients with PBC and controls by PCR amplification of Chlamydia specific 16S rRNA and (c) the presence of Chlamydia proteins in liver samples of patients with PBC and controls by immunohistochemical staining. By immunoblotting, C. trachomatis and C. pneumoniae specific serological antibodies were found in 52/57 (91.2%) AMA positive PBC, 7/33 (21/2%) of AMA negative PBC, 1/25 (4%) PSC, 0/15 (0%) Sjorgen's syndrome and 0/20 (0%) systemic lupus erythematosus patients and 0/20 (0%) healthy volunteers at 1:200 sera dilution. PBC sera reacted to Chlamydia and E. coli lysates in western blots up to a maximum of 10(-4) dilution. However, PCR amplification of the Chlamydia specific 16S rRNA gene was negative in 25/25 PBC livers but positive in 1/4 PSC liver, 3/6 in other liver disease controls and 1/4 normal liver samples. While two commercially available specific monoclonal antibodies stained positive controls (Chlamydia infected HEp-2 cells) they failed to detect Chlamydia antigens in PBC livers. The detection of Chlamydia specific antibodies but not Chlamydia rRNA gene and Chlamydia antigens in PBC suggests that Chlamydia infection is not involved in PBC.


Cells of the synovium in rheumatoid arthritis. Osteoclasts.
Osteoclasts are multinucleated cells of hematopoietic origin and are the primary bone resorbing cells. Numerous osteoclasts are found within the synovial tissue at sites adjacent to bone, creating resorption pits and local bone destruction. They are equipped with specific enzymes and a proton pump that enable them to degrade bone matrix and solubilize calcium, respectively. The synovial tissue of inflamed joints has a particularly high potential to accumulate osteoclasts because it harbors monocytes/macrophages, which function as osteoclast precursors, as well as cells that provide the specific molecular signals that drive osteoclast formation. Osteoclasts thus represent a link between joint inflammation and structural damage since they resorb mineralized tissue adjacent to the joint and destroy the joint architecture.


Spatial variation in T1 of healthy human articular cartilage of the knee joint.
The longitudinal relaxation time T(1) of native cartilage is frequently assumed to be constant. To redress this, the spatial variation of T(1) in unenhanced healthy human knee cartilage in different compartments and cartilage layers was investigated. Knees of 25 volunteers were examined on a 1.5 T MRI system. A three-dimensional gradient-echo sequence with a variable flip angle, in combination with parallel imaging, was used for rapid T(1) mapping of the whole knee. Regions of interest (ROIs) were defined in five different cartilage segments (medial and lateral femoral cartilage, medial and lateral tibial cartilage and patellar cartilage). Pooled histograms and averaged profiles across the cartilage thickness were generated. The mean values were compared for global variance using the Kruskal-Wallis test and pairwise using the Mann-Whitney U-test. Mean T(1) decreased from 900-1100 ms in superficial cartilage to 400-500 ms in deep cartilage. The averaged T(1) value of the medial femoral cartilage was 702+/-68 ms, of the lateral femoral cartilage 630+/-75 ms, of the medial tibial cartilage 700+/-87 ms, of the lateral tibial cartilage 594+/-74 ms and of the patellar cartilage 666+/-78 ms. There were significant differences between the medial and lateral compartment (p<0.01). In each cartilage segment, T(1) decreased considerably from superficial to deep cartilage. Only small variations of T(1) between different cartilage segments were found but with a significant difference between the medial and lateral compartments.


Harvey Cushing's innovative attempt at xenotransplanting a rabbit spinal cord in a patient after resection of a peripheral nerve tumor in 1902.
A review of Harvey Cushing's surgical cases at Johns Hopkins Hospital revealed new information about his early work using nerve xenografts to repair peripheral nerve injuries. The Johns Hopkins Hospital surgical records from 1896 to 1912 were reviewed. A single case in which Cushing used a xenograft to repair a peripheral nerve defect was selected for further study. In August 1902, a 23-year-old woman presented with tingling and numbness in her left foot and focal tenderness in the popliteal region. Cushing performed an exploratory operation, revealing an encapsulated tumor originating from the internal popliteal nerve. After resecting the segment of involved nerve, Cushing harvested the spinal cord from a rabbit and used it to span the 18-cm defect. At a 5-month postoperative follow-up, according to Cushing's clinical notes, the patient had partially regained some sensation in her leg and foot. Seven months later, the patient presented with a local tumor recurrence, and her leg was amputated. An examination of the amputated specimen demonstrated that the xenograft was still intact without gross evidence of xenograft rejection. Despite its questionable functional success, we report a previously unpublished operative case by Harvey Cushing in which a rabbit spinal cord was transplanted into a human to bridge a sciatic nerve gap. This sheds light on the potential for animal tissue as a source for the treatment of neurological disease in humans.


Mechano-regulation of Peptide-MHC Class I Conformations Determines TCR Antigen Recognition.
TCRs recognize cognate pMHCs to initiate T cell signaling and adaptive immunity. Mechanical force strengthens TCR-pMHC interactions to elicit agonist-specific catch bonds to trigger TCR signaling, but the underlying dynamic structural mechanism is unclear. We combined steered molecular dynamics (SMD) simulation, single-molecule biophysical approaches, and functional assays to collectively demonstrate that mechanical force induces conformational changes in pMHCs to enhance pre-existing contacts and activates new interactions at the TCR-pMHC binding interface to resist bond dissociation under force, resulting in TCR-pMHC catch bonds and T cell activation. Intriguingly, cancer-associated somatic mutations in HLA-A2 that may restrict these conformational changes suppressed TCR-pMHC catch bonds. Structural analysis also indicated that HLA polymorphism might alter the equilibrium of these conformational changes. Our findings not only reveal critical roles of force-induced conformational changes in pMHCs for activating TCR-pMHC catch bonds but also have implications for T cell-based immunotherapy.


Radical cystectomy in the treatment of bladder cancer: oncological outcome and survival predictors.
To better understand the result of radical cystectomy in the treatment of bladder cancer, we analyzed our data and reported the oncological outcomes and survival predictors. Patients underwent radical cystectomy for bladder transitional cell carcinoma between March 1995 and July 2007 were evaluated. The clinical course, pathological characteristics, and clinical outcomes were described and analyzed. A total of 148 patients (98 men and 50 women) with a median age of 66.7 years (range: 23.8-83.3) were included in the study. Median follow-up was 64 months. The perioperative mortality was 2.7%. The 5-year recurrence-free survival (RFS) and overall survival (OS) for all 148 patients was 61% and 53%, respectively. The 5-year RFS and OS were 68% and 62% for pT2, 65% and 59% for pT3, 11% and 9% for pT4, and 37% and 31% for nodal-positive disease, respectively. The number of positive lymph nodes was significantly associated with survival: 5-year RFS and OS were 54% and 33%, for patients with only 1-3 positive lymph nodes, whereas, all patients with >or= 4 positive lymph nodes had recurrence. On multivariate analysis, age > 60 years, pT4 tumors, and lymph node involvement had a negative impact on survival. Radical cystectomy can be curative in a significant portion of patients with organ-confined (T2 or less) and extravesical (pT3) bladder cancer. Age > 60 years, pT4 tumors, and nodal metastases were associated with poor prognosis. Patients with limited lymph node involvement (1-3 nodes) can be cured by surgery alone, whereas a more extensive lymph node metastasis (>or= 4 nodes) eventually results in recurrence. Concomitant prostate cancer is of low grade and early stage, and is clinically insignificant.


Rehabilitation of severely atrophic maxillae with fixed implant-supported prostheses using zygomatic implants placed using the sinus slot technique: clinical report on a series of 21 patients.
The purpose of this article is to describe the management of patients with extreme maxillary atrophy. Their treatment consisted of maxillary fixed prostheses supported by conventional implants placed in residual anatomic structures in conjunction with zygomatic implants positioned using the sinus slot technique of Stella and Warner. A retrospective chart review was conducted of all patients who received zygomatic implants between January 2000 and January 2005. The preoperative evaluations included panoramic digital radiographs and computed tomographic scan to identify the anatomic structures and detect the presence of pathology. All intra- and postoperative complications were recorded. Screw-fixed restorations were placed 4 to 6 months after implant placement. After prosthetic restoration, all patients received a minimum of 12 months' follow-up. Twenty-one patients (11 women and 10 men) with severe maxillary atrophy underwent treatment with zygomatic implants placed using the sinus slot technique. Mean patient age was 54.1 years (range, 31 to 75 years). One patient presented with ectodermal dysplasia. A total of 89 conventional implants and 40 zygomatic implants were placed. During surgery, the sinus membrane was perforated in all cases; however, there were no significant postoperative complications. One patient presented with an ecchymosis. Two conventional implants failed; none of the 40 zygomatic implants failed. Mean follow-up after placement of the implants was 29 months, during which time the prostheses and implants remained stable and functional. Zygomatic implants, when positioned in conjunction with premaxillary implants, can facilitate the surgical rehabilitation of patients presenting with severe maxillary resorption, as an alternative to bone grafting.


Does methodology affect the ability to monitor tobacco control activities? implications for HEDIS and other performance measures.
It is unclear whether methodological differences in sample size, survey methods, and analysis approach significantly affect the ability to accurately monitor tobacco control activities and to make rate comparisons. Questionnaires were sent to 64,764 members of nine health plans in diverse settings soon after their visit to a primary care clinician. Of these 41,677 completed responses were received. We compared responses received by mail and by telephone follow-up for the percentage of smokers, characteristics of smokers, and their rates of reporting physician cessation counseling. Overall, 10.2% were current cigarette smokers, but the proportion was 8.6% for mail responders and 17.2% for phone follow-up responders. Smokers identified by phone follow-up were different from mail responders in most demographic and smoking characteristics and their reports of clinical smoking cessation activities differed for six of nine clinician smoking cessation actions. Calculating advice rates as a proportion of visits produced lower rates with more dispersion among plan rates than doing so without accounting for visit variation. Smoking surveys using only mailed questionnaires dramatically undersample smokers, especially in some demographic groups. Comparisons of tobacco counseling among health plans can be improved by ensuring an adequate sample size and response rate and by analyzing by frequency of quit advice.


Effects of low-level microwave irradiation on amphetamine hyperthermia are blockable by naloxone and classically conditionable.
In a series of experiments, we investigated the effects of pulsed low-level microwave irradiation on amphetamine-induced hyperthermia in the rat. Rats were irradiated in a 2,450-MHz cylindrical waveguide exposure system at 1 mW/cm2, 2 mus pulses, 500 pps, average SAR of 0.6 W/kg. Acute (45 min) exposure to microwaves attenuated amphetamine-induced hyperthermia. This effect was blocked by pretreatment of the animals with the narcotic antagonist naloxone. In another experiment, rats were subjected to ten daily sessions of microwave exposure (45 min/session). On day 11, amphetamine-induced hyperthermia was studied in the animals immediately after a session of either microwave or sham exposure. Similar to the acute effect, amphetamine-induced hyperthermia was attenuated in rats irradiated with microwaves (unconditioned effect). In the sham-irradiated animals we observed a potentiation of the amphetamine-induced hyperthermia, which was a conditioned effect of microwaves. Thus, the conditioned effect (potentiation) was opposite in direction to the unconditioned effect (attenuation). No tolerance developed to the unconditioned effect after subchronic exposure. Furthermore, both conditioned and unconditioned effects of microwaves on amphetamine-induced hyperthermia could be blocked by treatment with naloxone. These data suggest that microwave irradiation may activate endogenous opioids, which in turn alter the actions of psychoactive drugs, and the effect of microwaves on drug action can be classically conditioned.


Identification of seroreactive proteins in the culture filtrate antigen of Mycobacterium avium ssp. paratuberculosis human isolates to sera from Crohn's disease patients.
The etiology of Crohn's disease (CD) is unresolved, but it is likely that an interplay of host genetic factors and environmental triggers is relevant. Mycobacterium paratuberculosis (MAP) has been focused upon as one of these triggers because it causes a similar chronic inflammatory bowel disease in animals. However, the differences among MAP antigens isolated from humans (H-MAP) and cattle (B-MAP) have not been well characterized. In this study, culture filtrate (CF) proteins from MAP isolates were tested with sera from CD patients and healthy controls in enzyme-linked immunosorbent assay (ELISA). Antibody produced by seven CD patients reacted differently according to the antigen source: strong reactivity was seen to H-MAP CF, but not to B-MAP CF. Six proteins, ModD, PepA, transaldolase, EchA9, MAP2120c, and MAP2950c, in H-MAP CF reacting specifically with CD patient sera were identified by liquid chromatography-electrospray ionization-MS. Bioinformatic analysis revealed that ModD and PepA were the same proteins reacting with sera from cattle infected with MAP. The elevated antibody responses of CD patients to rModD and rPepA were confirmed by ELISA (P<0.001). These results support previous studies showing ModD and PepA as key antigens for the diagnosis of MAP infections. The study also identified additional proteins potentially useful in the design of assays for human MAP infections.


Study of optical phase transduction on localized surface plasmon resonance for ultrasensitive detection.
Localized surface plasmon resonance (LSPR) has shown its remarkable applications in biosensing, bioimaging, and nanophotonics. Unlike surface plasmon polariton (SPP), the current studies regarding LSPR as biosensor were restricted in probing the extinction spectra, and thus limit the performance in biosensing and bioimaging. Here, we reveal that optical phase of LSPR provides an acute change at resonance beyond extinction spectra, which permits an ultra-high sensitivity in phase interrogation. We found that optical phases of LSPR show two orders of magnitude higher sensing resolution than extinction spectra among the same nanostructures. For the first time, we demonstrated the feasibility of probing optical phase transduction in LSPR for biosensing, and the sensitivity is superior to not only the extinction spectra among the same metallic nanostructures, but also the LSPR sensors among the current literatures. In summary, the exploitation of LSPR by phase interrogation essentially complements the sensitivity insufficiency of LSPR, and provides new access to understanding and using the rich physics of LSPR.


A non-sense mutation in Cd36 gene is associated with protection from severe malaria.
We sought genetic evidence for the importance of host-parasite interactions involving CD36 in severe malaria. We identified a non-sense mutation in Cd36 gene and looked at the influence of this mutation on the outcome of malaria infection in 693 African children with severe malaria and a similar number of ethnically matched controls. We showed that heterozygosity for this mutation is associated with protection from severe disease (OR 0.74, 95% CI 0.55-0.99; p=0.036). These findings suggest that this Cd36 mutation might have a complex effect on malaria infection by decreasing parasite sequestration, and also by decreasing host immune responses.


Tea and human health: the dark shadows.
Tea is one of the most popularly consumed beverage. Depending on the manufacturing process, different varieties of tea can be produced. The antioxidative and antimutagenic potential of tea in cardiovascular diseases, cancer and obesity have long been studied. These therapeutic and nutritional benefits of tea can be attributed to the presence of flavanoids. However, these flavanoids also have certain detrimental effects on human health when their consumption exceeds certain limits. The toxicity of these flavanoids can be attributed to the formation of reactive oxygen species in the body which causes damage to the DNA, lipid membranes etc. The aim of this review is to summarize briefly, the less studied evidences of various forms of toxicity associated with tea and its harmful effects on human health.


Baclofen for alcohol withdrawal.
The treatment baclofen can rapidly reduce symptoms of severe alcohol withdrawal syndrome (AWS) in alcoholic patients, with a significant reduction in the cost. Baclofen is easy to manage, and rare euphoria, craving and other pleasant effects are reported by patients treated with baclofen. To assess the efficacy and safety of baclofen for patients with AWS. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (October 2012), MEDLINE (1966 to October 2012), EMBASE (1980 to October 2012) and CINAHL (1982 to October 2012). We also searched registers of ongoing trials, for example ClinicalTrials.gov, Controlled-trials.com, EUDRACT, etc. At the same time, we handsearched the references quoted in the identified trials, and contacted researchers, pharmaceutical companies and relevant trial authors seeking information about unpublished or uncompleted trials. All searches included the non-English language literature. All randomized controlled clinical trials (RCTs) evaluating baclofen versus placebo or any other treatment for patients with AWS. Uncontrolled, non-randomized or quasi-randomized trials were excluded. Both parallel group and cross-over design were included. Two review authors independently assessed references retrieved for possible inclusion. All disagreements were resolved by an independent party. Study authors were contacted for additional information. Adverse effects information was collected from the trials. We identified a total of 113 references from all electronic databases searched excluding duplicates. After screening of titles and abstracts, full papers of 10 studies were obtained and assessed for eligibility. Finally, two RCTs with 81 participants were eligible according to the inclusion criteria. Regarding the efficacy, one study suggested that both baclofen and diazepam significantly decreased the Clinical Institute Withdrawal Assessment of Alcohol Scale Revised (CIWA-Ar) score, without any significant difference between the two interventions. The other study showed no significant difference in CIWA-Ar score between baclofen and placebo but a significantly decreased dependence on high-dose benzodiazepines with baclofen compared to placebo. Meanwhile, only one study reported the safety outcomes and there were no side effects in either the baclofen or diazepam groups. The evidence for recommending baclofen for AWS is insufficient. More well designed RCTs are needed to prove its efficacy and safety.


Reducing HIV needle risk behaviors among injection-drug users in the Midwest: an evaluation of the efficacy of standard and enhanced interventions.
This study compares the impact of a standard and an enhanced intervention on the needle-use behaviors reported by injection-drug users (IDUs) living in a low-seroprevalence area in the Midwest. Data on the drug- and needle-use practices of 381 IDUs completing a standard (n = 232) or an enhanced (n = 149) intervention who were followed-up five to nine months after a baseline interview were analyzed using bivariate and multivariate techniques. The results indicate that IDUs who participated in the enhanced intervention reported safer needle practices than standard intervention IDUs at follow-up. In addition, less frequent injectors were much more likely to adopt safer needle-use practices than were daily drug injectors, regardless of intervention track. The results suggest that more intensive interventions have advantages over minimalist efforts--in specific contexts. This finding has important implications for the HIV needle risk-reduction efforts targeting IDUs.


[Ochratoxin A genotoxicity, relation to renal tumors].
Ochratoxin A (OTA) is a mycotoxin which has been implicated in Balkan Endemic Nephropathy (BEN), a disease characterized by tubulonephritis and may be involved in the high incidence of urinary tract tumors associated to BEN. The prevalence of human ochratoxicosis is being determined in Tunisia. 100% of people suffering from chronic interstitial nephropathy of unknown etiology were ochratoxin A positive. These nephropathies are similar to Balkan Endemic Nephropathy. We prove an OTA genotoxic effects in patient suffering from this kind of nephropathy. OTA-DNA adducts formation has been detected in DNA of kidney tissues (biopsy). DNA adducts which are covalent complex between OTA and DNA base (Guanine), constitute first steps of the carcinogenesis process.


A novel point mutation (C571T) in the tissue-non-specific alkaline phosphatase gene in a case of adult-type hypophosphatasia.
Hypophosphatasia (HOPS) is an inheritable disorder characterized by defective skeletal mineralization, deficiency of tissue-non-specific alkaline phosphatase (TNSALP) activity and premature loss of deciduous teeth. The gene for TNSALP is located on chromosome 1p34-36.1 and consists of 12 exons and 11 introns. In this study we analysed the genomic TNSALP gene from a patient with HOPS, her family, and unrelated normal controls. The proband was a 52-year-old Japanese woman with adult onset HOPS. The patient showed deficiency in alkaline phosphatase (ALP) activity, increased urinary excretion of phosphoethanolamine and severe periodontal disease. Genomic DNA was extracted from the peripheral leukocytes of the subjects. Based on published sequence data in the TNSALP gene, 11 pairs of polymerase chain reaction (PCR) primers were used to amplify the coding exons. The PCR amplified samples were subjected to PCR-single strand conformation polymorphism (SSCP) analysis and PCR-allele specific oligonucleotide (ASO) analysis. By PCR-SSCP analysis of the patient's genomic DNA, fragments containing exon 5 revealed abnormal mobility. This abnormal mobility (exon 5) was also found in the genomic DNA in her mother's sister, but were not detected in her father, brothers or sisters, and unrelated normal controls. Sequencing analysis of the abnormal band extracted from the SSCP gel revealed a C to T transition at nucleotide position 571 (C571T) in exon 5. This mutation resulted in a substitution of Ala-115 with a Val in the mature TNSALP polypeptide. PCR-ASO analysis also confirmed this missense point mutation. The result of this study showed that the pro-band has inherited the C571T mutation in exon 5 from her mother alone and the disease in this family was inherited as an autosomal dominant trait from the pedigree. The C571T mutation is a new missense point mutation and appears to cause significant changes in the structure and function of TNSALP because Ala-115 is highly conserved in rat TNSALP and human tissue-non-specific, intestinal and placental ALPs.


Structure and concentrating ability in the avian kidney.
We quantified various aspects of the morphology of the kidney in seven bird species and related these measures to urinary concentrating ability (the concentration of ureteral urine in dehydrated animals) for six of the species. Kidney mass, number of glomeruli, and number of medullary cones all tended to increase with body mass. Smaller birds, with smaller kidneys, had smaller nephrons with smaller glomeruli. Lengths of medullary cones tended to increase with body mass and were exceptionally long in the macaroni penguin. The proportion of nephrons that were mammalian-type (MT, with loops of Henle) ranged from 7% (ring-necked pheasant) to 30% (zebra finch, glaucous-winged gull) and was unrelated to kidney mass. The percent of kidney mass comprised of medullary cones varied from 5 to 13%, unrelated to kidney mass. The number of reptilian-type (without loops of Henle) nephrons associated with each medullary cone tended to increase with kidney mass. Of the variables examined, length of the medullary cones, and hence of the longest loops of Henle, was most strongly correlated with urinary concentrating ability; however, this correlation was negative. Concentrating ability was also strongly negatively correlated with body mass (small birds concentrate better). No significant relation existed between concentrating ability and proportion of MT nephrons. Our data suggest that, in a broad interspecific comparison, the quantitative extent of the renal medulla is not the primary determinant of urinary concentrating ability in birds.


Activated human monocytes inhibit the intracellular multiplication of Legionnaires' disease bacteria.
We have examined the interaction between virulent egg yolk-grown L. pneumophila, Philadelphia 1 strain, and in vitro-activated human monocytes, under antibiotic-free conditions. Freshly explanted human monocytes activated by incubation with concanavalin A (Con A) and human lymphocytes inhibited the intracellular multiplication of L. pneumophila. Both Con A and lymphocytes were required for activation. Con A was consistently maximally effective at greater than or equal to 4 mug/ml. Monocytes activated by incubation with cell-free filtered supernatant from Con A-sensitized mononuclear cell cultures also inhibited the intracellular multiplication of L. pneumophil a. The most potent supernatant was obtained from mononuclear cell cultures incubated with greater than or equal to 15 mug/ml Con A for 48 h. The degree of monocyte inhibition of L. pneumophila multiplication was proportional to the length of time monocytes were preincubated with supernatant (48 {greater than} 24 {greater than} 12 h) and to the concentration of supernatant added (40 percent {greater than} 20 percent {greater than} 10 percent {greater than} 5 percent). Monocytes treated with supernatant daily were more inhibitory than monocytes treated initially only. With time in culture, monocytes progressively lost a limited degree of spontaneous inhibitory capacity and also lost their capacity to respond to supernatant with inhibition of L. pneumophila multiplication. Supernatant-activated monocytes inhibited L. pneumophila multiplication in two ways. They phagocytosed fewer bacteria, and they slowed the rate of intracellular multiplication of bacteria that were internalized. As was the case with nonactivated monocytes, antibody had no effect on the rate of intracellular multiplication in supernatant-activated monocytes. Neither supernatant-activated nor nonactivated monocytes killed L. pneumophila in the absence of antibody. Both killed a limited proportion of these bacteria in the presence of antibody and complement. We have previously reported that anti-L, pneumophila antibody and complement neither promote effective killing of L. pneumophila by human polymorphonuclear leukocytes and monocytes nor inhibit the rate of L. pneumophila multiplication in monocytes. These findings and our present report that activated monocytes do inhibit L. pneumophila multiplication indicate that cell-mediated immunity plays a major role in host defense against Legionnaires' disease.


Isolation and characterization of kinetoplast DNA from bloodstream form of Trypanosoma brucei.
We have used restriction endonucleases PstI, EcoRI, HapII, HhaI, and S1 nuclease to demonstrate the presence of a large complex component, the maxi-circle, in addition to the major mini-circle component in kinetoplast DNA (kDNA) networks of Trypanosoma brucei (East African Trypanosomiasis Research Organization [EATRO] 427). Endonuclease PstI and S1 nuclease cut the maxi-circle at a single site, allowing its isolation in a linear form with a mol wt of 12.2 x 10(6), determined by electron microscopy. The other enzymes give multiple maxi-circle fragments, whose added mol wt is 12-13 x 10(6), determined by gel electrophoresis. The maxi-circle in another T. brucei isolate (EATRO 1125) yields similar fragments but appears to contain a deletion of about 0.7 x 10(6) daltons. Electron microscopy of kDNA shows the presence of DNA considerably longer than the mini-circle contour length (0.3 micron) either in the network or as loops extending from the edge. This long DNA never exceeds the maxi-circle length (6.3 microns) and is completely removed by digestion with endonuclease PstI. 5-10% of the networks are doublets with up to 40 loops of DNA clustered between the two halves of the mini-circle network and probably represent a division stage of the kDNA. Digestion with PstI selectively removes these loops without markedly altering the mini-circle network. We conclude that the long DNA in both single and double networks represents maxi-circles and that long tandemly repeated oligomers of mini-circles are (virtually) absent. kDNA from Trypanosoma equiperdum, a trypanosome species incapable of synthesizing a fully functional mitochondrion, contains single and double networks of dimensions similar to those from T. brucei but without any DNA longer than mini-circle contour length. We conclude that the maxi-circle of trypanosomes is the genetic equivalent of the mitochondrial DNA (mtDNA) of other organisms.


Flicker fusion thresholds as a clinical identifier of a magnocellular-deficit dyslexic subgroup.
The magnocellular-dorsal system is well isolated by high temporal frequency. However, temporal processing thresholds have seldom been explored in developmental dyslexia nor its subtypes. Hence, performances on two, four-alternative forced-choice achromatic flicker fusion threshold tasks modulated at low (5%) and high (75%) temporal contrast were compared in dyslexic and neurotypical children individually matched for age and intelligence (8-12 years, n = 54 per group). As expected, the higher modulation resulted in higher flicker fusion thresholds in both groups. Compared to neurotypicals, the dyslexic group displayed significantly lower ability to detect flicker at high temporal frequencies, both at low and high temporal contrast. Yet, discriminant analysis did not adequately distinguish the dyslexics from neurotypicals, on the basis of flicker thresholds alone. Rather, two distinct dyslexic subgroups were identified by cluster analysis - one characterised by significantly lower temporal frequency thresholds than neurotypicals (referred to as 'Magnocellular-Deficit' dyslexics; 53.7%), while the other group ('Magnocellular-Typical' dyslexics; 46.3%) had comparable thresholds to neurotypicals. The two dyslexic subgroups were not differentially associated with phonological or naming speed subtypes and showed comparable mean reading rate impairments. However, correlations between low modulation flicker fusion threshold and reading rate for the two subgroups were significantly different (p = .0009). Flicker fusion threshold performances also showed strong classification accuracy (79.3%) in dissociating the Magnocellular-Deficit dyslexics and neurotypicals. We propose that temporal visual processing impairments characterize a previously unidentified subgroup of dyslexia and suggest that measurement of flicker fusion thresholds could be used clinically to assist early diagnosis and appropriate treatment recommendations for dyslexia.


Dendritic cell vaccination for metastatic melanoma: a 14-year monoinstitutional experience.
Although immunomodulating antibodies are highly effective in metastatic melanoma, their toxicity, related to the activation of T lymphocytes, can be severe. Anticancer vaccines promote a fairly specific response and are very well tolerated, but their effectiveness has yet to be demonstrated. We have been treating patients with advanced melanoma with an autologous dendritic cell vaccine since 2001; to better characterize the safety and efficacy of our product, we designed a retrospective study on all of our patients treated with the vaccine to date. We retrospectively reviewed both case report forms of patients included in clinical trials and medical records of those treated within a compassionate use program. Response was assessed according to the Response Evaluation Criteria In Solid Tumors criteria and toxicity has been graded according to CTCAE 4.0. Although the response rate has been rather low, the median overall survival of 11.4 months and the 1-year survival rate of 46.9% are encouraging, especially considering the fact that data were obtained in a heavily pretreated population and only about one quarter of the patients had received ipilimumab and/or BRAF inhibitors. Multivariate analysis confirmed that the development of an immune response was significantly correlated with a better prognosis (hazard ratio 0.54; P=0.019). The adverse events observed were generally mild and self-limiting. Our analysis confirms the excellent tolerability of our vaccine, making it a potential candidate for combination therapies. As efficacy seems largely restricted to immunoresponsive patients, future strategies should aim to increase the number of these patients.


Surveillance of vector populations and malaria transmission during the 2009/10 El Niño event in the western Kenya highlands: opportunities for early detection of malaria hyper-transmission.
Vector control in the highlands of western Kenya has resulted in a significant reduction of malaria transmission and a change in the vectorial system. Climate variability as a result of events such as El Niño increases the highlands suitability for malaria transmission. Surveillance and monitoring is an important component of early transmission risk identification and management. However, below certain disease transmission thresholds, traditional tools for surveillance such as entomological inoculation rates may become insensitive. A rapid diagnostic kit comprising Plasmodium falciparum circumsporozoite surface protein and merozoite surface protein antibodies in humans was tested for early detection of transmission surges in the western Kenya highlands during an El Niño event (October 2009-February 2010). Indoor resting female adult malaria vectors were collected in western Kenya highlands in four selected villages categorized into two valley systems, the U-shaped (Iguhu and Emutete) and the V-shaped valleys (Marani and Fort Ternan) for eight months. Members of the Anopheles gambiae complex were identified by PCR. Blood samples were collected from children 6-15 years old and exposure to malaria was tested using a circum-sporozoite protein and merozoite surface protein immunchromatographic rapid diagnostic test kit. Sporozoite ELISA was conducted to detect circum-sporozoite protein, later used for estimation of entomological inoculation rates. Among the four villages studied, an upsurge in antibody levels was first observed in October 2009. Plasmodium falciparum sporozoites were then first observed in December 2009 at Iguhu village and February 2010 at Emutete. Despite the upsurge in Marani and Fort Ternan no sporozoites were detected throughout the eight month study period. The antibody-based assay had much earlier transmission detection ability than the sporozoite-based assay. The proportion of An. arabiensis among An. gambiae s.l. ranged from 2.9-66.7% indicating a rearrangement of the sibling species of the An. gambiae s.l complex. This is possibly an adaptation to insecticide interventions and climate change. The changing malaria transmission rates in the western Kenya highlands will lead to more unstable transmission, decreased immunity and a high vulnerability to epidemics unless surveillance tools are improved and effective vector control is sustained.


A Combination of Constitutive Damage Model and Artificial Neural Networks to Characterize the Mechanical Properties of the Healthy and Atherosclerotic Human Coronary Arteries.
It has been indicated that the content and structure of the elastin and collagen of the arterial wall can subject to a significant alteration due to the atherosclerosis. Consequently, a high tissue stiffness, stress, and even damage/rupture are triggered in the arterial wall. Although many studies so far have been conducted to quantify the mechanical properties of the coronary arteries, none of them consider the role of collagen damage of the healthy and atherosclerotic human coronary arterial walls. Recently, a fiber family-based constitutive equation was proposed to capture the anisotropic mechanical response of the healthy and atherosclerotic human coronary arteries via both the histostructural and uniaxial data. In this study, experimental mechanical measurements along with histological data of the healthy and atherosclerotic arterial walls were employed to determine the constitutive damage parameters and remodeling of the collagen fibers. To do this, the preconditioned arterial tissues were excised from human cadavers within 5-h postmortem, and the mean angle of their collagen fibers was precisely determined. Thereafter, a group of quasistatic axial and circumferential loadings were applied to the arterial walls, and the constrained nonlinear minimization method was employed to identify the arterial parameters according to the axial and circumferential extension data. The remodeling of the collagen fibers during the tensile test was also predicted via Artificial Neural Networks algorithm. Regardless of loading direction, the results presented a noteworthy load-bearing capability and stiffness of the atherosclerotic arteries compared to the healthy ones (P < 0.005). Theoretical fiber angles were found to be consistent with the experimental histological data with less than 2 and 5° difference for the healthy and atherosclerotic arterial walls, respectively. The pseudoelastic damage model data were also compared with that of the experimental data, and interestingly, the arterial mechanical behavior for both the primary loading (up to the elastic region) and the discontinuous softening (up to the ultimate stress) was well addressed. The proposed model predicted well the mechanical response of the arterial tissue considering the damage of collagen fibers for both the healthy and atherosclerotic arterial walls.


Characterizing gradient echo signal decays in gynecologic cancers at 3T using a Gaussian augmentation of the monoexponential (GAME) model.
To assess whether R2* mapping with a standard Monoexponential (ME) or a Gaussian Augmentation of the Monoexponential (GAME) decay model better characterizes gradient-echo signal decays in gynecological cancers after external beam radiation therapy at 3T, and evaluate implications of modeling for noninvasive identification of intratumoral hypoxia. Multi-gradient-echo signals were acquired on 25 consecutive patients with gynecologic cancers and three healthy participants during inhalation of different oxygen concentrations at 3T. Data were fitted with both ME and GAME models. Models were compared using F-tests in tumors and muscles in patients, muscles, cervix, and uterus in healthy participants, and across oxygenation levels. GAME significantly improved fitting over ME (P < 0.05): Improvements with GAME covered 34% of tumor regions-of-interest on average, ranging from 6% (of a vaginal tumor) to 68% (of a cervical tumor) in individual tumors. Improvements with GAME were more prominent in areas that would be assumed hypoxic based on ME alone, reaching 90% as ME R2* approached 100 Hz. Gradient echo decay parameters at different oxygenation levels were not significantly different (P = 0.81). R2* may prove sensitive to hypoxia; however, inaccurate representations of underlying data may limit the success of quantitative assessments. Although the degree to which R2 or σ values correlate with hypoxia remains unknown, improved characterization with GAME increases the potential for determining any correlates of fit parameters with biomarkers, such as oxygenation status. J. MAGN. RESON. IMAGING 2016;44:1020-1030.


Dynamic CT technique for assessment of wrist joint instabilities.
To develop a 4D [three-dimensional (3D) + time] CT technique to capture high spatial and temporal resolution images of wrist joint motion so that dynamic joint instabilities can be detected before the development of static joint instability and onset of osteoarthritis (OA). A cadaveric wrist was mounted onto a custom motion simulator and scanned with a dual source CT scanner during radial-ulnar deviation. A dynamic 4D CT technique was utilized to reconstruct images at 20 equidistant time points from one motion cycle. 3D images of carpal bones were generated using volume rendering techniques (VRT) at each of the 20 time points and then 4D movies were generated to depict the dynamic joint motion. The same cadaveric wrist was also scanned after cutting all portions of the scapholunate interosseus ligament to simulate scapholunate joint instability. Image quality were assessed on an ordinal scale (1-4, 4 being excellent) by three experienced orthopedic surgeons (specialized in hand surgery) by scoring 2D axial images. Dynamic instability was evaluated by the same surgeons by comparing the two 4D movies of joint motion. Finally, dose reduction was investigated using the cadaveric wrist by scanning at different dose levels to determine the lowest radiation dose that did not substantially alter diagnostic image quality. The mean image quality scores for dynamic and static CT images were 3.7 and 4.0, respectively. The carpal bones, distal radius and ulna, and joint spaces were clearly delineated in the 3D VRT images, without motion blurring or banding artifacts, at all time points during the motion cycle. Appropriate viewing angles could be interactively selected to view any articulating structure using different 3D processing techniques. The motion of each carpal bone and the relative motion among the carpal bones were easily observed in the 4D movies. Joint instability was correctly and easily detected in the scan performed after the ligament was cut by observing the relative motion between the scaphoid and lunate bones. Diagnostic capability was not sacrificed with a volume CT dose index (CTDI(vol)) as low as 18 mGy for the whole scan, with estimated skin dose of approximately 33 mGy, which is much lower than the threshold for transient skin erythema (2000 mGy). The proposed dynamic 4D CT imaging technique generated high spatial and high temporal resolution images without requiring periodic joint motion. Preliminary results from this cadaveric study demonstrate the feasibility of detecting joint instability using this technique.


Ethical and legal issues in nursing home care.
Physicians who provide care for nursing home residents are regularly challenged by ethical and legal issues. Because nursing home care is complicated by numerous regulations and because nursing home residents have complex medical and social problems, some issues are unique to the long-term care setting and others present in unfamiliar ways. Some issues frequently encountered in this context are discussed: advance directives, competence and decision-making capacity, decisions about life-sustaining treatment, resident abuse, restraints, psychotropic medications, risk management, participation in research, and ethics committees. With knowledge of the legal and ethical framework and understanding of some of the common, complicated issues that arise, physicians should be better equipped to provide optimal care for nursing home residents.


Rearrangement of the bacterial chromosome: forbidden inversions.
The order of genes in the chromosome of enteric bacteria has been evolutionarily conserved despite the existence of mechanisms for rearrangement. Homologous chromosomal sequences in the same orientation recombine to form deletions or duplications. When homologous sequences in inverse orientation recombine, one expects to form an inversion of the intervening chromosomal segment. This expectation was tested by placing pairs of homologous sequences in inverse order at various points in the chromosome. Sequences at many pairs of sites (permissive) do recombine to generate the expected inversion, while the same sequences placed at other pairs of sites (nonpermissive) do not form an inversion. For the one nonpermissive interval tested, the missing inversion type can be constructed by an alternative transductional method; strains with this inversion are viable. Thus mechanistic limitations must prevent sequences at particular sites from undergoing the recombination event required to form an inversion.


Bacterial contamination of dental handpieces.
Bacterial contamination of water- and air-lines was investigated after artificial contamination and clinical use of dental handpieces. The effect of lubrication, disinfection and autoclaving on this contamination was also addressed. Bacterial growth was recorded in both the air- and water-lines during clinical and artificial contamination, with water-lines showing heavier contamination than air-lines. External and internal surfaces of handpieces still yielded bacterial growth after lubrication and disinfection, while heat sterilisation (autoclaving) rendered both internal and external surfaces sterile.


Exercise-recruited NK cells display exercise-associated eHSP-70.
It is hypothesized that increased plasma or serum concentrations of extracellular heat shock proteins (eHSP) serve as a danger signal to the innate immune system. Cellular binding of eHSP leads to activation of NK cells and monocytes, as measured by their increased cytokine production, mitotic division and killing capacity. We examined whether eHSP binds to NK lymphocytes in vivo in athletes performing endurance exercise in the heat. Eighteen trained male runners ran at 70% VO2max at 35 degrees C and 40% relative humidity. Venous blood collected before, after and 1.5 h after exercise was analysed for leukocyte distribution, phenotype and eHSP70. NK cell-enriched samples were examined for co-localization of CD94 and eHSP70 expression. Plasma eHSP-70 concentration was measured by ELISA. Subjects ran for approximately 50 min, which elicited a reversible leukocytosis. NK cell count increased 83% (p < 0.01) immediately after exercise, then decreased to 66% of the resting level 1.5 h after exercise (p < 0.05). Plasma eHSP concentration increased 167% after exercise and remained elevated (by up to 71%) 1.5 h after exercise (p < 0.01). eHSP was expressed on both NK cells and monocytes at all times; the count of NK cells positive for eHSP doubled from 0.04 +/- 0.02 10(9)/L (mean +/- SD) to 0.08 +/- 0.06 10(9)/L after exercise. In summary, exercise in the heat increased free plasma eHSP concentration, and the eHSP co-localized with CD94 on NK cells. These data confirm the link between exercise and activation of the innate immune system.


Service delivery in Kenyan district hospitals - what can we learn from literature on mid-level managers?
There is a growing emphasis on the need to tackle inadequate human resources for health (HRH) as an essential part of strengthening health systems; but the focus is mostly on macro-level issues, such as training, recruitment, skill mix and distribution. Few attempts have been made to understand the capability of health workers, their motivation and other structural and organizational aspects of systems that influence workforce performance. We have examined literature on the roles of mid-level managers to help us understand how they might influence service delivery quality in Kenyan hospitals. In the Kenyan hospital settings, these are roles that head of departments who are also clinical or nursing service providers might play. A computerized search strategy was run in Pub Med, Cochrane Library, Directory of Open Access Journals Social Science Research Network, Eldis, Google Scholar and Human Resources for Health web site databases using both free-text and MeSH terms from 1980 to 2011. In addition, citation searching from excluded and included articles was used and relevant unpublished literature systematically identified. A total of 23 articles were finally included in the review from over 7000 titles and abstracts initially identified. The most widely documented roles of mid-level managers were decision-making or problem-solving, strategist or negotiator and communicator. Others included being a therapist or motivator, goal setting or articulation and mentoring or coaching. In addition to these roles, we identified important personal attributes of a good manager, which included interpersonal skills, delegation and accountability, and honesty. The majority of studies included in the review concerned the roles that mid-level managers are expected to play in times of organizational change. This review highlights the possible significance of mid-level managers in achieving delivery of high-quality services in Kenyan public hospitals and strongly suggests that approaches to strengthen this level of management will be valuable. The findings from this review should also help inform empirical studies of the roles of mid-level managers in these settings.


Ebola virion attachment and entry into human macrophages profoundly effects early cellular gene expression.
Zaire ebolavirus (ZEBOV) infections are associated with high lethality in primates. ZEBOV primarily targets mononuclear phagocytes, which are activated upon infection and secrete mediators believed to trigger initial stages of pathogenesis. The characterization of the responses of target cells to ZEBOV infection may therefore not only further understanding of pathogenesis but also suggest possible points of therapeutic intervention. Gene expression profiles of primary human macrophages exposed to ZEBOV were determined using DNA microarrays and quantitative PCR to gain insight into the cellular response immediately after cell entry. Significant changes in mRNA concentrations encoding for 88 cellular proteins were observed. Most of these proteins have not yet been implicated in ZEBOV infection. Some, however, are inflammatory mediators known to be elevated during the acute phase of disease in the blood of ZEBOV-infected humans. Interestingly, the cellular response occurred within the first hour of Ebola virion exposure, i.e. prior to virus gene expression. This observation supports the hypothesis that virion binding or entry mediated by the spike glycoprotein (GP(1,2)) is the primary stimulus for an initial response. Indeed, ZEBOV virions, LPS, and virus-like particles consisting of only the ZEBOV matrix protein VP40 and GP(1,2) (VLP(VP40-GP)) triggered comparable responses in macrophages, including pro-inflammatory and pro-apoptotic signals. In contrast, VLP(VP40) (particles lacking GP(1,2)) caused an aberrant response. This suggests that GP(1,2) binding to macrophages plays an important role in the immediate cellular response.


Pathogenesis of migraine: from neurotransmitters to neuromodulators and beyond.
Here, in this review, we present our hypothesis of the migraine pathogenesis. We believe that migraine attacks derive from a top-down dysfunctional process that initiates in a hyperexcitable and hypoenergetic brain in the frontal lobe and downstream in abnormally activated nuclei of the pain matrix. This hypothesis derived from the results of the biochemical studies, mainly generated from our laboratory, on the possible metabolic shifts of tyrosine toward an activation of decarboxylase enzyme activity with an increased synthesis of traces amines, i.e. tyr, oct and syn, and an unphysiological synthesis of noradrenalin and dopamine. This metabolic shift is possibly favored by the reduced mitochondrial energy and high levels of glutamate in CNS of migraine patients. The unbalanced levels of neurotransmitters (DA and NE) and neuromodulators (tyr, oct and syn) in the synaptic dopaminergic and noradrenergic clefts of the pain matrix may activate, downstream, the trigeminal system that releases calcitonin gene-related G peptide. This induces the formation of an inflammatory soup, the sensitization of first trigeminal neuron and the migraine attack.


The elastin network: its relationship with collagen and cells in articular cartilage as visualized by multiphoton microscopy.
A combination of two-photon fluorescence (TPF), second harmonic generation (SHG) and coherent anti-Stokes Raman scattering (CARS) imaging has been used to investigate the elastin fibre network in healthy equine articular cartilage from the metacarpophalangeal joint. The elastin fibres were identified using their intrinsic two-photon fluorescence and immuno-staining was used to confirm the identity of these fibres. SHG was used to reveal the collagen matrix and the collagen fibre orientations were determined from their SHG polarization sensitivity, while CARS was used to clearly delineate the cell boundaries. Extensive elastin fibre networks were found in all the joint regions investigated. The elastin was found predominantly in the superficial zone (upper 50 microm) and was aligned parallel to the articular surface. Elastin was also detected in the pericellular matrix surrounding the superficial chondrocytes; however, individual fibres could not be resolved in this region. Variations in the density and organization of the fibres were observed in different regions on the joint surface.


Correlation between preoperative pain duration and percutaneous vertebroplasty outcome.
The duration of the fracture is considered by many practitioners to be an important predictor of outcome following vertebroplasty. We sought to define the impact of preprocedural pain duration on outcomes, including pain relief, improvement in function, and medication usage among patients treated with single-level vertebroplasty. Institutional review board approval was obtained before conducting this retrospective analysis of 321 patients undergoing single-level vertebroplasty at our institution. Fractures were categorized as acute (≤6 weeks, n = 153), subacute (6-24 weeks, n = 124), and chronic (>24 weeks, n = 44). Pain NRS (0-10) scores at rest and with activity and RDS were compared among 3 groups at baseline and post procedure. Also absolute and proportional improvement of pain NRS and RDS were compared among 3 groups by using ANOVA. Linear regression was performed between preoperative pain duration and symptom improvement for each group. Baseline RDS and pain NRS with activity and at rest were not significantly different among groups (P = .09, .30, and .91, respectively). Mean improvement in pain NRS with activity at 1 month postvertebroplasty in acute (improvement = 4.9 ± 3.5), subacute (improvement = 4.2 ± 3.2), and chronic fractures (improvement = 4.5 ± 3.2) was similar among groups (P = .28). Mean improvement in RDS at 1 month postprocedure was 9.6, 8.3, and 9.9, for acute, subacute, and chronic fractures, respectively (P = .56). There was no strong correlation between length of pain and symptom improvement. The age of fracture has minimal impact on outcome following single-level vertebroplasty, with good outcomes noted among patients with acute, subacute, and chronic fractures.


Entropy connects water structure and dynamics in protein hydration layer.
The enzyme Candida Antarctica lipase B (CALB) serves here as a model for understanding connections among hydration layer dynamics, solvation shell structure, and protein surface structure. The structure and dynamics of water molecules in the hydration layer were characterized for regions of the CALB surface, divided around each α-helix, β-sheet, and loop structure. Heterogeneous hydration dynamics were observed around the surface of the enzyme, in line with spectroscopic observations of other proteins. Regional differences in the structure of the biomolecular hydration layer were found to be concomitant with variations in dynamics. In particular, it was seen that regions of higher density exhibit faster water dynamics. This is analogous to the behavior of bulk water, where dynamics (diffusion coefficients) are connected to water structure (density and tetrahedrality) by excess (or pair) entropy, detailed in the Rosenfeld scaling relationship. Additionally, effects of protein surface topology and hydrophobicity on water structure and dynamics were evaluated using multiregression analysis, showing that topology has a somewhat larger effect on hydration layer structure-dynamics. Concave and hydrophobic protein surfaces favor a less dense and more tetrahedral solvation layer, akin to a more ice-like structure, with slower dynamics. Results show that pairwise entropies of local hydration layers, calculated from regional radial distribution functions, scale logarithmically with local hydration dynamics. Thus, the Rosenfeld relationship describes the heterogeneous structure-dynamics of the hydration layer around the enzyme CALB. These findings raise the question of whether this may be a general principle for understanding the structure-dynamics of biomolecular solvation.


Spatial localisation of transcripts of the Hox-C6 gene.
The Hox-C6 gene, in common with its Xenopus and human homologues, is organised as 3 exons with 2 distinct promoters (PRI and PRII) producing 2 different transcripts. The PRII promoter produces a 'typical' Hox transcript by splicing 2 exons separated by a 700 bp intron. The PRI promoter initiates transcription from a 3rd exon, 9 kbp 5' of PRII. This exon is spliced into the 1st exon of the PRII transcript at a point 3' of the translation start codon. This means that the predicted protein product of the PRI protein contains the Hox-C6 homeodomain but is truncated by 82 amino acids compared with the PRII product. In situ hybridisation using probes specific for PRI or PRII showed them to have essentially the same distribution in the developing nervous system and prevertebrae of 12.5 d embryos. However, the distribution of transcripts in the CNS was distinctly different from that reported previously for a probe containing the Hox-C6 homeobox.


Retrospective development of a novel resilience indicator using existing cohort data: The adolescent to adult health resilience instrument.
Cohort studies represent rich sources of data that can be used to link components of resilience to a variety of health-related outcomes. The Adolescent to Adult Health (Add Health) cohort study represents one of the largest data sets of the health and social context of adolescents transitioning into adulthood. It did not however use validated resilience scales in its data collection process. This study aimed to retrospectively create and validate a resilience indicator using existing data from the cohort to better understand the resilience of its participants. Questions asked of participants during one Add Health data collection time period (N = 15,701) were matched to items on a well-known and widely validated resilience scale called the Connor Davidson Resilience Scale. Factor analysis and psychometric analyses were used to refine and validate this novel Adolescent to Adult Health Resilience Instrument. Construct validity utilized participants' answers to the 10 item Center for Epidemiologic Studies Depression Scale, which has been used to validate other resilience scales. Factor analysis yielded an instrument with 13 items that showed appropriate internal consistency statistics. Resilience scores in our study were normally distributed with no ceiling or floor effects. Our instrument had appropriate construct validity, negatively correlating to answers on the depression scale (r = -0.64, p<0.001). We also found demographic differences in mean resilience scores: lower resilience scores were seen among women and those who reported lower levels of education and household income. It is possible to retrospectively construct a resilience indicator from existing cohort data and achieve good psychometric properties. The Adolescent to Adult Health Resilience Instrument can be used to better understand the relationship between resilience, social determinants of health and health outcomes among young adults using existing data, much of which is publicly available.


Towards Intelligent Integration and Sharing of Stem Cell Research Data.
Advancements in regenerative medicine have brought to the fore the need for increased standardization and sharing of stem cell product characterization to help drive these innovative interventions toward public availability. Although numerous attempts have been made to store this data, there is still a lack of a platform that incorporates heterogeneous stem cell information into a harmonized project-based framework. The aim of this project was to introduce and pilot-test an intelligent informatics solution which integrates diverse stem cell product characteristics with study subject and omics information. In the resulting platform, heterogeneous data is validated using predefined ontologies and stored in a NoSQL repository. Pilot-testing was performed on nine sponsored stem cell projects conducting preclinical and intervention evaluations. The pilot-testing demonstrated the robustness of the proposed platform, by seamlessly harmonizing diverse common data elements, and the potential of this platform for driving knowledge generation from the aggregation of this shared data.


Surface plasmon resonance sensor based on spectral interferometry: numerical analysis.
In this paper, we introduce a numerical simulation of a phase detecting surface plasmon resonance (SPR) scheme based on spectral interference. Based on the simulation, we propose a method to optimize various aspects of SPR sensors, which enables better performance in both measurement range (MR) and sensitivity. In the simulation, four parameters including the spectrum of the broadband light source, incident angle, Au film thickness, and refractive index of the prism coupler are analyzed. The results show that it is a good solution for better performance to use a warm white broadband (625-800 nm) light source, a divergence angle of the collimated incident light less than 0.02°, and an optimized 48 nm thick Au film when a visible broadband light source is used. If a near-IR light source is used, however, the Au film thickness should be somewhat thinner according the specific spectrum. In addition, a wider MR could be obtained if a prism coupler with higher refractive index is used. With all the parameters appropriately set, the SPR MR could be extended to 0.55 refractive index units while keeping the sensitivity at a level of 10(-8).


Suture Button Fixation Versus Syndesmotic Screws in Supination-External Rotation Type 4 Injuries: A Cost-Effectiveness Analysis.
In stress-positive, unstable supination-external rotation type 4 (SER IV) ankle fractures, implant selection for syndesmotic fixation is a debated topic. Among the available syndesmotic fixation methods, the metallic screw and the suture button have been routinely compared in the literature. In addition to strength of fixation and ability to anatomically restore the syndesmosis, costs associated with implant use have recently been called into question. This study aimed to examine the cost-effectiveness of the suture button and determine whether suture button fixation is more cost-effective than two 3.5-mm syndesmotic screws not removed on a routine postoperative basis. Economic and decision analysis; Level of evidence, 2. Studies with the highest evidence levels in the available literature were used to estimate the hardware removal and failure rates for syndesmotic screws and suture button fixation. Costs were determined by examining the average costs for patients who underwent surgery for unstable SER IV ankle fractures at a single level-1 trauma institution. A decision analysis model that allowed comparison of the 2 fixation methods was developed. Using a 20% screw hardware removal rate and a 4% suture button hardware removal rate, the total cost for 2 syndesmotic screws was US$20,836 and the total effectiveness was 5.846. This yielded a total cost of $3564 per quality-adjusted life-year (QALY) over an 8-year time period. The total cost for suture button fixation was $19,354 and the total effectiveness was 5.904, resulting in a total cost of $3294 per QALY over the same time period. A sensitivity analysis was then conducted to assess suture button fixation costs as well as screw and suture button hardware removal rates. Other possible treatment scenarios were also examined, including 1 screw and 2 suture buttons for operative fixation of the syndesmosis. To become more cost-effective, the screw hardware removal rate would have to be reduced to less than 10%. Furthermore, fixation with a single suture button continued to be the dominant treatment strategy compared with 2 suture buttons, 1 screw, and 2 screws for syndesmotic fixation. This cost-effectiveness analysis suggests that for unstable SER IV ankle fractures, suture button fixation is more cost-effective than syndesmotic screws not removed on a routine basis. Suture button fixation was a dominant treatment strategy, because patients spent on average $1482 less and had a higher quality of life by 0.058 QALYs compared with patients who received fixation with 2 syndesmotic screws. Assuming that functional outcomes and failure rates were equivalent, screw fixation only became more cost-effective when the screw hardware removal rate was reduced to less than 10% or when the suture button cost exceeded $2000. In addition, fixation with a single suture button device proved more cost-effective than fixation with either 1 or 2 syndesmotic screws.


Response of Horticultural Soil Microbiota to Different Fertilization Practices.
Environmentally friendly agricultural production necessitates manipulation of microbe-plant interactions, requiring a better understanding of how farming practices influence soil microbiota. We studied the effect of conventional and organic treatment on soil bacterial richness, composition, and predicted functional potential. 16S rRNA sequencing was applied to soils from adjacent plots receiving either a synthetic or organic fertilizer, where two crops were grown within treatment, homogenizing for differences in soil properties, crop, and climate. Conventional fertilizer was associated with a decrease in soil pH, an accumulation of Ag, Mn, As, Fe, Co, Cd, and Ni; and an enrichment of ammonia oxidizers and xenobiotic compound degraders (e.g., Candidatus Nitrososphaera, Nitrospira, Bacillus, Pseudomonas). Soils receiving organic fertilization were enriched in Ti (crop biostimulant), N, and C cycling bacteria (denitrifiers, e.g., Azoarcus, Anaerolinea; methylotrophs, e.g., Methylocaldum, Methanosarcina), and disease-suppression (e.g., Myxococcales). Some predicted functions, such as glutathione metabolism, were slightly, but significantly enriched after a one-time manure application, suggesting the enhancement of sulfur regulation, nitrogen-fixing, and defense of environmental stressors. The study highlights that even a single application of organic fertilization is enough to originate a rapid shift in soil prokaryotes, responding to the differential substrate availability by promoting soil health, similar to recurrent applications.


Interactions between dorsal-ventral patterning genes lmx1b, engrailed-1 and wnt-7a in the vertebrate limb.
The vertebrate limb has characteristic morphological features that distinguish dorsal and ventral regions. For example, humans and most other mammals have nails on the dorsal surface of their digits, while the ventral surface is covered by skin or footpads. Internally, there is a high degree of organization along the dorsal-ventral axis. Extensor muscles are generally located dorsally while flexor muscles are generally located ventrally. The skeleton has subtle differences that allow for attachment of these muscles and distinct pools of motor neurons innervate either dorsal or ventral muscles. How is this complex arrangement of tissues generated? Recent studies have identified a molecular cascade of three factors that govern early events in dorsal-ventral limb patterning. Two of these factors, engrailed-1 and wnt-7a are expressed in the dorsal and ventral ectoderm respectively. The function of engrailed-1 is to repress the expression of wnt-7a in the ventral limb bud ectoderm. The third factor, a LIM-homeodomain transcription factor, Imx1b is induced in dorsal mesenchyme by wnt-7a and it is both necessary and sufficient to specify dorsal limb pattern. In this report, we examine genetic interactions between wnt-7a, engrailed-1, and Imx1b by analyzing the phenotypes of mice that are double mutants for Imx1b and either wnt-7a or engrailed-1. These studies indicate that Imx1b is the only target of wnt-7a and engrailed-1 that is of consequence for dorsal-ventral patterning. Moreover, this genetic analysis suggests that Imx1b plays additional roles in anterior-posterior patterning and growth that were not previously appreciated.


The Global Impact of COVID-19 on the Care of People With Endometriosis.
Endometriosis is a chronic condition affecting ~10% of women globally. Little is known about the impact of the coronavirus disease 2019 (COVID-19) pandemic on their care. This brief report is aimed to explore the impact of COVID-19 on the care of people with endometriosis around the world, their priorities in relation to their clinical care during and coming out of the pandemic, and whether they believed that endometriosis makes them more vulnerable to COVID-19. An internet-based survey collected data in five languages between May 11, 2020, and June 8, 2020. Only participants with a surgical or radiological diagnosis of endometriosis aged 18 years or over were included. A total of 6,729 eligible respondents completed the survey with 80.7% [95% CI (79.7, 81.6)] reporting a negative impact on their care. This included difficulties obtaining medication (20.3%), cancelled/postponed gynaecology appointments (50.0%), and cancelled/postponed procedures (37.2%). More than half worried that their endometrioses make them more vulnerable to COVID-19 [54.2%; 95% CI (53.0, 55.4)]. The top three priorities were remarkably consistent around the world: contact with gynaecologists, knowing when procedures would be performed, and support with mental health (20.3% prioritising this aspect during the pandemic and 13.0% as restrictions begin to ease). This study shows the substantial impact the COVID-19 pandemic has had on people with endometriosis and describes how they would like care prioritised moving forwards. The findings regarding significant support needs for mental health add further weight to the growing recognition of attending to such issues as part of good patient-centred care.


Neural bases of stereopsis across visual field of the alert macaque monkey.
Left and right retinal images of an object seen by the 2 eyes can occupy slightly disparate horizontal and/or vertical locations. The role of horizontal disparity (HD) in stereoscopic vision is well established, but the functional contribution of vertical disparity (VD) remains unclear. Various psychophysical studies have shown that HD and VD are used differently by the visual system depending on their location in the visual field, whether near the center of gaze or more peripheral. We show this horizontal/vertical distinction at the cellular level in monkey primary visual cortex (area V1). The range of VD encoding is reduced in central but not in the peripheral representation of the visual field. Moreover, neurons respond selectively to particular combinations of both types of disparities depending on the coded orientation as predicted by the disparity energy model. The preferred orientations of neurons near the fovea present a vertical bias that is well suited for stereopsis based on HD selectivity alone. In the periphery, instead, preferred orientations are radially biased, which allows a peripheral detector to convey the same depth signal based on either HD or VD. Such an organization has functional implications in both the perceptual and oculomotor domains.


Skeletal muscle in cancer cachexia: the ideal target of drug therapy.
Cancer cachexia is a debilitating and life-threatening syndrome that accounts for at least 20% of deaths in neoplastic patients. Cancer cachexia significantly impairs quality of life and response to anti-neoplastic therapies, increasing morbidity and mortality of cancer patients. The loss of lean body mass is the main characteristic of cancer cachexia and the principal cause of function impairment, fatigue and respiratory complications. It is the result of an imbalance between protein synthesis and protein degradation, the mechanisms underlying such alteration being multiple and partially known. Current therapy of cancer cachexia continues to be extremely poor. However, in the last decade, the attention has focused just on the skeletal muscle, as a potential target of therapy, with the aim to discover drugs capable to inhibit the catabolic processes and to stimulate the anabolic pathways. The skeletal muscle has been faced at different levels such as the mediators (cytokines and tumor-derived factors), the receptors (TNF-alpha and androgen receptors), the proteolytic pathways (calpains and ubiquitin-proteasome), the intracellullar signalling pathways (NF-kB, AP-1, FOXO, PKR), and the negative modulators of muscle growth/hypertrophy (myostatin, GSK3-beta). Most of the drugs that have been tested have shown to be effective, at least in experimental models of cancer cachexia. It remains to define their safety, tolerance and efficacy in humans through large, adequate, clinical trials. However, the impression is that there is a light at the back of the tunnel.