Grant writing in the home health arena: the proposal.
If at first you don't get funded, try, try, try again. Match your program with another funder. Some funders, such as private foundations, have ongoing deadlines. Grant funding is extremely competitive and can be political. Network with funders. Also network with board members, businesses, etc., who may know someone who serves on the grant funders review committee. Take a grant writing workshop and have your proposal reviewed by someone who can provide feedback. Gather grant-writing resources in the form of books, workshop materials, and Websites. Lastly, try to keep abreast of the trends in the grant field. The latest trend I have heard is an interest in having the problem statement become more positive. Focus on the strengths upon which you can build rather than the weaknesses of a community. Grant money is available from many resources in differing amounts. Test your ability at a local level. Begin developing a track record, then work to the state and federal levels. It is an exciting and challenging opportunity to better your community.


Antiproliferative activity of novel imidazopyridine derivatives on castration-resistant human prostate cancer cells.
Metastatic prostate cancer (mPCa) relapses after a short period of androgen deprivation therapy and becomes the castration-resistant prostate cancer (CR PCa); to which the treatment is limited. Hence, it is imperative to identify novel therapeutic agents towards this patient population. In the present study, antiproliferative activities of novel imidazopyridines were compared. Among three derivatives, PHE, AMD and AMN, examined, AMD showed the highest inhibitory activity on LNCaP C-81 cell proliferation, following dose- and time-dependent manner. Additionally, AMD exhibited significant antiproliferative effect against a panel of PCa cells, but not normal prostate epithelial cells. Further, when compared to AMD, its derivative DME showed higher inhibitory activities on PCa cell proliferation, clonogenic potential and in vitro tumorigenicity. The inhibitory activity was apparently in part due to the induction of apoptosis. Mechanistic studies indicate that AMD and DME treatments inhibited both AR and PI3K/Akt signaling. The results suggest that better understanding of inhibitory mechanisms of AMD and DME could help design novel therapeutic agents for improving the treatment of CR PCa.


How does the cervical spine respond to hyperkyphosis correction in Scheuermann's disease?
This study aimed to quantify the response of the cervical spine to the surgical correction of Scheuermann's kyphosis (SK) and to postoperative proximal junctional kyphosis (PJK). Fifty-nine patients (mean age 14.6 ± 2.3 years) were enrolled in the study: 35 patients in a thoracic SK (T-SK) group and 24 in a thoracolumbar SK (TL-SK) group. The mean follow-up period was 47.2 ± 17.6 months. Radiographic data, PJK-related complications, and patient-reported outcomes were compared between groups. The global kyphosis significantly decreased postoperatively, and similar correction rates were observed between the two groups (mean 47.1% ± 8.6% [T-SK] vs 45.8% ± 9.4% [TL-SK], p = 0.585). The cervical lordosis (CL) in the T-SK group notably decreased from 21.4° ± 13.3° to 13.1° ± 12.4° after surgery and was maintained at 14.9° ± 10.7° at the latest follow-up, whereas in the TL-SK group, CL considerably increased from 7.2° ± 10.7° to 11.7° ± 11.1° after surgery and to 13.8° ± 8.9° at the latest follow-up. PJK was identified in 16 patients (27.1%). Its incidence in the TL-SK group was notably higher than it was in the T-SK group (41.6% [n = 10] vs 17.1% [n = 6], p = 0.037). Compared with non-PJK patients, PJK patients had greater CL and lower pain scores on the Scoliosis Research Society-22 questionnaire (p < 0.05). Hyperkyphosis correction eventually resulted in reciprocal changes in the cervical spine, with CL notably decreased in the T-SK group but significantly increased in the TL-SK group. Patients developing PJK have increased CL, which seems to have a negative effect on patients' health-related quality of life.


Ribonucleic acid synthesis by spermatozoa from the rat and hamster.
Spermatozoa from the cauda of the epididymis of the hamster and rat were incubated with [5-(3)H]uridine and glucose. By using a procedure avoiding bacterial and other cellular contamination, sonic extracts were prepared and digested with deoxyribonuclease and Pronase. Radioactive RNA of high molecular weight was isolated by two methods: (a) gel filtration on Sephadex G-75 columns and (b) polyacrylamide-gel electrophoresis in which it migrated in the region of 28S and 23S RNA markers. The macromolecules were alkali-labile and hydrolysed by ribonuclease. From (3)H radioactivity and E(260) of the isolated RNA the rate of incorporation of uridine into RNA of spermatozoa was calculated to be 0.1-0.5nmol/h per mg of RNA.


Multicentric osteolysis with nodulosis and arthropathy (MONA) with cardiac malformation, mimicking polyarticular juvenile idiopathic arthritis: case report and literature review.
The 'vanishing bone' syndrome multicentric osteolysis with nodulosis and arthropathy (MONA) is a rare chronic skeleton disorder caused by matrix metalloproteinase 2 (MMP2) deficiency, mimicking erosive polyarticular juvenile idiopathic arthritis. MONA is characterised by facial dysmorphism, subcutaneous fibrocollagenous nodules, carpal and tarsal osteolysis and interphalangeal joint erosions. We present the case of a 5-year-old boy with double outlet right ventricle, ventricular septal defect, coarctation of the aorta and MONA. Previously, a total of 24 cases of MONA have been reported of which six also had congenital cardiac malformations. Despite treatment attempts of our patient with methotrexate, eternacept and prednisolone, serial X-ray studies documented continuous severe bone degeneration. The case documents the natural history of MONA and establishes a link between MMP2 deficiency and heart development, and given the recurring cardiac association, we suggest that all MONA patients be examined for possible cardiac defects.


Elevated oxidase and esterase levels associated with permethrin tolerance in Anopheles gambiae from Kenyan villages using permethrin-impregnated nets.
The permethrin tolerance (PT) of a population of the mosquito Anopheles gambiae (Diptera: Culicidae) increased following the introduction of permethrin-impregnated nets for malaria control in certain villages near Kisumu, western Kenya. Using a biochemical test that indirectly measures oxidases associated with permethrin resistance, we found that this population had higher oxidase levels than a comparison population from villages without impregnated nets. Mosquitoes from a colony of An. gambiae selected for PT, the RSP (reduced susceptibility to permethrin) strain, were exposed to permethrin with or without the oxidase inhibitor piperonyl butoxide (PB). Significantly higher mortality rates occurred when permethrin was synergized by PB, presumably by suppression of oxidases responsible for PT. An unselected (UNS) colony of An. gambiae that was more susceptible than RSP in a permethrin-susceptibility bioassay (i.e. LT50 22 min for UNS, vs. 42min for RSP) was compared with the RSP colony for levels of oxidases and esterases. The levels of both enzymes were very significantly higher in the RSP strain (P<0.0001). We speculate that use of impregnated nets selected for higher oxidase and esterase levels in An. gambiae to metabolize permethrin acquired from the nets. Both oxidase and esterase mechanisms could confer cross-resistance to other pyrethroids.


Serengeti migratory wildebeest: facilitation of energy flow by grazing.
Dense concentrations of migratory wildebeest leaving the Serengeti Plains in late May 1974 reduced green plant biomass by almost 400 grams per square meter, 85 percent of the initial standing crop. However, this grazing prevented senescence and stimulated net primary productivity of the grasslands. Thomson's gazelles leaving the plains a month later were significantly associated with areas previously grazed by wildebeest, and this association was still evident at the end of the dry season, 6 months later.


Genome-wide functional analysis of cotton (Gossypium hirsutum) in response to drought.
Cotton is one of the most important crops for its natural textile fibers in the world. However, it often suffered from drought stress during its growth and development, resulting in a drastic reduction in cotton productivity. Therefore, study on molecular mechanism of cotton drought-tolerance is very important for increasing cotton production. To investigate molecular mechanism of cotton drought-resistance, we employed RNA-Seq technology to identify differentially expressed genes in the leaves of two different cultivars (drought-resistant cultivar J-13 and drought-sensitive cultivar Lu-6) of cotton. The results indicated that there are about 13.38% to 18.75% of all the unigenes differentially expressed in drought-resistant sample and drought-sensitive control, and the number of differentially expressed genes was increased along with prolonged drought treatment. DEG (differentially expression gene) analysis showed that the normal biophysical profiles of cotton (cultivar J-13) were affected by drought stress, and some cellular metabolic processes (including photosynthesis) were inhibited in cotton under drought conditions. Furthermore, the experimental data revealed that there were significant differences in expression levels of the genes related to abscisic acid signaling, ethylene signaling and jasmonic acid signaling pathways between drought-resistant cultivar J-13 and drought-sensitive cultivar Lu-6, implying that these signaling pathways may participate in cotton response and tolerance to drought stress.


Novel Citronellyl-Based Photoprobes Designed to Identify ER Proteins Interacting with Dolichyl Phosphate in Yeast and Mammalian Cells.
Dolichyl phosphate-linked mono- and oligosaccharides (DLO) are essential intermediates in protein N-glycosylation, C- and O-mannosylation and GPI anchor biosynthesis. While many membrane proteins in the endoplasmic reticulum (ER) involved in the assembly of DLOs are known, essential proteins believed to be required for the transbilayer movement (flip-flopping) and proteins potentially involved in the regulation of DLO synthesis remain to be identified. The synthesis of a series of Dol-P derivatives composed of citronellyl-based photoprobes with benzophenone groups equipped with alkyne moieties for Huisgen "click" chemistry is now described to utilize as tools for identifying ER proteins involved in regulating the biosynthesis and transbilayer movement of lipid intermediates. In vitro enzymatic assays were used to establish that the photoprobes contain the critical structural features recognized by pertinent enzymes in the dolichol pathway. ER proteins that photoreacted with the novel probes were identified by MS. The potential of the newly designed photoprobes, m-PAL-Cit-P and p-PAL-Cit-P, for identifying previously unidentified Dol-P-interacting proteins is supported by the observation that they are enzymatically mannosylated by Man-P-Dol synthase (MPDS) from Chinese Hamster Ovary (CHO) cells at an enzymatic rate similar to that for Dol-P. MS analyses reveal that DPM1, ALG14 and several other yeast ER proteins involved in DLO biosynthesis and lipid-mediated protein O-mannosylation photoreacted with the novel probes. The newly-designed photoprobes described in this paper provide promising new tools for the identification of yet to be identified Dol-P interacting ER proteins in yeast and mammalian cells, including the Dol-P flippase required for the "re-cycling" of the glycosyl carrier lipid from the lumenal monolayer of the ER to the cytoplasmic leaflet for new rounds of DLO synthesis.


Advances in plastic surgery.
Recent progress in plastic surgery has been rapid and many new techniques have been developed. Reconstructive procedures have been advanced by a better understanding of the anatomy of the blood supply to skin and muscle, with the subsequent development of the use of axial flaps, musculocutaneous flaps and neurosensory flaps. Burn treatment has advanced greatly, making it possible to successfully treat larger and more complicated burns. The development of microsurgery has made possible free-flap transfer and replantation of amputated parts. Advances in surgical procedures on the hands include a realization that primary repair of lacerated tendons and nerves will give good results. Replacement joints have been developed that can be used in hands for joints destroyed by arthritis or trauma. Craniofacial surgery is a new field of endeavor in plastic surgery, involving new techniques that can be used to treat exophthalmos of Graves' disease and the facial deformities resulting from gigantism and acromegaly. Head and neck procedures have advanced, with the emphasis on immediate reconstruction using new flaps. Techniques for treating cleft lip and palate have been refined. Encouraging results have been reported in the treatment of nevus flammeus with argon lasers. In aesthetic surgical procedures, the aim is for safety and consistent long-lasting results. Improved understanding of the physiology and treatment of radionecrosis has evolved.


Gynecologic cancer disparities: a report from the Health Disparities Taskforce of the Society of Gynecologic Oncology.
To review the extent of health disparities in gynecologic cancer care and outcomes and to propose recommendations to help counteract the disparities. We searched the electronic databases PubMed and the Cochrane Library. We included studies demonstrating quantifiable differences by race and ethnicity in the incidence, treatment, and survival of gynecologic cancers in the United States (US). Most studies relied on retrospective data. We focused on differences between Black and White women, because of the limited number of studies on non-Black women. White women have a higher incidence of ovarian cancer compared to Black women. However, the all-cause ovarian cancer mortality in Black women is 1.3 times higher than that of White women. Endometrial and cervical cancer mortality in Black women is twice that of White women. The etiology of these disparities is multifaceted. However, much of the evidence suggests that equal care leads to equal outcomes for Black women diagnosed with gynecologic cancers. Underlying molecular factors may play an additional role in aggressive tumor biology and endometrial cancer disparities. Gynecologic cancer disparities exist between Black and White women. The literature is limited by the lack of large prospective trials and adequate numbers of non-Black racial and ethnic groups. We conclude with recommendations for continued research and a multifaceted approach to eliminate gynecologic cancer disparities.


Atypical (dysplastic) nevi: outcomes of surgical excision and association with melanoma.
To evaluate the effect of surgical excision, performed after biopsy diagnosis of dysplastic nevus, on final diagnosis, melanoma prevention, and melanoma detection. Outcome study using retrospective review conducted in an academic dermatopathology practice (Boston Medical Center Skin Pathology Laboratory) that receives specimens from community and academic practices across the United States. Consecutive patient pathology samples of dysplastic nevi and cutaneous melanomas evaluated between September 1, 1999 and March 1, 2011, and identified using systematized nomenclature of medicine codes were included. In dysplastic nevi cases, the rate of clinically significant change in diagnosis and the rate of melanoma detection as a result of excision. In melanoma cases, the rate and characteristics of association with dysplastic nevus. Of dysplastic nevi, 196 of 580 (34%) showed a positive biopsy margin, increasing with grade of atypia (P < .001); 127 of 196 with positive biopsy margin received excision (65%), performed more often as grade of atypia increased (P < .001). Two excisions (2 of 127, 1.6%) resulted in a clinically significant change in diagnosis, from biopsy-diagnosed moderately-to-severely dysplastic nevi before excision to melanoma in situ after excision. In melanomas (n = 216), in situ and superficial spreading subtypes were more often associated with dysplastic nevi (20% and 18%, respectively) (P = .002), most often of moderate-to-severe or severe grade. Excision of biopsy-diagnosed mildly or moderately dysplastic nevi is unlikely to result in a clinically significant change in diagnosis, and risk of transformation to melanoma appears very low. Moderately-to-severely and severely dysplastic nevi are more often associated with melanoma, and excision may be beneficial for melanoma detection or prevention.


Training using short-time features for OSA discrimination.
Heart rate variability (HRV) is one of the promising directions for a simple and noninvasive way for obstructive sleep apnea syndrome detection (OSA). The interaction between the sympathetic and parasympathetic systems on the HRV recordings, gives rise to several non-stationary components added to the signal. Aiming to improve the classifier accuracy for obstructive sleep apnoea detection, the use of more appropriated techniques for leading with non-stationarity and mixed dynamics, are needed. This work aims at searching a convenient training strategy of combining the feature set to be further fed in to the classifier, which should take into consideration the different dynamics in the HRV signal. Therefore, a set of the short-time features, extracted from a given HRV time-varying decomposition, and selected by spectral splitting is considered. Additionally, three methods of projection are used: none, simple, and multivariate. Finally, the different approaches are tested and compared, using k-nn and support vector machines (SVM) classifiers. Attained results show that using continuous wavelet transform with short-time features and multivariate projection, followed by a SVM classifier, allow to obtain a suitable OSA detection.


The over-pruning hypothesis of autism.
This article outlines the over-pruning hypothesis of autism. The hypothesis originates in a neurocomputational model of the regressive sub-type (Thomas, Knowland & Karmiloff-Smith, 2011a, 2011b). Here we develop a more general version of the over-pruning hypothesis to address heterogeneity in the timing of manifestation of ASD, including new computer simulations which reconcile the different observed developmental trajectories (early onset, late onset, regression) via a single underlying atypical mechanism; and which show how unaffected siblings of individuals with ASD may differ from controls either by inheriting a milder version of the pathological mechanism or by co-inheriting the risk factors without the pathological mechanism. The proposed atypical mechanism involves overly aggressive synaptic pruning in infancy and early childhood, an exaggeration of a normal phase of brain development. We show how the hypothesis generates novel predictions that differ from existing theories of ASD including that (1) the first few months of development in ASD will be indistinguishable from typical, and (2) the earliest atypicalities in ASD will be sensory and motor rather than social. Both predictions gain cautious support from emerging longitudinal studies of infants at-risk of ASD. We review evidence consistent with the over-pruning hypothesis, its relation to other current theories (including C. Frith's under-pruning proposal; C. Frith, 2003, 2004), as well as inconsistent data and current limitations. The hypothesis situates causal accounts of ASD within a framework of protective and risk factors (Newschaffer et al., 2012); clarifies different versions of the broader autism phenotype (i.e. the implication of observed similarities between individuals with autism and their family members); and integrates data from multiple disciplines, including behavioural studies, neuroscience studies, genetics, and intervention studies.


[Effect of human serum lipoproteins on various indices of thyroid function in rats].
It was shown that 7 to 10 days' injection of lipoproteins (LPs), isolated from the human blood serum according to Burstein and Scholnick method, induces significant inhibition of the rat thyroid iodine-absorbing function. Alpha-LPs exert more evident inhibiting effect than beta + pre- beta-LPs, and beta + pre- beta-LPs from the oncological patients' blood serum have more pronounced inhibiting effect comparatively to the same fraction of the donors; blood serum. 10-days' LP injection is accompanied by thyroxine inhibition and iodothyrozine/iodothyronine ratio rise in the thyroid tissue. In the experiments in vitro and in vivo several Lp fractions decreased thyrotropin-stimulating effect on AMP accumulation in the rat thyroid gland. Possible mechanisms of LP action on the thyroid function are discussed. The study of LP effect on the thyroid function in homologous system is necessary. It is suggested that hyperlipidemia (hyperlipoproteinemia) is one of the factors, contributing to the thyroid function decrease with age and in patients with malignant tumors.


Fabrication and Evaluation of a Novel Non-Invasive Stretchable and Wearable Respiratory Rate Sensor Based on Silver Nanoparticles Using Inkjet Printing Technology.
The respiration rate (RR) is a key vital sign that links to adverse clinical outcomes and has various important uses. However, RR signals have been neglected in many clinical practices for several reasons and it is still difficult to develop low-cost RR sensors for accurate, automated, and continuous measurement. This study aims to fabricate, develop and evaluate a novel stretchable and wearable RR sensor that is low-cost and easy to use. The sensor is fabricated using the soft lithography technique of polydimethylsiloxane substrates (PDMS) for the stretchable sensor body and inkjet printing technology for creating the conductive circuit by depositing the silver nanoparticles on top of the PDMS substrates. The inkjet-printed (IJP) PDMS-based sensor was developed to detect the inductance fluctuations caused by respiratory volumetric changes. The output signal was processed in a Wheatstone bridge circuit to derive the RR. Six different patterns for a IJP PDMS-based sensor were carefully designed and tested. Their sustainability (maximum strain during measurement) and durability (the ability to go bear axial cyclic strains) were investigated and compared on an automated mechanical stretcher. Their repeatability (output of the sensor in repeated tests under identical condition) and reproducibility (output of different sensors with the same design under identical condition) were investigated using a respiratory simulator. The selected optimal design pattern from the simulator evaluation was used in the fabrication of the IJP PDMS-based sensor where the accuracy was inspected by attaching it to 37 healthy human subjects (aged between 19 and 34 years, seven females) and compared with the reference values from e-Health nasal sensor. Only one design survived the inspection procedures where design #6 (array consists of two horseshoe lines) indicated the best sustainability and durability, and went through the repeatability and reproducibility tests. Based on the best pattern, the developed sensor accurately measured the simulated RR with an error rate of 0.46 ± 0.66 beats per minute (BPM, mean ± SD). On human subjects, the IJP PDMS-based sensor and the reference e-Health sensor showed the same RR value, without any observable differences. The performance of the sensor was accurate with no apparent error compared with the reference sensor. Considering its low cost, good mechanical property, simplicity, and accuracy, the IJP PDMS-based sensor is a promising technique for continuous and wearable RR monitoring, especially under low-resource conditions.


[Roentgeno-radiological diagnosis of rhinosinusogenic brain abscesses].
Analysis is made of the data obtained in the use of a complex of diagnostic ++roentgeno-radiological methods in 26 patients with rhinosinusogenous abscesses of the brain. There are convincing examples that the complex (cerebral angiography, gamma-topography of the brain, computer-aided tomography, NMR tomography) enables the identification of the reliable and informative sings of the localization, size, spreading, multiplicity and multicompartmental nature of brain abscesses.


Onset and quality of sedation after intramuscular administration of dexmedetomidine and hydromorphone in various muscle groups in dogs.
To compare onset time and quality of sedation achieved by IM injection of hydromorphone and dexmedetomidine into either the semimembranosus, cervical, gluteal, or lumbar muscle groups in dogs. Prospective, randomized, crossover study. 7 dogs. Each dog was assigned to receive each treatment in random order, and at least 1 week elapsed between treatments. Dogs were sedated with dexmedetomidine and hydromorphone combined and injected IM into the assigned muscle group. An observer unaware of group assignments assessed physiologic variables every 5 minutes for 30 minutes, and a videographic recording was obtained. Recordings were evaluated by 16 individuals who were unaware of group assignments; these reviewers assessed time to onset of sedation and assigned a sedation score to each dog every 5 minutes. Resting pulse and respiratory rates did not differ among injection site groups. The semimembranosus site had a significantly higher sedation score than all other sites, and the cervical site had a significantly higher sedation score than the lumbar and gluteal sites. The semimembranosus and cervical sites had significantly shorter time to onset of sedation than did the gluteal and lumbar sites. When the combination of dexmedetomidine and hydromorphone was used to induce sedation in dogs, rapid and profound sedation was achieved with IM injection into the semimembranosus muscle.


Wavelength Dependence of Light-Induced Cycloadditions.
The wavelength-dependent conversion of two rapid photoinduced ligation reactions, i.e., the light activation of o-methylbenzaldehydes, leading to the formation of reactive o-quinodimethanes (photoenols), and the photolysis of 2,5-diphenyltetrazoles, affording highly reactive nitrile imines, is probed via a monochromatic wavelength scan at constant photon count. The transient species are trapped by cycloaddition with N-ethylmaleimide, and the reactions are traced by high resolution mass spectrometry and nuclear magnetic resonance spectroscopy. The resulting action plots are assessed in the context of Beer-Lambert's law and provide combined with time-dependent density functional theory and multireference calculations an in-depth understanding of the underpinning mechanistic processes, including conical intersections. The π → π* transition of the carbonyl group of the o-methylbenzaldehyde correlates with a highly efficient conversion to the cycloadduct, showing no significant wavelength dependence, while conversion following the n → π* transition proceeds markedly less efficient at longer wavelengths. The influence of absorbance and reactivity has critical consequences for an effective reaction design: At high concentrations of o-methylbenzaldehydes (c = 8 mmol L-1), photoligations with N-ethylmaleimide (possible for λ ≤ 390 nm) are ideally performed at 330 nm, whereas at high light penetration regimes at lower concentrations (c = 0.3 mmol L-1), 315 nm irradiation leads to the highest conversion. Activation and trapping of 2,5-diphenyltetrazoles (possible for λ ≤ 322 nm) proceeds best at a wavelength shorter than 295 nm, irrespective of concentration.


Myosin VIIa Supports Spermatid/Organelle Transport and Cell Adhesion During Spermatogenesis in the Rat Testis.
The biology of transport of spermatids and spermatid adhesion across the seminiferous epithelium during the epithelial cycle remains largely unexplored. Nonetheless, studies have implicated the role of motor proteins in these cellular events. In this article, we report findings to unravel the role of myosin VIIa, an F-actin-based barbed (+)-end-directed motor protein, to support cellular transport and adhesion in the testis. Using RNA interference to knock down myosin VIIa in Sertoli cells cultured in vitro as a study model was shown to perturb the Sertoli cell tight junction permeability barrier, mediated through disorganization of actin- or microtubule (MT)-based cytoskeletons owing to disruptive changes on the spatiotemporal expression of F-actin or MT-regulatory proteins. Consistent with these in vitro findings, knockdown of myosin VIIa in the testis in vivo also induced disorganization of the actin- and MT-based cytoskeletons across the seminiferous epithelium, mediated by disruptive changes in the spatiotemporal expression of actin- and MT-based regulatory proteins. More important, the transport of spermatids and organelles across the epithelium, as well as cell adhesion, was grossly disrupted. For instance, step 19 spermatids failed to be transported to the adluminal compartment near the tubule lumen to undergo spermiation; in this manner, step 19 spermatids were persistently detected in stage IX and XII tubules, intermingling with step 9 and 12 spermatids, respectively. Also, phagosomes were detected near the tubule lumen in stage I to III tubules when they should have been degraded near the base of the seminiferous epithelium via the lysosomal pathway. In summary, myosin VIIa motor protein was crucial to support cellular transport and adhesion during spermatogenesis.


Drug trials that have influenced our practice in the treatment of venous thromboembolism.
Heparin and oral anticoagulants have been the mainstay of antithrombotic therapy for the prevention and treatment of venous thromboembolism for over 50 years. Randomized trials have established their efficacy and have been used to refine the optimal dose and duration of therapy for different indications. Low-dose, subcutaneous, standard heparin and low molecular weight heparin (LMWH) provide effective primary prophylaxis, higher doses being indicated for patients who are at highest risk. OA is an alternative in high risk patients, particularly if there are persistent risk factors. Heparin and OA can be started concomitantly when treating patients with acute VTE. At least 4 days of adjusted dose standard heparin, or fixed dose LMWH, should be administered, and heparin should not be stopped until therapeutic OA is established. Acute DVT can be treated as an outpatient with fixed dose LMWH. In general, OA, with an International Normalization Ratio of 2.0-3.0, should be continued for 3 to 6 months. The optimal duration of OA may differ between patients who have VTE associated with a transient or a continuing (including "idiopathic") risk factors; however, this remains to be defined. New antithrombotic agents, such as direct thrombin inhibitors, are in the preliminary stages of evaluation for the prevention and treatment of VTE.


The insulin-like growth factor system and the fetal brain: effects of poor maternal nutrition.
The insulin-like growth factor (IGF) signaling system plays indispensable roles in pre- and post-natal brain growth and development. A large body of studies using both in vivo null mutant and transgenic mice and in vitro neuronal culture techniques indicate that IGF-I acts directly on the brain while IGF-II effects are mediated to a large extent by IGF-II control of placental growth. It appears that all of the mechanisms, except migration, that are involved in normal brain development, e.g., proliferation, apoptosis, maturation and differentiation, are influenced by IGF-I. While IGF system members are produced in the brain, recent reports in post-natal animals indicate that normal brain health and function are dependent upon transfer of circulating IGF-I from the liver and its transfer across the blood brain barrier. Data showing that this phenomenon applies to pre-natal brain growth and development would make an important contribution to fetal physiology. A number of kinase pathways are able to participate in IGF signaling in brain with respect to nutrient restriction; among the most important are the PI3K/AKT, Ras-Raf-MEK-ERK and mTOR-nutrient sensing pathways. Both maternal and fetal IGF-I peripheral plasma concentrations are greatly reduced in nutrient restriction while IGF-II does not appear to be affected. Nutrient restriction also affects IGF binding protein concentrations while effects on the IGF-I receptor appear to vary with the paradigm. Studies on the effects of nutrient restriction on the fetal primate brain in relation to activity of the IGF system are needed to determine the applicability of rodent studies to humans.


Patient Satisfaction With Medications for Opioid Use Disorder Treatment via Telemedicine: Brief Literature Review and Development of a New Assessment.
Telemedicine is increasingly being used to treat patients with opioid use disorder (OUD). It has particular value in rural areas of the United States impacted by the opioid crisis as these areas have a shortage of trained addiction medicine providers. Patient satisfaction significantly impacts positive clinical outcomes in OUD treatment and thus is of great clinical interest. Yet little is known regarding patient satisfaction with the increasingly important platform of telemedicine-delivered medications for opioid use disorder (tMOUD). The goal of this review is to provide a summary of the existing literature regarding patient satisfaction with tMOUD. We also submit a novel survey based on an existing framework designed to assess tMOUD satisfaction, and present pilot data (N = 14) acquired from patients engaged in rural tMOUD care. Telemedicine provides a feasible method for delivering MOUD in rural areas, and our survey provides a useful assessment to measure patient satisfaction with tMOUD. In light of the pressing need for innovative and technology-driven solutions to the opioid epidemic (especially in light of the COVID-19 pandemic), future research should focus on the development and refinement of tools to assess the important implementation goal of patient satisfaction.


Effects of Catechin, Quercetin and Taxifolin on Redox Parameters and Metabolites Linked with Renal Health in Rotenone-toxified Rats.
Nephrotoxicity, with the attendant risk of progression to kidney failure, is a growing problem in many parts of the world. Current orthodox treatment options for nephrotoxicity and kidney failure are limited and there is need for alternative or complementary approaches. This study aimed at evaluating the effect of three structurally related flavonoids, catechin, quercetin and taxifolin on renal redox and metabolite biochemical disturbances in rotenone intoxicated animals. Male Wistar rats were administered 1.5 mg/kg rotenone (s.c.) for ten days followed by post-treatment with catechin (5, 10 or 20 mg/kg), quercetin (5, 10, or 20 mg/kg) and taxifolin (0.25, 0.5 or 1.0 mg/kg) (s.c.), for 3 days. Renal redox indices and levels of renal-related metabolites (creatinine, urea and uric acid) were assessed after sacrifice of animals. Catechin, quercetin and taxifolin significantly attenuated rotenone-induced effects on oxidative stress markers and metabolites linked to renal health. Quercetin was clearly more effective than catechin. The activity demonstrated by taxifolin, despite being administered at the lowest doses, was compelling. The results highlight the potential of these phytochemicals in the management of renal dysfunction. The findings additionally suggest a correlation between the structure of the flavonoids and their activity but also indicate that additional structural considerations beyond conventionally acknowledged ones may be involved.


Intact and top-down characterization of biomolecules and direct analysis using infrared matrix-assisted laser desorption electrospray ionization coupled to FT-ICR mass spectrometry.
We report the implementation of an infrared laser onto our previously reported matrix-assisted laser desorption electrospray ionization (MALDESI) source with ESI post-ionization yielding multiply charged peptides and proteins. Infrared (IR)-MALDESI is demonstrated for atmospheric pressure desorption and ionization of biological molecules ranging in molecular weight from 1.2 to 17 kDa. High resolving power, high mass accuracy single-acquisition Fourier transform ion cyclotron resonance (FT-ICR) mass spectra were generated from liquid- and solid-state peptide and protein samples by desorption with an infrared laser (2.94 mum) followed by ESI post-ionization. Intact and top-down analysis of equine myoglobin (17 kDa) desorbed from the solid state with ESI post-ionization demonstrates the sequencing capabilities using IR-MALDESI coupled to FT-ICR mass spectrometry. Carbohydrates and lipids were detected through direct analysis of milk and egg yolk using both UV- and IR-MALDESI with minimal sample preparation. Three of the four classes of biological macromolecules (proteins, carbohydrates, and lipids) have been ionized and detected using MALDESI with minimal sample preparation. Sequencing of O-linked glycans, cleaved from mucin using reductive beta-elimination chemistry, is also demonstrated.


The 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitor pravastatin enhances neurite outgrowth in hippocampal neurons.
Epidemiological studies demonstrate a relationship between statin [3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor] usage and reduced risk of developing Alzheimer's disease. To determine whether statins affect neuronal development, we treated cultured rat hippocampal neurons with pravastatin. After 4-48 h of treatment, pravastatin significantly increased the number of neurites produced by each cell and caused a corresponding increase in levels of the membrane phospholipid phosphatidylcholine. Pravastatin treatment also significantly increased neurite length and branching but did not affect cellular cholesterol levels. Co-incubation with mevalonate, but not cholesterol, abolished the stimulatory effect of pravastatin on neurite outgrowth. Treatment of neurons with isoprenoids also abolished the effect of pravastatin on neurite growth, suggesting that pravastatin may stimulate neuritogenesis by preventing isoprenylation of signaling molecules such as the Rho family of small GTPases. A specific inhibitor of geranylgeranylation, but not farnesylation, mimicked the stimulatory effect of pravastatin on neuritogenesis. Pravastatin treatment significantly decreased levels of membrane-associated RhoA. These data suggest that pravastatin treatment increases neurite outgrowth and may do so via inhibiting the activity of geranylgeranylated proteins such as RhoA.


Phylogenetic Reappraisal of the Genus Monomorphina (Euglenophyceae) Based on Molecular and Morphological Data.
A morphological and molecular examination of the genus Monomorphina was conducted on 46 strains isolated mainly from Korea. The strains were divided into two types based on morphological data: Monomorphina aenigmatica and M. pyrum - like species. Phylogenetic analysis based on a combined data set of nuclear SSU and LSU and plastid SSU and LSU rDNA showed that the strains could be divided into eight clades: Clade A of M. aenigmatica, Clade B of the isolates (M. pyropsis) from Michigan, USA, Clade C of M. pseudopyrum, Clade D of the isolates (M. pyroria) from Bremen, Germany, Clade E of M. soropyrum, Clade F of M. pyriformis, Clade G of M. parapyrum, and Clade H of M. pyrum. Six of these clades came from strains that would be considered M. pyrum sensu Kosmala et Zakryś, one of which could be recognized as a traditional species (M. pyrum) and five were designated as new species; each species had unique molecular signatures at nr SSU rDNA helix 17 and 17' and spacer E23_14'-E23_15. The species of Monomorphina had a wide range of genetic diversity with interspecies sequence similarity of 85.6%-97.1% and intraspecies similarity of 96.4%-99.9%. Our results suggested that genetic diversity found in the M. pyrum complex justifies the recognition of a minimum of eight species within this genus, based on specific molecular signatures and gene divergence of the nr SSU rDNA sequences.


Tilt sensitivity of the two-grating interferometer.
Fringe formation in the two-grating interferometer is analyzed in the presence of a small parallelism error between the diffraction gratings assumed in the direction of grating shear. Our analysis shows that with partially coherent illumination, fringe contrast in the interference plane is reduced in the presence of nonzero grating tilt with the effect proportional to the grating tilt angle and the grating spatial frequencies. Our analysis also shows that for a given angle between the gratings there is an angle between the final grating and the interference plane that optimizes fringe contrast across the field.


Clinical outcomes of serum potassium in patients with percutaneous coronary intervention: insights from a large single-center registry.
Serum potassium homeostasis plays an important role in myocardial electrical stability, but the impact of altered serum potassium levels on the major adverse cardiovascular and cerebral events (MACCE) in patients with percutaneous coronary intervention (PCI) has not been evaluated. To evaluate the association between serum potassium level and the risk of MACCE in PCI patients. This retrospective study involved 8,263 in-patients from a single-center registry who were successfully treated with PCI between January 2003 and December 2020. Clinical data were collected for 24 h after admission. Data were analyzed from June 2003 to December 2021. The primary outcome was MACCE, defined as a composite of all-cause death, myocardial infarction, revascularization, stroke, and heart failure-related hospitalization. The median [interquartile range (IQR)] follow-up for all patients was 4.0 (2.1, 5.8) years, and 1,632 patients (19.7%) were diagnosed with MACCE. High serum potassium levels were associated with a 20% increased risk of MACCE (hazard ratio [HR]: 1.20, 95% confidence interval [CI]: 1.05-1.38, P = 0.008) and 72% increased risk of all-cause death (HR: 1.72, 95% CI: 1.39-2.14, P < 0.001). Multivariate Cox analysis showed that the risk of MACCE was higher in patients at the highest quartile of serum potassium (Q4 vs. Q1: adjusted HR: 1.18, 95% CI: 1.02-1.35, P = 0.026). Moreover, a higher serum potassium level was always associated with a higher risk of all-cause death (Q4 vs. Q1: adjusted HR: 1.50, 95% CI: 1.17-1.91, P = 0.001). A U-shaped relationship between serum potassium levels, MACCE, and all-cause death was derived in patients undergoing PCI. Serum potassium levels, maintained within the range of 3.8-4.0 mmol/L before PCI, exhibited the lowest risk of associated MACCE and all-cause death. Our results demonstrate that the serum potassium level could be associated with higher risks of MACCE and all-cause death in PCI patients. In particular, serum potassium levels maintained at 3.8-4.0 mmol/L before PCI could lower the risk of MACCE and all-cause death.


Reversible splenial lesion syndrome in neuroleptic malignant syndrome.
Reversible focal lesions in the splenium of the corpus callosum (SCC) or reversible splenial lesion syndrome are rare and little is known about their pathophysiology. The authors describe a case of a 65-year-old female who presented with fever, abnormal behaviour and mild hypernatremia. She was on neuropsychiatric treatment for bipolar disorder but denied any history of seizure. After an extensive workout to exclude infection, a clinical diagnosis of neuroleptic malignant syndrome (NMS) was made. Initial magnetic resonance imaging (MRI) of the brain showed a lesion in the SCC characterized by high-signal intensity on T2-weighted and FLAIR sequences with reduced signal intensity on T1-weighted sequence. Diffuse weighted imaging (DWI) showed restricted diffusion. There was no enhancement following Gadolinium administration. The follow-up MRI 8 weeks later showed complete resolution of the SCC lesion. While the pathophysiology of reversible SCC lesions is still unclear, this case highlights the need to consider NMS in the differential diagnosis of reversible splenial lesion of the corpus callosum.


Characterization of porcine CD205.
Dendritic cells express a type cell-surface receptor, CD205 that plays a role in antigen capture and delivery to the endocytic pathway. Besides DCs, high CD205 expression is also detected on thymic epithelial cells but B cells, macrophages, and T cells have limited or no expression. CD205 has been characterized in several animal species except swine. The aim of this work was to characterize porcine CD205 and mRNA expression on different cells and tissues involved in immune responses. A complete porcine CD205 sequence of 5175bp was obtained from porcine thymus cDNA by PCR gene-walking strategy and this gene encoded a protein of 1723 amino acids. The multi-domain structure reported for murine, human, and bovine CD205 was also conserved in porcine with an overall amino acid identity of 74, 81, and 85%, respectively. Quantitative RT-PCR analysis of the CD205 mRNA profiles in normal porcine tissues and cells showed that thymus and Langerhans cells expressed the highest levels. Further characterization of porcine CD205 will lead to better understanding of the role of this receptor and development of contemporary strategies for antigen targeting to DCs in swine.


Genomic and biochemical insights into the specificity of ETS transcription factors.
ETS proteins are a group of evolutionarily related, DNA-binding transcriptional factors. These proteins direct gene expression in diverse normal and disease states by binding to specific promoters and enhancers and facilitating assembly of other components of the transcriptional machinery. The highly conserved DNA-binding ETS domain defines the family and is responsible for specific recognition of a common sequence motif, 5'-GGA(A/T)-3'. Attaining specificity for biological regulation in such a family is thus a conundrum. We present the current knowledge of routes to functional diversity and DNA binding specificity, including divergent properties of the conserved ETS and PNT domains, the involvement of flanking structured and unstructured regions appended to these dynamic domains, posttranslational modifications, and protein partnerships with other DNA-binding proteins and coregulators. The review emphasizes recent advances from biochemical and biophysical approaches, as well as insights from genomic studies that detect ETS-factor occupancy in living cells.


IFN-γ is an independent risk factor associated with mortality in patients with moderate and severe COVID-19 infection.
Innate and adaptive immune responses have been evaluated in infected patients with COVID-19. The severity of the disease has been supposed to be associated with some profile not reported with other bacterial and viral pneumonia. We proposed a study in patients with moderate to severe COVID-19 infection to evaluate the interleukin patterns and its role as prognosis factors. A prospective cohort with moderate and severe cases of COVID-19 infection from June to July 2020. Blood samples from patients were collected regularly to evaluate IFN-γ, TNF-α, IL-4, IL-6, and IL-10. Clinical, laboratory, radiological data, and outcomes were recorded. The outcome variable was in-hospital death, survival, mechanical ventilation, and admission at the intensive care unit. Data are presented in median and interquartile range [IQR]. We evaluated the Th1 and Th2 responses according to evolution, distinguishing possible predictive markers. The IFN-γ median of 323 pg/mL [IQR 166-570] was found in patients who died and 208 pg/mL [IQR 155-392] in the survival group (p = 0.017). IFN-γ was also higher in the early stages of the disease (394 pg/mL [IQR 229-575] against 162 pg/mL [IQR 117-259], p < 0.001). IL-4 that was increased in late-stage (182 pg/mL [IQR 162-199] against 131 pg/mL [IQR 124-152], p < 0.001) but not associated with mortality. Also, death was also related to male gender (relative risk = 1.5 [95 % confidence interval = 1.1-2.0]). Our results suggest that the activation of the host immune response between Th1 or Th2 in COVID-19 infection may be related to the final result between discharge or death. This implies an attempt to control cytokines, such as IFN-γ, with combined therapies for clinical treatment.


Targeting non-pulmonary vein triggers in persistent atrial fibrillation: results from a prospective, multicentre, observational registry.
We evaluated the efficacy of an ablation strategy empirically targeting pulmonary veins (PVs) and posterior wall (PW) and the prevalence and clinical impact of extrapulmonary trigger inducibility and ablation in a large cohort of patients with persistent atrial fibrillation (PerAF). A total of 1803 PerAF patients were prospectively enrolled. All patients underwent pulmonary vein antrum isolation (PVAI) extended to the entire PW. A standardized protocol was performed to confirm persistent PVAI and elicit any triggers originating from non-PV sites. All non-PV triggers initiating sustained atrial tachyarrhythmias were ablated. Ablation of non-PV sites triggering non-sustained runs (<30 s) of atrial tachyarrhythmias or promoting frequent premature atrial complexes (≥10/min) was left to operator's discretion. Overall, 1319 (73.2%) patients had documented triggers from non-PV areas. After 17.4 ± 8.5 months of follow-up, the cumulative freedom from atrial tachyarrhythmias among patients without inducible non-PV triggers (n = 484) was 70.2%. Patients with ablation of induced non-PV triggers had a significantly higher arrhythmia control than those whose triggers were not ablated (67.9% vs. 39.4%, respectively; P < 0.001). After adjusting for clinically relevant variables, patients in whom non-PV triggers were documented but not ablated had an increased risk of arrhythmia relapse (hazard ratio: 2.39; 95% confidence interval: 2.01-2.83; P < 0.001). Pulmonary vein antrum isolation extended to the entire PW might provide acceptable long-term arrhythmia-free survival in PerAF patients without inducible non-PV triggers. In our population of PerAF patients, non-PV triggers could be elicited in ∼70% of PerAF patients and their elimination significantly improved outcomes.


Guidelines for the control and prevention of meticillin-resistant Staphylococcus aureus (MRSA) in healthcare facilities.
Meticillin-resistant Staphylococcus aureus (MRSA) remains endemic in many UK hospitals. Specific guidelines for control and prevention are justified because MRSA causes serious illness and results in significant additional healthcare costs. Guidelines were drafted by a multi-disciplinary group and these have been finalised following extensive consultation. The recommendations have been graded according to the strength of evidence. Surveillance of MRSA should be undertaken in a systematic way and should be fed back routinely to healthcare staff. The inappropriate or unnecessary use of antibiotics should be avoided, and this will also reduce the likelihood of the emergence and spread of strains with reduced susceptibility to glycopeptides, i.e. vancomycin-intermediate S. aureus/glycopeptide-intermediate S. aureus (VISA/GISA) and vancomycin-resistant S. aureus (VRSA). Screening for MRSA carriage in selected patients and clinical areas should be performed according to locally agreed criteria based upon assessment of the risks and consequences of transmission and infection. Nasal and skin decolonization should be considered in certain categories of patients. The general principles of infection control should be adopted for patients with MRSA, including patient isolation and the appropriate cleaning and decontamination of clinical areas. Inadequate staffing, especially amongst nurses, contributes to the increased prevalence of MRSA. Laboratories should notify the relevant national authorities if VISA/GISA or VRSA isolates are identified.


Disorders of motion and depth.
Damage to the human homologue of area MT produces a motion perception deficit similar to that found in the monkey with MT lesions. Even temporary disruption of MT processing with transcranial magnetic stimulation can produce a temporary akinetopsia [127]. Motion perception deficits, however, also are found with a variety of subcortical lesions and other neurologic disorders that can best be described as causing a disconnection within the motion processing stream. The precise role of these subcortical structures, such as the cerebellum, remains to be determined. Simple motion perception, moreover, is only a part of MT function. It undoubtedly has an important role in the perception of depth from motion and stereopsis [112]. Psychophysical studies using aftereffects in normal observers suggest a link between stereo mechanisms and the perception of depth from motion [9-11]. There is even a simple correlation between stereo acuity and the perception of depth from motion [128]. Future studies of patients with cortical lesions will take a closer look at depth perception in association with motion perception and should provide a better understanding of how motion and depth are processed together.


Functional modification of the guanine nucleotide regulatory protein after desensitization of turkey erythrocytes by catecholamines.
Densensitization of turkey erythrocytes by exposure to the beta-adrenergic agonist (-)isoproterenol leads to decreased activation of adenylate cyclase by agonist, NaF, and guanyl-5'-yl imido diphosphate, with no reduction in the number of beta-adrenergic receptors. Interactions between the receptor and the guanine nucleotide regulatory protein (N protein) also seem to be impaired. These observations suggest that a component distal to the beta-adrenergic receptor may be a locus of modification. Accordingly we examined the N protein to determine whether it was altered by desensitization. The rate at which (-)isoproterenol stimulated the release of [3H]GDP from the N protein was substantially lower in membranes prepared from desensitized cells, providing further evidence for uncoupling of the receptor and the N protein. The amount of N protein in membranes from control and desensitized cells was compared by labeling the 42,000 Mr component of the N protein with [32P]NAD+ and cholera toxin; no significant difference was found. However, significantly more N protein (p less than .001) was solubilized by cholate extraction of desensitized membranes, suggesting an altered association of the N protein with the membrane after desensitization. The functional activity of the N protein was measured by reconstitution of cholate extracts of turkey erythrocyte membranes into S49 lymphoma cyc- membranes. Reconstitution of (-)isoproterenol stimulation of adenylate cyclase activity was reduced significantly (p less than .05) after desensitization. These observations suggest that desensitization of the turkey erythrocyte by (-)isoproterenol results in functional modifications of the guanine nucleotide regulatory protein, leading to impaired interactions with the beta-adrenergic receptor and reduced activation of adenylate cyclase.


The effects of social support on women's health during pregnancy, labor and delivery, and the postpartum period.
This review of the literature on social support and its relationship to maternal health indicates that emotional, tangible, and informational support are positively related to mothers' mental and physical health around the time of childbirth. The importance of various types of support changes with the changing needs of women as they move from pregnancy to labor and delivery, and then to the postpartum period. During pregnancy, emotional and tangible support provided by the spouse and others is related to the expectant mother's mental well-being. In addition, informational support in the form of prenatal classes is related to decreased maternal physical complications during labor and delivery, and to improved physical and mental health postpartum. Mothers who have the support of a companion during labor and delivery experience fewer childbirth complications and less postpartum depression. Mothers' postpartum mental health is related to both the emotional support and practical help (eg, housework and child care activities) provided by the husband and others. Health care providers are in a unique position to educate prospective parents about the importance of social support around the time of childbirth and may play a critical role in mobilizing support systems for new mothers.


Analysis of comorbidities and multimorbidity in adult patients in the International Severe Asthma Registry.
Investigation for the presence of asthma comorbidities is recommended by the Global Initiative for Asthma because their presence can complicate asthma management. To understand the prevalence and pattern of comorbidities and multimorbidity in adults with severe asthma and their association with asthma-related outcomes. This was a cross-sectional study using data from the International Severe Asthma Registry from 22 countries. A total of 30 comorbidities were identified and categorized a priori as any of the following: (1) potentially type 2-related comorbidities, (2) potentially oral corticosteroid (OCS)-related comorbidities, or (3) comorbidities mimicking or aggravating asthma. The association between comorbidities and asthma-related outcomes was investigated using multivariable models adjusted for country, age at enrollment, and sex (ie male or female). Of the 11,821 patients, 69%, 67%, and 55% had at least 1 potentially type 2-related, potentially OCS-related, or mimicking or aggravating comorbidities, respectively; 57% had 3 or more comorbidities, and 33% had comorbidities in all 3 categories. Patients with allergic rhinitis, nasal polyposis, and chronic rhinosinusitis experienced 1.12 (P = .003), 1.16 (P < .001), and 1.29 times (P < .001) more exacerbations per year, respectively, than those without. Patients with nasal polyposis and chronic rhinosinusitis were 40% and 46% more likely (P < .001), respectively, to have received long-term (LT) OCS. All assessed potential OCS-related comorbidities (except obesity) were associated with a greater likelihood of LTOCS use (odds ratios [ORs]: 1.23-2.77) and, except for dyslipidemia, with a greater likelihood of uncontrolled asthma (ORs: 1.29-1.68). All mimicking or aggravating comorbidities assessed were associated with more exacerbations (1.24-1.68 times more), all (except bronchiectasis) with increased likelihood of uncontrolled asthma (ORs: 1.57-1.81), and all (except chronic obstructive pulmonary disease) with increased likelihood of LTOCS use (ORs: 1.37-1.57). A greater number of comorbidities was associated with worse outcomes. In a global study, comorbidity or multimorbidity is reported in most adults with severe asthma and is associated with poorer asthma-related outcomes. The International Severe Asthma Registry database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization Studies (European Network Centres for Pharmacoepidemiology and Pharmacovigilance [ENCEPP]/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EMA 2014; EUPAS44024) and with all applicable local and international laws and regulations, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=48848). Governance was provided by ADEPT (registration number: ADEPT1121).


Diet, fatty acids, and regulation of genes important for heart disease.
Diets rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs), such as alpha-linoleic acid, eicosapentaenoic acid, and docosahexaenoic acid, are associated with decreased incidence and severity of coronary heart disease. Similarly, conjugated linoleic acids (CLAs), which are found in meat and dairy products, have beneficial effects against atherosclerosis, diabetes, and obesity. The effects of n3-PUFAs and CLAs are in contrast to fatty acids with virtually identical structures, such as linoleic acid and arachidonic acid (ie, n-6 PUFAs). This article discusses the possibility that cognate receptors exist for fatty acids or their metabolites that are able to regulate gene expression and coordinately affect metabolic or signaling pathways associated with coronary heart disease. Three nuclear receptors are emphasized as fatty acid receptors that respond to dietary and endogenous ligands: peroxisome proliferator activated receptors, retinoid X receptors, and liver X receptors.


Denoising of high-resolution single-particle electron-microscopy density maps by their approximation using three-dimensional Gaussian functions.
Cryo-electron microscopy (cryo-EM) of frozen-hydrated preparations of isolated macromolecular complexes is the method of choice to obtain the structure of complexes that cannot be easily studied by other experimental methods due to their flexibility or large size. An increasing number of macromolecular structures are currently being obtained at subnanometer resolution but the interpretation of structural details in such EM-derived maps is often difficult because of noise at these high-frequency signal components that reduces their contrast. In this paper, we show that the method for EM density-map approximation using Gaussian functions can be used for denoising of single-particle EM maps of high (typically subnanometer) resolution. We show its denoising performance using simulated and experimental EM density maps of several complexes.


Heat shock protein 90 inhibition by 17-DMAG attenuates abdominal aortic aneurysm formation in mice.
Abdominal aortic aneurysm (AAA) is a common degenerative vascular disease whose pathogenesis is associated with activation of multiple signaling pathways including Jun NH2-terminal kinases (JNK) and NF-κB. It is now well recognized that these pathways are chaperoned by the heat shock protein 90 (Hsp90), suggesting that inhibition of Hsp90 may be a novel strategy for inhibiting AAAs. The aim of this study is to investigate whether inhibition of Hsp90 by 17-DMAG (17-dimethyl-aminothylamino-17-demethoxy-geldanamycin) attenuates ANG II-induced AAA formation in mice, and, if so, to elucidate the mechanisms involved. Apolipoprotein E-null mice were infused with ANG II to induce AAA formation and simultaneously treated by intraperitoneal injection with either vehicle or 17-DMAG for 4 wk. ANG II infusion induced AAA formation in 80% of mice, which was accompanied by increased matrix metalloproteinase (MMP) activity, enhanced tissue inflammation, oxidative stress, and neovascularization. Importantly, these effects were inhibited by 17-DMAG treatment. Mechanistically, we showed that 17-DMAG prevented the formation and progression of AAA through its inhibitory effects on diverse biological pathways including 1) by blocking ANG II-induced phosphorylation of ERK1/2 and JNK that are critically involved in the regulation of MMPs in vascular smooth muscle cells, 2) by inhibiting IκB kinase expression and expression of MCP-1, and 3) by attenuating ANG II-stimulated angiogenic processes critical to AAA formation. Our results demonstrate that inhibition of Hsp90 by 17-DMAG effectively attenuates ANG II-induced AAA formation by simultaneously inhibiting vascular inflammation, extracellular matrix degradation, and angiogenesis, which are critical in the formation and progression of AAAs.


Oscillatory behavior of nanodroplets.
Molecular dynamics (MD) simulations were performed in order to investigate the phenomenon of free oscillations of nanodroplets and the extent to which the continuum theory for such oscillations holds at nanoscales. The effect of temperature on these oscillations is also studied. The surface tension, a key property for the phenomenon of interest, was evaluated and compared with the experimental values of argon, showing that with an appropriate choice of the cutoff distance in the MD simulations, it is possible to predict the surface tension with good approximation. Nanoscale capillary waves on the free surface of the droplet were observed and compared to continuum theoretical predictions of the same. The nanodroplet interface thickness calculated based on continuum theory for these waves agreed well with the molecular dynamics calculation of the interface thickness. The frequencies of the oscillation of the droplet were calculated for all the studied temperatures and compared with the classical continuum theory. Although the simulated system cannot be considered strictly as a continuum, a good overall agreement was found.


Supramolecular complexation of alkali cations through mechanochemical reactions between crystalline solids.
The organometallic zwitterion [Co(III)(eta(5)-C(5)H(4)COOH)(eta(5)-C(5)H(4)COO)] reacts quantitatively as a solid polycrystalline phase with a number of crystalline alkali salts MX (M = K(+), Rb(+), Cs(+), NH(4) (+); X = Cl(-), Br(-), I(-), PF(6)(-), although not in all cation/anion permutations) to afford supramolecular complexes of the formula [Co(III)(eta(5)-C(5)H(4)COOH)(eta(5)-C(5)H(4)COO)](2).M(+)X(-). In some cases, the mechanochemical complexation requires kneading of the two solids with a catalytic amount of water. The characterization of the solid-state products has been achieved by a combination of X-ray single-crystal and powder-diffraction experiments. The hydrogen-bonding interactions have been investigated by solid-state NMR spectroscopy. The mechanochemical reactions imply a profound solid-state rearrangement accompanied by breaking and forming of O-H...O hydrogen-bonding interactions between the organometallic molecules. All compounds could also be obtained by solution crystallization of the inorganic salts in the presence of the organometallic unit. The solid-state complexation of alkali cations by the organometallic zwitterion has been described as a special kind of solvation process taking place in the solid state.


Endobronchial ultrasound: new insight for the diagnosis of sarcoidosis.
A diagnosis of sarcoidosis should be substantiated by pathological means in order to thoroughly exclude other diseases. The role of real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of sarcoidosis has not been reported. The purpose of the present study is to evaluate the diagnostic yield of EBUS-TBNA in demonstrating the pathological features of sarcoidosis. In total, 65 patients with suspected sarcoidosis, with enlarged hilar or mediastinal lymph nodes on computed tomography, were included in the study. Patients with a suspected or known malignancy or previously established diagnosis of sarcoidosis were excluded. Convex probe endobronchial ultrasonography integrated with a separate working channel was used for EBUS-TBNA. Surgical methods were performed in those in whom no granulomas were detected by EBUS-TBNA. Patients were followed up clinically. EBUS-TBNA was performed on a total of 77 lymph node stations in 65 patients. A final diagnosis of sarcoidosis was made for 61 (93.8%) of the patients. The remaining four patients were diagnosed as having Wegener's granulomatosis (n=1) or indefinite (n=3). In patients with a final diagnosis of sarcoidosis, EBUS-TBNA demonstrated noncaseating epithelioid cell granulomas in 56 (91.8%) of the patients. No complications were reported. Endobronchial ultrasound-guided transbronchial needle aspiration proved to be a safe procedure with a high yield for the diagnoses of sarcoidosis.


Anomalous Coronary Arteries That Need Intervention: Review of Pre- and Postoperative Imaging Appearances.
Coronary artery anomalies constitute a diverse group of abnormalities, ranging from anatomic variants to those having hemodynamic consequences. This review focuses on major anomalies that have clinical implications requiring treatment, including anomalous origin of the coronary artery from the opposite sinus with interarterial course specifically with an intramural course, coronary artery origin from the pulmonary artery, and coronary artery fistula. Comprehensive imaging evaluation is necessary to precisely delineate the anatomy as well as pathophysiologic aspects of the anomaly before determining treatment options for a specific patient. Coronary computed tomographic angiography provides elegant depiction of coronary arterial anatomy and the relationship of the vessel to the adjacent structures, with the ability to perform three-dimensional reconstructions. Magnetic resonance (MR) imaging is emerging as an alternative noninvasive imaging strategy, particularly in young individuals, due to the lack of ionizing radiation and avoidance of iodinated contrast agents. This review describes the roles and recent technical advancements in computed tomography and MR imaging pertinent to coronary artery imaging. Additionally, this article will familiarize readers with the cross-sectional imaging appearance of clinically relevant coronary anomalies, hemodynamic considerations, and complex decision making. The different management strategies used for these anomalies, such as coronary unroofing, reimplantation, bypass grafting, Takeuchi repair, and surgical and interventional closure of fistulas, as well as specific posttreatment complications, are also discussed. ©RSNA, 2017.


Understanding school-going adolescent's preferences for accessing HIV and contraceptive care: findings from a discrete choice experiment among learners in Gauteng, South Africa.
Many Adolescents in Sub-Saharan Africa do not access HIV and reproductive health services optimally. To improve uptake of these services, it is important to understand the Learners' preferences for how services are delivered so that implementation strategies can reflect this. A discrete choice experiment (DCE) was used to elicit preferences. The DCE was completed between 07/2018 and 09/2019 and conducted in 10 high schools situated in neighbourhoods of varying socio-economic status (SES) in Gauteng (South Africa). Learners aged ≥ 15 years (Grades 9-12) were consented and enrolled in the DCE. Parental consent and assent were required if < 18 years old. Conditional logistic regression was used to determine preferred attributes for HIV and contraceptive service delivery. Results were stratified by gender and neighbourhood SES quintile (1 = Lowest SES; 5 = Highest SES). 805 Learners were enrolled (67% female; 66% 15-17 years; 51% in grades 9-10). 54% of Learners in quintile 1 schools had no monthly income (family support, grants, part-time jobs etc.); 38% in quintile 5 schools had access to R100 ($7.55) per month. Preferences for accessing HIV and contraceptive services were similar for male and female Learners. Learners strongly preferred services provided by friendly, non-judgmental staff (Odds ratio 1.63; 95% Confidence Interval: 1.55-1.72) where confidentiality was ensured (1.33; 1.26-1.40). They preferred services offered after school (1.14; 1.04-1.25) with value-added services like free Wi-Fi (1.19; 1.07-1.32), food (1.23; 1.11-1.37) and youth-only waiting areas (1.18; 1.07-1.32). Learners did not have a specific location preference, but preferred not to receive services within the community (0.82; 0.74-0.91) or school (0.88; 0.80-0.96). Costs to access services were a deterrent for most Learners irrespective of school neighbourhood; female Learners were deterred by costs ≥$3.85 (0.79; 0.70-0.91); males by costs ≥ R100 ($7.55) (0.86; 0.74-1.00). Preferences that encourage utilisation of services do not significantly differ by gender or school neighbourhood SES. Staff attitude and confidentiality are key issues affecting Learners' decisions to access HIV and contraceptive services. Addressing how healthcare providers respond to young people seeking sexual and reproductive health services is critical for improving adolescents' uptake of these services.


Dietary phospholipids, hepatic lipid metabolism and cardiovascular disease.
An increasing number of studies in experimental animals suggest that dietary phospholipids might be of benefit in the treatment of fatty liver disease. This raises the possibility that synthetic or naturally occurring phospholipid isolates could be used as hepatoprotective nutraceuticals or functional foods. The aim of the present article is to review published data describing the beneficial effects of dietary phospholipids on hepatic lipid metabolism and their potential to affect atherosclerosis and cardiovascular disease. Consistent results have been obtained supporting the concept that phospholipid from various sources (i.e., soybean, safflower, egg and fish roe) can reduce liver lipid levels. The primary site of action for this effect appears to be in the intestinal lumen, where dietary phospholipids are able to interfere with neutral sterol absorption. Results have also been obtained suggesting that dietary phospholipids can stimulate bile acid and cholesterol secretion. Additional work suggests that dietary phospholipids can have a beneficial effect on plasma lipid and lipoprotein levels. The concept of using naturally occurring compounds such as phospholipid to treat or prevent hepatic steatosis is very attractive. Controlled human trials are, however, required to verify the efficacy of this approach. It is also important that additional research be conducted to determine the extent to which certain phospholipids have the ability to increase plasma HDL levels and potentially affect the onset or development of cardiovascular disease.


HZE Radiation Non-Targeted Effects on the Microenvironment That Mediate Mammary Carcinogenesis.
Clear mechanistic understanding of the biological processes elicited by radiation that increase cancer risk can be used to inform prediction of health consequences of medical uses, such as radiotherapy, or occupational exposures, such as those of astronauts during deep space travel. Here, we review the current concepts of carcinogenesis as a multicellular process during which transformed cells escape normal tissue controls, including the immune system, and establish a tumor microenvironment. We discuss the contribution of two broad classes of radiation effects that may increase cancer: radiation targeted effects that occur as a result of direct energy deposition, e.g., DNA damage, and non-targeted effects (NTE) that result from changes in cell signaling, e.g., genomic instability. It is unknown whether the potentially greater carcinogenic effect of high Z and energy (HZE) particle radiation is a function of the relative contribution or extent of NTE or due to unique NTE. We addressed this problem using a radiation/genetic mammary chimera mouse model of breast cancer. Our experiments suggest that NTE promote more aggressive cancers, as evidenced by increased growth rate, transcriptomic signatures, and metastasis, and that HZE particle NTE are more effective than reference γ-radiation. Emerging evidence suggest that HZE irradiation dampens antitumor immunity. These studies raise concern that HZE radiation exposure not only increases the likelihood of developing cancer but also could promote progression to more aggressive cancer with a greater risk of mortality.


Polysaccharides PS-G and protein LZ-8 from Reishi (Ganoderma lucidum) exhibit diverse functions in regulating murine macrophages and T lymphocytes.
Bioactive components in Ganoderma lucidum mainly include polysaccharides (PS-G) and immunomodulatory protein Ling Zhi-8 (LZ-8). These components may have diverse regulatory functions in the immune system. However, the PS-G preparations from different procedures still contained partial LZ-8 residue, indicating that the specific target and regulating function of PS-G and LZ-8 were not fully understood. In the present study, PS-G was subjected to 15% TCA for removing proteins and the LZ-8 detection using anti-LZ-8 monoclonal antibodies showed a remarkable 89.7% protein reduction of the deproteinized PS-G (dpPS-G). The Saccharomyces cerevisiae which expressed recombinant LZ-8 protein (rLZ-8) without glycosylation was generated and then compared with dpPS-G in the induction toward murine primary macrophage and T lymphocytic cells. The peritoneal macrophages from TLR4-deficient and wild type mice revealed that TLR4 was a putative receptor of dpPS-G, mediating the TNF-alpha, IL-1beta and IL-12p70 cytokine production and CD86, MHC II expression on macrophages, while rLZ-8 enhanced the production of IL-1beta, IL-12p70, CD86, and MHC II expression by another obscure route. rLZ-8-treated macrophages enhanced the release of IFN-gamma and IL-2 by murine CD4(+) and CD8(+) T cells, whereas dpPS-G treatment did not enhance the release of IFN-gamma and IL-2. Furthermore, although the direct rLZ-8-treatment conduced dramatic CD154, CD44 expression on CD3(+) T cells and increased IL-2, IFN-gamma secretion on CD4(+) and CD8(+) T cells, the dpPS-G was incapable of priming CD3(+), CD4(+) or CD8(+) T cells unitarily. Taken together, these results demonstrated that LZ-8 could activate murine macrophages and T lymphocytes but PS-G was merely the activator for macrophages, suggesting their diverse roles in activating the innate and adaptive immunity.


Inactivation of monazomycin-induced voltage-dependent conductance in thin lipid membranes. II. Inactivation produced by monazomycin transport through the membrane.
At sufficiently large conductances, the voltage-dependent conductance induced in thin lipid membranes by monazomycin undergoes inactivation. This is a consequence of depletion of monazomycin from the membrane solution interface, as monazomycin crosses the membrane to the opposite (trans) side from which it was added. The flux of monazomycin is directly proportional to the monazomycin-induced conductance; at a given conductance it is independent of monazomycin concentration. We conclude that when monazomycin channels break up, some or all of the molecules making up a channel are deposited on the trans side. We present a model for the monazomycin channel: approximately five molecules, each spanning the membrane with its NH3+ on the trans side and an uncharged hydrophilic (probably sugar) group anchored to the cis side, form an aqueous channel lined by--OH groups. The voltage dependence arises from the flipping by the electrical field of molecules lying parallel to the cis surface into the "spanned state;" the subsequent aggregation of these molecules into channels is, to a first approximation, voltage independent. The channel breakup that deposits monomers on the trans side involves the collapsing of the channel in such a way that the uncharged hydrophilic groups remain in contact with the water in the channel as they close the channel from behind. We also discuss the possibility that inactivation of sodium channels in nerve involves the movement from one side of the membrane to the other of the molecules (or molecule) forming the channel.


Comparison of dynamic contour tonometry with goldmann applanation tonometry.
The dynamic contour tonometer (DCT; Pascal tonometer) is a novel tonometer designed to measure intraocular pressure (IOP) independent of corneal properties. The purpose of this study was a comparison of the DCT with the Goldmann applanation tonometer (GAT) with respect to mean of IOP readings, the influence of ocular structural factors on IOP readings, and both intra- and interobserver variability, in a large group of healthy subjects. In a prospective study of 228 eyes, IOP measurements by GAT and DCT were compared, and the effects of central corneal thickness (CCT), corneal curvature, axial length, and anterior chamber depth were analyzed. To evaluate intra- and interobserver variability, IOP was measured in eight eyes by four observers. There was a high concordance between the IOP readings obtained by DCT and GAT. However, IOP readings were consistently higher with DCT than with GAT (median difference: +1.7 mm Hg, interquartile range [25th-75th percentile] = 0.8-2.7 mm Hg). In contrast to GAT, multivariable regression analysis showed no significant effect of corneal thickness, corneal curvature, astigmatism, anterior chamber depth, and axial length on DCT readings. For repeated measurements the intraobserver variability was 0.65 mm Hg for the DCT and 1.1 mm Hg for the GAT (P = 0.008). Interobserver variability was 0.44 mm Hg for the DCT and 1.28 mm Hg for the GAT (P = 0.017). IOP measurements by DCT are highly concordant with IOP readings obtained from GAT but do not vary in CCT and have a lower intra- and interobserver variability. DCT seems to be an appropriate method of tonometry for routine clinical use.


Language recovery after left hemispherectomy in children with late-onset seizures.
We investigated the language capabilities of the isolated right hemisphere in 6 children (age, 7-14 years) after left hemidecorticectomy for treatment of Rasmussen's syndrome. Patients were right-handed before surgery and had at least 5 years of normal language development before the onset of seizures. Language testing included speech sound (phoneme) discrimination, single word and phrasal comprehension, repetition, and naming. Within 4 to 16 days after surgery, patients showed improved phoneme discrimination compared with their performance shortly before surgery. Other language functions remained severely impaired until at least 6 months after surgery. By 1 year after surgery, receptive functions were comparable with, or surpassed, patient presurgery performance. Although word repetition was intact by 1 year after surgery, naming remained impaired, and patient speech was limited largely to production of single words. These results suggest that the right hemisphere is innately capable of supporting multiple aspects of phoneme processing. Recovery of higher level receptive and, to a lesser extent, expressive language functions is attributed to plasticity of the right hemisphere, which appears to persist beyond the proposed critical period for language acquisition and lateralization.


Inflammation-dependent and independent airway remodelling in asthma.
The pathology of asthma is characterized by airway inflammation (granulocytic (GA) or paucigranulocytic (PGA)) and remodelling of airway structures. However, the relationship between inflammatory phenotypes and remodelling is unclear. We hypothesized that some features of airway remodelling are dependent on granulocytic airway inflammation while others are not. Post-mortem airway sections from control subjects (n = 48) and cases of asthma with (n = 51) or without (n = 29) granulocytic inflammation in the inner airway wall were studied. The thickness of the airway smooth muscle (ASM) layer, basement membrane and inner and outer airway walls, the size and number of ASM cells, the volume fraction of extracellular matrix within the ASM layer, ASM shortening and luminal mucus were estimated. Airway dimensions were compared between the three subject groups. In cases of PGA, only the thickness of the ASM layer and basement membrane was increased compared with control subjects. In cases of GA, not only the ASM and basement membrane were increased in thickness, but there was also increased inner and outer airway wall thickness and increased narrowing of the airway lumen due to ASM shortening and mucus obstruction, compared with control subjects. Granulocytic inflammation was observed more often in cases of fatal asthma. These findings suggest that inner and outer wall thickening coexists with inflammation, whereas thickening of the ASM layer and basement membrane may be present even in the absence of inflammation. Remodelling of the ASM layer and basement membrane may therefore be less susceptible to anti-inflammatory therapy.


Assessment of Kinematics and Electromyography Following Arthroscopic Single-Tendon Rotator Cuff Repair.
The increasing demand for rotator cuff (RC) repair patients to return to work as soon as they are physically able has led to exploration of when this is feasible. Current guidelines from our orthopedic surgery clinic recommend a return to work at 9 weeks postoperation. To more fully define capacity to return to work, the current study was conducted using a unique series of quantitative tools. To date, no study has combined 3-dimensional (3D) motion analysis with electromyography (EMG) assessment during activities of daily living (ADLs), including desk tasks, and commonly prescribed rehabilitation exercise. To apply a quantitative, validated upper extremity model to assess the kinematics and muscle activity of the shoulder following repair of the supraspinatus RC tendon compared to that in healthy shoulders. A prospective, cross-sectional comparison study. All participants were evaluated during a single session at the Medical College of Wisconsin Department of Orthopaedic Surgery's Motion Analysis Laboratory. Ten participants who were 9-12 weeks post-operative repair of a supraspinatus RC tendon tear and 10 participants with healthy shoulders (HS) were evaluated. All participants were evaluated with 3D motion analysis using a validated upper extremity model and synchronized EMG. Data from the 2 groups were compared using multivariate Hotelling T2 tests with post hoc analyses based on Welch t-tests. Participants' thoracic and thoracohumeral joint kinematics, temporal-spatial parameters, and RC muscle activity were measured by applying a quantitative upper extremity model during 10 ADLs and 3 rehabilitation exercises. These included tasks of hair combing, drinking, writing, computer mouse use, typing, calling, reaching to back pocket, pushing a door open, pulling a door closed, external rotation, internal rotation, and rowing. There were significant differences of the thoracohumeral joint motion in only a few of the tested tasks: comb maximal flexion angle (P = .004), pull door internal/external rotation range of motion (P = .020), reach abduction/adduction range of motion (P = .001), reach flexion/extension range of motion (P = .001), reach extension minimal angle (P = .025), active external rotation maximal angle (P = .012), and active external rotation minimal angle (P = .004). The thorax showed significantly different kinematics of maximal flexion angle during the call (P = .011), mouse (P = .007), and drink tasks (P = .005) between the 2 groups. The EMG data analysis showed significantly increased subscapularis activity in the RC repair group during active external rotation. Although limited abduction was expected due to repair of the supraspinatus tendon, only a single ADL (reaching to back pocket) had a significantly reduced abduction range of motion. Thoracic motion was shown to be used as a compensatory strategy during seated ADLs. Less flexion of the thorax may create passive shoulder flexion at the thoracohumeral joint in efforts to avoid active flexion. The RC repair group participants were able to accomplish the ADLs within the same time frame and through thoracohumeral joint kinematics similar to those in the healthy shoulder group participants. In summary, this study presents a quantification of the effects of RC repair and rehabilitation on the ability to perform ADLs. It may also point to a need for increased rehabilitation focus on either regaining external rotation strength or range of motion following RC repair to enhance recovery and return to the workforce. III.


[Toxicity of Glucantime. A case].
N-methylglucamine antimoniate (Glucantime) is used to treat visceral leishmaniasis but may give rise to serious and sometimes lethal complications: cardiac, hepatic, renal and haematological disease. These may be prevented by respecting the maximal suggested dosage of 6 cg/kg/day, regular clinical checks of pulse, blood pressure and temperature, biological follow-up of serum creatinin, transaminases and routine electrocardiography.


[Asynchronous asymmetry (sexual and lateral differentiation--a consequence of asynchronous evolution)].
In the paper is presented a unified interpretation of sex differentiation and lateral asymmetry as asynchronous evolution. The operative subsystems, i.e. the male and the left hemisphere of the brain evolutionize earlier than the conservative ones, i.e. the female and the right hemisphere. New functions appear at first in males and after many generations they are transferred to females. The leading centers of their control are at first originated in the left hemisphere, then they are translocated to the right one. The criterion for functions localization in the hemisphere is their evolutionary age: new functions are controlled by the left hemisphere, old functions by the right one. Therefore the left hemisphere is socio-cultural, ethnic, the right one is biological, special. The theory explains from a single standpoint the phenomena of sex, handedness, nervous crossover, as well as many know facts, and predicts the new ones.


Phase 1/2 trial of avelumab combined with utomilumab (4-1BB agonist), PF-04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies.
Immune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4-1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4-1BB agonist), PF-04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies. The primary end point in this six-arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune-related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the duration of response, progression-free survival, and overall survival. Forty patients were included (35% with cervical cancer, 30% with endometrial cancer, and 35% with ovarian cancer). Most patients (n = 33; 83%) were enrolled in arms A-C (no radiation). Among 35 patients who were evaluable for efficacy, the ORR was 2.9%, and the DCR was 37.1%, with a median duration of stable disease of 5.4 months (interquartile range, 4.1-7.3 months). Patients with cervical cancer in arm A (avelumab and utomilumab; n = 9 evaluable patients) achieved an ORR of 11% and a DCR of 78%. The median progression-free survival was 2.1 months (95% CI, 1.8-3.5 months), and overall survival was 9.4 months (95% CI, 5.6-11.9 months). No dose-limiting toxicities or grade 3-5 immune-related adverse events were observed. The findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted.


Analysis of the activation mechanism of Pseudomonas stutzeri cytochrome c peroxidase through an electron transfer chain.
The activation mechanism of Pseudomonas stutzeri cytochrome c peroxidase (CCP) was probed through the mediated electrochemical catalysis by its physiological electron donor, P. stutzeri cytochrome c-551. A comparative study was carried out, by performing assays with the enzyme in the resting oxidized state as well as in the mixed-valence activated form, using cyclic voltammetry and a pyrolytic graphite membrane electrode. In the presence of both the enzyme and hydrogen peroxide, the peak-like signal of cytochrome c-551 is converted into a sigmoidal wave form characteristic of an E(r)C'(i) catalytic mechanism. An intermolecular electron transfer rate constant of (4 ± 1) × 10(5) M(-1) s(-1) was estimated for both forms of the enzyme, as well as a similar Michaelis-Menten constant. These results show that neither the intermolecular electron transfer nor the catalytic activity is kinetically controlled by the activation mechanism of CCP in the case of the P. stutzeri enzyme. Direct enzyme catalysis using protein film voltammetry was unsuccessful for the analysis of the activation mechanism, since P. stutzeri CCP undergoes an undesirable interaction with the pyrolytic graphite surface. This interaction, previously reported for the Paracoccus pantotrophus CCP, induces the formation of a non-native conformation state of the electron-transferring haem, which has a redox potential 200 mV lower than that of the native state and maintains peroxidatic activity.


Non-collinear quasi phase matching and annular profiles in difference frequency generation with focused Gaussian beams.
We present and experimentally test a simple model for difference frequency generation (DFG) in periodically-poled crystals with gaussian pumping beams. Focusing of input beams originates several non-collinear quasi-phase-matching configurations of the interacting wavevectors, which contribute to the idler output field. In this picture, we accurately describe a number of effects, such as the occurrence of annular idler intensity profiles and the asymmetric trend of DFG power vs temperature. Finally, we quantitatively test the model by means of an indirect measurement of the crystal poling period.


Women and the 1993-1994 health reform debate: issues and questions.
Provides a review of the major issues raised during the 1993-1994 national health reform debate, with emphasis on the implications of these issues for women's health. I begin with an overview of the current health care system and the access to care by women in it, based in part on their health characteristics. The need to reform the current system is noted, along with a discussion of the major issues and proposals debated during 1993-1994, the years of the 103d US Congress. Questions are raised that could enable women's health advocates and activist women health care consumers to assess the implications for women of various future health reform proposals.


Efficacy of pentosan polysulfate in in vitro models of lysosomal storage disorders: Fabry and Gaucher Disease.
Gaucher and Fabry diseases are the most prevalent sphingolipidoses. Chronic inflammation is activated in those disorders, which could play a role in pathogenesis. Significant degrees of amelioration occur in patients upon introduction of specific therapies; however, restoration to complete health status is not always achieved. The idea of an adjunctive therapy that targets inflammation may be a suitable option for patients. PPS is a mixture of semisynthetic sulfated polyanions that have been shown to have anti-inflammatory effects in mucopolysaccharidosis type I and II patients and animal models of type I, IIIA and VI. We hypothesized PPS could be a useful adjunctive therapy to inflammation for Gaucher and Fabry diseases. The objective of this work is to analyze the in vitro effect of PPS on inflammatory cytokines in cellular models of Gaucher and Fabry diseases, and to study its effect in Gaucher disease associated in vitro bone alterations. Cultures of peripheral blood mononuclear cells from Fabry and Gaucher patients were exposed to PPS. The secretion of proinflammatory cytokines was significantly reduced. Peripheral blood cells exposed to PPS from Gaucher patients revealed a reduced tendency to differentiate to osteoclasts. Osteoblasts and osteocytes cell lines were incubated with an inhibitor of glucocerebrosidase, and conditioned media was harvested in order to analyze if those cells secrete factors that induce osteoclastogenesis. Conditioned media from this cell cultures exposed to PPS produced lower numbers of osteoclasts. We could demonstrate PPS is an effective molecule to reduce the production of proinflammatory cytokines in in vitro models of Fabry and Gaucher diseases. Moreover, it was effective at ameliorating bone alterations of in vitro models of Gaucher disease. These results serve as preclinical supportive data to start clinical trials in human patients to analyze the effect of PPS as a potential adjunctive therapy for Fabry and Gaucher diseases.


Rapid axonal transport in focally demyelinated sciatic nerve.
Focal demyelination was produced in rat sciatic nerve by unilateral intraneural injection of anti-galactocerebroside serum. A functional lesion was confirmed by the presence of nerve conduction block. Histologically, this corresponded to demyelination of 50-70% of the fibers in nerve cross sections; axonal structures appeared intact. At the time of maximal demyelination (7 d), 35S-methionine or 3H-fucose was injected bilaterally into the spinal cord ventral horn. At later times (5 hr-7 d), the sciatic nerve was removed and radioactivity in successive nerve segments was quantitated. The transport rates (approximately 260 mm/d) and the composition of transported proteins and glycoproteins (separated on 7-15% polyacrylamide gradient gels) were not altered in lesioned nerves relative to contralateral control nerves. Light microscopic autoradiographic analysis revealed a similar localization of axonally transported and deposited glycoproteins in demyelinated and control fibers. Initially (8 hr), the majority of label was over axons. Labeled glycoproteins remaining in the nerve after 1 week were retained mainly in axolemmal regions. We conclude that acute focal primary demyelination does not lead to major alterations in the transport or deposition of newly synthesized macromolecules.