Cylindroma and eccrine spiradenoma coexistent in the same lesion.
Two patients complained of having a tender nodule. One patient had the nodule on the scalp and the other on the face. Each nodule contained a cylindroma and an adjacent eccrine spiradenoma. While eccrine spiradenoma is of eccrine derivation, the origin of cylindroma is controversial because of variable histochemical and enzyme histochemical findings. The presence of cylindroma and eccrine spiradenoma in one clinical nodule contributes circumstantial evidence for the similar derivation of both tumors.


Thermal-induced hydrophilicity enhancement of titanium dental implant surfaces.
Titanium surface characteristics, including microtopography, chemical composition, and wettability, are essential features to achieve osseointegration of dental implants, but the choice of a particular surface topography is still a debated topic among clinicians. An increased level of implant surface hydrophilicity has been demonstrated to ameliorate osseointegration and shorten healing times. The aim of this work is to develop and test a suitable thermal-based method to enhance titanium surface wettability without modifying other characteristics of the implant surface. For this function, titanium discs with different surface topography have been thermally treated by testing different temperatures and excluding those that led to evident chromatic and morphological modifications. The selected surface gain in wettability after the treatment was assessed through contact angle measurement, chemistry modifications through x-ray photoelectron spectroscopy (XPS) analysis, and microtopography through scanning electron microscopy (SEM). Results showed a great enhancement in hydrophilicity on the tested surfaces without any other modification in terms of surface chemical composition and topography. A possible limitation of this method could be the persistent, although relatively slow, biological aging of the surfaces after the treatment. The present findings indicate that the described treatment could be a safe and effective method to enhance dental titanium hydrophilicity and thus its biological performance.


Ultrasound-guided percutaneous cryoneurolysis providing postoperative analgesia lasting many weeks following a single administration: a replacement for continuous peripheral nerve blocks?: a case report.
Cryoneurolysis entails using low temperatures to reversibly ablate nerves, with a subsequent analgesia duration measured in weeks or months. Previously, clinical applications for acute pain were limited because treatment originally required exposing the target nerve surgically. However, three developments have now made it possible to provide prolonged postoperative analgesia by cryoneurolysis: 1) new portable, hand-held cryoneurolysis devices, 2) ultrasound machine proliferation, and, 3) anesthesiologists trained in ultrasound-guided peripheral nerve block administration. This report is the first to describe the use of a single preoperative administration of ultrasound-guided percutaneous cryoneurolysis to provide multiple weeks of analgesia following shoulder rotator cuff repair and total knee arthroplasty. Considering the significant benefits of cryoanalgesia relative to continuous peripheral nerve blocks (e.g., lack of catheter/pump care, extremely long duration), this analgesic modality may be a practical alternative for the treatment of prolonged post-surgical pain in a select group of surgical patients.


Tumor-stroma ratio predicts recurrence in patients with colon cancer treated with neoadjuvant chemotherapy.
Neoadjuvant chemotherapy represents a new treatment approach to locally advanced colon cancer. The aim of this study was to analyze the ability of tumor-stroma ratio (TSR) to predict disease recurrence in patients with locally advanced colon cancer treated with neoadjuvant chemotherapy. This study included 65 patients with colon cancer treated with neoadjuvant chemotherapy in a phase II trial. All patients were planned for three cycles of capecitabine and oxaliplatin before surgery. Hematoxylin and eosin stained tissue sections from surgically resected primary tumors were sampled and analyzed by conventional microscopy. Patients were divided into stroma-high (>50%, i.e. TSR low) and stroma-low (≤50%, i.e. TSR high) for the comparison with clinical data. A low TSR was found in 47% of the surgically resected primary tumors and correlated to a significantly higher T- and N-category compared, to tumors with a high TSR (p < .01). A low TSR was also significantly associated with disease recurrence (p = .008), translating into significant differences in disease free survival (DFS) and overall survival, p < .002. The 5-year DFS rate for patients with a low TSR was 55%, compared to 94% in the group of patients with a high TSR. TSR assessed in the surgically resected primary tumor from patients with locally advanced colon cancer treated with neoadjuvant chemotherapy provides prognostic value and may serve as a relevant parameter in selecting patients for post-operative treatment.


Detection of alpha(2u)-globulin and its bound putative pheromones in the preputial gland of the Indian commensal rat (Rattus rattus) using mass spectrometry.
The role of pheromones and pheromone-binding proteins in the laboratory rat has been extensively investigated. However, we have previously reported that the preputial gland of the Indian commensal rat produces a variety of pheromonal molecules and preputial glands would seem to be the predominant source for pheromonal communication. The presence of pheromone-binding proteins has not yet been identified in the preputial gland of the Indian commensal rat; therefore, the experiments were designed to unravel the alpha(2u)-globulin (alpha2u) and its bound volatiles in the commensal rat. Total preputial glandular proteins were first fractionated by sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS-PAGE) and subsequently analyzed by mass spectrometry. Further, we purified alpha2u and screened for the presence of bound pheromonal molecules with the aid of gas chromatography/mass spectrometry (GC/MS). A novel alpha2u was identified with a high score and this protein has not been previously described as present in the preputial gland of Indian commensal rats. This novel alpha2u was then characterized by tandem mass spectrometry (MS/MS). Peptides with m/z values of 969, 1192, 1303 and 1876 were further fragmented with the aid of MS/MS and generated de novo sequences which provided additional evidence for the presence of alpha2u in the preputial gland. Finally, we identified the presence of farnesol 1 and 2 bound to alpha2u. The present investigation confirms the presence of alpha2u (18.54 kDa) in the preputial gland of the Indian commensal rat and identifies farnesol 1 and 2 as probably involved in chemo-communication by the Indian commensal rat.


Is there still a role for traditional disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis?
Rheumatoid arthritis is a chronic and debilitating disease, affecting an estimated 1% of the population worldwide. The past decade has witnessed an explosion in our understanding of the pathophysiology of rheumatoid arthritis and therefore in our ability to more effectively target the disease process. Although a cure remains elusive, remission is an approachable goal. There has been a complete remodeling of the traditional "pyramid" by rheumatologists, who now treat rheumatoid arthritis earlier and more aggressively than ever before. Standard single therapy with disease-modifying antirheumatic drugs, which was previously the final step in treating rheumatoid arthritis, is now practically bypassed in the deluge of information suggesting that combinations of disease-modifying antirheumatic drugs or newer biologic therapy is more effective. It is difficult to assimilate all the data and develop a rational approach; however, the bottom line is often the deciding factor: the newer agents are tremendously expensive. The intent of this article is to review recent and relevant trials in the treatment of rheumatoid arthritis, suggest a treatment algorithm, and argue that traditional disease-modifying antirheumatic drugs continue to play a pivotal role.


Starving affects CDX gene expression during small intestinal development in the chick.
The small intestine of the chicken undergoes intensive changes in the immediate posthatch period, increasing in size and developing crypts, villi and mature enterocytes. During this time, chicks are also transferring from nutrition based on the lipid-rich yolk to exogenous carbohydrate-rich feeds. The cdx homeobox genes participate in axial patterning and in definition of cell identity in embryos, and some cdx genes remain active postpartum in organs such as the intestine. In this study, the transcription patterns of two of these genes, cdxA and cdxB, were examined in the small intestine of the embryo and posthatch chick; in addition, the effects on these genes of starving for 48 h at hatch were examined. Both cdx transcription factors were upregulated toward the time of hatch and were observed in proliferating enterocytes; this enhanced expression continued posthatch. Distribution of cdxA changed with age and was found at higher concentrations in mature enterocytes. Starving from 0 to 48 h posthatch retarded growth and decreased enterocyte proliferation and expression of cdxA and cdxB. After access to feed, expression of cdx genes was enhanced. Chicken homeobox genes cdxA and cdxB are expressed in all enterocytes during embryonic and posthatch development; however, cdxA may have a role in enterocyte maturation posthatch. CdxB was expressed later in development then previously reported.


Identification of a novel metalloproteinase and its role in juvenile development of the tobacco hornworm, Manduca sexta (Linnaeus).
Matrix metalloproteinases (MMPs) are a class of zinc-dependent endopeptidases that are highly conserved across numerous taxa, from bacteria to humans. Recently, MMPs have been identified in several insect species and are hypothesized to function in immunity and development. In this study, we identify a putative MMP and correlate its proteolytic activity and gene and protein expression in the tracheae with developmental stage. Ms-MMP gene expression increases 10-fold during molting, which is accompanied by an increase in both protein expression and gelatinolytic activity. To directly test the hypothesis that Ms-MMP plays a critical role in juvenile development of Manduca sexta, we injected a broad-spectrum MMP inhibitor and recorded its effects on growth and development. Inhibition of MMPs caused a delay in juvenile development and decreased growth rates. Understanding the function of MMPs will help us better understand molting and control of body size in insects. Furthermore, elucidating functions for MMPs in lower taxa may yield critical information about the evolution of the numerous MMPs found in vertebrates.


The Effect of Multiple Assessments on Delirium Detection: a Pilot Study.
Delirium is characterized by fluctuating attention or arousal, with high prevalence in the orthopaedic ward. Our aim was to: 1) establish the prevalence of delirium on an orthopaedic ward, and 2) compare delirium prevalence using a single geriatrician assessment vs. multiple 3D-CAM (3-Minute Diagnostic Interview for Confusion Assessment Method) assessments during the day. We hypothesized that multiple assessments would increase the detection rate due to the fluctuating nature of delirium. Comparative study conducted at an academic hospital in Hamilton, Ontario. Participants included patients 65 years and older admitted to the orthopaedic ward (n=55). After a geriatrician made the first assessment of delirium by 3D-CAM on each patient, teams with specialized geriatrics training re-assessed participants up to four times. Delirium rates based on first assessment were compared to cumulative end-of-day rates to determine if detection increased with multiple assessments. The prevalence of delirium was 30.9% (17 participants) using multiple assessments. Of these cases, 13 (76.4%) were detected in the initial geriatrician assessment. In patients with hip fractures, 70.6% (12 of 17) were identified as delirious by multiple assessments. As symptoms fluctuate, multiple daily CAM assessments may increase the identification of delirium in orthopaedic inpatients.


Community-Engaged Attribute Mapping: Exploring Resources and Readiness to Change the Rural Context for Obesity Prevention.
Individual risk factors for obesity are well-known, but environmental characteristics that influence individual risk, especially in rural communities, are not confirmed. Rural communities face unique challenges to implementing environmental strategies, such as walkability, aimed at supporting weight healthy lifestyles. Cooperative Extension, a community-embedded weight health partner, convened and engaged community members in self-exploration of local resources and readiness to change environmental characteristics perceived to promote unhealthy eating and inactivity. This approach leveraged Extension's mission, which includes connecting rural communities with land-grant university resources. HEAL MAPPS™ (Healthy Eating Active Living Mapping Attributes using Participatory Photographic Surveys) was developed as a participatory action research methodology. Adopted by Extension community partners, HEAL MAPPS™ involved residents in photomapping, characterizing, and communicating lived experiences of their rural community, and prioritizing interventions to change the obesogenic context. Extension educators serving rural communities in six Western U.S. states were trained to implement HEAL MAPPS™. Extension engaged community members who mapped and evaluated their encounters with environmental attributes that shape their dietary and activity patterns. The method partnered residents with decision makers in identifying issues, assessing resources and readiness, and prioritizing locally relevant environmental strategies to reduce access disparities for rural populations with high obesity risk. HEAL MAPPS™ revealed differences in resource availability, accessibility, and affordability within and among rural communities, as well as in readiness to address the obesogenic context. Extension functioned successfully as the backbone organization, and local community health partner, cooperatively implementing HEAL MAPPS™ and engaging constituents in shaping weight healthy environments.


Hydroxyurea-induced expression of glutathione peroxidase 1 in red blood cells of individuals with sickle cell anemia.
Chronic redox imbalance in erythrocytes of individuals with sickle cell disease (SCD) contributes to oxidative stress and likely underlies common etiologies of hemolysis. We measured the amounts of six antioxidant enzymes-SOD1, catalase, glutathione peroxidase 1 (GPx1), as well as peroxiredoxins (Prxs) I, II, and VI-in red blood cells (RBCs) of SCD patients and control subjects. The amounts of SOD1 and Prx VI were reduced by about 17% and 20%, respectively, in SCD RBCs compared with control cells. The amounts of Prx II and GPx1 did not differ between SCD and normal RBCs. However, about 18% of Prx II was inactivated in SCD RBCs as a result of oxidation to sulfinic Prx II, whereas inactive Prx II was virtually undetectable in control cells. Furthermore, GPx1 activity was reduced by about 33% in SCD RBCs, and the loss of activity was correlated with hemolysis in SCD patients. RBCs from SCD patients taking hydroxyurea demonstrated 90% higher GPx1 activity than did those from untreated SCD patients, with no differences seen for the other catalytic antioxidants. Hydroxyurea induced GPx1 expression in multiple cultured cell lines in a manner dependent on both p53 and NO-cGMP signaling pathways. GPx1 expression represents a previously unrecognized potential benefit of hydroxyurea treatment in SCD patients.


Molecular or Metabolic Reprograming: What Triggers Tumor Subtypes?
Tumor heterogeneity is reflected and influenced by genetic, epigenetic, and metabolic differences in cancer cells and their interactions with a complex microenvironment. This heterogeneity has resulted in the stratification of tumors into subtypes, mainly based on cancer-specific genomic or transcriptomic profiles. Subtyping can lead to biomarker identification for personalized diagnosis and therapy, but stratification alone does not explain the origins of tumor heterogeneity. Heterogeneity has traditionally been thought to arise from distinct mutations/aberrations in "driver" oncogenes. However, certain subtypes appear to be the result of adaptation to the disrupted microenvironment caused by abnormal tumor vasculature triggering metabolic switches. Moreover, heterogeneity persists despite the predominance of single oncogenic driver mutations, perhaps due to second metabolic or genetic "hits." In certain cancer types, existing subtypes have metabolic and transcriptomic phenotypes that are reminiscent of normal differentiated cells, whereas others reflect the phenotypes of stem or mesenchymal cells. The cell-of-origin may, therefore, play a role in tumor heterogeneity. In this review, we focus on how cancer cell-specific heterogeneity is driven by different genetic or metabolic factors alone or in combination using specific cancers to illustrate these concepts. Cancer Res; 76(18); 5195-200. ©2016 AACR.


Uremic encephalopathy and other brain disorders associated with renal failure.
Kidney failure is one of the leading causes of disability and death and one of the most disabling features of kidney failure and dialysis is encephalopathy. This is probably caused by the accumulation of uremic toxins. Other important causes are related to the underlying disorders that cause kidney failure, particularly hypertension. The clinical manifestations of uremic encephalopathy include mild confusional states to deep coma, often with associated movement disorders, such as asterixis. Most nephrologists consider cognitive impairment to be a major indication for the initiation of renal replacement therapy with dialysis with or without subsequent transplantation. Sleep disorders, including Ekbom's syndrome (restless legs syndrome) are also common in patients with kidney failure. Renal replacement therapies are also associated with particular neurologic complications including acute dialysis encephalopathy and chronic dialysis encephalopathy, formerly known as dialysis dementia. The treatments and prevention of each are discussed.


Supporting the pandemic response and timely access to COVID-19 vaccines: a case for stronger priority setting and health system governance in Nigeria.
Priority setting and health system governance are critical for optimising healthcare interventions and determining how best to allocate limited resources. The COVID-19 pandemic has buttressed the need for these especially now that vaccines are available to curb the spread of the disease. In many low- and middle-income countries (LMICs), vaccine coverage remains low, due in large part to sub-optimal priority setting and health system governance which has led to inequities in access and has fuelled vaccine hesitancy. An analysis of the situation in Nigeria identified key issues that have affected the health system response to COVID-19 and impeded timely access to the vaccine. These include weak vaccine procurement strategies, limited evidence on strategies for prioritising recipients and approaches for rolling out mass vaccination programmes for the entire population, lack of a communication strategy to reduce the incidence of vaccine hesitancy and failures to proactively address vaccine hesitancy through the implementation of vaccination programmes. Nigeria and other many other LMICs are still facing the prospect of subsequent and potentially worsening waves of the COVID-19 pandemic. Without effective priority setting, there is a risk that the country will not accelerate vaccine rollout quickly enough to achieve high coverage rates that will ensure herd immunity. In the context of existing weaknesses in health system governance, there is an urgent need to strengthen priority settings in Nigeria and identify and implement context-specific solutions that can improve vaccine coverage for the population.


Parish nursing: a system approach. Suggestions for planning and implementing parish partnerships.
The Parish Nurse Program at Chicago-based Resurrection Health Care Corporation (RHCC) sponsors partnerships between the corporation and parishes in the Chicago area to provide holistic, preventive healthcare services; access to appropriate resources; and witness to Jesus' healing mission. In RHCC's program, a parish nurse's role includes acting as a personal health counselor, discussing health concerns with parishioners and visiting them at home, in hospitals, and in nursing homes. The parish nurse also serves as a health educator, referral source for community resources, and facilitator for volunteer and support groups. The first step in introducing a parish nurse program is alerting staff within the organization and the surrounding community about the program. One way the parish nurse program director can do this is by developing a communications plan with the system's marketing and public relations staff. Members of a parish nurse program steering committee, the system's vice president for mission effectiveness, and professional peers should then work together to create supporting documents (e.g., job descriptions and pay grades) and an implementation plan. After the program basics are in place, partners can be sought and assessed. When a partnership is established, recruitment and orientation of the parish nurse begins. Once hired, the parish nurse should participate in the system's and the parish's orientation and continuing education sessions. A parish nurse with no previous experience as such should meet with an experienced parish nurse to get advice on interacting with parishioners and hospital and parish staff.


Chemotherapeutic deletion of CTG repeats in lymphoblast cells from DM1 patients.
Myotonic dystrophy type 1 (DM1) is caused by the expansion of a (CTG).(CAG) repeat in the DMPK gene on chromosome 19q13.3. At least 17 neurological diseases have similar genetic mutations, the expansion of DNA repeats. In most of these disorders, the disease severity is related to the length of the repeat expansion, and in DM1 the expanded repeat undergoes further elongation in somatic and germline tissues. At present, in this class of diseases, no therapeutic approach exists to prevent or slow the repeat expansion and thereby reduce disease severity or delay disease onset. We present initial results testing the hypothesis that repeat deletion may be mediated by various chemotherapeutic agents. Three lymphoblast cell lines derived from two DM1 patients treated with either ethylmethanesulfonate (EMS), mitomycin C, mitoxantrone or doxorubicin, at therapeutic concentrations, accumulated deletions following treatment. Treatment with EMS frequently prevented the repeat expansion observed during growth in culture. A significant reduction of CTG repeat length by 100-350 (CTG).(CAG) repeats often occurred in the cell population following treatment with these drugs. Potential mechanisms of drug-induced deletion are presented.


Using deep neural networks and interpretability methods to identify gene expression patterns that predict radiomic features and histology in non-small cell lung cancer.
Purpose: Integrative analysis combining diagnostic imaging and genomic information can uncover biological insights into lesions that are visible on radiologic images. We investigate techniques for interrogating a deep neural network trained to predict quantitative image (radiomic) features and histology from gene expression in non-small cell lung cancer (NSCLC). Approach: Using 262 training and 89 testing cases from two public datasets, deep feedforward neural networks were trained to predict the values of 101 computed tomography (CT) radiomic features and histology. A model interrogation method called gene masking was used to derive the learned associations between subsets of genes and a radiomic feature or histology class [adenocarcinoma (ADC), squamous cell, and other]. Results: Overall, neural networks outperformed other classifiers. In testing, neural networks classified histology with area under the receiver operating characteristic curves (AUCs) of 0.86 (ADC), 0.91 (squamous cell), and 0.71 (other). Classification performance of radiomics features ranged from 0.42 to 0.89 AUC. Gene masking analysis revealed new and previously reported associations. For example, hypoxia genes predicted histology ( > 0.90 AUC ). Previously published gene signatures for classifying histology were also predictive in our model ( > 0.80 AUC ). Gene sets related to the immune or cardiac systems and cell development processes were predictive ( > 0.70 AUC ) of several different radiomic features. AKT signaling, tumor necrosis factor, and Rho gene sets were each predictive of tumor textures. Conclusions: This work demonstrates neural networks' ability to map gene expressions to radiomic features and histology types in NSCLC and to interpret the models to identify predictive genes associated with each feature or type.


Surgical Treatment Guidelines for Digital Deformity Associated With Intrinsic Muscle Spasticity (Intrinsic Plus Foot) in Adults With Cerebral Palsy.
Intrinsic plus foot deformity has primarily been associated with cerebral palsy and involves spastic contracture of the intrinsic musculature with resultant toe deformities. Digital deformity is caused by a dynamic imbalance between the intrinsic muscles in the foot and extrinsic muscles in the lower leg. Spastic contracture of the toes frequently involves curling under of the lesser digits or contracture of the hallux into valgus or plantarflexion deformity. Patients often present with associated pressure ulcers, deformed toenails, shoe or brace fitting challenges, and pain with ambulation or transfers. Four different patterns of intrinsic plus foot deformity have been observed by the authors that likely relate to the different patterns of muscle involvement. Case examples are provided of the 4 patterns of intrinsic plus foot deformity observed, including global intrinsic plus lesser toe deformity, isolated intrinsic plus lesser toe deformity, intrinsic plus hallux valgus deformity, and intrinsic plus hallux flexus deformity. These case examples are presented to demonstrate each type of deformity and our approach for surgical management according to the contracture pattern. The surgical approach has typically involved tenotomy, capsulotomy, or isolated joint fusion. The main goals of surgical treatment are to relieve pain and reduce pressure points through digital realignment in an effort to decrease the risk of pressure sores and allow more effective bracing to ultimately improve the patient's mobility.


Brain-derived neurotrophic factor-induced gene expression reveals novel actions of VGF in hippocampal synaptic plasticity.
Synaptic strengthening induced by brain-derived neurotrophic factor (BDNF) is associated with learning and is coupled to transcriptional activation. However, identification of the spectrum of genes associated with BDNF-induced synaptic plasticity and the correlation of expression with learning paradigms in vivo has not yet been studied. Transcriptional analysis of BDNF-induced synaptic strengthening in cultured hippocampal neurons revealed increased expression of the immediate early genes (IEGs), c-fos, early growth response gene 1 (EGR1), activity-regulated cytoskeletal-associated protein (Arc) at 20 min, and the secreted peptide VGF (non-acronymic) protein precursor at 3 hr. The induced genes served as prototypes to decipher mechanisms of both BDNF-induced transcription and plasticity. BDNF-mediated gene expression was tyrosine kinase B and mitogen-activated protein kinase-dependent, as demonstrated by pharmacological studies. Single-cell transcriptional analysis of Arc after whole-cell patch-clamp recordings indicated that increased gene expression correlated with enhancement of synaptic transmission by BDNF. Increased expression in vitro predicted elevations in vivo: VGF and the IEGs increased after trace eyeblink conditioning, a hippocampal-dependent learning paradigm. VGF protein was also upregulated by BDNF treatment and was expressed in a punctate manner in dissociated hippocampal neurons. Collectively, these findings suggested that the VGF neuropeptides may regulate synaptic function. We found a novel function for VGF by applying VGF peptides to neurons. C-terminal VGF peptides acutely increased synaptic charge in a dose-dependent manner, whereas N-terminal peptide had no effect. These observations indicate that gene profiling in vitro can reveal new mechanisms of synaptic strengthening associated with learning and memory.


Actin capping protein: an essential element in protein kinase signaling to the myofilaments.
Actin capping protein (CapZ) binds the barbed ends of actin at sarcomeric Z-lines. In addition to anchoring actin, Z-discs bind protein kinase C (PKC). Although CapZ is crucial for myofibrillogenesis, its role in muscle function and intracellular signaling is unknown. We hypothesized that CapZ downregulation would impair myocardial function and disrupt PKC-myofilament signaling by impairing PKC-Z-disc interaction. To test these hypotheses, we examined transgenic (TG) mice in which cardiac CapZ protein is reduced. Fiber bundles were dissected from papillary muscles and detergent extracted. Some fiber bundles were treated with PKC activators phenylephrine (PHE) or endothelin (ET) before detergent extraction. We simultaneously measured Ca2+-dependent tension and actomyosin MgATPase activity. CapZ downregulation increased myofilament Ca2+ sensitivity without affecting maximum tension or actomyosin MgATPase activity. Maximum tension and actomyosin MgATPase activity were decreased after PHE or ET treatment of wild-type (WT) muscle. Fiber bundles from TG hearts did not respond to PHE or ET. Immunoblot analysis revealed an increase in myofilament-associated PKC-epsilon after PHE or ET exposure of WT preparations. In contrast, myofilament-associated PKC-epsilon was decreased after PHE or ET treatment in TG myocardium. Protein levels of myofilament-associated PKC-beta were decreased in TG ventricle. C-protein and troponin I phosphorylation was increased after PHE or ET treatment in WT and TG hearts. Basal phosphorylation levels of C-protein and troponin I were higher in TG myocardium. These results indicate that downregulation of CapZ, or other changes associated with CapZ downregulation, increases cardiac myofilament Ca2+ sensitivity, inhibits PKC-mediated control of myofilament activation, and decreases myofilament-associated PKC-beta.


Fixation duration surpasses pupil size as a measure of memory load in free viewing.
Oculomotor behavior reveals, not only the acquisition of visual information at fixation, but also the accumulation of information in memory across subsequent fixations. Two candidate measures were considered as indicators of such dynamic visual memory load: fixation duration and pupil size. While recording these measures, we displayed an arrangement of 3, 4 or 5 targets among distractors. Both occurred in various orientations. Participants searched for targets and reported whether in a subsequent display one of them had changed orientation. We determined to what extent fixation duration and pupil size indicate dynamic memory load, as a function of the number of targets fixated during the search. We found that fixation duration reflects the number of targets, both when this number is within and above the limit of working memory capacity. Pupil size reflects the number of targets only when it exceeds the capacity limit. Moreover, the duration of fixations on successive targets but not on distractors increases whereas pupil size does not. The increase in fixation duration with number of targets both within and above working memory capacity suggests that in free viewing fixation duration is sensitive to actual memory load as well as to processing load, whereas pupil size is indicative of processing load only. Two alternative models relating visual attention and working memory are considered relevant to these results. We discuss the results as supportive of a model which involves a temporary buffer in the interaction of attention and working memory.


[Morphological and immunohistochemical characteristic of oral mucosa in patients with inflammatory bowel disease].
The aim of presented study was to investigate the morphological and immunohistochemical characteristics of the oral mucosa in patients with Crohn's disease and ulcerative colitis. The study involved 40 patients aged from 18 to 64 years, among them 30 patients with Crohn's disease and 10 patients with ulcerative colitis. Clinical, endoscopic, morphometric and immunohistochemical study have shown that Crohn's disease is characterized by generalized inflammation in the gastrointestinal tract with signs of immune inflammation in the mouth, whereas in ulcerative colitis the pathologic process is limited to the colon. In this context, the defeat of the oral mucosa can be regarded as a distinct phenotypic characteristic of the localization of Crohn's disease, with some differential-diagnostic and prognostic criteria.


Femtosecond soliton mode-locked laser based on ytterbium-doped photonic bandgap fiber.
We demonstrate a solid-core ytterbium-doped photonic bandgap fiber laser passively mode-locked with a semiconductor saturable absorber. Gain and anomalous dispersion simultaneously provided by the photonic crystal fiber allow for an all-fiber subpicosecond soliton oscillator. We also discuss the effect of higher-order dispersion in photonic bandgap fiber on laser performance.


Radiologists Make More Errors Interpreting Off-Hours Body CT Studies during Overnight Assignments as Compared with Daytime Assignments.
Background There is increasing research attention on the impact of overnight work on radiologist performance. Prior studies on overnight imaging interpretive errors have focused on radiology residents, not on the relative performance of board-eligible or board-certified radiologists at night compared with during the day. Purpose To analyze the rate of clinically important interpretation errors on CT examinations of the abdomen, pelvis, or both ("body CT studies") committed by radiology fellows working off-hours based on day or night assignment. Materials and Methods Between July 2014 and June 2018, attending physicians at one tertiary care institution reviewed all body CT studies independently interpreted off-hours by radiologists in an academic fellowship within 10 hours of initial interpretation. Discrepancies affecting acute or follow-up clinical care were classified as errors. In this retrospective study, the error rate for studies interpreted during the day (between 7:00 am and 5:59 pm) was compared with that of studies interpreted at night (between 6:00 pm and 6:59 am). Error rate in the first half of day and night assignments was compared with error rate in the latter half. Statistical analyses used χ2 tests and general estimating equations; significance was defined as P < .05. Results There were 10 090 body CT studies interpreted by 32 radiologists. Forty-four of 2195 daytime studies (2.0%) had errors compared with 240 of 7895 nighttime studies (3.0%; P = .02). Twenty-two of 32 (69%) radiologists had higher error rates for night cases (P = .03). There were more errors in the last half of a night assignment (125 of 3358, 3.7%; P = .002) compared with the first half (115 of 4537, 2.5%). Conclusion On the basis of a subspecialty review, clinically important off-hours body CT interpretation errors occurred more frequently overnight and more frequently in the latter half of assignments, with more radiologists having worse error rates at night compared with the day. © RSNA, 2020 See also the editorial by Bruno in this issue.


Electrospun formulations of bevacizumab for sustained release in the eye.
Medicines based on vascular endothelial growth factor (VEGF) neutralising antibodies such as bevacizumab have revolutionized the treatment of age related macular degeneration (AMD), a common blinding disease, and have great potential in preventing scarring after surgery or accelerating the healing of corneal injuries. However, at present frequent invasive injections are required to deliver these antibodies. Such administration is uncomfortable for patients and expensive for health service providers. Much effort is thus focused on developing dosage forms that can be administered less frequently. Here we use electrospinning to prepare a solid form of bevacizumab designed for prolonged release while maintaining antibody stability. Electrospun fibers were prepared with bevacizumab encapsulated in the core, surrounded by a poly-ε-caprolactone sheath. The fibers were generated using aqueous bevacizumab solutions buffered at two different pH values: 6.2 (the pH of the commercial product; Fbeva) and 8.3 (the isoelectric point of bevacizumab; FbevaP). The fibers had smooth and cylindrical morphologies, with diameters of ca. 500nm. Both sets of bevacizumab loaded fibers gave sustained release profiles in an in vitro model of the subconjunctival space of the eye. Fbeva displayed first order kinetics with t1/2 of 11.4±4.4 days, while FbevaP comprises a zero-order reservoir type release system with t1/2 of 52.9±14.8 days. Both SDS-PAGE and surface plasmon resonance demonstrate that the bevacizumab in FbevaP did not undergo degradation during fiber fabrication or release. In contrast, the antibody released from Fbeva had degraded, and failed to bind to VEGF. Our results demonstrate that pH control is crucial to maintain antibody stability during the fabrication of core/shell fibers and ensure release of functional protein. Bevacizumab is a potent protein drug which is highly effective in the treatment of degenerative conditions in the eye. To be effective, frequent injections into the eye are required, which is deeply unpleasant for patients and expensive for healthcare providers. Alternative methods of administration are thus highly sought after. In our work, we use the electrospinning technique to prepare fiber-based formulations loaded with bevacizumab. By careful control of the experimental parameters we are able to stabilize the protein during processing and ensure a constant rate of release over more than two months in vitro. These fibers could thus be used to reduce the frequency of dosing required, reducing cost and improving patient outcomes.


Molecular and phenotypic characterization of atypical Williams-Beuren syndrome.
Williams-Beuren syndrome (WBS) is a multisystemic genomic disorder typically caused by a recurrent ˜1.5-1.8 Mb deletion on 7q11.23. Atypical deletions can provide important insight into the genotype-phenotype correlations. Here, we report the phenotypic and molecular characterization of a girl with a de novo 81.8 kb deletion in the WBS critical region, which involves the ELN and LIMK1 genes only. The patient presented at 2 months of age with extensive vascular abnormalities, mild facial dysmorphism and delays in her fine motor skills. We discuss potential molecular mechanisms and the role of ELN and LIMK1 in the different phenotypic features. We compare the findings in our patient with previously reported overlapping deletions. The phenotypic variability among these patients suggests that other factors are important in the phenotype and possibly include: position effects related to copy number variation size, variations in the non-deleted alleles, genetic modifiers elsewhere in the genome, or reduced penetrance for specific phenotypes.


Deep learning in radiology: An overview of the concepts and a survey of the state of the art with focus on MRI.
Deep learning is a branch of artificial intelligence where networks of simple interconnected units are used to extract patterns from data in order to solve complex problems. Deep-learning algorithms have shown groundbreaking performance in a variety of sophisticated tasks, especially those related to images. They have often matched or exceeded human performance. Since the medical field of radiology mainly relies on extracting useful information from images, it is a very natural application area for deep learning, and research in this area has rapidly grown in recent years. In this article, we discuss the general context of radiology and opportunities for application of deep-learning algorithms. We also introduce basic concepts of deep learning, including convolutional neural networks. Then, we present a survey of the research in deep learning applied to radiology. We organize the studies by the types of specific tasks that they attempt to solve and review a broad range of deep-learning algorithms being utilized. Finally, we briefly discuss opportunities and challenges for incorporating deep learning in the radiology practice of the future. Level of Evidence: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:939-954.


Regular, Intense Exercise Training as a Healthy Aging Lifestyle Strategy: Preventing DNA Damage, Telomere Shortening and Adverse DNA Methylation Changes Over a Lifetime.
Exercise training is one of the few therapeutic interventions that improves health span by delaying the onset of age-related diseases and preventing early death. The length of telomeres, the 5'-TTAGGG n -3' tandem repeats at the ends of mammalian chromosomes, is one of the main indicators of biological age. Telomeres undergo shortening with each cellular division. This subsequently leads to alterations in the expression of several genes that encode vital proteins with critical functions in many tissues throughout the body, and ultimately impacts cardiovascular, immune and muscle physiology. The sub-telomeric DNA is comprised of heavily methylated, heterochromatin. Methylation and histone acetylation are two of the most well-studied examples of the epigenetic modifications that occur on histone proteins. DNA methylation is the type of epigenetic modification that alters gene expression without modifying gene sequence. Although diet, genetic predisposition and a healthy lifestyle seem to alter DNA methylation and telomere length (TL), recent evidence suggests that training status or physical fitness are some of the major factors that control DNA structural modifications. In fact, TL is positively associated with cardiorespiratory fitness, physical activity level (sedentary, active, moderately trained, or elite) and training intensity, but is shorter in over-trained athletes. Similarly, somatic cells are vulnerable to exercise-induced epigenetic modification, including DNA methylation. Exercise-training load, however, depends on intensity and volume (duration and frequency). Training load-dependent responses in genomic profiles could underpin the discordant physiological and physical responses to exercise. In the current review, we will discuss the role of various forms of exercise training in the regulation of DNA damage, TL and DNA methylation status in humans, to provide an update on the influence exercise training has on biological aging.


The effects of post-partum drops in body condition on indices of energy metabolism in mid-lactation Holstein cows.
Evaluation of energy metabolism indices in mid-lactation Holstein cows is critical to monitor health status. Aims: The objective of this study was to assess the effects of low (≤0.75) vs. high (>0.75) drops in body condition score (BCS) until day 60 post-partum on energy metabolism indices during mid-lactation in Holstein cows. Twenty-eight Holstein cows were included in the study from the day of calving to day 120 of lactation. Whole blood samples were taken on 60, 90, and 120 days in milk (DIM). Serum was analyzed for insulin, glucose, non-esterified fatty acids (NEFA) and beta-hydroxybutyrate (BHB) levels. In cows with low BCS drop (LoD group), insulin did not change significantly through days 60 to 120 of lactation, but increased in high drop cows (HiD group) (P<0.001). Glucose concentrations decreased linearly in the LoD cows (P=0.039) and showed a quadratic increase in the HiD group on day 90 (P=0.028). Concentrations of non-esterified fatty acids showed both linear (P=0.04) and quadratic (P=0.002) changes in the HiD group. The HiD cows had significantly higher concentrations of insulin on day 120 (P=0.017) compared to the LoD group. Glucose concentration was lower (P<0.01) in HiD cows on 60 DIM. The concentration of non-esterified fatty acids was higher in HiD cows on day 90 (P<0.01). Surrogate indices of insulin resistance (calculated based on the concentrations of the measured metabolites) were different between the groups on day 90, indicating decreased insulin sensitivity in the HiD cows. Greater depletion of body reserves during early lactation may result in some inconsistencies in energy metabolism during mid-lactation periods. Controlling BCS loss during early lactation may help alleviate such alterations possibly through modifying insulin sensitivity of the tissues.


NCCTG N0821 (Alliance): a phase II first-line study of pemetrexed, carboplatin, and bevacizumab in elderly patients with advanced nonsquamous non-small-cell lung cancer with good performance status.
We hypothesized that the combination of bevacizumab, carboplatin, and pemetrexed will be an effective first-line regimen in fit, elderly patients with nonsquamous non-small-cell lung cancer. Treatment-naïve, stage IIIB/IV nonsquamous non-small-cell lung cancer patients more than 70 years old with good performance status (Eastern Cooperative Oncology Group performance status 0-1) and adequate organ function were eligible. Carboplatin area under the curve 6, pemetrexed 500 mg/m, and bevacizumab 15 mg/kg were administered on day 1 of each 21-day cycle (up to six cycles) followed by maintenance pemetrexed and bevacizumab. The primary end point of 6-month progression-free survival rate of at least 70% was assessed using a one-stage binomial design. Quality of life (QOL) questionnaires were administered. Polymorphisms in genes encoding relevant proteins (drug targets, transport, and metabolism proteins) were correlated with treatment outcome. Fifty-seven eligible patients were enrolled. Median age was 74.5 years. Median treatment cycles received was 6. The most common grade 3 or higher non-hematologic adverse events were fatigue (26%) and hypertension (11%); 16% had grade 4 neutropenia and 6.5% had grade 4 thrombocytopenia. Three patients experienced grade 3/4 hemorrhagic events (one pulmonary, two gastrointestinal). Primary end point of PFS6 was 60% (95% confidence interval [CI]: 45.9-73%). Median PFS was 7.0 months (95% CI: 5.9-10.1), median overall survival was 13.7 months (95% CI: 9.4-16.8). Polymorphic KDR and VEGFA variants correlated with survival and toxicity, respectively. There was no significant change in overall QOL scores over time. This regimen is feasible and did not decrease the QOL in this study population. However, it did not meet the primary efficacy end point.


Innate immune cells in inflammation and cancer.
The innate immune system has evolved in multicellular organisms to detect and respond to situations that compromise tissue homeostasis. It comprises a set of tissue-resident and circulating leukocytes primarily designed to sense pathogens and tissue damage through hardwired receptors and eliminate noxious sources by mediating inflammatory processes. While indispensable to immunity, the inflammatory mediators produced in situ by activated innate cells during injury or infection are also associated with increased cancer risk and tumorigenesis. Here, we outline basic principles of innate immune cell functions in inflammation and discuss how these functions converge upon cancer development.


Identification of HPCAL1 as a specific autophagy receptor involved in ferroptosis.
Selective macroautophagy/autophagy maintains cellular homeostasis through the lysosomal degradation of specific cellular proteins or organelles. The pro-survival effect of selective autophagy has been well-characterized, but the mechanism by which it drives cell death is still poorly understood. Here, we use a quantitative proteomic approach to identify HPCAL1 (hippocalcin like 1) as a novel autophagy receptor for the selective degradation of CDH2 (cadherin 2) during ferroptosis. HPCAL1-dependent CDH2 depletion increases susceptibility to ferroptotic death by reducing membrane tension and favoring lipid peroxidation. Site-directed mutagenesis aided by bioinformatic analyses revealed that the autophagic degradation of CDH2 requires PRKCQ (protein kinase C theta)-mediated HPCAL1 phosphorylation on Thr149, as well as a non-classical LC3-interacting region motif located between amino acids 46-51. An unbiased drug screening campaign involving 4208 small molecule compounds led to the identification of a ferroptosis inhibitor that suppressed HPCAL1 expression. The genetic or pharmacological inhibition of HPCAL1 prevented ferroptosis-induced tumor suppression and pancreatitis in suitable mouse models. These findings provide a framework for understanding how selective autophagy promotes ferroptotic cell death.Abbreviations: ANXA7: annexin A7; ARNTL: aryl hydrocarbon receptor nuclear translocator like; CCK8: cell counting kit-8; CDH2: cadherin 2; CETSAs: cellular thermal shift assays; CPT2: carnitine palmitoyltransferase 2; DAMP, danger/damage-associated molecular pattern; DPPH: 2,2-diphenyl-1-picrylhydrazyl; DFO: deferoxamine; EBNA1BP2: EBNA1 binding protein 2; EIF4G1: eukaryotic translation initiation factor 4 gamma 1; FBL: fibrillarin; FKBP1A: FKBP prolyl isomerase 1A; FTH1: ferritin heavy chain 1; GPX4: glutathione peroxidase 4; GSDMs: gasdermins; HBSS: Hanks' buffered salt solution; HMGB1: high mobility group box 1; HNRNPUL1: heterogeneous nuclear ribonucleoprotein U like 1; HPCAL1: hippocalcin like 1; H1-3/HIST1H1D: H1.3 linker histone, cluster member; IKE: imidazole ketone erastin; KD: knockdown; LDH: lactate dehydrogenase; LIR: LC3-interacting region; MAGOH: mago homolog, exon junction complex subunit; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MDA: malondialdehyde; MLKL: mixed lineage kinase domain like pseudokinase; MPO: myeloperoxidase; MTOR: mechanistic target of rapamycin kinase; OE: overexpressing; OSTM1: osteoclastogenesis associated transmembrane protein 1; PRKC/PKC: protein kinase C; PRKAR1A: protein kinase cAMP-dependent type I regulatory subunit alpha; PRDX3: peroxiredoxin 3; PTGS2: prostaglandin-endoperoxide synthase 2; ROS: reactive oxygen species; SLC7A11: solute carrier family 7 member 11; SLC40A1: solute carrier family 40 member 1; SPTAN1: spectrin alpha, non-erythrocytic 1; STS: staurosporine; UBE2M: ubiquitin conjugating enzyme E2 M; ZYX: zyxin.


Generating lineage-specific markers to study Drosophila development.
To generate cell- and tissue-specific expression patterns of the reporter gene lacZ in Drosophila, we have generated and characterized 1,426 independent insertion strains using four different P-element constructs. These four transposons carry a lacZ gene driven either by the weak promoter of the P-element transposase gene or by partial promoters from the even-skipped, fushi-tarazu, or engrailed genes. The tissue-specific patterns of beta-galactosidase expression that we are able to generate depend on the promoter utilized. We describe in detail 13 strains that can be used to follow specific cell lineages and demonstrate their utility in analyzing the phenotypes of developmental mutants. Insertion strains generated with P-elements that carry various sequences upstream of the lacZ gene exhibit an increased variety of expression patterns that can be used to study Drosophila development.


Superior biolubricant from a species of red microalga.
The rheological properties of the sulfated polysaccharide of the red microalga Porphyridium sp., a heteropolymer with a molecular weight of 3-5 x 10(6) Da, indicated that this material might be an excellent candidate for lubrication applications: the viscosity of the polysaccharide is stable over a range of temperatures, pH values, and salinities. In this study, various rheological and lubricant properties of the polysaccharide were evaluated in comparison with those of a widely used biolubricant, hyaluronic acid. The viscosity of the Porphyridium sp. polysaccharide remained essentially unchanged in a temperature range of 25-70 degrees C. In tribology tests on a ball-on-flat ceramic pair, the values for the friction coefficient and wear rate for the pair lubricated with polysaccharide were remarkably lower than those for hyaluronic acid, especially at high loads. In a test on a steel ring/ultrahigh-molecular-weight polyethylene (UHMWPE) block pair, the wear tracks on the surface of the UHMWPE were more pronounced for hyaluronic acid than for the polysaccharide. Atomic force microscopy showed that the polysaccharide was effectively adsorbed onto mica surfaces, forming ultrathin coating layers in the nanometer range. As is required for biolubricant applications, the polysaccharide was not degraded by hyaluronidase. The stability of the Porphyridium sp. polysaccharide to heat and to hyaluronidase combined with its ability to reduce friction and wear indicate its potential as an advantageous biolubricant.


Prosthodontic complications with implant overdentures: a systematic literature review.
Problems associated with a complete denture, such as lack of stability and retention, can be solved with the use of implant-retained or implant-supported overdentures. However, controversy exists as to the anchorage system used and indications for both the maxilla and mandible. The purpose of this review was to identify the prosthetic complications associated with the different attachment mechanisms used for implant-supported or implant-retained overdentures. A search of the MEDLINE and PubMed databases was conducted to find articles in English and German peer-reviewed journals published between 1980 and 2008. The search focused on randomized controlled clinical trials and prospective studies with follow-up periods of at least 5 years that contained clinical data regarding success, failure, and prosthetic complications. The search yielded a limited number of randomized controlled clinical trials referring to implant-supported or implant-retained overdentures. Very few studies have prospectively compared prosthetic complications for a period longer than 5 years after delivery of the prosthesis. Implant-supported or implant-retained overdentures in the mandible provide predictable results with improved stability, retention, and patient satisfaction. Scientific evidence shows a lower rate of implant survival and a higher frequency of prosthetic complications for maxillary implant-retained or implant-supported overdentures. Although the literature presents considerable information on complications of implant prostheses, variations in study design preclude proper analysis of certain complications. Well-designed longitudinal studies are required to establish evidence-based treatment planning principles.


Distinct roles of Bcl-2 and Bcl-Xl in the apoptosis of human bone marrow mesenchymal stem cells during differentiation.
Adult mesenchymal stem cells (MSCs) can be maintained over extended periods of time before activation and differentiation. Little is known about the programs that sustain the survival of these cells. Undifferentiated adult human MSCs (hMSCs) did not undergo apoptosis in response to different cell death inducers. Conversely, the same inducers can readily induce apoptosis when hMSCs are engaged in the early stages of differentiation. The survival of undifferentiated cells is linked to the expression of Bcl-Xl and Bcl-2 in completely opposite ways. Bcl-Xl is expressed at similar levels in undifferentiated and differentiated hMSCs while Bcl-2 is expressed only in differentiated cells. In undifferentiated hMSCs, the down-regulation of Bcl-Xl is associated with an increased sensitivity to apoptosis while the ectopic expression of Bcl-2 induced apoptosis. This apoptosis is linked to the presence of cytoplasmic Nur 77 in undifferentiated hMSCs. In hMSCs, the expression of Bcl-2 depends on cellular differentiation and can be either pro- or anti-apoptotic. Bcl-Xl, on the other hand, exhibits an anti-apoptotic activity under all conditions.


Yoga and meditation for menopausal symptoms in breast cancer survivors-A randomized controlled trial.
Breast cancer survivors have only very limited treatment options for menopausal symptoms. The objective of this trial was to evaluate the effects of a 12-week traditional Hatha yoga and meditation intervention on menopausal symptoms in breast cancer survivors. Patients were randomly assigned either to a 12-week yoga and meditation intervention or to usual care. The primary outcome measure was total menopausal symptoms (Menopause Rating Scale [MRS] total score). Secondary outcome measures included MRS subscales, quality of life (Functional Assessment of Cancer Therapy-Breast), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue), depression, and anxiety (Hospital Anxiety and Depression Scale). Outcomes were assessed at week 12 and week 24 after randomization. In total, 40 women (mean age ± standard deviation, 49.2 ± 5.9 years) were randomized to yoga (n = 19) or to usual care (n = 21). Women in the yoga group reported significantly lower total menopausal symptoms compared with the usual care group at week 12 (mean difference, -5.6; 95% confidence interval, -9.2 to -1.9; P = .004) and at week 24 (mean difference, -4.5; 95% confidence interval, -8.3 to -0.7; P = .023). At week 12, the yoga group reported less somatovegetative, psychological, and urogenital menopausal symptoms; less fatigue; and improved quality of life (all P < .05). At week 24, all effects persisted except for psychological menopausal symptoms. Short-term effects on menopausal symptoms remained significant when only women who were receiving antiestrogen medication (n = 36) were analyzed. Six minor adverse events occurred in each group. Yoga combined with meditation can be considered a safe and effective complementary intervention for menopausal symptoms in breast cancer survivors. The effects seem to persist for at least 3 months.


Preclinical Evaluation of Inhalational Spectinamide-1599 Therapy against Tuberculosis.
The lengthy treatment time for tuberculosis (TB) is a primary cause for the emergence of multidrug resistant tuberculosis (MDR-TB). One approach to improve TB therapy is to develop an inhalational TB therapy that when administered in combination with oral TB drugs eases and shortens treatment. Spectinamides are new semisynthetic analogues of spectinomycin with excellent activity against Mycobacterium tuberculosis (Mtb), including MDR and XDR Mtb strains. Spectinamide-1599 was chosen as a promising candidate for development of inhalational therapy. Using the murine TB model and intrapulmonary aerosol delivery of spectinamide-1599, we characterized the pharmacokinetics and efficacy of this therapy in BALB/c and C3HeB/FeJ mice infected with the Mtb Erdman strain. As expected, spectinamide-1599 exhibited dose-dependent exposure in plasma, lungs, and ELF, but exposure ratios between lung and plasma were 12-40 times higher for intrapulmonary compared to intravenous or subcutaneous administration. In chronically infected BALB/c mice, low doses (10 mg/kg) of spectinamide-1599 when administered thrice weekly for two months provide efficacy similar to that of higher doses (50-100 mg/kg) after one month of therapy. In the C3HeB/FeJ TB model, intrapulmonary aerosol delivery of spectinamide-1599 (50 mg/kg) or oral pyrazinamide (150 mg/kg) had limited or no efficacy in monotherapy, but when both drugs were given in combination, a synergistic effect with superior bacterial reduction of >1.8 log10 CFU was observed. Throughout the up to eight-week treatment period, intrapulmonary therapy was well-tolerated without any overt toxicity. Overall, these results strongly support the further development of intrapulmonary spectinamide-1599 as a combination partner for anti-TB therapy.


[Fragile X syndrome confirmed by molecular analysis: a case-control study with pre and post-puberal patients].
The fragile X syndrome (FRAXA) is the most common cause of inherited mental retardation. However, it has been frequently underdiagnosed in pediatric population. The characterization of the most significant pre and post-puberal clinical features observed among patients that are positive for the FMR-1 mutation, is useful as a screening tool for ordering the DNA test. Therefore, a screening program for FRAXA has been conducted in a sample of 104 mentally retarded individuals (92 males and 12 females), comprehending familial history and physical examination in order to determine the clinical characteristics. The molecular test for the disease was performed in all individuals. Seventeen patients (14 males) were positive for the FMR-1 mutation. Familial mental retardation and poor eye contact were the most common clinical findings with statistical significance (p<0.05) in FRAXA pre and post-puberal patients. The post-puberal patients presented, as opposed to the control group, large ears, broad forehead and macroorchidism.


New genes in Drosophila quickly become essential.
To investigate the origin and evolution of essential genes, we identified and phenotyped 195 young protein-coding genes, which originated 3 to 35 million years ago in Drosophila. Knocking down expression with RNA interference showed that 30% of newly arisen genes are essential for viability. The proportion of genes that are essential is similar in every evolutionary age group that we examined. Under constitutive silencing of these young essential genes, lethality was high in the pupal stage and also found in the larval stages. Lethality was attributed to diverse cellular and developmental defects, such as organ formation and patterning defects. These data suggest that new genes frequently and rapidly evolve essential functions and participate in development.


Effects of conditioning activity mode, rest interval and effort to pause ratio on post-activation performance enhancement in taekwondo: a randomized study.
Introduction: The present study assessed the effects of conditioning activities, using different effort-to-pause ratios and rest intervals, on taekwondo physical performance. Methods: Twenty-one athletes (13 males and 8 females) (Mean ± SD; age = 20.4 ± 1.4 years) performed a control (CC) and twelve experimental conditions. Each condition contained a standard warm-up (i.e., CC: running at 9 km/h for 10 min) and conditioning activities comprising plyometrics P) or repeated high-intensity techniques (RT) using 1:6, 1:9 and self-selected rest (SSR) ratios, and two rest intervals (3 and 7 min). Athletes then performed a battery of fitness tests: countermovement jump (CMJ), taekwondo specific agility (TSAT), 10s and multiple frequency speed kick test (FSKT-10s and FSKT-mult, respectively). Results: All of the preloads provided higher performance outputs compared to the control trial (all p < 0.05). For CMJ, 1:6 ratio with 3 min induced lower values with RT compared to P (p = 0.037) and 1:9 ratio using 3 min induced higher values with RT compared to P (p = 0.027). Additionally, 1:6 ratio using 7 min induced higher values with RT compared to P (p = 0.016). For FSKT-10, 3 min using 1:6 induced higher values with P compared to RT, while RT induced higher values with 7 min using 1:6 ratio compared to P (both p < 0.001). Moreover, 3 min using 1:9 ratio induced higher values with P compared to RT (p = 0.034), while RT induced higher values with 1:9 ratio using 7 min compared to P (p < 0.001). Finally, 3 min using SSR ratio induced higher values with RT compared to P (p = 0.034). Conclusion: Plyometrics and RT activities improved performance with plyometrics requiring shorter rest interval to induce potentiation effects compared to RT, which required longer interval.


Optometric management of patients with Alzheimer's disease.
The earliest symptoms of Alzheimer's disease (AD) may be visual. AD is an age-related, progressive dementia. At least 7% of Americans over 65 years of age are afflicted, and it ranks as the fourth leading cause of death in the United States. A review of the literature was performed to delineate the visual manifestations of Alzheimer's disease. Abnormal visual perception and visuospatial processing are common among patients with AD Visual acuity, pupillary light reflexes, and the ocular fundus do not appear to be specifically affected by AD. Whether AD impairs color vision is controversial. Stereopsis may also be affected. True visual-field defects are rarely found. Although not universally reported, some studies of contrast sensitivity functions show abnormal sensitivity possibly at low spatial frequencies. The electroretinogram is normal, while the visual evoked response is frequently abnormal. As primary eye care providers, optometrists must properly identify and refer individuals with suspected Alzheimer's disease to the appropriate specialist, as well as manage their visual welfare.


Quantifying Biophoton Emissions From Human Cells Directly Exposed to Low-Dose Gamma Radiation.
Biophoton emission leading to bystander effects (BEs) was shown in beta-irradiated cells; however, technical challenges precluded the analysis of the biophoton role in gamma-induced BEs. The present work was to design an experimental approach to determine if, what type, and how many biophotons could be produced in gamma-irradiated cells. Photon emission was measured in HCT116 p53+/+ cells irradiated with a total dose of 22 mGy from a cesium-137 source at a dose rate of 45 mGy/min. A single-photon detection unit was used and shielded with lead to reduce counts from stray gammas reaching the detector. Higher quantities of photon emissions were observed when the cells in a tissue culture vessel were present and being irradiated compared to a cell-free vessel. Photon emissions were captured at either 340 nm (in the ultraviolet A [UVA] range) or 610 nm. At the same cell density, radiation exposure time, and radiation dose, HCT116 p53+/+ cells emitted 2.5 times more UVA biophotons than 610-nm biophotons. For the first time, gamma radiation was shown to induce biophoton emissions from biological cells. As cellular emissions of UVA biophotons following beta radiation lead to BEs, the involvement of cellular emissions of the same type of UVA biophotons in gamma radiation-induced BEs is highly likely.


[Yifei Sanjie Pills alleviates cancer-related skeletal muscle atrophy in mice possibly by lowering inflammatory insulin resistance].
To evaluate the effects of Yifei Sanjie Pills (YFSJ) on weight, strength, pathology, glycogen and lipid contents and metabolism of skeletal muscles in tumor-bearing mice and explore the therapeutic mechanism of YFSJ for cancer-related skeletal muscle atrophy. Sixteen female ICR mice bearing intraperitoneal Lewis lung adenocarcinoma xenografts were randomized into model group and YFSJ treatment group (daily dose of 4 g/kg for 21 days, n=8), with another 8 normal mice as the normal control group. The changes in body weight and gastrocnemius muscle weight of the mice were recorded. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the drug components in YFSJ entering the blood. Enzyme-linked immunosorbent assay was used to detect serum blood glucose and insulin concentrations and inflammatory cytokine levels in the serum and gastrocnemius. RNA-seq was performed to analyze the signaling pathways involved in the pathologies of the gastrocnemius muscle, and lipid contents in the muscle were observed using Oil red O staining. Adenosine triphosphatase staining was used to assess the metabolic intensity of the gastrocnemius muscle, and inflammatory cell infiltration and P-AKT level were evaluated using immunohistochemical staining; the contents of creatine kinase, lactate dehydrogenase and myoglobin in the gastrocnemius muscle were also detected. Treatment with YFSJ significantly increased skeletal muscle strength and gastrocnemius muscle weight (P < 0.001) and reduced the levels of gastrocnemius muscle injury markers in the tumor-bearing mice (P < 0.01). RNA-seq and LC-MS showed that YFSJ alleviated gastrocnemius muscle injury in the tumor-bearing mice possibly by improving inflammatory infiltration, insulin resistance and lipid metabolism (P < 0.05). YFSJ lowered inflammatory cytokine levels in both the serum and gastrocnemius muscle (P < 0.05), reduced pro-inflammatory cell infiltration, increased P-AKT level, and improved glycogen and lipid contents and metabolic levels in the gastrocnemius muscle. YFSJ alleviates cancer-related skeletal muscle atrophy possibly by reducing inflammatory insulin resistance.


Rhinocerebral zygomycosis in a diabetic patient.
Rhinocerebral zygomycosis is the most frequent form of fungal infection caused by members of the Zygomycetes class. A fatal case of rhinocerebral zygomycosis caused by Rhizopus (oryzae) arrhizus with histopathological and mycological diagnosis is reported in a diabetic patient.


Eastern Association for the Surgery of Trauma practice management guidelines for hemorrhage in pelvic fracture--update and systematic review.
Hemorrhage from pelvic fracture is common in victims of blunt traumatic injury. In 2001, the Eastern Association for the Surgery of Trauma (EAST) published practice management guidelines for the management of hemorrhage in pelvic trauma. Since that time there have been new practice patterns and larger experiences with older techniques. The Practice Guidelines Committee of EAST decided to replace the 2001 guidelines with an updated guideline and systematic review reflecting current practice. Building on the previous systematic literature review in the 2001 EAST guidelines, a systematic literature review was performed to include references from 1999 to 2010. Prospective and retrospective studies were included. Reviews and case reports were excluded. Of the 1,432 articles identified, 50 were selected as meeting criteria. Nine Trauma Surgeons, an Interventional Radiologist, and an Orthopedic Surgeon reviewed the articles. The EAST primer was used to grade the evidence. Six questions regarding hemorrhage from pelvic fracture were addressed: (1) Which patients with hemodynamically unstable pelvic fractures warrant early external mechanical stabilization? (2) Which patients require emergent angiography? (3) What is the best test to exclude extrapelvic bleeding? (4) Are there radiologic findings which predict hemorrhage? (5) What is the role of noninvasive temporary external fixation devices? and (6) Which patients warrant preperitoneal packing? Hemorrhage due to pelvic fracture remains a major cause of morbidity and mortality in the trauma patient. Strong recommendations were made regarding questions 1 to 4. Further study is needed to answer questions 5 and 6.


Colloidal Alloyed Quantum Dots with Enhanced Photoluminescence Quantum Yield in the NIR-II Window.
Semiconductor quantum dots (QDs) with photoluminescence (PL) emission at 900-1700 nm (denoted as the second near-infrared window, NIR-II) exhibit much-depressed photon absorption and scattering, which has stimulated extensive researches in biomedical imaging and NIR devices. However, it is very challenging to develop NIR-II QDs with a high photoluminescence quantum yield (PLQY) and excellent biocompatibility. Herein, we designed and synthesized an alloyed silver gold selenide (AgAuSe) QD with a bright emission from 820 to 1170 nm and achieved a record absolute PLQY of 65.3% at 978 nm emission among NIR-II QDs without a toxic element and a long lifetime of 4.58 μs. It is proved that the high PLQY and long lifetime are mainly attributed to the prevented nonradiative transition of excitons, probably resulted from suppressing cation vacancies and crystal defects from the high mobility of Ag ions by alloying Au atoms. These high-PLQY QDs with nontoxic heavy metal exhibit great application potential in bioimaging, light emitting diodes (LEDs), and photovoltaic devices.


Postcopulatory female choice increases the fertilization success of novel males in the field cricket, Gryllus vocalis.
Although recent studies have demonstrated that female crickets prefer novel males to previous mates, the relative contribution of pre- and postcopulatory behaviors to this advantage remain unknown, as do the reproductive consequences to males. I paired females either with previous or novel mates, and recorded the latency to mating and the time after mating at which the female removed the male's spermatophore, terminating sperm transfer. Females that mated with familiar males removed their spermatophores sooner than females that mated with novel males. Females paired with novel males also mated more quickly than females paired with familiar males, but this difference was not statistically significant. A molecular-based paternity analysis was used to determine whether the postcopulatory preference of females for novel males influences a male's fertilization success. Females were assigned to either mate three times with the same male and then once with a novel male, or four times with four different males. The paternity of the last male was higher when the female previously had mated repeatedly with the same male than when she had mated previously with different males. These results suggest that female spermatophore removal behavior influences male paternity such that novel males receive a fertility benefit.


Characterization of lipopolysaccharide-induced macrophage gene expression.
A cDNA library from LPS-treated murine peritoneal macrophages has been screened by differential hybridization with radiolabeled cDNA from untreated and LPS-treated macrophages. Six clones hybridizing with mRNA sequences present in LPS-treated cells but not in controls were selected for further characterization. When the recombinant bacteriophage DNA from each clone was used as a probe in Northern analysis of total RNA from LPS-treated macrophages, inducible mRNA ranging from 1.45 to 6.4 kb were seen. In five of six cases, the mRNA expression was undetectable in untreated macrophage cultures. All but one clone identified mRNA that were inducible even in the presence of cycloheximide, indicating the independence of such gene expression from protein synthesis; none of the genes were superinduced by this treatment. The time course of expression differed among the individual genes. Four were induced transiently, whereas two showed stable increasing accumulation through an 8-h period after stimulation. In addition, four of the genes were seen within 30 min of stimulation, whereas two were seen only after 2 to 4 h. Two genes were induced only by treatment with LPS, whereas four were also induced in response to other agents, including IFN-gamma, macrophage CSF, and PMA. The insert sequences from these recombinant clones did not hybridize with a set of cDNA encoding other inducible gene products, including TNF, IL-1, ornithine decarboxylase, c-myc, c-fos, JE, or KC. Thus, these six cDNA appear to encode inducible macrophage genes that are distinct from one another as well as from a selection of previously described early genes. Although their functional identity remains indeterminate, they may encode previously described early proteins induced in macrophages treated with LPS.


Our experience in developing and operating the Airway Intervention Registry for Recurrent Respiratory Papillomatosis (AIR-RRP): national data collection.
Recurrent respiratory papillomatosis (RRP) is characterised by benign wart-like growths in the respiratory tract caused by the human papillomavirus (HPV). These warts vary in size and grow quickly, causing voice changes and airway obstruction. Whilst the condition is rare, RRP is more common and aggressive in children. There is currently no curative treatment for HPV, therefore RRP is managed by maintaining a safe airway and a serviceable voice by repeated surgery to remove the growths. A lack of specific diagnostic codes prevents reliable case ascertainment of RRP from routine administrative databases such as Hospital Episode Statistics. In 2017 a cross-sectional survey identified 918 RRP patients in the UK, half of whom had received surgical intervention for RRP in the previous 12 months with 16 different interventions. Randomised controlled trials for RRP interventions are difficult due to the rarity of the disease, variation in severity and progression and non-standard care across the NHS. Consequently, there is a lack of definitive efficacy and safety evidence. The only national guidance for RRP interventions is "Radiofrequency cold ablation for respiratory papillomatosis" (NICE IPG434, 2017) which recommended further data collection due to lack of evidence. However, due to the wide variation in RRP management across the NHS, clinical opinion favoured that any data collection should include a comparison of safety and efficacy of all RRP interventions in order to advise which improved patient outcomes and quality of life. To address lack of evidence, and inform the future care of RRP patients, we developed a registry and used it to collect real-world data from patients receiving treatment for RRP in NHS hospitals across the UK. The purpose of this paper is to share lessons learned from this national data collection exercise to inform future clinical registry development.


How to learn the International Standards to document remaining Autonomic Function after Spinal Cord Injury (ISAFSCI) content: Self-study through booklet is not enough.
To investigate the baseline knowledge of autonomic functions and specifically the International Standards to document remaining Autonomic Function after Spinal Cord Injury (ISAFSCI) among medical students and to present the effective methods in learning of the ISAFSCI. Interventional training session. A tertiary hospital. 37 medical students. Before training, a self-rating questionnaire including 24 concepts extracted from the ISAFSCI was administrated to the students. Then students were divided into two groups. One group (N = 19) had a one-hour ISAFSCI booklet self-study (BSS), while the other group (N = 18) received a one-hour lecture-based learning (LBL) about the ISAFSCI. After BSS/LBL, all students were examined by a 15-question written test on the knowledge of ISAFSCI. Baseline knowledge self-rating questionnaire before training and comparison of post-training performance on the written test between the BSS and LBL groups. Before training, students were familiar with only 8 out of the 24 concepts within the questionnaire (demonstrating baseline knowledge rate beyond 50%). Significant difference in post-training performance (P<0.05) between BBS and LBL groups was noted for 5 of 15 items tested, including hypohydrosis, broncho-pulmonary system, lower urinary tract function, bowel function and female sexual function. All questions except the one regarding hypohydrosis were answered with greater than 80% accuracy by LBL group. Use of ISAFSCI booklet alone for self-study by medical students is not sufficient to obtain bassline knowledge of autonomic discussions after SCI. It is recommended that formal lecture or presentation should be used to improve the effectiveness of learning the ISAFSCI for medical students.


Prosodic predictors of upcoming positive or negative content in spoken messages.
This article examines potential prosodic predictors of emotional speech in utterances perceived as conveying that good or bad news is about to be delivered. Speakers were asked to call an experimental confederate to inform her about whether or not she had been given a job she had applied for. A perception study was then performed in which initial fragments of the recorded utterances, not containing any explicit lexical cues to emotional content, were presented to listeners who had to rate whether good or bad news would follow the utterance. The utterances were then examined to discover acoustic and prosodic features that distinguished between good and bad news. It was found that speakers in the production study were not simply reflecting their own positive or negative mood during the experiment, but rather appeared to be influenced by the valence of the positive or negative message they were preparing to deliver. Positive and negative utterances appeared to be judged differently with respect to a number of perceived attributes of the speakers' voices (like sounding hesitant or nervous). These attributes correlated with a number of automatically obtained acoustic features.


Ellis-van Creveld Syndrome in Grey Alpine Cattle: Morphologic, Immunophenotypic, and Molecular Characterization.
Ellis-van Creveld (EvC) syndrome is a human autosomal recessive disorder caused by a mutation in either the EVC or EVC2 gene, and presents with short limbs, polydactyly, and ectodermal and heart defects. The aim of this study was to understand the pathologic basis by which deletions in the EVC2 gene lead to chondrodysplastic dwarfism and to describe the morphologic, immunohistochemical, and molecular hallmarks of EvC syndrome in cattle. Five Grey Alpine calves, with a known mutation in the EVC2 gene, were autopsied. Immunohistochemistry was performed on bone using antibodies to collagen II, collagen X, sonic hedgehog, fibroblast growth factor 2, and Ki67. Reverse transcription polymerase chain reaction was performed to analyze EVC1 and EVC2 gene expression. Autopsy revealed long bones that were severely reduced in length, as well as genital and heart defects. Collagen II was detected in control calves in the resting, proliferative, and hypertrophic zones and in the primary and secondary spongiosa, with a loss of labeling in the resting zone of 2 dwarfs. Collagen X was expressed in hypertrophic zone in the controls but was absent in the EvC cases. In affected calves and controls, sonic hedgehog labeled hypertrophic chondrocytes and primary and secondary spongiosa similarly. FGF2 was expressed in chondrocytes of all growth plate zones in the control calves but was lost in most EvC cases. The Ki67 index was lower in cases compared with controls. EVC and EVC2 transcripts were detected. Our data suggest that EvC syndrome of Grey Alpine cattle is a disorder of chondrocyte differentiation, with accelerated differentiation and premature hypertrophy of chondrocytes, and could be a spontaneous model for the equivalent human disease.


Morphine for the treatment of pain in sickle cell disease.
Pain is a hallmark of sickle cell disease (SCD) and its treatment remains challenging. Opioids are the major family of analgesics that are commonly used for treating severe pain. However, these are not always effective and are associated with the liabilities of their own. The pharmacology and multiorgan side effects of opioids are rapidly emerging areas of investigation, but there remains a scarcity of clinical studies. Due to opioid-induced endothelial-, mast cell-, renal mesangial-, and epithelial-cell-specific effects and proinflammatory as well as growth influencing signaling, it is likely that when used for analgesia, opioids may have organ specific pathological effects. Experimental and clinical studies, even though extremely few, suggest that opioids may exacerbate existent organ damage and also stimulate pathologies of their own. Because of the recurrent and/or chronic use of large doses of opioids in SCD, it is critical to evaluate the role and contribution of opioids in many complications of SCD. The aim of this review is to initiate inquiry to develop strategies that may prevent the inadvertent effect of opioids on organ function in SCD, should it occur, without compromising analgesia.


The Symptom Burden and Quality of Life in Cancer Patients in the Gaza Strip, Palestine: A Cross-Sectional Study.
Cancer is the second leading cause of death in the Gaza Strip, Palestine, but there is an absence of evidence systematically assessing symptom burden and quality of life (QoL) using validated tools. Our objective was to assess associations between socio-demographic and disease-related characteristics, symptom burden and QoL in a sample of cancer patients accessing outpatient services in the Gaza Strip. A cross-sectional, descriptive survey using interviews and medical record review involving patients with cancer accessing oncology outpatient services at Al Rantisi Hospital and European Gaza Hospital (EGH) in the Gaza Strip was employed. Socio-demographic and disease-related data, the Lebanese version of the Memorial Symptom Assessment Scale (MSAS-Leb), and the Arabic version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) were collected. Multiple linear regression was used to judge the relative influence of determinants of QoL. Of 414 cancer patients approached, 385 patients consented to participation. The majority were women (64.7%) with a mean age of 52 years (SD = 16.7). Common cancer diagnoses were breast (32.2%), haematological (17.9%) and colorectal (9.1%). The median number of symptoms was 10 (IQR 1.5-18.5). Mean overall QoL was 70.5 (SD 19.9) with common physical and psychological symptoms identified. A higher burden of symptoms was associated with marital status, education and income. Limited access to both opioids and psychological support were reported. A high symptom burden was identified in outpatients with cancer. Increasing provision and access to supportive care for physical and psychological symptoms should be prioritised alongside exploring routine assessment of symptom burden and QoL.


[Tables estimating glomerular filtration rate from plasma creatinine].
Chronic kidney disease (CKD) and its related complications have become an important health and social problem. Very expensive resources are required in end-stage renal disease, and both complications of CKD as well as the important associated cardiovascular risk demand for interventions long before renal substitution therapies are needed. Thus, early diagnosis of CKD is currently considered of paramount importance, and it is based essentially upon the estimation of the glomerular filtration rate by formulae such as the abbreviated equation of the MDRD study. Nevertheless, in spite of international published recommendations, an automatic calculation to estimate the glomerular filtration rate (GFR) from serum creatinine is not reported by most laboratories yet and the need for creatinine assay standardisation is far from being implemented. Thus, we have designed some tables to show the creatinine value corresponding to different GFR for ages between 20 and 90 y/o, at 5 years intervals and in both sexes with both the MDRD-4 and MDRD-IDMS equations (Modification of Diet in Renal Disease-Isotope Dilution Mass Spectrometry). Moreover, we have created a global table including an estimation of GFR from plasma creatinine, age and sex by the MDRD-IDMS formula, the recommended for those laboratories which measure serum creatinine with assays aligned to the reference method. These tables aim to increase the awareness of the different assays for serum creatinine and to facilitate the diagnosis of CKD converting serum creatinine into GFR. This action should allow not only the early detection but also the possibility to establish the appropriate medical actions recommended after CKD detection.


Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist.
Naturally occurring mutations of G protein-coupled receptors (GPCRs) causing misfolding and failure to traffic to the cell surface can result in disease states. Some small-molecule orthosteric ligands can rescue such misfolded receptors, presumably by facilitating their correct folding and shuttling to the plasma membrane. Here we show that a cell-permeant, allosterically binding small-molecule agonist (Org 42599) rescues the folding and cell surface expression, and therefore target cell signaling, of mutant human luteinizing hormone (LH) receptors (A593P and S616Y) that cause Leydig cell hypoplasia in man. Both mutant receptors were retained in the cytoplasm whereas WT receptor localized at the cell membrane, and binding of LH to cells expressing the mutant receptors was markedly lower than to those expressing the WT receptor. Incubation with Org 42599 increased mutant receptor expression, cell surface localization, and the proportion of mutant receptor in the mature glycosylated form. Importantly, although LH stimulated little (S616Y) or no (A593P) activation of cells expressing mutant receptors, incubation of cells with Org 42599 facilitated rescue of expression and stimulation by the native ligand, LH. Although Org 42599 could activate these receptors, it could not displace (125)I-labeled human LH binding to the WT receptor, indicating that it acts in an allosteric manner. Here we demonstrate a small-molecule GPCR allosteric agonist that functionally rescues intracellularly retained mutant LH receptors by facilitating their cell surface expression. This approach may have application for treatment of infertile patients bearing such mutations and, more broadly, for other misfolded GPCR mutants resulting in human pathologic processes.


A theoretical framework for the study of adult cognitive plasticity.
Does plasticity contribute to adult cognitive development, and if so, in what ways? The vague and overused concept of plasticity makes these controversial questions difficult to answer. In this article, we refine the notion of adult cognitive plasticity and sharpen its conceptual distinctiveness. According to our framework, adult cognitive plasticity is driven by a prolonged mismatch between functional organismic supplies and environmental demands and denotes the brain's capacity for anatomically implementing reactive changes in behavioral flexibility (i.e., the possible range of performance and function). We distinguish between 2 interconnected but distinct cognitive outcomes of adult cognitive plasticity: alterations in processing efficiency and alterations in representations. We demonstrate the usefulness of our framework in evaluating and interpreting (a) increments in frontal brain activations in the course of normal aging and (b) the effects of cognitive training in adulthood and old age. Finally, we outline new research questions and predictions generated by the present framework and recommend design features for future cognitive-training studies.


Variable resistance to zinc intoxication among Streptococcus agalactiae reveals a novel IS1381 insertion element within the zinc efflux transporter gene czcD.
Streptococcus agalactiae, also known as group B Streptococcus, is an important human and animal pathogen. Zinc (Zn) is an essential trace element for normal bacterial physiology but intoxicates bacteria at high concentrations. Molecular systems for Zn detoxification exist in S. agalactiae, however the degree to which Zn detoxification may vary among different S. agalactiae isolates is not clear. We measured resistance to Zn intoxication in a diverse collection of clinical isolates of S. agalactiae by comparing the growth of the bacteria in defined conditions of Zn stress. We found significant differences in the ability of different S. agalactiae isolates to resist Zn intoxication; some strains such as S. agalactiae 18RS21 were able to survive and grow at 3.8-fold higher levels of Zn stress compared to other reference strains such as BM110 (6.4mM vs 1.68mM Zn as inhibitory, respectively). We performed in silico analysis of the available genomes of the S. agalactiae isolates used in this study to examine the sequence of czcD, which encodes an efflux protein for Zn that supports resistance in S. agalactiae. Interestingly, this revealed the presence of a mobile insertion sequence (IS) element, termed IS1381, in the 5' region of czcD in S. agalactiae strain 834, which was hyper-resistant to Zn intoxication. Interrogating a wider collection of S. agalactiae genomes revealed identical placement of IS1381 in czcD in other isolates from the clonal-complex-19 (CC19) 19 lineage. Collectively, these results show a resistance spectrum among S. agalactiae isolates enables survival in varying degrees of Zn stress, and this phenotypic variability has implications for understanding bacterial survival in metal stress.


Neurodevelopment and mood stabilizers.
Mood disorders and schizophrenia share a number of common properties, including: genetic susceptibility; differences in brain structure and drug based therapy. Some genetic loci may even confer susceptibility for bipolar mood disorder and schizophrenia, and some atypical antipsychotic drugs are used as mood stabilizers. As schizophrenia is associated with aberrant neurodevelopment, could this also be true for mood disorders? Such changes could arise pre- or post-natal, however the recent interest in neurogenesis in the adult brain has suggested involvement of these later processes in the origins of mood disorders. Interestingly, the common mood stabilizing drugs, lithium, valproic acid (VPA) and carbamazepine, are teratogens, affecting a number of aspects of animal development. Recent work has shown that lithium and VPA interfere with normal cell development, and all three drugs affect neuronal morphology. The molecular basis for mood stabilizer action in the treatment of mood is unknown, however these studies have suggested both targets and potential mechanisms. Lithium directly inhibits two evolutionarily conserved signal transduction pathways: the protein kinase Glycogen Synthase Kinase-3 (GSK-3) and inositol signaling. VPA can up-regulate gene expression through inhibition of histone deacetylase (HDAC) and indirectly reduce GSK-3 activity. VPA effects are not conserved between cell types, and carbamazepine has no effect on the GSK-3 pathway. All three mood stabilizers suppress inositol signaling, results further supported by studies on the enzyme prolyl oligopeptidase (PO) and the sodium myo-inositol transporter (SMIT). Despite these intriguing observations, it remains unclear whether GSK-3, inositol signaling or both underlie the origins of bipolar disorder.


Stability of mixtures of ondansetron and haloperidol stored in infusors at different temperatures.
Mixing different drugs for use in continuous infusion systems is a common practice in palliative care, but analytical study of compatibility and stability is not always available. The objective of this work is to study the stability of solutions of ondansetron and haloperidol at different concentrations and temperatures all prepared in 0.9% NaCl and stored in infusors, with all cases protected from light. The high performance liquid chromatography-Ultraviolet (HPLC-UV) method was employed for the determination of the drugs. The concentrations of the admixtures were 0.15-0.25 mg/mL and 0.3-0.4 mg/mL of haloperidol and ondansetron, respectively, with a storage temperature of 25°C and 37°C. All solutions were initially clear and colourless, but visible particles appear, in all cases, into the infusers after 2 days since their preparation. From the results obtained we can conclude that the mixtures prepared in the conditions previously described are stable less than 48 hours.


Glucokinase is an integral component of the insulin granules in glucose-responsive insulin secretory cells and does not translocate during glucose stimulation.
The association of glucokinase with insulin secretory granules has been shown by cell microscopy techniques. We used MIN6 insulin-secretory cells and organelle fractionation to determine the effects of glucose on the subcellular distribution of glucokinase. After permeabilization with digitonin, 50% of total glucokinase remained bound intracellularly, while 30% was associated with the 13,000g particulate fraction. After density gradient fractionation of the organelles, immunoreactive glucokinase was distributed approximately equally between dense insulin granules and low-density organelles that cofractionate with mitochondria. Although MIN6 cells show glucose-responsive insulin secretion, glucokinase association with the granules and low-density organelles was not affected by glucose. Subfractionation of the insulin granule components by hypotonic lysis followed by sucrose gradient centrifugation showed that glucokinase colocalized with the granule membrane marker phogrin and not with insulin. PFK2 (6-phosphofructo-2-kinase-2/fructose-2,6-bisphosphatase)/FDPase-2, a glucokinase-binding protein, and glyceraldehyde phosphate dehydrogenase, which has been implicated in granule fusion, also colocalized with glucokinase after hypotonic lysis or detergent extaction of the granules. The results suggest that glucokinase is an integral component of the granule and does not translocate during glucose stimulation.


The biological effects of acute psychosocial stress on delay discounting.
Organisms prefer to receive rewards sooner rather than later because they excessively discount the subjective value of future rewards, a phenomenon called delay discounting. Recent studies have reported an association between cortisol-which is secreted by the hypothalamic-pituitary-adrenal (HPA) axis-and delay discounting. However, no study has examined whether acutely induced psychosocial stress modulates delay discounting. Thus, the present study examined the effect of acute psychosocial stress and its hormonal and inflammatory correlates on the rate of delay discounting. To accomplish this purpose, we assessed the participants' discounting rates using the questionnaire version with inter-temporal choice before and after an acute psychosocial stress task (the Trier Social Stress Test; TSST). The results demonstrated that TSST increased rates of delay discounting in only cortisol responders (not in non-responders), indicating the possible influence of the pathway from the HPA axis to the dopaminergic systems under acute stress. Furthermore, the findings of correlation analysis indicated a U-shaped relationship between baseline level of C-reactive protein and delay discounting rate, suggesting a complex relationship between inflammatory markers and delay discounting rate.