Solitary fibrous tumor of the spinal cord: a clinicopathologic study of two cases.
Two cases of solitary fibrous tumor of the spinal cord are described. The patients were two men, 36 and 47 years old. Clinically, they sought medical care because of progressive paresthesias or urinary incontinence caused by a nodular, fairly circumscribed intraspinal tumor of the cervical and thoracic spinal cord, respectively. Preoperative magnetic resonance images suggested meningioma. In both cases, laminectomy with tumor resection was carried out. Microscopically, the tumors featured short spindle cells haphazardly enmeshed in a collagenized ground substance. No atypia, necrosis, or significant mitotic activity was recognized. Tumor cells were positive for CD34, bcl2, vimentin, and, in one case, CD99. Both patients recovered from symptoms and are alive and well 12 and 18 months, respectively, after surgical resection. The differential diagnosis includes meningioma, schwannoma, and hemangiopericytoma, all of which may occur in the spinal canal. A careful morphologic approach and the judicious use of immunohistochemistry may assist in distinguishing among these conditions, although some irreducible difficulties may be posed by hemangiopericytoma. Although solitary fibrous tumor of the spinal cord presents with fairly comparable clinical, instrumental, and pathologic patterns, we believe that compilation of more cases is needed to segregate it as a distinct clinicopathologic entity.


Obesity and physical inactivity: the relevance of reconsidering the notion of sedentariness.
The population statistics of most countries of the world are indicating that industrialization and computerization have been associated with an increase in sedentariness and more recently with a significant shift from healthy weight to overweight. In general, this change in the overweight/obesity prevalence is attributed by health professionals to suboptimal diet and physical activity practices. However, recent data raised the possibility that excess weight gain might also be the outcome of changes imposed by our '24-hour', hectic lifestyle. Parallel to an increase in body weight, one has observed a reduction in sleep time and an increase in knowledge-based work (KBW) that appear as a growing necessity in a context of economic competitiveness and globalization. Sleep and cognitive work both exert a trivial effect on energy expenditure and may thus be considered as sedentary activities. However, their respective effect on energy intake is opposite. Indeed, an increase in the practice of the most sedentary activity, i.e. sleep, is associated with a hormonal profile facilitating appetite control whereas KBW appears as a stimulus favoring a significant enhancing effect on food intake. Television viewing is another example of sedentary activity that has been shown to increase the intake of high-density foods. These observations demonstrate that the modern way of living has favored a change in human activities whose impact goes well beyond what has traditionally been attributed to a lack of physical exercise. Therefore, we will need to reconsider the notion of 'sedentariness' which includes several activities having opposing effects on energy balance.


Clinical effectiveness and cost-effectiveness of the use of the thyroxine/thyroxine-binding globulin ratio to detect congenital hypothyroidism of thyroidal and central origin in a neonatal screening program.
Since the introduction of screening for congenital hypothyroidism (CH) in 1974, the optimal laboratory strategy has been the subject of debate. To assess the clinical effectiveness and cost-effectiveness of various types of thyroxine (T(4))-based strategies to screen for CH. In the Netherlands, since January 1, 1995, a primary T(4) determination with supplemental thyroid-stimulating hormone (TSH) and T(4)-binding globulin (TBG) measurements has been used. Results were calculated from cumulative findings for 1181079 children screened between January 1, 1995, and December 31, 2000. Rates of detection of patients with CH of thyroidal origin (CH-T) or CH of central origin (CH-C), false-positive rates, laboratory costs, and costs of initial diagnostic evaluations. All known infants (n = 393) with CH-T and 92% (n = 66) of infants with CH-C were detected on the basis of low T(4) levels, TSH elevation, and/or low T(4)/TBG ratios. If the decision to refer had been based solely on TSH elevation, then 94% of patients with CH-T and none of the patients with CH-C would have been detected. If low T(4) levels (<or=-3.0 SD) and TSH elevation had been used as the criteria for referral, then the rates of detection would have been 96% for CH-T and 31% for CH-C. The false-positive rates for the 3 approaches were 0.5, 3.3, and 4.7 cases per case detected, respectively. The introduction of the T(4)/TBG ratio into a program using a primary T(4) with supplemental TSH approach generates an extra cost of 11206 dollars per additional case detected. The average costs to detect 1 patient are comparable for the 3 approaches. In addition, our data revealed a substantially greater prevalence of CH-C than reported previously (1 case per 16404 children, compared with earlier estimates of 1 case per 26000 infants to 1 case per 29000 infants). The T(4) plus TSH plus TBG approach is a recommendable strategy for neonatal CH screening. It offers outstanding detection of patients with CH-C, in addition to those with CH-T, with acceptable costs.


Polyoxometalate-biomolecule conjugates: a new approach to create hybrid drugs for cancer therapeutics.
Some polyoxometalate (POM) clusters have demonstrated attractive anticancer properties. Unfortunately, their cytotoxicity upon normal cell is one of fateful side effects obstructing their further clinic application as inorganic drugs. In this communication, we report a new approach to create hybrid drugs potentially for cancer therapeutics. At first, the POM cluster bioconjugates were created by attaching the bioactive ligands on an amine grafted POM via simple amidation reaction. The cytotoxicity study with breast cancer cells (MCF-7 and MDA-MB-231) and non-cancerous breast epithelial cell (MCF-10A) showed that rationally selected ligands with cancer-cell targeting ability on POM-biomolecule conjugates can impart enhanced anti-tumor activity and selectivity, thus representing a new concept to develop novel POM-biomolecule hybrid drugs with the potential synergistic effect: increased bioactivity and lower side effect.


Cell assembly formation and structure in a piriform cortex model.
The piriform cortex is rich in recurrent excitatory synaptic connections between pyramidal neurons. We asked how such connections could shape cortical responses to olfactory lateral olfactory tract (LOT) inputs. For this, we constructed a computational network model of anterior piriform cortex with 2000 multicompartment, multiconductance neurons (500 semilunar, 1000 layer 2 and 500 layer 3 pyramids; 200 superficial interneurons of two types; 500 deep interneurons of three types; 500 LOT afferents), incorporating published and unpublished data. With a given distribution of LOT firing patterns, and increasing the strength of recurrent excitation, a small number of firing patterns were observed in pyramidal cell networks: first, sparse firings; then temporally and spatially concentrated epochs of action potentials, wherein each neuron fires one or two spikes; then more synchronized events, associated with bursts of action potentials in some pyramidal neurons. We suggest that one function of anterior piriform cortex is to transform ongoing streams of input spikes into temporally focused spike patterns, called here "cell assemblies", that are salient for downstream projection areas.


Usefulness of the bispectral index during cardiopulmonary resuscitation -A case report-.
The usefulness of using the bispectral index (BIS) for monitoring during cardiopulmonary resuscitation (CPR) is not clearly understood. However, BIS has been a popular anesthetic monitoring device used during operations. The case presented is of a pregnant woman going into cardiac arrest due to an amniotic fluid embolism during a Cesarean section. CPR was performed, but neither the return of spontaneous circulation (ROSC) nor the return of consciousness was achieved, despite 50 min of effective CPR. However, CPR was continued based on BIS. ROSC was achieved, and an alert consciousness state was reached 1 day postoperation. This finding suggests that BIS be used as a basic monitoring device during CPR and that it may help in deciding to continue CPR.


Personality and its association with self-management in multiple sclerosis.
In a healthcare system which aims to empower the patient, self-management becomes increasingly important. In Multiple Sclerosis, an effective self-management is associated with various favorable health-related outcomes like improvement in quality of life, the reduction of depression and anxiety symptoms, and reduced healthcare costs. This study investigates the association between the Big Five personality traits and self-management including activity in self-help groups. People with MS were recruited via several paths within Germany (e.g. medical practices, social events and the German MS society). The final study sample consisted of 682 participants who answered a multidimensional questionnaire. This comprised the Big-Five-Inventory-10 for personality, the Health Education Impact Questionnaire (heiQ) for self-management competencies, questions for participation in self-help groups, and socio-demographic and clinical variables. Multivariate regression analyses showed that personality could explain a greater amount of variance of self-management than socio-demographic and clinical variables. Neuroticism was the strongest predictor and correlated negatively with all heiQ-dimensions of self-management. In contrast, in logistic regression analysis none of the Big Five traits became significant in predicting the activity in self-help groups. As expected, personality plays an important role regarding self-management. Ideally, a time-saving personality assessment should be considered in routine clinical practice to identify patients at risk; however, at a minimum, personality traits should be considered in consultations with their neurologists. They may need help to understand the benefits of effective self-management and should receive support to improve their self-management skills and to reduce their neuroticism to lower the risk of secondary complications.


Sailing in a sea of perplexity: Family caregivers' experience of patients with delirium.
Family caregivers play an important role for patients admitted to the intensive care unit (ICU), and delirium is a common clinical syndrome. Little is known about the experiences of family caregivers when a relative is a patient with delirium, especially for caregivers in Asian cultures. To understand the experience of family caregivers with a family member as a patient with delirium in the ICU in Taiwan. A descriptive qualitative study with in-depth face-to-face semi-structured interviews. Interviews were conducted with 20 family caregivers of 20 patients with delirium in the ICU of a hospital in northern Taiwan. The core theme describing the phenomenon of family caregivers of a patient with delirium was "Sailing in a sea of perplexity," which described family caregivers' uncertainty of navigating the ICU and providing support for a relative. Three subthemes described the core theme: (a) perplexity of the ICU environment, (b) perplexity of making decisions, and (c) perplexity of Chinese cultural constraints. "Sailing in a sea of perplexity" underscores how uncertainty among family caregivers of patients with delirium in ICUs can lead to feelings of fear and anxiety. Therefore, nursing professionals should not only focus on patient care but also be sensitive to caregivers' feelings of uncertainty and their cultural beliefs. Unfamiliarity and lack of knowledge about intensive care and patient treatments were a source of family caregivers' perplexity. To reduce uncertainty, we recommend increased communication between staff and caregivers. Hospitals can also provide information on their websites, including treatment of delirium and visitation hours. Information access could be enhanced by developing a smartphone app linked to a QR code that families can scan to obtain information, which would be useful during restricted visitation.


Additive effects of vertebrate predators on insects in a Puerto Rican coffee plantation.
A variety of studies have established the value of shaded coffee plantations as habitat for birds. While the value of birds as biological controls in coffee has received some attention, the interactions between birds and other predators of insects have not been tested. We used exclosures to examine the effects of vertebrate predators on the arthropods associated with coffee, in particular the coffee leafminer (Leucoptera coffeella) and the flatid planthopper Petrusa epilepsis, in a shaded coffee plantation in Puerto Rico. We used a 2 x 2 factorial design with four treatments: exclusion of birds, lizards, birds and lizards, and control (no exclusion). Abundance of insects > 5 mm increased when birds or both birds and lizards were removed. Birds and lizards had an additive effect for insects < 5 mm and for all insects combined. Coffee leafminers showed a weak response to removal of predators while planthopper abundance increased significantly in the absence of avian predators. Arthropod predators and parasitoids did not differ significantly between treatments. Our findings suggest that vertebrate insectivores have an additive effect on insects in coffee and may help control abundances of some coffee pests. Equally important, we present evidence suggesting that they do not interfere with other known natural enemies of coffee pests.


Selective production of retinol by engineered Saccharomyces cerevisiae through the expression of retinol dehydrogenase.
Retinol is a fat-soluble vitamin A that is widely used in the food and pharmaceutical industries. Currently, retinol is commercially produced by chemical synthesis. Microbial production of retinol has been alternatively explored but restricted to a mixture of retinoids including retinol, retinal, and retinoic acid. Thus, we introduced heterologous retinol dehydrogenase into retinoids mixture-producing Saccharomyces cerevisiae for the selective production of retinol using xylose. Expression of human RDH10 and Escherichia coli ybbO led to increase in retinol production, but retinal remained as a major product. In contrast, S. cerevisiae harboring human RDH12 produced retinol selectively with negligible production of retinal. The resulting strain (SR8A-RDH12) produced retinol only. However, more glycerol was accumulated due to intracellular redox imbalance. Therefore, Lactococcus lactis noxE coding for H2 O-forming NADH oxidase was additionally introduced to resolve the redox imbalance. The resulting strain produced 52% less glycerol and more retinol with a 30% higher yield than a parental strain. As the produced retinol was not stable, we examined culture and storage conditions including temperature, light, and antioxidants for the optimal production of retinol. In conclusion, we achieved selective production of retinol efficiently from xylose by introducing human RDH12 and NADH oxidase into S. cerevisiae.


Antifungal activity of 4% chlorhexidine and 2% sodium hypochlorite against Candida albicans biofilms.
The purpose of this study was to determine the antifungal efficacy of 4% chlorhexidine (CHX) and 2% sodium hypochlorite (NaOCl) on 24-hour Candida albicans biofilms. Candida albicans biofilms were developed on acrylic resin specimens, which were randomly assigned to 1 of 5 groups (n = 3 per group) exposed to 1 mL of 4% CHX for 2, 4, 6, 8, or 10 minutes. Biofilms in contact with 1 mL of distilled water or 2% NaOCl for 10 minutes were used as positive and negative controls (n = 3 per group), respectively. Specimens were analyzed with confocal laser scanning microscopy and a cell viability assay technique. The biovolume of the live subpopulation of the biofilm was calculated with biofilm image analysis software. Statistically significant differences (P < 0.05) in the biovolume of surviving cells were found among the positive control group and the 4-, 6-, 8-, and 10-minute experimental periods. The biovolumes found after 6-10 minutes of exposure to chlorhexidine were significantly different (P < 0.05) from the biovolume after 2 minutes of exposure. The most effective decrease of the biovolume was found after the use of the negative control (sodium hypochlorite) solution. Exposure to 10 minutes of 2% NaOCl removed fungal cells more effectively than all the experimental groups (P < 0.05). The 4% CHX solution showed an antifungal activity against C albicans biofilms but failed to decrease the biovolume to the levels of 2% NaOCl, which eliminated viable cells more effectively and appeared to be more effective in disrupting the attached biofilms.


Bone marrow involvement: Atypical presentation of early-onset childhood sarcoidosis.
Childhood sarcoidosis is a chronic multisystemic, non-caseating granulomatous disease of unknown etiology. Early-onset disease classically presents with a triad of skin rash, uveitis, and arthritis, but bone marrow involvement is rare. We report a 9-1/2-year old Indian female child who presented with bleeding manifestation, skin rash, uveitis, and arthritis. Bone marrow biopsy showed multiple non-necrotizing granulomas comprising epithelioid cells, mature lymphocytes, and multinucleated giant cells with few eosinophils in the background, with negative staining for acid-fast bacilli or fungi. She was treated successfully with oral prednisolone. This is the first report of an early-onset childhood sarcoidosis with bone marrow involvement from India.


Expression analysis of apoptosis-related markers TP53, BCL-2, BAX and c-MYC in female genital tract sarcomas.
Most female genital tract sarcomas are highly malignant and fatal. Their aggressive growth pattern and poor response to chemotherapy are the major causes of death. Deregulation of the apoptosis pathway is related to tumorigenesis and chemodrug resistance. The purpose of this study was to investigate the expression status and relationship of the apoptosis-related markers TP53, BCL-2, BAX and c-MYC in this group of tumors. In addition, correlations of these markers with clinicopathologic findings and their prognostic significance were also examined. Paraffin blocks of female genital tract sarcoma tissue from 54 patients were obtained after pathology review. Protein expression of TP53, BCL-2, BAX and c-MYC was examined using immunohistochemical staining with standard procedures. A semiquantitative method was used to assess the staining result where scoring 1-3 was negative and 4-9 was positive for expression. The mutual relationships between TP53, BCL-2, BAX and c-MYC were examined. Associations between expression of the apoptotic markers and tumor stage as well as outcome were also analyzed. We found that all 4 of the apoptosis-related markers were frequently expressed in female genital tract sarcomas. Of the 54 cases, 24 (44%) were positive for TP53, 23 (43%) for BCL-2, 25 (46%) for BAX, and 30 (56%) for c-MYC. A significant positive association was observed between BAX and c-MYC (p < 0.001). There was no significant difference for the expression status of the 4 markers in early and late stage tumors. In prognostic analysis, overexpression of TP53, late stage, and age were significant prognostic factors in both univariate and multivariate analyses. Since changes in TP53, BCL-2, BAX and c-MYC frequently occur in female genital tract sarcomas, deregulation of apoptosis appears to be involved in the pathogenesis of this group of tumors. This mechanism may occur early in tumorigenesis and include the c-MYC/BAX apoptotic pathway or BCL-2. However, TP53 mutation may play a crucial role in this process, and clinically, it could be used as a prognostic indicator.


Evaluation of the effectiveness of a water lift system in the sinus membrane-lifting operation as a sinus surgical instrument.
The effectiveness of a Water Lift System in the sinus membrane-lifting operation was examined. This investigation focused on the capability of this equipment to reduce the risk of Schneiderian membrane perforation. A preliminary clinical study on the use of the Water Lift System in sinus membrane elevation to place implants through the sinus floor was conducted. A total of 70 sinus membrane-lifting operations were performed on patients with various bone heights ranging from 1.2 to 9.9 mm (most commonly in the range of 4-6 mm) through the lateral approach (four cases) or the crestal approach (66 cases). In all of the cases performed using the lateral approach, sinus membrane perforation did not occur. In the 66 cases performed using the crestal approach, Schneiderian membrane tearing occurred in two cases. The membrane tearing occurred during elevation of the Schneiderian membrane but not when a hole was drilled to access the Schneiderian membrane. One case of membrane tearing resulted from previous inflammation in the maxillary sinus, and the other case of membrane tearing was caused by application of excessive hydraulic pressure. In addition, similar outcomes were obtained and no microbial infections were observed in a total of 68 successful cases. In this study, the Water Lift System was confirmed to effectively reduce the risk of Schneiderian membrane perforation during the sinus membrane-lifting operation. We conclude that the Water Lift System deserves to be considered as a sinus surgical instrument, which ensures safety in the sinus membrane-lifting operation.


Aetiology of colorectal cancer and relevance of monogenic inheritance.
Although diet and lifestyle are associated with the development of colorectal malignancies, the only clearly identified aetiological factors in colorectal cancer are inheritance (hereditary non-polyposis colorectal cancer (HNPCC) and familial polyposis), inflammatory bowel diseases, papillomavirus, and acquired immunodeficiency syndrome (AIDS). Our aim was to determine what proportion of colorectal neoplasms could be attributed to these specific factors. Data from a colorectal cancer registry were analysed over a 15 year period, during which nearly 2500 cases were recorded. In patients with suspected HNPCC, microsatellite instability and immunohistochemical expression of proteins encoded by the main DNA mismatch repair genes were assessed. In families with unstable neoplasms, constitutional mutations of the mismatch repair genes hMSH2, hMLH1, and hMSH6 were evaluated by single strand conformation polymorphism analysis and sequencing. Inflammatory bowel diseases, familial polyposis, and AIDS were rare causes of colorectal cancer (three, three, and one case, respectively). Anal squamous carcinoma developed in 27 patients (1.0%) and could be attributed to papillomavirus infection. In 58 patients (from 34 families) a clinical diagnosis of HNPCC was established (2.4%). In total, cases with a known aetiology were 92 (3.7% of all patients). Microsatellite instability was detected in 15 cancers from HNPCC families, and germline mutations in six families (12 patients, 0.5% of the total). Families with unstable tumours, with or without mutations, were clinically similar, suggesting the involvement of the mismatch repair system even when mutations were not detected. The study suggests that the aetiology of colorectal malignancies remains elusive in the large majority of cases. Among specific causes, HNPCC represents the most frequent. However, with a population based approach, constitutional mutations of the main genes involved in HNPCC can be detected in only 20% of cases.


Novel Bronchoscopic Management of Airway Bleeding With Absorbable Gelatin and Thrombin Slurry.
Airway bleeding, either spontaneous or as a result of bronchoscopy, is associated with significant morbidity and mortality. Multiple bronchoscopic techniques are available to achieve complete hemostasis or as a bridge to definitive therapies. We report our experience on the feasibility of endobronchial instillation of an absorbable gelatin and thrombin slurry (GTS) for the treatment of spontaneous hemoptysis and procedure-related bleeding. We identified 13 cases in which GTS was used for endobronchial hemostasis when standard bronchoscopic measures like cold saline, epinephrine, and in some cases balloon occlusion were not successful. GTS was delivered through the working channel of the bronchoscope in 10 cases and through the distal port of a bronchial blocker in the remaining 3 cases. Median age was 69 years (range, 52 to 79 y). Eight cases corresponded to spontaneous hemoptysis and 5 cases to diagnostic or therapeutic procedures. Bleeding was considered severe in 9 (70%) cases. All but 1 case were associated with malignancy. Hemostasis was achieved in 10 (77%) cases by using standard measures in addition to GTS. No patient adverse events at 30 days or damage to the equipment were identified. Bronchoscopic instillation of an absorbable GTS is feasible and may be used in cases of spontaneous or procedure-related bleeding in addition to conventional measures. It can be delivered through the working channel of the bronchoscope or through the distal port available in some bronchial blockers. Controlled studies are necessary to determine the safety and efficacy of this novel technique.


Assessment of risk factors and human papillomavirus (HPV) related pathogenetic mechanisms of CIN in HIV-positive and HIV-negative women. Study design and baseline data of the HPV-PathogenISS study.
In women with HIV-associated immunosuppression, HPV infections have an increased risk of progression to high-grade cervical intraepithelial neoplasia (CIN). With the HAART-induced prolonged survival and more protracted clinical course of AIDS, progression of CIN to cervical cancer (CC) has become a clinically relevant issue, and the mechanisms responsible for HIV-HPV interactions need further elucidation. The study design and analysis of the baseline data of our new project are presented. This project is a combination of a prospective cohort study of HIV- and HIV+ women, and a retrospective analysis of CIN lesions and cervical cancer. Up to the present, 244 women have been enrolled (17 HIV+) and subjected to epidemiological interview, colposcopic examination, sampling for HPV testing and typing (PCR, InnoLiPA), and HPV serology. The retrospective series of biopsies were analysed for 13 biomarkers (monitoring key molecular events) using immunohistochemistry and tested for HPV by PCR and TaqMan. HIV- and HIV+ women differ in their exposure status to many of the key epidemiological risk factors of cervical cancer, the most significant ones being number of sexual partners (p = 0.0001), age at onset of sexual activity (p = 0.002), and contraception (yes-no) (p = 0.009). The differences in the baseline clinical observations are less dramatic; HIV-positive women had more frequent HSIL PAP tests (p = 0.040), CIN2 or higher in cervical biopsy (p = 0.049), and external genital warts (p = 0.019). The factors predicting intermediate endpoint markers of cervical cancer, i.e., HSIL PAP smear, ATZ2 in colposcopy, and high-grade CIN in biopsy were analysed in univariate and multivariate regression models. All factors significant in univariate analysis were entered in the multivariate model; HIV-status and Pap smear history maintained their independent predictive power of the HSIL Pap test. The most powerful predictor of ATZ2 colposcopy was HSIL in Pap test. Only the HSIL Pap test and ATZ2 colposcopy remained significant independent predictors of high-grade CIN (p = 0.0001 and p = 0.008, respectively) in the multivariate model. The three intermediate endpoint markers are closely interrelated, but predicted in part by different covariantes in the causal pathway to cervical cancer. To elucidate whether the increased risk of HIV-positive women to high-grade CIN is due a) to their different exposure status to the risk factors, b) to the direct effects of HIV, or c) to molecular interactions between HIV and HPV, we need to complete these analyses separately in HIV+ and HIV- women.


Nonkeratinizing undifferentiated nasopharyngeal carcinoma: a case report.
Nasopharyngeal carcinoma, a malignant neoplasm of squamous origin, is an uncommon neoplasm in the United States, although it is a significant cause of morbidity and mortality in southeast Asia and northern Africa. These lesions arise most frequently from the lateral wall of the nasopharynx and may be locally aggressive or metastasize regionally or distantly. A 46-year-old African American male presented to our institution with a 5-month history of nasal congestion. Imaging studies revealed a mass filling the right sphenoid sinus and eroding into the adjacent sinuses and temporal bone. A biopsy was performed, and immediate imprint cytology showed two populations of cells, lymphoid cells and cohesive clusters of cells with prominent nucleoli. A diagnosis favoring nasopharyngeal carcinoma was rendered, and subsequent histology showed a nonkeratinizing undifferentiated nasopharyngeal carcinoma. Nasopharyngeal carcinoma, particularly in its nonkeratinizing undifferentiated form, may mimic inflammatory and lymphoproliferative disorders. Careful examination for the distinct cytologic features is necessary for accurate diagnosis and subsequent treatment.


A length-adjustable vacuum-powered artificial muscle for wearable physiotherapy assistance in infants.
Soft pneumatic artificial muscles are increasingly popular in the field of soft robotics due to their light-weight, complex motions, and safe interfacing with humans. In this paper, we present a Vacuum-Powered Artificial Muscle (VPAM) with an adjustable operating length that offers adaptability throughout its use, particularly in settings with variable workspaces. To achieve the adjustable operating length, we designed the VPAM with a modular structure consisting of cells that can be clipped in a collapsed state and unclipped as desired. We then conducted a case study in infant physical therapy to demonstrate the capabilities of our actuator. We developed a dynamic model of the device and a model-informed open-loop control system, and validated their accuracy in a simulated patient setup. Our results showed that the VPAM maintains its performance as it grows. This is crucial in applications such as infant physical therapy where the device must adapt to the growth of the patient during a 6-month treatment regime without actuator replacement. The ability to adjust the length of the VPAM on demand offers a significant advantage over traditional fixed-length actuators, making it a promising solution for soft robotics. This actuator has potential for various applications that can leverage on demand expansion and shrinking, including exoskeletons, wearable devices, medical robots, and exploration robots.


Low-Risk Antenatal Care Enhanced by Telemedicine: A Practical Guideline Model.
To develop a protocol for hybrid low-risk prenatal care adapted to Brazilian guidelines, merging reduced face-to-face consultations and remote monitoring. The PubMed, Embase, and Cochrane Library databases were systematically searched on telemedicine and antenatal care perspectives and adaptation of the low-risk prenatal care protocols recommended by the Ministry of Health and by the Brazilian Federation of Gynecology and Obstetrics Associations. Five relevant articles and three manuals were included in the review, for presented criteria to develop this clinical guideline. We identified, in these studies, that the schedule of consultations is unevenly distributed among the gestational trimesters, and ranges from 7 to 14 appointments. In general, the authors propose one to two appointments in the first trimester, two to three appointments in the second trimester, and two to six appointments in the third trimester. Only three studies included puerperal evaluations. The routine exams recommended show minimal variations among authors. To date, there are no validated Brazilian protocols for prenatal care by telemedicine. The included studies showed that pregnant women were satisfied with this form of care, and the outcomes of interest, except for hypertensive diseases, were similar between the groups exposed to traditional and hybrid prenatal care. The presented guideline comprises the Ministry of Health recommendations for low-risk prenatal care and reduces exposure to the hospital environment and care costs. A randomized clinical trial, to be developed by this group, will provide real-world data on safety, effectiveness, satisfaction, and costs.


Teenage Cancer Trust education & advocacy program: 'lets talk about it' a United Kingdom approach.
Cancer in the United Kingdom is viewed as a taboo subject, particularly with young people, who can enter adulthood with little knowledge about cancer and are often misinformed about the facts. Evidence suggests this lack of information can lead to significant delays in cancer diagnosis. Within the education system in the United Kingdom, there is no provision for cancer education, but as cancer is likely to affect more people each year, the Teenage Cancer Trust education program 'Let's talk about it' aims to improve knowledge and awareness of cancer in secondary schools and offers advice on healthy living to all young people.


Detection and evaluation of feline oncornavirus-induced cell surface antigen(s) shed from cells in vitro.
A method for preparation of soluble feline oncornavirus-induced cell surface antigens was described. This technique relied upon the natural release of antigen(s) from FL-74 feline lymphoblastoid cells during their maintenance at 37 degrees in serum-deficient medium. When concentrated and clarified spent medium from 4-day cultures was tested for its antigen content by inhibition of humoral cytotoxicity, it was found that this natural production of soluble antigen provided more feline oncornavirus-associated cell membrane antigen per cell than did a solubilization procedure in which papain was used. The shed antigen preparation was immunogenic in cats, eliciting humoral antibody that was reactive with the surface of FL-74 Cells and feline sarcoma virus-transformed nonproducer mink cells but was not reactive with feline leukemia virus in a virus neutralization assay.


The effect of alpha-phenyl-N-t-butylnitrone on ionizing radiation-induced apoptosis in U937 cells.
Ionizing radiation induces the production of reactive oxygen species (ROS), which play an important causative role in apoptotic cell death. alpha-Phenyl-N-t-butylnitrone (PBN) is one of the most widely used spin-trapping compounds for investigating the existence of free radicals in biological systems. We investigated the effects of PBN on ionizing radiation-induced apoptosis in U937 cells. Upon exposure to 2 Gy of gamma-irradiation, there was a distinct difference between the control cells and the cells pre-treated with 2 mM PBN for 2 h in regard to apoptotic parameters, cellular redox status, mitochondria function and oxidative damage to cells. PBN effectively suppressed morphological evidence of apoptosis and DNA fragmentation in U937 cells exposed to ionizing radiation. The [GSSG]/[GSH+GSSG] ratio and the generation of intracellular ROS were higher and the [NADPH]/[NADP+ +NADPH] ratio was lower in control cells compared to PBN-treated cells. The ionizing radiation-induced mitochondrial damage reflected by the altered mitochondrial permeability transition, the increase in the accumulation of ROS, and the reduction of ATP production were significantly higher in control cells compared to PBN-treated cells. PBN pre-treated cells showed significant inhibition of apoptotic features such as activation of caspase-3, up-regulation of Bax and p53, and down-regulation of Bcl-2 compared to control cells upon exposure to ionizing radiation. This study indicates that PBN may play an important role in regulating the apoptosis induced by ionizing radiation presumably through scavenging of ROS.


Mutations in the eIF(iso)4G translation initiation factor confer high resistance of rice to Rice yellow mottle virus.
We report here evidence of the role that the isoform of the eukaryotic translation initiation factor 4G (eIF(iso)4G) plays in naturally occurring resistance in plant/virus interactions. A genetic and physical mapping approach was developed to isolate the Rymv1 locus controlling the high recessive resistance to Rice yellow mottle virus (RYMV) in the rice (Oryza sativa) variety Gigante. The locus was mapped to a 160-kb interval containing a gene from the eIF(iso)4G family. The stable transformation of a resistant line with the cDNA of this gene, derived from a susceptible variety, resulted in the loss of resistance in transgenic plants. The allelic variability of this gene was analysed in three resistant and 17 susceptible varieties from different cultivated rice species or subspecies. Compared with susceptible varieties, resistant varieties present specific alleles, characterized by either amino acid substitutions or short amino-acid deletions in the middle domain of the protein. The structure of this domain was modelled and showed that the substitutions were clustered on a small surface patch. This suggests that this domain may be involved in an interaction with the virus.


Rapid Hydrogen and Oxygen Atom Transfer by a High-Valent Nickel-Oxygen Species.
Terminal high-valent metal-oxygen species are key reaction intermediates in the catalytic cycle of both enzymes (e.g., oxygenases) and synthetic oxidation catalysts. While tremendous efforts have been directed toward the characterization of the biologically relevant terminal manganese-oxygen and iron-oxygen species, the corresponding analogues based on late-transition metals such as cobalt, nickel or copper are relatively scarce. This scarcity is in part related to the "Oxo Wall" concept, which predicts that late transition metals cannot support a terminal oxido ligand in a tetragonal environment. Here, the nickel(II) complex (1) of the tetradentate macrocyclic ligand bearing a 2,6-pyridinedicarboxamidate unit is shown to be an effective catalyst in the chlorination and oxidation of C-H bonds with sodium hypochlorite as terminal oxidant in the presence of acetic acid (AcOH). Insight into the active species responsible for the observed reactivity was gained through the study of the reaction of 1 with ClO- at low temperature by UV-vis absorption, resonance Raman, EPR, ESI-MS, and XAS analyses. DFT calculations aided the assignment of the trapped chromophoric species (3) as a nickel-hypochlorite species. Despite the fact that the formal oxidation state of the nickel in 3 is +4, experimental and computational analysis indicate that 3 is best formulated as a NiIII complex with one unpaired electron delocalized in the ligands surrounding the metal center. Most remarkably, 3 reacts rapidly with a range of substrates including those with strong aliphatic C-H bonds, indicating the direct involvement of 3 in the oxidation/chlorination reactions observed in the 1/ClO-/AcOH catalytic system.


Challenges and opportunities for discovery of disease biomarkers using urine proteomics.
Modern medicine has experienced a tremendous explosion in knowledge about disease pathophysiology, gained largely from understanding the molecular biology of human disease. Recent advances in mass spectrometry and proteomics now allow for simultaneous identification and quantification of thousands of unique proteins and peptides in complex biological tissues and fluids. In particular, proteomic studies of urine benefit from urine's less complex composition as compared to serum and tissues, and have been used successfully to discover novel markers of a variety of infectious, autoimmune, oncological, and surgical conditions. This perspective discusses the challenges of such studies that stem from the compositional variability and complexity of human urine, as well as instrumental sampling limitations and the effects of noise and selection bias. Strategies for the design of observational clinical trials, physical and chemical fractionation of urine specimens, mass spectrometry analysis, and functional data annotation are outlined. Rigorous translational investigations using urine proteomics are likely to discover novel and accurate markers of both rare and common diseases. This should aid the diagnosis, improve stratification of therapy, and identify novel therapeutic targets for a variety of childhood and adult diseases, all of which will be essential for the development of personalized and predictive medicine of the future.


Effect of dietary cholesterol and polyunsaturated fats on plasma and liver lipids in guinea pigs.
Weanling male Hartley guinea pigs were fed for 6 weeks on a regular chow supplemented with 5% polyunsaturated fats (safflower, linseed, or evening primrose oil) or 5% saturated fats (hydrogenated coconut oil) with or without the addition of 1% cholesterol to the diet. Cholesterol feeding resulted in slower growth, hyperlipidemia, and a fatty liver. Cholesterol contents (predominantly in the form of cholesterol esters) in plasma and liver were increased, but the increase of plasma cholesterol was significantly reduced when unsaturated fats in place of saturated fat were added to the diet. The essential fatty acid contents in plasma and liver lipids were modulated by the dietary fats and by the cholesterol feeding. The latter reduced the proportions of 20:4 (n-6), but increased or had no effect on the levels of 18:2 (n-6). These results led to a reduced ratio of 20:4 (n-6)/18:2 (n-6), suggesting that cholesterol feeding may impair the desaturase activities.


Basal metabolic rate and body fatness of adult men in northern Mexico.
To investigate the possibility that overprediction of basal metabolic rate (BMR) of tropical populations is related to differences in fatness between tropical and temperate populations, 32 Mexican men aged 18-40 years underwent measurements of BMR and body fat content. The men were divided into four body mass index (BMI) groups (< 20, 20-25, 25-30 and 30-40). The mean weight was 78 (range 52-119) kg and the mean height was 1.75 (range 1.61-1.89) m. BMR was measured in the subjects after an overnight stay in a residential unit by a Deltatrac ventilated hood indirect calorimetry system. Body fat content was determined by 2H2O dilution. The relationship between BMR and body weight was analysed by linear regression and the equations derived were compared to the values predicted using the FAO/WHO/UNU (1985) equations. The FAO/WHO/UNU equations overestimated measured BMR by 9.8%, 9.6%, 7.8% and 5.5% in the four groups. The overall difference was 8.2%, which was statistically significant (P < 0.001). The intercepts of the two equations were significantly different (P < 0.001) by 532 kJ/day, but there was no significant difference between the slopes of the two regression equations. There was no significant difference between BMR/kg fat-free mass in the four BMI groups. The results therefore do not support the possibility that the overprediction of BMR in tropical populations by international prediction equations based on body weight is accounted for by differences in fatness between tropical and temperate populations.


Maximum Temperature and Solar Radiation as Predictors of Bipolar Patient Admission in an Emergency Psychiatric Ward.
Environmental variables can regulate behavior in healthy subjects. Recently, some authors investigated the role of meteorological variables in bipolar patients with an impact on both the onset and course of bipolar disorder (BD). The aim of this study was to investigate the impact of meteorological variables and other indexes in bipolar hospitalized patients. We examined all patients admitted to the Psychiatric Inpatient Unit of San Luigi Gonzaga Hospital, Orbassano (Turin, Italy) from September 2013 to August 2015, collecting several socio-demographic and clinical characteristics. Seven hundred and thirty patients were included. Compared to the day of admission of control individuals, patients with BD were admitted on a day that presented higher minimum, medium, and maximum temperature, higher maximum humidity, higher solar radiation, and higher hours of sunshine. After logistic regression analysis, admissions to the emergency psychiatric ward due to a primary diagnosis of BD were associated with maximum temperature and solar radiation. The current study provides a novel perspective on the question surrounding seasonal mood patterns in patients with BD. A greater awareness of all possible precipitating factors is needed to inform self-management and psycho-educational programs as well as to improve resilience regarding affective recurrences in the clinical practice.


GROWTH REGULATING FACTOR5 stimulates Arabidopsis chloroplast division, photosynthesis, and leaf longevity.
Arabidopsis (Arabidopsis thaliana) leaf development relies on subsequent phases of cell proliferation and cell expansion. During the proliferation phase, chloroplasts need to divide extensively, and during the transition from cell proliferation to expansion, they differentiate into photosynthetically active chloroplasts, providing the plant with energy. The transcription factor GROWTH REGULATING FACTOR5 (GRF5) promotes the duration of the cell proliferation period during leaf development. Here, it is shown that GRF5 also stimulates chloroplast division, resulting in a higher chloroplast number per cell with a concomitant increase in chlorophyll levels in 35S:GRF5 leaves, which can sustain higher rates of photosynthesis. Moreover, 35S:GRF5 plants show delayed leaf senescence and are more tolerant for growth on nitrogen-depleted medium. Cytokinins also stimulate leaf growth in part by extending the cell proliferation phase, simultaneously delaying the onset of the cell expansion phase. In addition, cytokinins are known to be involved in chloroplast development, nitrogen signaling, and senescence. Evidence is provided that GRF5 and cytokinins synergistically enhance cell division and chlorophyll retention after dark-induced senescence, which suggests that they also cooperate to stimulate chloroplast division and nitrogen assimilation. Taken together with the increased leaf size, ectopic expression of GRF5 has great potential to improve plant productivity.


Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis.
In several autoimmune diseases, including multiple sclerosis (MS), a compromised regulatory T cell (Treg) function is believed to be critically involved in the disease process. In vitro, the biologically active metabolite of vitamin D has been shown to promote Treg development. A poor vitamin D status has been linked with MS incidence and MS disease activity. In the present study, we assess a potential in vivo correlation between vitamin D status and Treg function in relapsing remitting MS (RRMS) patients. Serum levels of 25-hydroxyvitamin D (25(OH)D) were measured in 29 RRMS patients. The number of circulating Tregs was assessed by flow-cytometry, and their functionality was tested in vitro in a CFSE-based proliferation suppression assay. Additionally, the intracellular cytokine profile of T helper cells was determined directly ex-vivo by flow-cytometry. Serum levels of 25(OH)D correlated positively with the ability of Tregs to suppress T cell proliferation (R = 0.590, P = 0.002). No correlation between 25(OH)D levels and the number of Tregs was found. The IFN-gamma/IL-4 ratio (Th1/Th2-balance) was more directed towards IL-4 in patients with favourable 25(OH)D levels (R = -0.435, P = 0.023). These results show an association of high 25(OH)D levels with an improved Treg function, and with skewing of the Th1/Th2 balance towards Th2. These findings suggest that vitamin D is an important promoter of T cell regulation in vivo in MS patients. It is tempting to speculate that our results may not only hold for MS, but also for other autoimmune diseases. Future intervention studies will show whether modulation of vitamin D status results in modulation of the T cell response and subsequent amelioration of disease activity.


Simplified Mechanical Tests Can Simulate Physiological Mechanics of a Fixation Construct for Periprosthetic Femoral Fractures.
Plate fractures after fixation of a Vancouver Type B1 periprosthetic femoral fracture (PFF) are difficult to treat and could lead to severe disability. However, due to the lack of direct measurement of in vivo performance of the PFF fixation construct, it is unknown whether current standard mechanical tests or previous experimental and computational studies have appropriately reproduced the in vivo mechanics of the plate. To provide a basis for the evaluation and development of appropriate mechanical tests for assessment of plate fracture risk, this study applied loads of common activities of daily living (ADLs) to implanted femur finite element (FE) models with PFF fixation constructs with an existing or a healed PFF. Based on FE simulated plate mechanics, the standard four-point-bend test adequately matched the stress state and the resultant bending moment in the plate as compared with femur models with an existing PFF. In addition, the newly developed constrained three-point-bend tests were able to reproduce plate stresses in models with a healed PFF. Furthermore, a combined bending and compression cadaveric test was appropriate for risk assessment including both plate fracture and screw loosening after the complete healing of PFF. The result of this study provides the means for combined experimental and computational preclinical evaluation of PFF fixation constructs.


Automated Quantification of Human Osteoclasts Using Object Detection.
A balanced skeletal remodeling process is paramount to staying healthy. The remodeling process can be studied by analyzing osteoclasts differentiated in vitro from mononuclear cells isolated from peripheral blood or from buffy coats. Osteoclasts are highly specialized, multinucleated cells that break down bone tissue. Identifying and correctly quantifying osteoclasts in culture are usually done by trained personnel using light microscopy, which is time-consuming and susceptible to operator biases. Using machine learning with 307 different well images from seven human PBMC donors containing a total of 94,974 marked osteoclasts, we present an efficient and reliable method to quantify human osteoclasts from microscopic images. An open-source, deep learning-based object detection framework called Darknet (YOLOv4) was used to train and test several models to analyze the applicability and generalizability of the proposed method. The trained model achieved a mean average precision of 85.26% with a correlation coefficient of 0.99 with human annotators on an independent test set and counted on average 2.1% more osteoclasts per culture than the humans. Additionally, the trained models agreed more than two independent human annotators, supporting a more reliable and less biased approach to quantifying osteoclasts while saving time and resources. We invite interested researchers to test their datasets on our models to further strengthen and validate the results.


[Management of isolated angiomyolipoma of the kidney].
Four patients presented isolated angiomyolipomas of kidney in the absence of any form of phakomatosis such as Bourneville's disease. The tumor was removed by partial nephrectomy in only one case, after histology of a fresh specimen confirming the presence of an angiomyolipoma without signs of cancer. In another patient it was impossible to perform conservative surgery because of dissemination of the angiomyolipoma throughout the kidney. Symptomatology suggestive of the disorder includes lumbar pain, kidney tumor and more rarely hematuria. Diagnosis is difficult despite availability of ultrasound and CT scan imaging, which has supplanted renal arteriography. Confirmation requires histology of a fresh specimen. Operative treatment is essential to avoid the risk of intra- and peri-tumoral hemorrhage, particularly during pregnancy. Partial nephrectomy or excision of tumor is possible when the diagnosis has been established, if excision involves healthy parenchyma and if after strict hemostasis at least one third of renal parenchyma remains.


Factors affecting the outcome of fecal microbiota transplantation for patients with irritable bowel syndrome.
A previous study that introduced a Fecal microbiota transplantation (FMT) protocol with a high efficacy applied a combination of favorable factors. The present study aimed to evaluate some of these factors. This study included 186 patients with IBS randomized 1:1:1 into transplant administered to the colon (single LI), to the duodenum (single SI), or to the duodenum twice with a 1-week interval (repeated SI). The patients provided a fecal sample and were asked to complete five questionnaires at baseline and at 3, 6, and 12 months after FMT. The fecal bacteria composition and dysbiosis index (DI) were analyzed using 16S rRNA gene PCR DNA amplification/probe hybridization covering regions V3-V9. The response rate was significantly higher in single SI than in single LI at 12 months after FMT. Symptoms and quality of life improved in all the treated groups at all time intervals after FMT. The abdominal symptoms were significantly reduced and the quality of life improved for repeated SI compared with for single SI. DI significantly decreased in all the treated groups at all observation times after FMT. The bacterial profiles changed in all groups at all observation intervals. However, these changes differed between single LI and single SI/repeated SI. Administrating transplant to the small intestine had a long-term higher response rate than that administrated to the large intestine, and led to long-term colonization of beneficial bacteria. Repeating FMT had more effect on symptoms and quality of life than a single FMT. (www. gov: NCT04236843).


Discriminative stimulus effects of ethanol and 3 alpha-hydroxy-5 alpha-pregnan-20-one in relation to menstrual cycle phase in cynomolgus monkeys (Macaca fascicularis).
The present study was designed to characterize the discriminative stimulus effects of ethanol and the neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) in nonhuman primates as a function of menstrual cycle phase. Female cynomolgus monkeys (Macaca fascicularis) were trained in a two-lever procedure to discriminate 1.0 g/kg ethanol (IG, 30 min pretreatment) from water using food reinforcement. A cumulative dosing procedure was used to assess changes in the potency of ethanol and an endogenous anxiolytic steroid in the follicular versus the luteal phase of the menstrual cycle. Plasma progesterone and allopregnanolone levels were determined within 24 h of testing to verify phase of menstrual cycle. The monkeys were more sensitive to the discriminative stimulus effects of ethanol and the ethanol-like effects of the endogenous neuroactive steroid allopregnanolone during the luteal phase of the menstrual cycle. These findings suggest that changes in the endogenous levels of ovarian-derived progesterone and allopregnanolone alter sensitivity to the discriminative stimulus effects of ethanol.


Adequate symptom relief justifies hepatic resection for benign disease.
The purpose of this study was to evaluate the long-term results of partial liver resection for benign liver lesions. All patients operated on for benign liver lesions from 1991 to 2002 were included. Information was retrieved from medical records, the hospital registration system and by a telephonic questionnaire. Twenty-eight patients with a median age of 41 years (17-71) were operated on (M/F ratio 5/23). The diagnosis was haemangioma in 8 patients, FNH in 6, HCA in 13 and angiomyolipoma in 1. Eight patients were known to have relevant co-morbidity. Median operating time was 207 minutes (45-360). The morbidity rate was 25% and no postoperative mortality was observed. Twenty-two patients (79%) had symptoms (mainly abdominal pain) prior to surgery. Twenty-five patients were reached for a questionnaire. The median follow up was 55 months (4-150). In 89% of patients preoperative symptoms had decreased or disappeared after surgery. Four patients developed late complications. Long-term follow up after liver surgery for benign liver lesions shows considerable symptom relief and patient satisfaction. In addition to a correct indication these results justify major surgery with associated morbidity and mortality.


Prostacyclin and acetylcholine as screening agents for acute pulmonary vasodilator responsiveness in primary pulmonary hypertension.
Epoprostenol sodium (prostacyclin) administered intravenously is considered the standard for assessing the ability of the pulmonary circulation to vasodilate. At present, epoprostenol sodium is an investigational drug that has limited availability. In contrast, acetylcholine, also a pulmonary vasodilator, is readily available. Therefore, we assessed the feasibility of using acetylcholine as an alternative to prostacyclin in testing for the capacity of the pulmonary vasculature to vasodilate. Twenty-three patients with primary pulmonary hypertension (mean pulmonary arterial pressure, 58.5 +/- 13.4 mm Hg) received incremental infusions of prostacyclin and acetylcholine to predetermined maximal infusion rates as part of a battery of vasodilator agents administered according to standard protocols (mean, 5.4 +/- 1.2 agents/patient; range, 3-8 agents/patient); the administration of the different agents was timed to avoid synergistic effects. Of all the agents tested, prostacyclin and acetylcholine were most consistently effective in evoking acute pulmonary vasodilation, and both seemed to distinguish patients capable of manifesting acute pulmonary vasodilation from those who were not. However, at maximal doses set by protocol, prostacyclin generally elicited a greater vasodilator response than acetylcholine. The difference in magnitude of response may have been due to use of prescribed dosages of acetylcholine that were submaximal. In other respects, the two agents were similar; both were equally well-tolerated, and side effects were mild and resolved rapidly when the vasodilator infusions were stopped. We conclude that in the majority of patients with primary pulmonary hypertension, acetylcholine appears to be an effective and available substitute for prostacyclin in screening for pulmonary vasodilator responsiveness.


Spectroscopy of 171Yb in an optical lattice based on laser linewidth transfer using a narrow linewidth frequency comb.
We propose a novel, high-performance, and practical laser source system for optical clocks. The laser linewidth of a fiber-based frequency comb is reduced by phase locking a comb mode to an ultrastable master laser at 1064 nm with a broad servo bandwidth. A slave laser at 578 nm is successively phase locked to a comb mode at 578 nm with a broad servo bandwidth without any pre-stabilization. Laser frequency characteristics such as spectral linewidth and frequency stability are transferred to the 578-nm slave laser from the 1064-nm master laser. Using the slave laser, we have succeeded in observing the clock transition of (171)Yb atoms confined in an optical lattice with a 20-Hz spectral linewidth.


Toward planning target volume margin reduction for the prostate using intrafraction motion correction with online kV imaging and automatic detection of implanted gold seeds.
The imaging application Auto Beam Hold (ABH) allows for the online analysis of 2-dimensional kV images acquired during treatment. ABH can automatically detect fiducial markers and initiate a beam interrupt. In this study, we investigate the practical use and results of this intrafraction monitoring tool for patients with prostate cancer who have implanted gold seeds treated with a RapidArc technique. A total of 105 patients were included. For setup, the seeds were lined up using 2 orthogonal 2-dimensional kV images. After the setup procedure, ABH was applied at an interval of 3 seconds. The software requires a maximum-allowed deviation to be defined for each seed, which is referred to as a deviation limit (DL). Online, the ABH application evaluates the position of the seeds and indicates for each seed whether or not it exceeds the DL. Patients were divided in 3 groups. For the first group ABH was used with the DL at 6 mm, which corresponds to the planning target volume (PTV) margin. For the second group, the DL was set at 5 mm with an unchanged PTV margin of 6 mm. For the third group, the PTV margin was reduced to 5 mm with a DL of 5 mm. Offline, we performed an analysis of the number of beam stops and resulting re-setups. ABH initiated a beam interrupt 223 times (13%) during a total of 1736 sessions. By decreasing the DL from 6 mm to 5 mm, the amount of workload for re-setups increased from 6% (group 1) to 14% (groups 2 and 3). Re-setup, 3-dimensional shifts larger than the PTV margin were found in 44%, 35%, and 45% for groups 1,2, and 3, respectively. Intrafraction imaging of prostate position during treatment using automatic detection of implanted gold seeds was successfully implemented. PTV margins were safely reduced from 6mm to 5mm without a substantial increase in workload.


Effect of COVID-19 on vaccination coverage in Brazil.
During the COVID-19 pandemic, recommendations for maintaining physical distance, restricted mobility measures, as well as fear of mass transmission by going to health centers have significantly contributed to the general vaccination coverage, which by and large is decreasing worldwide; thus, favoring the potential re-emergence of vaccine-preventable diseases. In this study, we have used the existing data on vaccination coverage during the pre-pandemic (2019) as well as the pandemic (2020) period to evaluate the impact of coronavirus outbreaks during the vaccination drive in Brazil. Furthermore, we have accumulated data since 2015 among the different regions of the country to acquire more consistent information. The various vaccines analyzed in our study were meningococcal C conjugate, Triple antigen vaccine, 10-valent pneumococcal conjugate, and BCG; subsequently, the data were obtained from the National Disease Notification System. This study revealed that the ongoing immunization drive saw a steep decline of around 10 to 20% during the (2019-2020) pandemic period in Brazil. These results provide strong evidence towards the decreasing trends following the vaccination programs during the COVID-19 pandemic period in Brazil. Furthermore, our results also highlight the importance of adopting widespread multi-component interventions to improve vaccination uptake rates.


Hyperintense Vessels on T2-PROPELLER-FLAIR in Patients with Acute MCA Stroke: Prediction of Arterial Stenosis and Perfusion Abnormality.
Fluid-attenuated inversion recovery hyperintense vessels in stroke represent leptomeningeal collateral flow. We presumed that FLAIR hyperintense vessels would be more closely associated with arterial stenosis and perfusion abnormality in ischemic stroke on T2-PROPELLER-FLAIR than on T2-FLAIR. We retrospectively reviewed 35 patients with middle cerebral territorial infarction who underwent MR imaging. FLAIR hyperintense vessel scores were graded according to the number of segments with FLAIR hyperintense vessels in the MCA ASPECTS areas. We compared the predictability of FLAIR hyperintense vessels between T2-PROPELLER-FLAIR and T2-FLAIR for large-artery stenosis. The interagreement between perfusion abnormality and FLAIR hyperintense vessels was assessed. In subgroup analysis (9 patients with MCA horizontal segment occlusion), the association of FLAIR hyperintense vessels with ischemic lesion volume and perfusion abnormality volume was evaluated. FLAIR hyperintense vessel scores were significantly higher on T2-PROPELLER-FLAIR than on T2-FLAIR (3.50 ± 2.79 versus 1.21 ± 1.47, P < .01), and the sensitivity for large-artery stenosis was significantly improved on T2-PROPELLER-FLAIR (93% versus 68%, P = .03). FLAIR hyperintense vessels on T2-PROPELLER-FLAIR were more closely associated with perfusion abnormalities than they were on T2-FLAIR (κ = 0.64 and κ = 0.27, respectively). In subgroup analysis, FLAIR hyperintense vessels were positively correlated with ischemic lesion volume on T2-FLAIR, while the mismatch of FLAIR hyperintense vessels between the 2 sequences was negatively correlated with ischemic lesion volume (P = .01). In MCA stroke, FLAIR hyperintense vessels were more prominent on T2-PROPELLER-FLAIR compared with T2-FLAIR. In addition, FLAIR hyperintense vessels on T2-PROPELLER-FLAIR have a significantly higher sensitivity for predicting large-artery stenosis than they do on T2-FLAIR. Moreover, the areas showing FLAIR hyperintense vessels on T2-PROPELLER-FLAIR were more closely associated with perfusion abnormality than those on T2-FLAIR.


B cell depleting therapy for multiple sclerosis overlapping with neuromyelitis optica spectrum disorder.
Multiple sclerosis and neuromyelitis optica spectrum disorder are currently thought to be independent entities. Some patients display intermediate manifestations that fit the criteria for both diseases without positive relevant serobiomarkers. An overall standard and consensus for the diagnosis and treatment of these overlapping patients have not been reached. We describe a patient with frequently relapsing demyelinating episodes and repeatedly adjusted treatment regimens due to diagnostic difficulties. This case did not respond adequately to glucocorticoid plus azathioprine or to interferon. Benefits were finally obtained by using rituximab, an anti-CD20 specific monoclonal antibody targeting B cells. Treatments targeting B cell mediated humoral immunity such as rituximab, may be a safe and appropriate choice for these challenging demyelinating cases, especially in Asian population.


Carepath for overcoming psychosis early (COPE): first 5 years of clinical operation and prospective research in the Cavan-Monaghan early intervention service.
As Ireland confronts the many challenges of broadening the introduction of early intervention services (EIS) for first episode psychosis (FEP) as national policy, this article describes Carepath for Overcoming Psychosis Early (COPE), the EIS of Cavan-Monaghan Mental Health Service, and presents prospective research findings during its first 5 years of operation. COPE was launched as a rural EIS with an embedded research protocol in early 2012, following an education programme for general practitioners (GPs). Here, operational activities are documented and research findings presented through to late 2016. During this period, 115 instances of FEP were incepted into COPE, 70.4% via their GP and 29.6% via the Emergency Department. The annual rate of inception was 24.8/100,000 of population aged > 15 years and was 2.1-fold more common among men than women. Mean duration of untreated psychosis was 5.7 months and median time from first psychotic presentation to initiation of antipsychotic treatment was zero days. Assessments of psychopathology, neuropsychology, neurology, premorbid functioning, quality of life, insight, and functionality compared across 10 DSM-IV psychotic diagnoses made at six months following presentation indicated minimal differences between them, other than more prominent negative symptoms in schizophrenia and more prominent mania in bipolar disorder. COPE illustrates the actuality of introducing and the challenges of operating a rural EIS for FEP. Prospective follow-up studies of the 5-year COPE cohort should inform on the effectiveness of this EIS model in relation to long-term outcome in psychotic illness across what appear to be arbitrary diagnostic boundaries at FEP.


Phlegm and filters.
Male mass radiography volunteers aged 40 or more were questioned about their sputum production and cigarette consumption in relation to type (filter or plain) smoked. Of 10,414 volunteers, 3,045 smoked filter cigarettes and 2,393 smoked plain cigarettes. The rate of persistent daily sputum of filter smokers (31.9%) was significantly lower than that of plain cigarette smokers (37.2%). A similar pattern was maintained when age and cigarette consumption were standardized. These figures are thought to understate the less injurious nature of filter cigarettes, since more than half of the filter smokers with persistent sputum developed this while previously smoking plain cigarettes.Whatever the reasons for the less injurious nature of filter cigarettes, it seems that cigarette smokers unable to stop smoking might suffer less from chronic bronchitis if they changed to filter cigarettes.


Promoter and upstream regulatory activities of the mouse cellular retinoic acid-binding protein-I gene.
The promoter and its upstream regulatory region of the mouse cellular retinoic acid-binding protein I (crabp-I) gene were examined in transgenic mouse embryos, a mouse embryonal carcinoma cell line P19, and a mouse embryonic fibroblast cell line 3T6. In transgenic mouse embryos, a beta-galactosidase reporter gene under the control of crabp-I promoter and its upstream regulatory region displayed a very specific pattern of expression characteristic of crabp-I gene expression during developmental stages. In tissue culture systems, the minimal promoter of this gene was identified, and regions containing positive and negative regulatory activities were dissected from the upstream 3-kilobase sequence using assays for transient reporter activity. It is concluded that the minimal promoter of the mouse crabp-I gene is located between 120 and 150 base pairs upstream from the transcription initiation site. Several cell type-specific positive and negative regulatory regions for this promoter have been identified. A region encoding a common negative regulatory activity in both P19 and 3T6 cells is also inhibitory to two heterologous promoters, and specific protein-DNA interactions between this DNA fragment and nuclear extracts of P19 and 3T6 are demonstrated by gel retardation experiments.


Induction of programmed cell death (apoptosis) by influenza virus infection in tissue culture cells.
The process of cell death caused by influenza virus infection in cultured MDCK and HeLa cells was analysed. This infection gave rise to nuclear fragmentation and chromatin condensation accompanied by chromosomal DNA fragmentation into oligonucleosomes. Chromosomal DNA fragmentation progressed concomitantly with cell lysis of MDCK cells and HeLa cells, producing high and low yields of virus particles, respectively, indicating that the extent of cell lysis was not proportional to the virus production. The endonuclease inhibitor zinc blocked DNA fragmentation in MDCK cells. Cycloheximide inhibited DNA fragmentation as well as cell lysis. Inhibition occurred when the drug was added to the medium within 2 h after infection but not efficiently at 4 h or later. Infection induced the Fas Ag gene, which encodes a possible apoptosis-mediating molecule, in the early infectious stage followed by the expression of Fas Ag on the cell surface. These results suggested that influenza virus infection causes apoptotic death of cultured cells, and their fate might be determined at an early stage of the infection by induction of an apoptotic gene.


Mitochondrial fission in endothelial cells after simulated ischemia/reperfusion: role of nitric oxide and reactive oxygen species.
Ischemia (I)/reperfusion (RP)-induced endothelial cell (EC) injury is thought to be due to mitochondrial reactive oxygen species (mtROS) production. MtROS have been implicated in mitochondrial fission. We determined whether cultured EC exposure to simulated I/RP causes morphological changes in the mitochondrial network and the mechanisms behind those changes. Because shear stress results in nitric oxide (NO)-mediated endothelial mtROS generation, we simulated I/RP as hypoxia (H) followed by oxygenated flow over the ECs (shear stress of 10dyn/cm(2)). By exposing ECs to shear stress, H, H/reoxygenation (RO), or simulated I/RP and employing MitoTracker staining, we assessed the differential effects of changes in mechanical forces and/or O(2) levels on the mitochondrial network. Static or sheared ECs maintained their mitochondrial network. H- or H/RO-exposed ECs underwent changes, but mitochondrial fission was significantly less compared to that in ECs exposed to I/RP. I/RP-induced fission was partially inhibited by antioxidants, a NO synthase inhibitor, or an inhibitor of the fission protein dynamin-related protein 1 (Drp1) and was accompanied by Drp1 oligomerization and phosphorylation (Ser616). Hence, shear-induced NO, ROS (including mtROS), and Drp1 activation are responsible for mitochondrial fission in I/RP-exposed ECs, and excessive fission may be an underlying cause of EC dysfunction in postischemic hearts.


Automated fragment formula annotation for electron ionisation, high resolution mass spectrometry: application to atmospheric measurements of halocarbons.
Non-target screening consists in searching a sample for all present substances, suspected or unknown, with very little prior knowledge about the sample. This approach has been introduced more than a decade ago in the field of water analysis, together with dedicated compound identification tools, but is still very scarce for indoor and atmospheric trace gas measurements, despite the clear need for a better understanding of the atmospheric trace gas composition. For a systematic detection of emerging trace gases in the atmosphere, a new and powerful analytical method is gas chromatography (GC) of preconcentrated samples, followed by electron ionisation, high resolution mass spectrometry (EI-HRMS). In this work, we present data analysis tools to enable automated fragment formula annotation for unknown compounds measured by GC-EI-HRMS. Based on co-eluting mass/charge fragments, we developed an innovative data analysis method to reliably reconstruct the chemical formulae of the fragments, using efficient combinatorics and graph theory. The method does not require the presence of the molecular ion, which is absent in [Formula: see text]40% of EI spectra. Our method has been trained and validated on >50 halocarbons and hydrocarbons, with 3-20 atoms and molar masses of 30-330 g mol[Formula: see text], measured with a mass resolution of approx. 3500. For >90% of the compounds, more than 90% of the annotated fragment formulae are correct. Cases of wrong identification can be attributed to the scarcity of detected fragments per compound or the lack of isotopic constraint (no minor isotopocule detected). Our method enables to reconstruct most probable chemical formulae independently from spectral databases. Therefore, it demonstrates the suitability of EI-HRMS data for non-target analysis and paves the way for the identification of substances for which no EI mass spectrum is registered in databases. We illustrate the performances of our method for atmospheric trace gases and suggest that it may be well suited for many other types of samples. The L-GPL licenced Python code is released under the name ALPINAC for ALgorithmic Process for Identification of Non-targeted Atmospheric Compounds.


Surface-associated antigen induces permeabilization of primary mouse B-cells and lysosome exocytosis facilitating antigen uptake and presentation to T-cells.
B-cell receptor (BCR)-mediated antigen internalization and presentation are essential for humoral memory immune responses. Antigen encountered by B-cells is often tightly associated with the surface of pathogens and/or antigen-presenting cells. Internalization of such antigens requires myosin-mediated traction forces and extracellular release of lysosomal enzymes, but the mechanism triggering lysosomal exocytosis is unknown. Here, we show that BCR-mediated recognition of antigen tethered to beads, to planar lipid-bilayers or expressed on cell surfaces causes localized plasma membrane (PM) permeabilization, a process that requires BCR signaling and non-muscle myosin II activity. B-cell permeabilization triggers PM repair responses involving lysosomal exocytosis, and B-cells permeabilized by surface-associated antigen internalize more antigen than cells that remain intact. Higher affinity antigens cause more B-cell permeabilization and lysosomal exocytosis and are more efficiently presented to T-cells. Thus, PM permeabilization by surface-associated antigen triggers a lysosome-mediated B-cell resealing response, providing the extracellular hydrolases that facilitate antigen internalization and presentation.


Thimerosal induces toxic reaction in non-sensitized animals.
The effects of injection of thimerosal solution on nonsensitized animals was investigated. Intrafootpad injection of thimerosal solution in nonsensitized mice resulted in a swelling response which peaked 1 h after injection and lasted for more than 24 h. Histopathological examination showed that there were severe edema and infiltration of polymorphonuclear neutrophils at the site of injection. An increased vascular permeability was observed after cutaneous injection of thimerosal solution on the back of nonsensitized rats. Since mercuric chloride and methyl mercury induced severer reactions, and thiosalicylic acid had no effect, mercury contained in thimerosal would have caused the reactions observed in this study. These results suggest that part of these hypersensitivity reactions against thimerosal observed among patients were possibly induced by the toxic effect of thimerosal. Therefore, thimerosal contained as a preservative in vaccine may augment the side-effects of the vaccination.


Large-scale extraction of accurate drug-disease treatment pairs from biomedical literature for drug repurposing.
A large-scale, highly accurate, machine-understandable drug-disease treatment relationship knowledge base is important for computational approaches to drug repurposing. The large body of published biomedical research articles and clinical case reports available on MEDLINE is a rich source of FDA-approved drug-disease indication as well as drug-repurposing knowledge that is crucial for applying FDA-approved drugs for new diseases. However, much of this information is buried in free text and not captured in any existing databases. The goal of this study is to extract a large number of accurate drug-disease treatment pairs from published literature. In this study, we developed a simple but highly accurate pattern-learning approach to extract treatment-specific drug-disease pairs from 20 million biomedical abstracts available on MEDLINE. We extracted a total of 34,305 unique drug-disease treatment pairs, the majority of which are not included in existing structured databases. Our algorithm achieved a precision of 0.904 and a recall of 0.131 in extracting all pairs, and a precision of 0.904 and a recall of 0.842 in extracting frequent pairs. In addition, we have shown that the extracted pairs strongly correlate with both drug target genes and therapeutic classes, therefore may have high potential in drug discovery. We demonstrated that our simple pattern-learning relationship extraction algorithm is able to accurately extract many drug-disease pairs from the free text of biomedical literature that are not captured in structured databases. The large-scale, accurate, machine-understandable drug-disease treatment knowledge base that is resultant of our study, in combination with pairs from structured databases, will have high potential in computational drug repurposing tasks.


Cloning and molecular analysis of the Salmonella enterica ansP gene, encoding an L-asparagine permease.
A gene (ansP), which encodes an L-asparagine permease, has been isolated from a cosmid library of Salmonella enterica during screening for recombinant clones which encode L-asparaginase. Nucleotide sequence analysis reveals that the gene product is a polypeptide of 497 amino acid residues, containing 12 putative transmembrane segments. The calculated molecular mass is 54 kDa, although maxicell analysis by SDS-PAGE gave an apparent molecular mass of 37 kDa. Comparison of the deduced amino acid sequence with sequence databases showed significant homology with a family of basic and aromatic amino acid permeases. Strains containing the cloned ansP gene demonstrated a many-fold increase in L-asparagine uptake in comparison with control strains.


Temporal trends (1975 through 1990) in the incidence and case-fatality rates of primary ventricular fibrillation complicating acute myocardial infarction. A communitywide perspective.
As part of a population-based study of acute myocardial infarction, we examined changes over time in the incidence and in-hospital case-fatality rates of primary ventricular fibrillation complicating acute myocardial infarction. Patients with validated acute myocardial infarction hospitalized at 16 hospitals in the Worcester, Mass, metropolitan area between 1975 and 1990 comprised the study sample. During the 15-year study period, 5.1% of patients developed primary ventricular fibrillation in the setting of uncomplicated acute myocardial infarction, with this rate remaining relatively constant over time. Both age- and multivariable-adjusted analyses showed no significant trend in the incidence rates of primary ventricular fibrillation during the study period. The in-hospital case-fatality rate for patients with primary ventricular fibrillation was significantly elevated compared with the rate for those without primary ventricular fibrillation and uncomplicated acute myocardial infarction (48.3% versus 1.5%, P < .001). No significant change over time was noted in in-hospital case-fatality rates associated with primary ventricular fibrillation while controlling for a variety of short-term prognostic factors. The results of this communitywide observational study suggest that neither the incidence nor the prognosis associated with primary ventricular fibrillation resulting from acute myocardial infarction has improved over time.


Mitogenic polypeptide of the mammalian seminiferous epithelium: biochemical characterization and partial purification.
A mitogenic polypeptide, previously identified in Sertoli cells of the prepuberal mouse (Feig, L. A., A. R. Bellvé, N. Horbach-Erickson, and M. Klagsbrun, 1980, Proc. Natl. Acad. Sci. USA., 77:4774-4778), now has been shown to exist in Sertoli cells of the adult mouse and in the seminiferous epithelium of several other mammalian species, including the rat, guinea pig, and calf. The levels of this seminiferous growth factor (SGF) are not appreciably reduced in adult mouse testes following hypophysectomy. SGF purified from either the adult mouse or newborn calf seminiferous epithelium has a molecular weight (Mr) of 15,700 and a pl between 4.8 and 5.8, when exposed to denaturing conditions. Furthermore, SGF from these two mammalian species probably has few exposed hydrophobic domains and has a strong propensity to aggregate into multiple, high Mr species. A purification sequence based on these biochemical properties has enabled a greater than 350-fold enrichment of SGF activity from the calf seminiferous epithelium. The protocol involves a sequence of: (a) ammonium sulfate precipitation, (b) DEAE-cellulose ion exchange chromatography, (c) gel filtration chromatography on Bio-Gel P150 in 1.0 M ammonium acetate, (d) hydrophobic chromatography on dodecyl agarose, and (e) gel filtration chromatography in 6.0 M guanidine hydrochloride. Subsequent analysis of this purified preparation by SDS PAGE, followed by silver staining, reveals approximately 7 polypeptides with Mr between 14,000 and 20,000.


Disruption of reproductive aging in female and male rats by gestational exposure to estrogenic endocrine disruptors.
Polychlorinated biphenyls (PCBs) are industrial contaminants and known endocrine-disrupting chemicals. Previous work has shown that gestational exposure to PCBs cause changes in reproductive neuroendocrine processes. Here we extended work farther down the life spectrum and tested the hypothesis that early life exposure to Aroclor 1221 (A1221), a mixture of primarily estrogenic PCBs, results in sexually dimorphic aging-associated alterations to reproductive parameters in rats, and gene expression changes in hypothalamic nuclei that regulate reproductive function. Pregnant Sprague Dawley rats were injected on gestational days 16 and 18 with vehicle (dimethylsulfoxide), A1221 (1 mg/kg), or estradiol benzoate (50 μg/kg). Developmental parameters, estrous cyclicity (females), and timing of reproductive senescence were monitored in the offspring through 9 months of age. Expression of 48 genes was measured in 3 hypothalamic nuclei: the anteroventral periventricular nucleus (AVPV), arcuate nucleus (ARC), and median eminence (females only) by real-time RT-PCR. Serum LH, testosterone, and estradiol were assayed in the same animals. In males, A1221 had no effects; however, prenatal estradiol benzoate increased serum estradiol, gene expression in the AVPV (1 gene), and ARC (2 genes) compared with controls. In females, estrous cycles were longer in the A1221-exposed females throughout the life cycle. Gene expression was not affected in the AVPV, but significant changes were caused by A1221 in the ARC and median eminence as a function of cycling status. Bionetwork analysis demonstrated fundamental differences in physiology and gene expression between cycling and acyclic females independent of treatment. Thus, gestational exposure to biologically relevant levels of estrogenic endocrine-disrupting chemicals has sexually dimorphic effects, with an altered transition to reproductive aging in female rats but relatively little effect in males.


Tolerance and outcomes of stereotactic radiosurgery combined with anti-programmed cell death-1 (pembrolizumab) for melanoma brain metastases.
Anti-programmed cell death-1 (anti-PD1) antibodies are currently the first-line treatment for patients with metastatic BRAF wild-type melanoma, alone or combined with the anti-CTLA4 monoclonal antibody, ipilimumab. To date, data on safety and the outcomes of patients treated with the anti-PD1 monoclonal antibodies, pembrolizumab (PB), or nivolumab, combined with stereotactic radiosurgery (SRS), for melanoma brain metastases (MBM) are scarce. We retrospectively reviewed all patients with MBM treated with PB combined with SRS between 2012 and 2015. The primary endpoint was neurotoxicity. The secondary endpoints were local, distant intracranial controls and overall survival (OS). Among 74 patients with MBM treated with SRS, 25 patients with a total of 58 MBM treated with PB combined with SRS within 6 months were included. Radiation necrosis, occurring within a median time of 6.5 months, was observed for four MBM (6.8%) in four patients. No other significant SRS-related adverse event was observed. After a median follow-up of 8.4 months, local control was achieved in 46 (80%) metastases and 17 (68%) patients. Perilesional oedema and intratumour haemorrhage appearing or increasing after SRS were associated with local progression (P<0.001). The median OS was 15.3 months (95% confidence interval: 4.6-26). The timing between SRS and PB administration did not seem to influence the risk of radiation necrosis, intracranial control or OS. SRS combined with PB was well tolerated and achieved local control in 80% of the lesions. Prolonged OS was observed compared with that currently yielded in this population of patients. Prospective studies are required to explore further the optimal ways to combine immunotherapy and SRS.


HIV and HTLV-I antibody studies: pregnant women in the 1960s, patients with AIDS, homosexuals, and individuals with tropical spastic paraparesis.
To investigate the possible occurrence of human immunodeficiency virus (HIV) or human T-cell lymphotropic virus, type I (HTLV-I) infections in the United States prior to 1979-1981, when acquired immune deficiency syndrome (AIDS) was first recognized, we tested sera from 310 pregnant women who participated in the Collaborative Perinatal Project during the period 1959-1964 for HIV and HTLV-I antibody. These samples included sera from 53 pregnant women who were intravenous drug users. The remainder were from women who had cervical epithelial abnormalities, who developed cervical carcinomas, who had had children with erythroblastosis fetalis, who had had children that developed malignant neoplasms early in life, or normal pregnant women. None of the 310 women had confirmed HIV or HTLV-I antibody. The rate of false-positive reactions with the HIV enzyme-linked immunosorbent assay (ELISA) antibody test in these long-frozen samples was similar to that observed in fresh sera. HIV antibody was detected in homosexual patients with AIDS; HTLV-I antibody was not detected in any of these sera. HTLV-I antibody was detected in 17 of 20 patients with tropical spastic paraparesis (TSP) and in two of seven patients with other neurological diseases diagnosed as transverse myelopathy and multiple sclerosis, and in none of nine normal controls; HIV antibody was not detected in any of these sera patients. Thus, we conclude that there was no serological evidence of infection with HIV or HTLV-I in the pregnant women studied; however, HIV antibody was present in all AIDS patients tested, and HTLV-I antibody was found in the majority of patients with TSP.


Evaluation of nurses awareness and practice of hemodialysis access care in Khartoum state, Sudan.
In hemodialysis (HD) wards, nurses play a pivotal role in HD access care. Unfortunately, guideline recommendations for routine preventive care are not always followed. This study was designed to evaluate nurses' awareness and practice of HD access care in Khartoum state, Sudan. The study included 50 randomly selected HD nurses. Nurses' knowledge was evaluated using a participant-filled questionnaire and their practice was evaluated by direct monitoring. Variables were summarized as frequencies and related to nurses' educational level. Females constituted 72% of study participants and 85% were university graduates. Half the nurses had more than two years experience in HD centers. Structured training on HD machines and HD access care was received by 56% and 54% of respondents respectively. All participants stated that proper HD access care helps prevent access infection but only 54% stated that it helps in preserving access function. Most nurses (98%) stated that hand hygiene in HD centers was necessary to prevent infection but only 70% were adherent to hand hygiene before access manipulation. Most nurses (98%) evaluated HD access function before connection but only 52% evaluated it for signs of infection. Nurses with a bachelor degree tended to be more adherent to hand hygiene (72.5 versus 42.9%, P=0.1) and the use of gloves (100% versus 85.7%, P=0.1) compared to nurses with a diploma degree, but the difference was not statistically significant. HD nurses adherence to the recommended infection control measures in studied HD centers was suboptimal. HD centers are required to organize adequate training on HD access care for their nursing staff.


Uterus transplantation for fertility preservation in patients with gynecologic cancer.
Cervical and endometrial cancer may impact women interested in future fertility in approximately 5-25% of cases. The recommended treatment for patients with early stage disease is hysterectomy and/or radiation leading to infertility. This is referred to as absolute uterine factor infertility. Such infertility was considered untreatable until 2014, when the first child was born after uterus transplantation. Thereafter, multiple births have been reported, mainly from women with Mayer-Rokitansky-Küster-Hauser syndrome, with congenital uterine absence, although also from a patient with iatrogenic uterine factor infertility caused by radical hysterectomy secondary to an early stage cervical cancer 7 years before uterus transplantation. A live birth after uterus transplantation may be considered promising for many who may not otherwise have this option.Uterus transplantation is a complex process including careful patient selection in both recipients and donors, in vitro fertilization, and complex surgery in the organ procurement procedure including harvesting the vessel pedicles with the thin-walled veins. Thereafter, the transplantation surgery with anastomosis to ensure optimal blood inflow and outflow of the transplanted organ. Knowledge regarding immunosuppression and pregnancy is essential. Lastly there is the hysterectomy component as the uterus must be removed. Multidisciplinary teams working closely are essential to achieve successful uterus transplantation and, ultimately, delivery of a healthy child. Both the living and deceased donor concept may be considered and we address both the advantages and disadvantages. This review summarizes the animal research thus far published on uterus transplantation, the suggested recipient selections including former gynecologic cancer patients, the living and deceased donor uterus transplantation concepts with reported results, and updated fertility outcomes.


Differential RNA methylation using multivariate statistical methods.
m6A methylation is a highly prevalent post-transcriptional modification in eukaryotes. MeRIP-seq or m6A-seq, which comprises immunoprecipitation of methylation fragments , is the most common method for measuring methylation signals. Existing computational tools for analyzing MeRIP-seq data sets and identifying differentially methylated genes/regions are not most optimal. They either ignore the sparsity or dependence structure of the methylation signals within a gene/region. Modeling the methylation signals using univariate distributions could also lead to high type I error rates and low sensitivity. In this paper, we propose using mean vector testing (MVT) procedures for testing differential methylation of RNA at the gene level. MVTs use a distribution-free test statistic with proven ability to control type I error even for extremely small sample sizes. We performed a comprehensive simulation study comparing the MVTs to existing MeRIP-seq data analysis tools. Comparative analysis of existing MeRIP-seq data sets is presented to illustrate the advantage of using MVTs. Mean vector testing procedures are observed to control type I error rate and achieve high power for detecting differential RNA methylation using m6A-seq data. Results from two data sets indicate that the genes detected identified as having different m6A methylation patterns have high functional relevance to the study conditions. The dimer software package for differential RNA methylation analysis is freely available at https://github.com/ouyang-lab/DIMER. Supplementary data are available at Briefings in Bioinformatics online.


Endothelial LSP1 Modulates Extravascular Neutrophil Chemotaxis by Regulating Nonhematopoietic Vascular PECAM-1 Expression.
During inflammation, leukocyte-endothelial cell interactions generate molecular signals that regulate cell functions. The Ca(2+)- and F-actin-binding leukocyte-specific protein 1 (LSP1) expressed in leukocytes and nonhematopoietic endothelial cells is pivotal in regulating microvascular permeability and leukocyte recruitment. However, cell-specific function of LSP1 during leukocyte recruitment remains elusive. Using intravital microscopy of cremasteric microvasculature of chimeric LSP1-deficient mice, we show that not neutrophil but endothelial LSP1 regulates neutrophil transendothelial migration and extravascular directionality without affecting the speed of neutrophil migration in tissue in response to CXCL2 chemokine gradient. The expression of PECAM-1-sensitive α6β1 integrins on the surface of transmigrated neutrophils was blunted in mice deficient in endothelial LSP1. Functional blocking studies in vivo and in vitro elucidated that α6β1 integrins orchestrated extravascular directionality but not the speed of neutrophil migration. In LSP1-deficient mice, PECAM-1 expression was reduced in endothelial cells, but not in neutrophils. Similarly, LSP1-targeted small interfering RNA silencing in murine endothelial cells mitigated mRNA and protein expression of PECAM-1, but not ICAM-1 or VCAM-1. Overexpression of LSP1 in endothelial cells upregulated PECAM-1 expression. Furthermore, the expression of transcription factor GATA-2 that regulates endothelial PECAM-1 expression was blunted in LSP1-deficient or LSP1-silenced endothelial cells. The present study unravels endothelial LSP1 as a novel cell-specific regulator of integrin α6β1-dependent neutrophil extravascular chemotactic function in vivo, effective through GATA-2-dependent transcriptional regulation of endothelial PECAM-1 expression.


Myosin with hypertrophic cardiac mutation R712L has a decreased working stroke which is rescued by omecamtiv mecarbil.
Hypertrophic cardiomyopathies (HCMs) are the leading cause of acute cardiac failure in young individuals. Over 300 mutations throughout β-cardiac myosin, including in the motor domain, are associated with HCM. A β-cardiac myosin motor mutation (R712L) leads to a severe form of HCM. Actin-gliding motility of R712L-myosin is inhibited, despite near-normal ATPase kinetics. By optical trapping, the working stroke of R712L-myosin was decreased 4-fold, but actin-attachment durations were normal. A prevalent hypothesis that HCM mutants are hypercontractile is thus not universal. R712 is adjacent to the binding site of the heart failure drug omecamtiv mecarbil (OM). OM suppresses the working stroke of normal β-cardiac myosin, but remarkably, OM rescues the R712L-myosin working stroke. Using a flow chamber to interrogate a single molecule during buffer exchange, we found OM rescue to be reversible. Thus, the R712L mutation uncouples lever arm rotation from ATPase activity and this inhibition is rescued by OM.