Characterization of a BMS-181174-resistant human bladder cancer cell line.
This study was undertaken to elucidate the mechanism of cellular resistance to BMS-181174, a novel analogue of mitomycin C (MMC), in a human bladder cancer cell line. The BMS-181174-resistant variant (J82/BMS) was established by repeated continuous exposures of parental cells (J82) to increasing concentrations of BMS-181174 (9-40 nM) over a period of about 17 months. A 2.6-fold higher concentration of BMS-181174 was required to kill 50% of J82/BMS cell line compared with J82. The J82/BMS cell line exhibited collateral sensitivity to 5-fluorouracil (5-FU), but was significantly more cross-resistant to MMC, melphalan, taxol, doxorubicin and VP-16. NADPH cytochrome P450 reductase and DT-diaphorase activities, which have been implicated in bioreductive activation of MMC, were significantly lower in the J82/BMS cell line than in J82. The cytotoxicity of BMS-181174, however, was not affected in either cell line by pretreatment with dicoumarol, which is an inhibitor of DT-diaphorase activity. These results argue against a role of DT-diaphorase in cellular bioactivation of BMS-181174, a conclusion consistent with that of Rockwell et al (Biochem Pharmacol, 50: 1239-1243, 1995). BMS-181174-induced DNA interstrand cross-link (DNA-ISC) frequency was markedly lower in J82/BMS cell line than in J82 at every drug concentration tested. The results of the present study suggest that cellular resistance to BMS-181174 in J82/BMS cell line may be due to reduced DNA-ISC formation. However, the mechanism of relatively lower BMS-181174 induced DNA-ISC formation in J82/BMS cell line than in parental cells remains to be clarified.


Pseudopelade of Brocq secondary to lichen planus.
Immunofluorescence studies as as the underlying cause of pseudopelade of Brocq (PPOB) in a middle-aged woman. The routine use of immunofluorescent studies in clinical cases of pseudopelade of Brocq might make more specific diagnoses possible.


Effect of dietary α-tocopherol on the bioavailability of lutein in laying hen.
Lutein and its isomer zeaxanthin have gained considerable interest as possible nutritional ingredient in the prevention of age-related macular degeneration (AMD) in humans. Egg yolk is a rich source of these carotenoids. As an oxidative sensitive component, antioxidants such as α-tocopherol (T) might contribute to an improved accumulation in egg yolk. To test this, chickens were fed lutein esters (LE) with and without α-tocopherol as an antioxidant. After depletion on a wheat-soya bean-based lutein-poor diet for 21 days, laying hens (n = 42) were equally divided into three groups and fed the following diets for 21 days: control (basal diet), a LE group (40 mg LE/kg feed) and LE + T group (40 mg LE plus 100 mg T/kg feed). Eggs and blood were collected periodically. Carotenoids and α-tocopherol in yolk and blood plasma were determined by HPLC. Egg yolk was also analysed for total carotenoids using a one-step spectrophotometric method (iCheck((™)) ). Lutein, zeaxanthin, α-tocopherol and total carotenoids in egg yolk were highest after 14 days of feeding and decreased slightly afterwards. At the end of the trial, eggs of LE + T group contained higher amount of lutein (13.72), zeaxanthin (0.65), α-tocopherol (297.40) and total carotenoids (21.6) compared to the LE group (10.96, 0.55, 205.20 and 18.0 mg/kg, respectively, p < 0.05). Blood plasma values of LE + T group contain higher lutein (1.3), zeaxanthin (0.06) and tocopherol (20.1) compared to LE group (1.02, 0.04 and 14.90 mg/l, respectively, p < 0.05). In conclusion, dietary α-tocopherol enhances bioavailability of lutein reflecting higher content in egg yolk and blood plasma. Improved bioavailability might be due to increased absorption of lutein in the presence of tocopherol and/or a greater stability of lutein/zeaxanthin due to the presence of α-tocopherol as an antioxidant.


Preliminary observations on soluble programmed cell death protein-1 as a prognostic and predictive biomarker in patients with metastatic melanoma treated with patient-specific autologous vaccines.
Because of its role as an immune checkpoint, levels of soluble programmed cell death protein-1 (sPD-1) could be useful as a prognostic biomarker or predictive biomarker in cancer patients treated with vaccines. Very low levels of sPD-1 may indicate lack of an existing anti-cancer immune response; very high levels may indicate an active immune response that is suppressed. In between these extremes, a decrease in PD-1 following injections of an anti-cancer vaccine may indicate an enhanced immune response that has not been suppressed. Blood samples obtained during a randomized trial in patients with metastatic melanoma were tested from 22 patients treated with a tumor cell vaccine (TCV) and 17 treated with a dendritic cell vaccine (DCV). Survival was better in DCV-treated patients. sPD-1 was measured at week-0, one week before the first of three weekly subcutaneous injections, and at week-4, one week after the third injection. The combination of a very low baseline sPD-1, or absence of a very high PD-1 at baseline followed by a decline in sPD-1 at week-4, was predictive of surviving three or more years in DCV-treated patients, but not TCV-treated. Among DCV-treated patients, these sPD-1 criteria appropriately classified 8/10 (80%) of 3-year survivors, and 6/7 (86%) of patients who did not survive three years. These preliminary observations suggest that sPD-1 might be a useful biomarker for melanoma patients being considered for treatment with this DCV vaccine, and/or to predict efficacy after only three injections, but this would have to be confirmed in larger studies.


Preoperative psychological resilience and recovery after hip fracture: Secondary analysis of the REGAIN randomized trial.
How psychological resilience influences postoperative outcomes remains poorly characterized. We tested the hypothesis that psychological resilience is associated with lower odds of death or new inability to walk independently and other outcomes at 60 days after hip fracture surgery. This was a pre-planned secondary analysis of a multicenter randomized trial comparing spinal versus general anesthesia for hip fracture surgery. We analyzed data on 1360 adults aged 50 years or older who were hospitalized for hip fracture surgery at one of 46 US or Canadian hospitals and provided psychological resilience data preoperatively as measured via the Brief Resilience Scale. Major exclusions were the inability to walk without human assistance before fracture and contraindications to spinal anesthesia. Death or new inability to walk independently at 60 days after surgery was the primary outcome; death or new nursing home residence at 60 days and 60-day mortality were secondary outcomes. Greater psychological resilience was associated with lower odds of death or new inability to walk at day 60 (adjusted odds ratio [aOR] 0.77; 95% Confidence Interval [CI], 0.61 to 0.98; p = 0.03). We observed a similar association between psychological resilience and outcomes among patients who did not experience complications after surgery (aOR 0.72; CI 0.55 to 0.94, p = 0.02), but not those who had complications (aOR 1.00; CI 0.59 to 1.69, p = 0.99). Psychological resilience was associated with lower odds of 60-day death or new nursing home residence (aOR 0.73; 95% CI 0.58 to 0.93; p < 0.001) but not with 60-day mortality (aOR 0.92; 95% CI 0.56 to 1.49; p = 0.73). Psychological resilience is associated with better outcomes for older adults after hip fracture surgery, but largely among those who do not have postoperative complications. Future interventions may focus on improving psychological resilience preoperatively or providing support to patients with lower psychological resilience.


The effects of a Pilates-based exercise rehabilitation program on functional outcome and fall risk reduction in an aging adult status-post traumatic hip fracture due to a fall.
Currently, little information describing the relationship of Pilates-based strength and stability exercises with fall risk in the geriatric population exists. The purpose of this report was to examine the impact of a Pilates-based rehabilitation (PBR) program on reducing fall risk in an aging adult status postfall with resulting hip fracture and open reduction and internal fixation. The patient was an 84-year-old woman admitted to a skilled nursing facility (SNF) after a right hip fracture resulting from a fall at home. The patient's relevant medical history included frequent falls due to loss of balance, a previous left hip fracture with resultant arthroplasty, and a stroke roughly 20 years prior. The patient received physical therapy and occupational therapy 6 days per week for 26 days in an SNF. The physical therapy intervention consisted of gait and transfer training, neuromuscular reeducation, and an adjunct of specialized PBR exercises for the following impairments: decreased core strength and awareness and poor dynamic stabilization during functional activities. The patient demonstrated increases in lower extremity strength and active range of motion, ambulation distance and speed, and transfer ability. The patient was able to return home and live with her husband while requiring only incidental assistance with activities of daily living. She was able to independently ambulate around her home with her rolling walker. Her fall risk was also reduced from initial evaluation based on several fall risk assessments, including the Four Square Step Test, the Berg Balance Scale, and the Timed Up and Go. This case illustrates the benefit of integrating PBR exercises into a standard SNF rehabilitation program, which may contribute to decreased fall risk.


Blood flow changes after orthognathic surgery: maxillary and mandibular subapical osteotomy.
Subapical osteotomies were performed in the left quadrant of the mandibles and maxillas of five dogs and six monkeys. Two indirect methods, the isotope fractionation (diffusible tracer) and particle distribution (nondiffusible tracer--15mu microspheres) were used to quantitate local blood flow. To examine the effect of the surgery, blood flows in the alveolar bone, mucosa, and dental pulp of the segmented left quadrant and the corresponding tissues in the right quadrant were calculated and compared. It was assumed that the blood flows to the nonoperated right quadrant could serve as the controls to those observed in the osteotomized segment. The fractional decrease in blood flows to tissues in the operated sides were similar in both experimental animals. The decrease was largest in the dental pulp, ranging from 54% to 82% on the average, and least for the mucosal tissue, ranging from 18% to 40%. Blood flows decreased by 48% to 74%, on the average, in the alveolar bone. In some animals, blood flow to mucosal tissue that served as the pedicle was actually greater than the blood flow in the corresponding tissue on the right side. After surgery, the cardiac output in the dogs averaged about 156 ml/min/kg as calculated from both the diffusible and nondiffusible data. In the monkeys in which only the microspheres were injected, the cardiac output averaged 99 ml/min/kg. The arterial blood pressure dropped 8 to 13 mm Hg on the average (dog, 108 to 100 mm Hg; monkeys, 94 to 81 mm Hg). The heart rate also decreased slightly in dogs, 158 to 139 beats/min on the average; however, it increased slightly after the surgery in the monkeys, 144 to 161 beats/min. Blood losses during surgery were replaced wtih lactated Ringer's solution and the transient decreases in blood pressure of about 20 to 35 mm Hg were not sufficient to produce any shut down of renal blood flow.


BindsNET: A Machine Learning-Oriented Spiking Neural Networks Library in Python.
The development of spiking neural network simulation software is a critical component enabling the modeling of neural systems and the development of biologically inspired algorithms. Existing software frameworks support a wide range of neural functionality, software abstraction levels, and hardware devices, yet are typically not suitable for rapid prototyping or application to problems in the domain of machine learning. In this paper, we describe a new Python package for the simulation of spiking neural networks, specifically geared toward machine learning and reinforcement learning. Our software, called BindsNET, enables rapid building and simulation of spiking networks and features user-friendly, concise syntax. BindsNET is built on the PyTorch deep neural networks library, facilitating the implementation of spiking neural networks on fast CPU and GPU computational platforms. Moreover, the BindsNET framework can be adjusted to utilize other existing computing and hardware backends; e.g., TensorFlow and SpiNNaker. We provide an interface with the OpenAI gym library, allowing for training and evaluation of spiking networks on reinforcement learning environments. We argue that this package facilitates the use of spiking networks for large-scale machine learning problems and show some simple examples by using BindsNET in practice.


Identification of a novel membrane transporter mediating resistance to organic arsenic in Campylobacter jejuni.
Although bacterial mechanisms involved in the resistance to inorganic arsenic are well understood, the molecular basis for organic arsenic resistance has not been described. Campylobacter jejuni, a major food-borne pathogen causing gastroenteritis in humans, is highly prevalent in poultry and is reportedly resistant to the arsenic compound roxarsone (4-hydroxy-3-nitrobenzenearsonic acid), which has been used as a feed additive in the poultry industry for growth promotion. In this study, we report the identification of a novel membrane transporter (named ArsP) that contributes to organic arsenic resistance in Campylobacter. ArsP is predicted to be a membrane permease containing eight transmembrane helices, distinct from other known arsenic transporters. Analysis of multiple C. jejuni isolates from various animal species revealed that the presence of an intact arsP gene is associated with elevated resistance to roxarsone. In addition, inactivation of arsP in C. jejuni resulted in 4- and 8-fold reductions in the MICs of roxarsone and nitarsone, respectively, compared to that for the wild-type strain. Furthermore, cloning of arsP into a C. jejuni strain lacking a functional arsP gene led to 16- and 64-fold increases in the MICs of roxarsone and nitarsone, respectively. Neither mutation nor overexpression of arsP affected the MICs of inorganic arsenic, including arsenite and arsenate, in Campylobacter. Moreover, acquisition of arsP in NCTC 11168 led to accumulation of less roxarsone than the wild-type strain lacking arsP. Together, these results indicate that ArsP functions as an efflux transporter specific for extrusion of organic arsenic and contributes to the resistance to these compounds in C. jejuni.


Changes in cross-bridge cycling underlie muscle weakness in patients with tropomyosin 3-based myopathy.
Nemaline myopathy, the most common non-dystrophic congenital myopathy, is caused by mutations in six genes, all of which encode thin-filament proteins, including NEB (nebulin) and TPM3 (α tropomyosin). In contrast to the mechanisms underlying weakness in NEB-based myopathy, which are related to loss of thin-filament functions normally exerted by nebulin, the pathogenesis of muscle weakness in patients with TPM3 mutations remains largely unknown. Here, we tested the hypothesis that the contractile phenotype of TPM3-based myopathy is different from that of NEB-based myopathy and that this phenotype is a direct consequence of the loss of the specific functions normally exerted by tropomyosin. To test this hypothesis, we used a multidisciplinary approach, including muscle fiber mechanics and confocal and electron microscopy to characterize the structural and functional phenotype of muscle fibers from five patients with TPM3-based myopathy and compared this with that of unaffected control subjects. Our findings demonstrate that patients with TPM3-based myopathy display a contractile phenotype that is very distinct from that of patients with NEB-based myopathy. Whereas both show severe myofilament-based muscle weakness, the contractile dysfunction in TPM3-based myopathy is largely explained by changes in cross-bridge cycling kinetics, but not by the dysregulation of sarcomeric thin-filament length that plays a prominent role in NEB-based myopathy. Interestingly, the loss of force-generating capacity in TPM3-based myopathy appears to be compensated by enhanced thin-filament activation. These findings provide a scientific basis for differential therapeutics aimed at restoring contractile performance in patients with TPM3-based versus NEB-based myopathy.


Magnetic resonance imaging of massive intracranial invasion by an ethmoidal adenoid cystic carcinoma (cylindroma).
Magnetic resonance imaging showed a massive intracranial invasion by an adenoid cystic carcinoma (cylindroma) originating from an ethmoid sinus. The tumor was excised and follow-up radiation therapy was planned because of bone involvement and superficial invasion of the right olfactory tract area.


Radioembolization (yttrium-90 microspheres) for primary and metastatic hepatic malignancies.
Radioembolization using radioactive yttrium-90-labeled microspheres is gaining a stronger foothold in the management of primary and metastatic hepatic cancers. The expanding literature reveals good and encouraging results in both retrospective and prospective reports as demonstrated by low acute or late toxicity and high response rates. This treatment modality, which is most beneficial in patients with good liver reserve and low Eastern Cooperative Oncology Group performance status, has led to improved time to liver progression and extended overall patient survival. Although the phase III trials of radioembolization are ongoing as a first-line treatment of patients with metastatic colorectal cancer, there are sufficient phase II and retrospective clinical data supporting its use in salvage therapy for most patients. Patients with hepatocellular cancer, neuroendocrine tumors, and other primary sites, including breast and lung, have also shown promising response and survival increases in multi-institutional experiences.


Liver pathology and cell proliferation after calcineurin inhibitors and antiproliferative drugs following partial hepatectomy in rats.
Immunosuppressants are the cornerstones of treatment after solid organ transplantation. This study investigated the pathology and cell proliferation following partial hepatectomy (PH) in rats undergoing immunosuppressive treatment. After 1 day, all rats were subjected to 70% PH. Groups A and B (n = 10) received calcineurin inhibitors subcutaneously: either FK506 or cyclosporine (CyA). Groups C and D (n = 10) received antiproliferative drugs: either mycophenolate mofetil (MMF) or sirolimus (SRL) by gavage. A control group (n = 5) received 1 mL of tap water daily. On postoperative day 2, all rats were sacrificed to obtain liver tissue for pathologic examination. Using immunohistochemistry we separately examined the hepatectomy surface and the liver parenchyma. In the parenchyma, the Ki-67 indices were higher in the CyA and FK506 groups and lower in the SRL and MMF groups compared with controls (P < .01). CyA had the highest and MMF the lowest values. On the hepatectomy surface, Ki-67 indices and TGF-alpha expressions were higher in the CyA group and lower in the SRL and MMF groups compared with the control group (P < .01). Slightly higher values in the FK506 group were not significantly different compared with the control group (P > .05). All groups other than FK506 showed prominent cholangiolar epithelial phenotypes compared with the control group. In the CyA and SRL groups, the number of cholangiolar cells was higher (P < .01), and in the MMF group lower than in the control group (P < .01). Among all groups, SRL had the highest values.


Surgical treatment of organic hyperinsulinism in infancy. Surgical procedure in the absence of a demonstrable insulinoma and a peroperative diagnosis of nesidioblastosis.
This study consists of a review of 5 children operated on for organic hyperinsulinism. The diagnosis could be established by demonstrating the repeated presence of elevated serum insulin levels during hypoglycaemia and/or a rapid glucose disappearance. From our experience with this series and by a review of the literature the following data are relevant to the management of these children. Because of the risk of brain damage there is no justification for prolonged diagnostic and therapeutic trials. Surgical exploration of the pancreas is indicated without delay. When during exploration no localised lesion can be found, the diagnosis "nesidioblastosis" can be established by frozen section evaluation. Whether a diagnosis of nesidioblastosis has been established or not, a 90-95% subtotal pancreatectomy has to be performed subsequently, because this operation will cure most of the children with organic hyperinsulinism, has negligible complications and preserves normal exocrine and endocrine pancreatic function. A near-total pancreatectomy has to be performed without delay in patients with recurrent hypoglycaemia caused by persisting organic hyperinsulinism after the first operation.


Assessment of iodine importance and needs for supplementation in school-aged children in Portugal.
Micronutrients are essential for child proper growth and development. Nutritional deficiencies of these elements have increasingly been a concern in Europe, as they are often related to the cognitive potential and physical lifelong consequences. However, being an essential trace element for thyroid function, iodine intake in the desired quantities becomes also very important for neurodevelopment, including for school-aged children. Therefore, the aim of this paper is to highlight the need for wider dissemination of the physiological importance of iodine among health professionals and the general population as well as the knowledge of iodine needs and possible supplementation within families with school-aged children. The present study is an observational, descriptive, cross-sectional evaluation of knowledge and perceptions of iodine physiological importance. An evaluation survey has been carried out based on knowledge of iodine needs and possible supplementation within families with school-aged children. It has been target at mothers with school-age children under 18 years old with residence in Portugal. Data are represented as frequency and percentages and association between variables was measured. The internet survey has been answered by around 691 mothers, corresponding to 811 children data validated; 47% (n = 381) girls and 53% (n = 430) boys. Mother's knowledge about iodine and the importance for the improvement of learning capacity is not independent of having health study/work area (χ2 at the 0.05 level). Nevertheless, it can be observed a slight association between mothers who agree with iodine supplementation and those who effectively supplement their child (χ2 9.315; Φ 0.116). Although use of iodized kitchen salt certainly changes the balance from sub-optimal to adequate iodine nutrition, only 8.8% (n = 61) reported using iodized salt. However, 87.6% (n = 605) assumed salt iodization importance without information. We believe that the findings of this survey have great public health importance for Portugal. While many countries have mandatory iodizes salt programmes, in Portugal iodine supplementation is not a current practice. Therefore, we suggest an urgent evaluation of iodine in Portugal, namely for school-aged children, where iodine deficiencies are critical, as well as a systematic information dissemination as a form of publicizing iodine supplementation needs.


Identification of tobacco-specific nitrosamines as disinfection byproducts in chloraminated water.
Tobacco-specific nitrosamines (TSNAs) exist in environmental waters; however, it is unknown whether TSNAs can be produced during water disinfection. Here we report on the investigation and evidence of TSNAs as a new class of disinfection byproducts (DBPs). Using five common TSNAs, including (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) as the targets, we first developed a solid phase extraction (SPE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) method capable of rapidly determining these TSNAs at levels as low as 0.02 ng/L in treated water. Using this highly sensitive method, we investigated the occurrence and formation potential (FP) (precursor test conducted in the presence of chloramines) of TSNAs in treated water from two wastewater treatment plants (WWTPs) and seven drinking water treatment plants (DWTPs). NNAL was detected in the FP samples, but not in the samples before the FP test, confirming NNAL as a DBP. NNK was detected in the treated wastewater before the FP test, but its concentration increased significantly after chloramination in two of three tests. Thus, NNK could be a DBP and/or a contaminant in wastewater. Moreover, these TSNAs were detected in FP tests of wastewater-impacted DWTP plant influents in 9 of 11 samples. However, TSNAs were not detected at full-scale DWTPs, except for at one DWTP with high ammonia where breakpoint chlorination was not achieved. The concentration of the sum of five TSNAs (0.3 ng/L) was 100-fold lower than NDMA, suggesting that TSNAs have a minor contribution to total nitrosamines in water. We examined several factors in the treatment process and found that chlorine or ozone may destroy TSNA precursors and granular activated carbon (GAC) treatment may remove the precursors. Further research is warranted into the efficiency of these processes at different DWTPs using sources of varying water quality.


Reciprocal Markov Modeling of Feedback Mechanisms Between Emotion and Dietary Choice Using Experience-Sampling Data.
With intensively collected longitudinal data, recent advances in the experience-sampling method (ESM) benefit social science empirical research, but also pose important methodological challenges. As traditional statistical models are not generally well equipped to analyze a system of variables that contain feedback loops, this paper proposes the utility of an extended hidden Markov model to model reciprocal the relationship between momentary emotion and eating behavior. This paper revisited an ESM data set (Lu, Huet, & Dube, 2011) that observed 160 participants' food consumption and momentary emotions 6 times per day in 10 days. Focusing on the analyses on feedback loop between mood and meal-healthiness decision, the proposed reciprocal Markov model (RMM) can accommodate both hidden ("general" emotional states: positive vs. negative state) and observed states (meal: healthier, same or less healthy than usual) without presuming independence between observations and smooth trajectories of mood or behavior changes. The results of RMM analyses illustrated the reciprocal chains of meal consumption and mood as well as the effect of contextual factors that moderate the interrelationship between eating and emotion. A simulation experiment that generated data consistent with the empirical study further demonstrated that the procedure is promising in terms of recovering the parameters.


A systematically combined genotype and functional combination analysis of CYP2E1, CYP2D6, CYP2C9, CYP2C19 in different geographic areas of mainland China--a basis for personalized therapy.
The cytochrome P450 is the major enzyme involved in drug metabolism. Single CYP genotypes and metabolic phenotypes have been widely studied, but no combination analysis has been conducted in the context of specific populations and geographical areas. This study is the first to systematically analyze the combined genotypes and functional combinations of 400 samples of major CYP genes--CYP2E1, CYP2D6, CYP2C9, and CYP2C19 in four geographical areas of mainland China. 167 different genotype combinations were identified, of which 25 had a greater than 1% frequency in the Chinese Han population. In addition, phenotypes of the four genes for each sample were in line with the predictions of previous studies of the four geographical areas. On the basis of the genotype classification, we were able to produce a systemic functional combinations analysis for the population. 25 of the combinations detected had at least two non-wild phenotypes and four showed a frequency above 1%. A bioinformatics analysis of the relationship between particular drugs and multi-genes was conducted. This is the first systematic study to analyze genotype combinations and functional combinations across whole Chinese population and could make a significant contribution in the field of personalized medicine and therapy.


Pediatric intestinal leiomyosarcomas: case report and review of the literature.
Primary intestinal leiomyosarcomas in children are rare tumors. Twenty-seven previous cases are documented in the literature with little information available on the treatment, survival, and prognostic factors surrounding these tumors. The authors report the 28th case of pediatric intestinal leiomyosarcoma and its follow-up, that of a newborn presenting with intestinal obstruction. Follow-up from all previously reported cases is not recorded and is needed. Our patient, like most children with this tumor, underwent complete excision with no evidence of recurrence at 5 years. Visceral metastases from these neoplasms are atypical, and recorded long-term prognosis may be favorable, unlike their counterpart in the adult population.


Diaphragmatic Morgagni hernia in adulthood: correct preoperative diagnosis is possible with newer imaging techniques.
Morgagni hernia is a rare type of diaphragmatic hernia. It is frequently associated with elusive clinical and radiological findings in the adult and consequently, diagnosis and appropriate therapy are usually delayed. We describe a case in which a Morgagni hernia presented as a right sided cardiophrenic mass on a routine chest X-ray. The diaphragmatic defect was further confirmed by computed tomography (CT), by a magnetic resonance imaging (MRI) of the chest. The defect was closed by a prolene mesh.


Complications of dermis-fat orbital implantation.
Primary dermis-fat implantation can be effectively performed in cases without pre-existing systemic vascular disease or orbital burns. Meticulous handling of the graft (using a Goeller trephine and Tenon's capsule traction sutures), filleting Tenon's capsule, and avoiding cautery of the graft bed may minimize graft necrosis and atrophy. Pyogenic granulomas of the conjunctival-graft interface and graft hirsutism are easily managed. Keratinization of the socket, graft wound dehiscence, donor site hematomas, and wound dehiscence are avoided with careful surgical technique. Secondary dermis-fat orbital implantation may add orbital volume and conserve the conjunctival fornices, but may also suffer a slightly increased frequency and amount of graft absorption.


Acetabular Protrusio in Patients With Osteogenesis Imperfecta: Risk Factors and Progression.
Osteogenesis imperfecta (OI) is a genetic disorder commonly associated with osteopenia, osteoporosis, bone fractures, bone deformities, and other clinical features. A frequent radiologic finding with OI is acetabular protrusio (AP). We hypothesized that AP develops in patients with OI over time. In addition, we hypothesized that AP also develops in patients with OI without radiographic evidence of AP on initial examination. Medical records and radiographs of 55 patients (109 hips) diagnosed with OI evaluated at our institution were retrospectively reviewed. Previously established radiographic criteria using the center-edge (CE) angle of Wiberg, position of the acetabulum relative to the iliopectineal line, crossing of the acetabulum across the ilioischial (Kohler) line, and position of the teardrop figure relative to the ilioischial (Kohler) line were utilized to assess AP severity. In addition, pharmacological treatments and patient factors including body mass index (BMI) were recorded. Radiographs of patients with OI that were taken ≥2 years apart were analyzed utilizing AP radiographic criteria to assess for changes. The changes in AP-related measurements were standardized by distance or degree per year. In addition, patient factors were evaluated for associations with AP development. In this series of 109 hips (55 patients), incidence of AP in earliest radiographs was 45% (49/109). Patients with OI type I and III demonstrated the highest incidence of AP (65%). Among the hips that did not meet the criteria for AP in their early radiographs, 24 (40%) were positive for AP by their latest radiograph. In the hips that initially presented with AP, 42% showed increased CE angles on later radiographs. Twenty-six hips (24%) showed either no observable changes or reduced CE angles. Risk factors that were significantly associated with greater odds of developing AP included (1) an age under 12; (2) a BMI>25; (3) presence of AP of the contralateral hip; and (4) female sex. Bisphosphonates, vitamin D, physical therapy, and other drugs related to treatment of OI reduced the risk of developing AP but did not achieve statistical significance. AP is a common finding in OI patients (54%). Among hips of OI patients that met criteria for AP in early radiographs, 42% (20/48) demonstrated greater CE angles in their latest radiographs. Similar changes were observed in OI patients who did not initially meet criteria for diagnosis for AP. However, CE angle measurements between the 2 groups did not significantly differ (P=0.71). In terms of Kohler line crossing, patients that met criteria for AP in early radiographs had significantly greater change per year than those that did not have AP criteria (P<0.05). The findings suggest AP may develop over time in patients with OI and may be influenced by patient factors such as age, sex, and BMI. In addition, unilateral AP may have a significant impact on the development of AP of the contralateral hip. Level IV-retrospective case series.


Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial.
Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are common forms of dementia that substantially affect quality of life. Currently, the only treatment licensed for PDD is rivastigmine, and there are no licensed treatments for DLB. We aimed to test the safety and efficacy of the N-methyl D-aspartate (NMDA) receptor antagonist memantine in patients with PDD or DLB. We did a parallel-group, 24-week, randomised controlled study of memantine (20 mg per day) versus placebo at four psychiatric and neurological outpatient clinics in Norway, Sweden, and the UK during 2005-08. Patients were included if they fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease (PD) and developed dementia according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM IV) criteria at least 1 year after the onset of motor symptoms (PDD) or met the revised consensus operationalised criteria for DLB. Patients were assigned to a computer-generated randomisation list. All physicians who had contact with patients were masked to treatment allocation. The primary outcome measure was clinical global impression of change (CGIC), which ranged from 1 to 7 points, and a low score means a better outcome. Analysis was by intention to treat based on the last observation carried forward. This trial is registered, number ISRCTN89624516. 72 patients with PDD or DLB were randomly assigned and started treatment: 34 with memantine and 38 with placebo. 56 (78%) completed the study. All withdrawals were owing to adverse events, but the proportion of withdrawals was similar in both groups. At week 24 the patients in the memantine group had better CGIC scores than those taking placebo (mean difference 0.7, 95% CI 0.04-1.39; p=0.03). With the exception of improved speed on attentional tasks in the memantine group (a quick test of cognition [AQT] form: difference 12.4, 95% CI 6.0-30.9; p=0.004), there were no significant differences between the groups in secondary outcome measures. Patients with DLB or PDD might benefit from treatment with memantine, which was well tolerated. Large-scale studies are now required to confirm our preliminary findings. The Western Norway Regional Health Authority; H Lundbeck A/S.


The shrimp superfamily Sergestoidea: a global phylogeny with definition of new families and an assessment of the pathways into principal biotopes.
The phylogenetic analysis of Sergestoidea based on 253 morphological characters and encompassing all 99 valid species confirmed all previously recognized genus-level clades. Analysis retrieved five major robust clades that correspond to families Luciferidae, Sergestidae, Acetidae fam.n., Sicyonellidae fam.n. and Petalidiumidae fam.n. Synonymy, emended diagnoses and composition of revealed family-level clades are provided. Three types of morphological characters were important in the phylogeny of the Sergestoidea: general external characters, copulatory organs, and photophores. Novel metrics to quantify the contribution of these character types were tested. General external characters were significant in supporting the major clades (80% of the families and nearly half of the genera). Copulatory organ characters and photophores greatly supported the medium-level clades: Lucifer, Belzebub, Petalidium, Neosergestes, Challengerosergia (copulatory organ characters) and Lucensosergia, Challengerosergia, Gardinerosergia, Phorcosergia (photophores). An evolutionary model of the Sergestoidea showing their pathways into their principal biotopes is proposed: the major clades evolved in a vertical direction (from epi- to bathypelagic); further divergence at the genus level occurred within vertical zones in a horizontal direction, with the invasion of the benthopelagic and neritic (shelf and estuarine) habitats and speciation within these domains.


Enhanced Disease Susceptibility1 Mediates Pathogen Resistance and Virulence Function of a Bacterial Effector in Soybean.
Enhanced disease susceptibility1 (EDS1) and phytoalexin deficient4 (PAD4) are well-known regulators of both basal and resistance (R) protein-mediated plant defense. We identified two EDS1-like (GmEDS1a/GmEDS1b) proteins and one PAD4-like (GmPAD4) protein that are required for resistance signaling in soybean (Glycine max). Consistent with their significant structural conservation to Arabidopsis (Arabidopsis thaliana) counterparts, constitutive expression of GmEDS1 or GmPAD4 complemented the pathogen resistance defects of Arabidopsis eds1 and pad4 mutants, respectively. Interestingly, however, the GmEDS1 and GmPAD4 did not complement pathogen-inducible salicylic acid accumulation in the eds1/pad4 mutants. Furthermore, the GmEDS1a/GmEDS1b proteins were unable to complement the turnip crinkle virus coat protein-mediated activation of the Arabidopsis R protein Hypersensitive reaction to Turnip crinkle virus (HRT), even though both interacted with HRT. Silencing GmEDS1a/GmEDS1b or GmPAD4 reduced basal and pathogen-inducible salicylic acid accumulation and enhanced soybean susceptibility to virulent pathogens. The GmEDS1a/GmEDS1b and GmPAD4 genes were also required for Resistance to Pseudomonas syringae pv glycinea2 (Rpg2)-mediated resistance to Pseudomonas syringae. Notably, the GmEDS1a/GmEDS1b proteins interacted with the cognate bacterial effector AvrA1 and were required for its virulence function in rpg2 plants. Together, these results show that despite significant structural similarities, conserved defense signaling components from diverse plants can differ in their functionalities. In addition, we demonstrate a role for GmEDS1 in regulating the virulence function of a bacterial effector.


Alpha-lipoic acid: physiologic mechanisms and indications for the treatment of metabolic syndrome.
In animal experiments, the potent antioxidant and free radical scavenger alpha-lipoic acid has been shown to cause weight loss, ameliorate insulin resistance and atherogenic dyslipidemia, as well as to lower blood pressure, all of these being components of the metabolic syndrome. Recent investigations on its mechanisms of action indicate that alpha-lipoic acid can affect central and peripheral modulation of 5'-AMP-activated protein kinase, activate PPAR-alpha and PPAR-gamma, modulate PPAR-regulated genes and upregulate the expression of PPAR-gamma mRNA and protein in cardiac tissue and aorta smooth muscle. To a large extent, these findings can explain the observed beneficial metabolic effects of alpha-lipoic acid, supporting its potential application as a therapeutic agent for the treatment of the metabolic syndrome.


Lithium activates the Wnt and phosphatidylinositol 3-kinase Akt signaling pathways to promote cell survival in the absence of soluble survival factors.
Mouse proximal tubular cells (BUMPT), when cultured in the absence of growth factors, activate a default apoptotic pathway. Although Wnt signaling antagonizes the effect of proapoptotic triggers, its role in regulating the default pathway of apoptosis is less well defined. The present study examines the hypothesis that lithium (Li(+)) and (2'Z,3'E)-6-bromoindirubin-3'-oxime (BIO), two glycogen synthase kinase-3beta (GSK3beta) inhibitors, promote survival of growth factor-deprived renal epithelial cells by activating the Wnt pathway. These studies demonstrate that Li(+) and BIO activate Wnt signaling as indicated by the following changes: phosphorylation (inhibition) of GSK3beta; decreased phosphorylation of beta-catenin (a GSK3beta substrate); nuclear translocation of beta-catenin; specific transcriptional activation of Tcf/catenin-responsive pTopflash constructs; and an increase in the expression of cyclin D1 (indicative of a promitogenic cell response). In addition, Li(+) or BIO significantly increases the phosphorylation (activation) of Akt, an anti-apoptotic protein, and inhibits apoptosis (decreases both annexin-V staining and caspase-3 activation), during serum deprivation. Inhibition of phosphatidylinositol 3-kinase (responsible for Akt activation) either by wortmanin or LY-294002 prevented Li(+)- or BIO-induced Akt phosphorylation and reduces cell survival without altering the phosphorylation state of GSK3beta. Li(+) or BIO also increases the expression of insulin-like growth factor-II (IGF-II), a potent proliferative signaling protein. Li(+) or BIO-free conditioned medium harvested from Li(+)- or BIO-exposed cells also induced Akt phosphorylation, mimicking the protective effect of the two GSK3beta inhibitors on serum-starved cells. Furthermore, the effect of conditioned medium on Akt phosphorylation could be inhibited by either LY-294002 or IGF-binding protein. BIO, a specific GSK3beta inhibitor, replicated the protective effect of Li(+) on cell viability, suggesting that GSK3beta activation is important for initiating the apoptotic pathway. Taken together, these data suggest that Li(+) or BIO promotes renal epithelial cell survival by inhibiting apoptosis through GSK3beta-dependent activation of the Wnt pathway and subsequent release of IGF-II. Extracellular IGF-II serves as an autocrine survival factor that is responsible, in part, for activating the anti-apoptotic phosphatidylinositol-3-kinase-Akt pathway during serum deprivation.


The application of miniplex primer sets in the analysis of degraded DNA from human skeletal remains.
A new set of multiplexed PCR primers has been applied to the analysis of human skeletal remains to determine their efficacy in analyzing degraded DNA. These primer sets, known as Miniplexes, produce shorter amplicons (50-280 base pairs (bp)) than standard short tandem repeat (STR) kits, but still utilize the 13 CODIS STR loci, providing results that are searchable on national DNA databases. In this study, a set of 31 different human remains were exposed to a variety of environmental conditions, extracted, and amplified with commercial and Miniplex DNA typing kits. The amplification efficiency of the Miniplex sets was then compared with the Promega PowerPlex 16 system. Sixty-four percent of the samples generated full profiles when amplified with the Miniplexes, while only 16% of the samples generated full profiles with the Powerplex 16 kit. Complete profiles were obtained for 11 of the 12 Miniplex loci with amplicon sizes less than 200 bp. These data suggest smaller PCR amplicons may provide a useful alternative to mitochondrial DNA for anthropological and forensic analysis of degraded DNA from human skeletal remains.


The PYHIN Protein p205 Regulates the Inflammasome by Controlling Asc Expression.
Members of the IFN-inducible PYHIN protein family, such as absent in melanoma-2 and IFN-γ-inducible protein (IFI)16, bind dsDNA and form caspase-1-activating inflammasomes that are important in immunity to cytosolic bacteria, DNA viruses, or HIV. IFI16 has also been shown to regulate transcription of type I IFNs during HSV infection. The role of other members of the PYHIN protein family in the regulation of immune responses is much less clear. In this study, we identified an immune-regulatory function for a member of the murine PYHIN protein family, p205 (also called Ifi205). Examination of immune responses induced by dsDNA and other microbial ligands in bone marrow-derived macrophages lacking p205 revealed that inflammasome activation by dsDNA, as well as ligands that engage the NLRP3 inflammasome, was severely compromised in these cells. Further analysis revealed that p205-knockdown cells showed reduced expression of apoptosis-associated speck-like molecule containing CARD domain (Asc) at the protein and RNA levels. p205 knockdown resulted in reduced binding of actively transcribing RNA polymerase II to the endogenous Asc gene, resulting in decreased transcription and processing of Asc pre-mRNA. Deletion of p205 in B16 melanoma cells using CRISPR/Cas9 showed a similar loss of Asc expression. Ectopic expression of p205 induced expression of an Asc promoter-luciferase reporter gene. Together, these findings suggest that p205 controls expression of Asc mRNA to regulate inflammasome responses. These findings expand on our understanding of immune-regulatory roles for the PYHIN protein family.


De minimus non curat lex--virtual thresholds for cancer initiation by tobacco specific nitrosamines--prospects for harm reduction by smokeless tobacco.
Whereas the impact of tobacco specific nitrosamines in smokers is obscured by the presence of numerous other carcinogens and promoters, for smokeless tobacco virtually all the carcinogenic potential is associated with 4-(nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN). In some countries exposure to smokeless tobacco with extremely high nitrosamine concentrations have been found to induce cancers in the head-neck region, whereas three recent large epidemiological studies failed to detect any such risk with respect to Swedish low-nitrosamine snuff. This review deals with quantitative aspects of DNA adduct formation from NNN and NNK in relation to the background levels ubiquitously found in healthy humans without known exposures to either tobacco or alkylating agents. The lack of significant increases of pro-mutagenic O6-methylations and DNA pyridyloxobutylations seen in smokers, as well as the negative outcome of the Swedish epidemiological studies, can be expected on basis of extrapolation of the dose response relationships found in rodents to actual exposures to NNK and NNN in Swedish snuff or from smoking. Sweden has the lowest prevalence of male smokers and smoking related diseases in the Western World, which has been ascribed to the fact that more than 20% of the grown up male population uses snuff. Smokeless tobacco represents an inexpensive and effective alternative to nicotine delivering products like nicotine patch, spray or gum. Considering that all other tobacco products are freely marketed, the ban on low-nitrosamine snuff in all countries in EU except Sweden is difficult to defend on either medical or ethical grounds.


Integrated Single-Cell and Transcriptome Sequencing Analyses Develop a Ubiquitination-Associated Signature in Gastric Cancer and Identified OTULIN as a Novel Biomarker.
Gastric cancer (GC) is the most commonly diagnosed digestive system malignancy with a dismal survival outcome. The prognostic value of ubiquitination-related genes (URGs) in GC has yet to be discovered. Two GC cohort datasets were obtained from the Cancer Genome Atlas Program (TCGA) and Gene Expression Omnibus (GEO) databases. Stepwise Cox analysis was employed to generate a signature. Then, we applied unsupervised clustering analysis to determine subclusters in GC based on URGs. Single-cell analysis was carried out to depict the cellular location of model genes. The CIBERSORT method was performed to estimate the immune landscape. Finally, preliminary wet lab work was utilized to disclose the potential effect of OTULIN. Our proposed signature was set up based on five URGs (OTULIN, UBE2C, USP1, USP2, and MAPT) which could serve as a risk classifier to categorize GC cases. In addition, it was demonstrated that the ubiquitination-associated model could depict the immune landscape and forecast immunotherapy response for GC patients. Furthermore, in vitro experiments determined the function and effect of OUTLIN in GC. We observed that the knockdown of OUTLIN could suppress cell viability and metastatic ability of GC cell lines. Our data lays the groundwork for a comprehensive investigation into the role of URGs in GC and determined OTULIN as a candidate GC biomarker.


Comparing the health state preferences of older persons, informal caregivers and healthcare professionals: a vignette study.
The Older Persons and Informal Caregivers Survey-Minimum Dataset (TOPICS-MDS) collects uniform information from research projects funded under the Dutch National Care for the Elderly Programme. To compare the effectiveness of these projects a preference-weighted outcome measure that combined multidimensional TOPICS-MDS outcomes into a composite endpoint (TOPICS-CEP) was developed based on the health state preferences of older persons and informal caregivers. To derive preference weights for TOPICS-CEP's components based on health state preferences of healthcare professionals and to investigate whether these weights differ between disciplines and differ from those of older persons and informal caregivers. Vignette studies were conducted. Participants assessed the general wellbeing of older persons described in vignettes on a scale (0-10). Mixed linear analyses were used to obtain and compare the preference weights of the eight TOPICS-CEP components: morbidities, functional limitations, emotional wellbeing, pain experience, cognitive problems, social functioning, self-perceived health, and self-perceived quality of life (QOL). Overall, 330 healthcare professionals, 124 older persons and 76 informal caregivers participated. The preference weights were not significantly different between disciplines. However, the professionals' preference weights differed significantly from those of older persons and informal caregivers. Morbidities and functional limitations were given more weight by older persons and informal caregivers than by healthcare professionals [difference between preference weights: 0.12 and 0.07] while the opposite was true for pain experience, social functioning, and self-perceived QOL [difference between preference weights: 0.13, 0.15 and 0.26]. It is important to recognize the discrepancies between the health state preferences of various stakeholders to (1) correctly interpret results when studying the effectiveness of interventions in elderly care and (2) establish appropriate healthcare policies. Furthermore, we should strive to include older persons in our decision making process through a shared decision making approach.


Multimodal approach to control postoperative pathophysiology and rehabilitation.
Major surgery is still associated with undesirable sequelae such as pain, cardiopulmonary, infective and thromboembolic complications, cerebral dysfunction, nausea and gastrointestinal paralysis, fatigue and prolonged convalescence. The key pathogenic factor in postoperative morbidity, excluding failures of surgical and anaesthetic technique, is the surgical stress response with subsequent increased demands on organ function. These changes in organ function are thought to be mediated by trauma-induced endocrine metabolic changes and activation of several biological cascade systems (cytokines, complement, arachidonic acid metabolites, nitric oxide, free oxygen radicals, etc). To understand postoperative morbidity it is therefore necessary to understand the pathophysiological role of the various components of the surgical stress response and to determine if modification of such responses may improve surgical outcome. While no single technique or drug regimen has been shown to eliminate postoperative morbidity and mortality, multimodal interventions may lead to a major reduction in the undesirable sequelae of surgical injury with improved recovery and reduction in postoperative morbidity and overall costs.


LDL-cholesterol versus non-HDL-to-HDL-cholesterol ratio and risk for coronary heart disease in type 2 diabetes.
We assessed the association between different blood lipid measures and risk of fatal/nonfatal coronary heart disease (CHD), which has been less analysed previously in type 2 diabetes. Observational study of 46,786 patients with type 2 diabetes, aged 30-70 years, from the Swedish National Diabetes Register, followed for a mean of 5.8 years until 2009. Baseline and updated mean low-density lipoprotein (LDL)-, high-density lipoprotein (HDL)-, non-HDL-cholesterol, and non-HDL-to-HDL-cholesterol ratio were measured. Hazard ratios (HR) for CHD with quartiles 2-4 of baseline lipid measures, with lowest quartile 1 as reference: 1.03-1.29-1.63 for LDL; 1.23-1.41-1.95 for non-HDL; 1.29-1.39-1.57 for HDL; and 1.31-1.67-2.01 for non-HDL:HDL, all p < 0.001 except for quartile 2 of LDL, when adjusted for clinical characteristics and nonlipid risk factors. A similar picture was seen with updated mean values. Splines with absolute 6-year CHD rates in a Cox model showed decreasing rates only down to around 3 mmol/l for LDL, with linearly decreasing rates to the lowest level of non-HDL:HDL. Non-HDL and HDL were independent additive risk factors for CHD risk. HRs per 1 SD continuous decrease in baseline or updated mean HDL were 1.14-1.17 when fully adjusted as above, and 1.08-1.13 when also adjusted for non-HDL (p < 0.001). HRs were 1.13-1.16 adjusted for LDL, and 1.22-1.26 adjusted for total cholesterol and triglycerides (p < 0.001). Splines showed progressively increasing 6-year CHD rates with lower HDL down to 0.5 mmol/l. This study suggests that lower levels of non-HDL:HDL are a better risk marker for CHD than LDL-cholesterol below 3 mmol/l.


Prognostic Classifier Based on Genome-Wide DNA Methylation Profiling in Well-Differentiated Thyroid Tumors.
Even though the majority of well-differentiated thyroid carcinoma (WDTC) is indolent, a number of cases display an aggressive behavior. Cumulative evidence suggests that the deregulation of DNA methylation has the potential to point out molecular markers associated with worse prognosis. To identify a prognostic epigenetic signature in thyroid cancer. Genome-wide DNA methylation assays (450k platform, Illumina) were performed in a cohort of 50 nonneoplastic thyroid tissues (NTs), 17 benign thyroid lesions (BTLs), and 74 thyroid carcinomas (60 papillary, 8 follicular, 2 Hürthle cell, 1 poorly differentiated, and 3 anaplastic). A prognostic classifier for WDTC was developed via diagonal linear discriminant analysis. The results were compared with The Cancer Genome Atlas (TCGA) database. A specific epigenetic profile was detected according to each histological subtype. BTLs and follicular carcinomas showed a greater number of methylated CpG in comparison with NTs, whereas hypomethylation was predominant in papillary and undifferentiated carcinomas. A prognostic classifier based on 21 DNA methylation probes was able to predict poor outcome in patients with WDTC (sensitivity 63%, specificity 92% for internal data; sensitivity 64%, specificity 88% for TCGA data). High-risk score based on the classifier was considered an independent factor of poor outcome (Cox regression, P < 0.001). The methylation profile of thyroid lesions exhibited a specific signature according to the histological subtype. A meaningful algorithm composed of 21 probes was capable of predicting the recurrence in WDTC.


The Impact of Artificial Intelligence on Data System Security: A Literature Review.
Diverse forms of artificial intelligence (AI) are at the forefront of triggering digital security innovations based on the threats that are arising in this post-COVID world. On the one hand, companies are experiencing difficulty in dealing with security challenges with regard to a variety of issues ranging from system openness, decision making, quality control, and web domain, to mention a few. On the other hand, in the last decade, research has focused on security capabilities based on tools such as platform complacency, intelligent trees, modeling methods, and outage management systems in an effort to understand the interplay between AI and those issues. the dependence on the emergence of AI in running industries and shaping the education, transports, and health sectors is now well known in the literature. AI is increasingly employed in managing data security across economic sectors. Thus, a literature review of AI and system security within the current digital society is opportune. This paper aims at identifying research trends in the field through a systematic bibliometric literature review (LRSB) of research on AI and system security. the review entails 77 articles published in the Scopus® database, presenting up-to-date knowledge on the topic. the LRSB results were synthesized across current research subthemes. Findings are presented. the originality of the paper relies on its LRSB method, together with an extant review of articles that have not been categorized so far. Implications for future research are suggested.


In utero electroporation as a tool for genetic manipulation in vivo to study psychiatric disorders: from genes to circuits and behaviors.
Many genetic risk factors for major mental disorders have key roles in brain development. Thus, exploring the roles for these genetic factors for brain development at the molecular, cellular, and neuronal circuit level is crucial for discovering how genetic disturbances affect high brain functions, which ultimately lead to disease pathologies. However, it is a tremendously difficult task, given that most mental disorders have genetic complexities in which many genetic risk factors have multiple roles in different cell types and brain regions over a time-course dependent manner. Furthermore, some genetic risk factors are likely to act epistatically in common molecular pathways. For this reason, a technique for spatial and temporal manipulation of multiple genes is necessary for understanding how genetic disturbances contribute to disease etiology. Here, the authors will review the said technique, in utero electroporation, which investigates the molecular disease pathways in rodent models for major mental disorders. This technique is also useful to examine the effect of genetic risks at the behavioral level. Furthermore, the authors will discuss the recent progress of this technology, such as inducible and cell type-specific targeting, as well as nonepisomal genetic manipulation, which provide further availability of this technique for research on major mental disorders.


Community-associated methicillin-resistant Staphylococcus aureus transmission in households of infected cases: a pooled analysis of primary data from three studies across international settings.
Diverse strain types of methicillin-resistant Staphylococcus aureus (MRSA) cause infections in community settings worldwide. To examine heterogeneity of spread within households and to identify common risk factors for household transmission across settings, primary data from studies conducted in New York (USA), Breda (The Netherlands), and Melbourne (Australia) were pooled. Following MRSA infection of the index patient, household members completed questionnaires and provided nasal swabs. Swabs positive for S. aureus were genotyped by spa sequencing. Poisson regression with robust error variance was used to estimate prevalence odds ratios for transmission of the clinical isolate to non-index household members. Great diversity of strain types existed across studies. Despite differences between studies, the index patient being colonized with the clinical isolate at the home visit (P < 0·01) and the percent of household members aged <18 years (P < 0·01) were independently associated with transmission. Targeted decolonization strategies could be used across geographical settings to limit household MRSA transmission.


The membrane-bound form of heparin-binding epidermal growth factor-like growth factor promotes survival of cultured renal epithelial cells.
To understand whether expression of membrane-anchored heparin binding epidermal growth factor (proHB-EGF) is involved in renal epithelial cell survival, rat membrane-bound HB-EGF precursor was stably transfected into a renal epithelial cell line, NRK 52E cells (NRKproHB-EGF). When exposed to 10% fetal calf serum (FCS), there were no differences in growth rates among wild-type (WT), vector-transfected (NRKvector), and NRKproHB-EGF. However, when cells were grown in the presence of 1% FCS, the growth rate of NRKproHB-EGF was 65% faster. When confluent cell monolayers were exposed to H2O2 or etoposide, WT or NRKvector exhibited significant apoptotic bodies and DNA laddering; in contrast, NRKproHB-EGF were resistant to both stimuli, as indicated by increased cell viability and marked decrease of apoptotic bodies and DNA laddering. When plated at high density onto plastic dishes without FCS, WT and NRKvector formed few attachments, did not proliferate, and underwent apoptosis. By day 3, no cells survived. Addition of exogenous recombinant HB-EGF (10(-8) M) to WT or NRKvector increased cell survival by <10% and incubation with conditioned media of NRKproHB-EGF had no effect. In contrast, NRKproHB-EGF attached and formed epithelial colonies, although they did not proliferate. After 3 days, cell viability was 84% of the initial cell number plated, and no evidence of apoptosis was present. When plated in 10% FCS, NRKproHB-EGF attachment to plastic substratum at 1, 2, and 3 h was 250% greater than that of WT or NRKvector. Addition of exogenous recombinant human HB-EGF to WT or NRKvector increased attachment by <50%. When grown on poly(2-hydroxyethyl methacrylate) or in the presence of the integrin receptor-blocking peptide GRGDTP, neither WT nor NRKvector attached to the substratum or formed cell-cell attachments. Compared with WT or NRKvector, NRKproHB-EGF exhibited 300% greater cell viability on either poly(2-hydroxyethyl methacrylate)-coated dishes or in the presence of GRGDTP and formed cell clusters. When plated at low density (1 x 10(3) cells/1.5-cm dish) or at high density in the presence of an anti-HB-EGF blocking antibody, NRKproHB-EGF failed to form epithelial colonies. Addition of formalin fixed NRKproHB-EGF promoted EGF receptor tyrosine phosphorylation in quiescent A431 cells and stimulated DNA synthesis and prevented H2O2-induced apoptosis in renal epithelial cells. These results indicate that membrane-bound HB-EGF promotes renal epithelial cell survival, possibly by promoting cell-matrix and cell-cell interactions. The failure of either conditioned media or exogenous HB-EGF to reproduce these findings suggests that juxtacrine or tightly coupled paracrine interactions underlie this cytoprotection.


[Activation of cyclophosphane when stored as a solution].
There was found an effect of nonenzymic activation of cyclophasphane when keeping its solution during 24 hours at 37 degrees C. The products, formed as a result of its hydrolysis, induce chromosome rearrangement in the L-fibroblast culture in vitro while cyclophosphane dissolved immediately before the injection into the cell culture does not show a marked cytogenetic effect.


The complete genome sequence of the Tanzanian strain of Cassava brown streak virus and comparison with the Ugandan strain sequence.
The complete genome sequence for an isolate of the Ugandan and Tanzanian strain types of Cassava brown streak virus have been determined using the novel approach of non-directed next generation sequencing. Comparison of the genome sequences revealed that CBSV is highly heterogeneous at the isolate level as well as the strain level. The isolate of the Ugandan strain was found to have a genome 9,070 nucleotides long coding for a polypeptide with 2,902 amino acid residues. The isolate of the Tanzanian strain was 9,008 nucleotides long and coded for a polypeptide with 2,916 amino acid residues. Nucleotide identity between the isolates across the genome was 76%, with protein encoding regions 57-77% and individual proteins had 65-91% amino acid similarity. In addition between the two strains four protein products (PIPO, CI, NIa-Vpg and coat protein) varied in size and an unusual HAM1-like protein, whilst of identical nucleotide length, was found to have the lowest homology. The implication of diversity of CBSV is discussed in the context of speciation, evolution, development of diagnostics, and breeding for resistance.


Inhibition of calcium imbalance protects hepatocytes from vanadium exposure-induced inflammation by mediating mitochondrial-associated endoplasmic reticulum membranes in ducks.
Vanadium (V) is an essential mineral element in animals, but excessive V can lead to many diseases, affecting the health of humans and animals. However, the molecular crosstalk between mitochondria-associated endoplasmic reticulum membranes (MAMs) and inflammation under V exposure is still at the exploratory stage. This study was conducted to determine the molecular crosstalk between MAMs and inflammation under V exposure in ducks. In this study, duck hepatocytes were treated with NaVO3 (0 μM, 100 μM, and 200 μM) and 2-aminoethyl diphenyl borate (2-APB) (IP3R inhibitor) alone or in combination for 24 h. The data showed that V exposure-induced cell vacuolization, enlarged intercellular space, and decreased density and viability. Meanwhile, hydrogen peroxide (H2O2), malonaldehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and reactive oxygen species (ROS) levels were upregulated under V treatment. In addition, excessive V could lead to a marked reduction in the MAMs structure, destruction of the membrane structure and overload of intracellular Ca2+ and mitochondrial Ca2+. Moreover, V treatment resulted in notable upregulation of the levels of MAMs-relevant factors (IP3R, Mfn2, Grp75, MCU, VDAC1) but downregulated the levels of IL-18, IL-1β, and lactate dehydrogenase (LDH) in the cell supernatant. Additionally, it also significantly elevated the levels of inflammation-relevant factors (NLRP3, ASC, caspase-1, MAVS, IL-18, IL-1β, and TXNIP). However, the inhibition of IP3R expression attenuated the V-induced variations in the above indicators. Collectively, our results revealed that the maintenance of calcium homeostasis could protect duck hepatocytes from V-induced inflammation injury via MAMs.


Growth control of lung cancer by interruption of 5-lipoxygenase-mediated growth factor signaling.
Signal transduction pathways shared by different autocrine growth factors may provide an efficient approach to accomplish clinically significant control of lung cancer growth. In this study, we demonstrate that two autocrine growth factors activate 5-lipoxygenase action of the arachidonic acid metabolic pathway in lung cancer cell lines. Both growth factors increased the production of 5(S)-hydrooxyeicosa-6E,8Z,11Z,14Z-tetraeno ic acid (5-HETE), a major early 5-lipoxygenase metabolic product. Exogenously added 5-HETE stimulated lung cancer cell growth in vitro. Inhibition of 5-lipoxygenase metabolism by selective antagonists resulted in significant growth reduction for a number of lung cancer cell lines. Primary clinical specimens and lung cancer cell lines express the message for the 5-lipoxygenase enzymes responsible for the generation of active metabolites. In vivo evaluation demonstrated that interruption of 5-lipoxygenase signaling resulted in enhanced levels of programmed cell death. These findings demonstrate that 5-lipoxygenase activation is involved with growth factor-mediated growth stimulation for lung cancer cell lines. Pharmacological intervention with lipoxygenase inhibitors may be an important new clinical strategy to regulate growth factor-dependent stages of lung carcinogenesis.


Flattop regulates basal body docking and positioning in mono- and multiciliated cells.
Planar cell polarity (PCP) regulates basal body (BB) docking and positioning during cilia formation, but the underlying mechanisms remain elusive. In this study, we investigate the uncharacterized gene Flattop (Fltp) that is transcriptionally activated during PCP acquisition in ciliated tissues. Fltp knock-out mice show BB docking and ciliogenesis defects in multiciliated lung cells. Furthermore, Fltp is necessary for kinocilium positioning in monociliated inner ear hair cells. In these cells, the core PCP molecule Dishevelled 2, the BB/spindle positioning protein Dlg3, and Fltp localize directly adjacent to the apical plasma membrane, physically interact and surround the BB at the interface of the microtubule and actin cytoskeleton. Dlg3 and Fltp knock-outs suggest that both cooperatively translate PCP cues for BB positioning in the inner ear. Taken together, the identification of novel BB/spindle positioning components as potential mediators of PCP signaling might have broader implications for other cell types, ciliary disease, and asymmetric cell division.


Ultra-processed foods and the nutritional dietary profile in Brazil.
OBJECTIVE To assess the impact of consuming ultra-processed foods on the nutritional dietary profile in Brazil. METHODS Cross-sectional study conducted with data from the module on individual food consumption from the 2008-2009 Pesquisa de Orçamentos Familiares (POF - Brazilian Family Budgets Survey). The sample, which represented the section of the Brazilian population aged 10 years or over, involved 32,898 individuals. Food consumption was evaluated by two 24-hour food records. The consumed food items were classified into three groups: natural or minimally processed, including culinary preparations with these foods used as a base; processed; and ultra-processed. RESULTS The average daily energy consumption per capita was 1,866 kcal, with 69.5% being provided by natural or minimally processed foods, 9.0% by processed foods and 21.5% by ultra-processed food. The nutritional profile of the fraction of ultra-processed food consumption showed higher energy density, higher overall fat content, higher saturated and trans fat, higher levels of free sugar and less fiber, protein, sodium and potassium, when compared to the fraction of consumption related to natural or minimally processed foods. Ultra-processed foods presented generally unfavorable characteristics when compared to processed foods. Greater inclusion of ultra-processed foods in the diet resulted in a general deterioration in the dietary nutritional profile. The indicators of the nutritional dietary profile of Brazilians who consumed less ultra-processed foods, with the exception of sodium, are the stratum of the population closer to international recommendations for a healthy diet. CONCLUSIONS The results from this study highlight the damage to health that is arising based on the observed trend in Brazil of replacing traditional meals, based on natural or minimally processed foods, with ultra-processed foods. These results also support the recommendation of avoiding the consumption of these kinds of foods.


Object discrimination with an artificial hand using electrical stimulation of peripheral tactile and proprioceptive pathways with intrafascicular electrodes.
Trans-radial amputee subjects were implanted with intrafascicular electrodes in the stumps of the median and ulnar nerves. Electrical stimulation through these electrodes was used to provide sensations of touch and finger position referred to the amputated hand. Two subjects were asked to identify different objects as to size and stiffness by manipulating them with a myo-electric hand without visual or auditory cues. Both subjects were provided with information about contact force with the objects via tactile sensations referred to their phantom hands. One subject, who was provided with information about finger position in the prosthetic hand via a different tactile sensation referred to his phantom hand, was unable to correctly identify the objects. The other subject, who received information about finger position via a proprioceptive sensation referred to his phantom hand, correctly identified the objects at a level statistically significantly above chance performance.


Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of marbofloxacin in calf serum, exudate and transudate.
Marbofloxacin is a fluoroquinolone antimicrobial drug used in cattle for the treatment of respiratory infections. In this investigation the pharmacokinetics (PK) of marbofloxacin were determined after intravenous and intramuscular dosing at a dosage of 2 mg/kg. In addition the ex vivo pharmacodynamics (PD) of the drug were determined in serum and three types of tissue cage fluid (transudate, inflammatory exudate generated by carrageenan and exudate generated by lipopolysaccharide). Marbofloxacin PK was characterized by a high volume of distribution after dosing by both routes (1.28 L/kg intravenous and 1.25 L/kg intramuscular). Corresponding area under the concentration-time curve (AUC) and elimination half-life (t(1/2)el) values were 9.99 and 10.11 microg h/mL and 4.23 and 4.33 h, respectively. Values of AUC for carrageenan-induced exudate, lipopolysaccharide-induced exudate and transudate were, respectively, 8.28, 7.83 and 7.75 microg h/mL after intravenous and 8.84, 8.53 and 8.52 microg h/mL after intramuscular dosing. Maximum concentration (Cmax) values were similar for the three tissue cage fluids after intravenous and intramuscular dosing. For in vivo PK data values of AUC: minimum inhibitory concentration (MIC) (AUIC) ratio for serum were 250 and 253, respectively, after intravenous and intramuscular dosing of marbofloxacin against a pathogenic strain of Mannheimia haemolytica (MIC=0.04 microg/mL). For all tissue cage fluids AUIC values were >194 and >213 after intravenous and intramuscular dosing, and Cmax/MIC ratios were 9 or greater, indicating a likely high level of effectiveness in clinical infections caused by M. haemolytica of MIC 0.04 microg/mL or less. This was confirmed by both in vitro (serum) and ex vivo (serum, exudate and transudate) measurements, which demonstrated a concentration-dependent killing profile for marbofloxacin against M. haemolytica. Ex vivo, after 24-h incubation, virtually all bacteria were killed (<10 cfu/mL) in all samples collected up to 9 h (serum), 24 h (carrageenan-induced exudate and transudate) and 36 h (lipopolysaccharide-induced exudate). Application of the sigmoid Emax equation to the ex vivo antibacterial data provided, for serum, AUIC24 h values of 37.1 for bacteriostasis, 46.3 for bactericidal activity and 119.6 for elimination of bacteria. These data may be used as a rational basis for setting dosing schedules which optimize clinical efficacy and minimize the opportunities for emergence of resistant organisms.


Text processing by digital voice recognition.
To evaluate digital voice recognition in free text mode. A standard medical text (182 words and punctuation marks) was dictated four times each by six people using a commercially available voice recognition system. The time used, including the time needed for making corrections, decreased from a median of 14.5 (6.3-18.8) minutes in the first session to a median of 6.7 (5.1-15.7) in the fourth session. the number of corrections necessary in the last session was a median of 20.5 (15-97)-i.e., 11% of the number of words in the text. All users described working with the system as highly strenuous. Dictating the same text with a dictaphone took median 1.4 (0.9-1.6) minutes and about five minutes of typing and correction time. Although the total time was about the same with the two methods, the time for the pathologist increased fourfold when using the voice recognition system. To obtain acceptable input speed, an appropriate template module is essential.


[The Family Health Strategy and healthcare for the elderly: experiences in three Brazilian cities].
This study focuses on healthcare for the elderly under the Family Health Strategy in three municipalities (counties) in the State of Rio de Janeiro, Brazil, specifically analyzing the organization of the healthcare network and the knowledge of six health teams, using interviews and focus groups. The study emphasized the central role of work by community health agents, the prioritization of program activities as compared to management of problems in the community covered by the strategy, a work overload in the health teams, disorganization of the healthcare networks, and lack of systemic approaches based on the basic contents of Geriatrics and Gerontology. The article concludes that there is a need for a healthcare network for the elderly consisting of hierarchically organized services and levels of care that provide support for the healthcare teams' work. The teams could also benefit from continuing education programs. The undergraduate medical curriculum should also include more course content in geriatrics and gerontology.


Fat emulsion for intravenous administration: clinical experience with intralipid 10%.
A 10% soybean oil emulsion (Intralipid 10%), used extensively in Europe for intravenous alimentation, has now been clinically evaluated in the United States. Controlled studies have shown that the soybean oil emulsion can be substituted for glucose to supply one-third to two-thirds of the total calories, and can be administered peripherally without significant vein irritation. Essential fatty acid deficiencies, frequently encountered in patients dependent on parenteral alimentation with fat-free solutions, are prevented and corrected by use of this preparation. Data on long-term tolerance to Intralipid 10% infusions are presented for 292 patients treated for more than 6,000 patient days. The soybean oil emulsion was usually well tolerated. Side effects were reported in two of 133 adults and 12 of 159 pediatric patients.


Genetic Ablation of the Cystine Transporter xCT in PDAC Cells Inhibits mTORC1, Growth, Survival, and Tumor Formation via Nutrient and Oxidative Stresses.
Although chemoresistance remains a primary challenge in the treatment of pancreatic ductal adenocarcinoma (PDAC), exploiting oxidative stress might offer novel therapeutic clues. Here we explored the potential of targeting cystine/glutamate exchanger (SLC7A11/xCT), which contributes to the maintenance of intracellular glutathione (GSH). Genomic disruption of xCT via CRISPR-Cas9 was achieved in two PDAC cell lines, MiaPaCa-2 and Capan-2, and xCT-KO clones were cultivated in the presence of N-acetylcysteine. Although several cystine/cysteine transporters have been identified, our findings demonstrate that, in vitro, xCT plays the major role in intracellular cysteine balance and GSH biosynthesis. As a consequence, both xCT-KO cell lines exhibited amino acid stress with activation of GCN2 and subsequent induction of ATF4, inhibition of mTORC1, proliferation arrest, and cell death. Tumor xenograft growth was delayed but not suppressed in xCT-KO cells, which indicated both the key role of xCT and also the presence of additional mechanisms for cysteine homeostasis in vivo. Moreover, rapid depletion of intracellular GSH in xCT-KO cells led to accumulation of lipid peroxides and cell swelling. These two hallmarks of ferroptotic cell death were prevented by vitamin E or iron chelation. Finally, in vitro pharmacologic inhibition of xCT by low concentrations of erastin phenocopied xCT-KO and potentiated the cytotoxic effects of both gemcitabine and cisplatin in PDAC cell lines. In conclusion, our findings strongly support that inhibition of xCT, by its dual induction of nutritional and oxidative cellular stresses, has great potential as an anticancer strategy. SIGNIFICANCE: The cystine/glutamate exchanger xCT is essential for amino acid and redox homeostasis and its inhibition has potential for anticancer therapy by inducing ferroptosis.


Hepatic STAT1-nuclear translocation and interleukin 28B polymorphisms predict treatment outcomes in hepatitis C virus genotype 1-infected patients.
We investigated associations between signal transducer and activator of transcription (STAT) 1 in pretreated liver tissues, interleukin (IL) 28B polymorphism and treatment response in hepatitis C virus (HCV)-infected patients treated with peginterferon and ribavirin. We performed immunostaining analysis of STAT1 in liver tissues and determined IL28B polymorphism at rs8099917. We then compared the results with treatment outcomes in HCV genotype 1 patients with high viral load who were receiving peginterferon plus ribavirin. In univariate analysis, younger age, white blood cell counts, virological responder, early virological responder (EVR), mild activity (A1) of liver inflammation grading, and lower STAT1 nuclear-stain of hepatocytes in zone 1, zone 2 and total zones of liver were associated with sustained virological responder (SVR). Multivariate analysis showed that EVR, age and hepatic STAT1 nuclear-stain in zone 2 of liver were independent predictors of SVR. It was also revealed that IL28B and STAT1-nuclear translocation in hepatocytes are independent predictors of response to treatment with peginterferon and ribavirin in chronic hepatitis C patients. Concomitant assessment of lower STAT1 nuclear-stain of hepatocytes and IL28B polymorphism is useful for prediction of SVR in HCV genotype 1 patients.


Outcomes after trimodality therapy for esophageal cancer: the impact of histology on failure patterns.
This retrospective analysis of patients undergoing neoadjuvant chemoradiation followed by surgical resection was performed to determine if histology or pathologic response affected local-regional control (LRC), survival outcomes or patterns of failure. We performed a review of 164 patients who underwent neoadjuvant chemoradiation followed by surgical resection from 1992 to 2006 for esophageal cancer. Information on patient characteristics, pathologic response, failure patterns, and survival was collected. Survival was estimated by the Kaplan-Meier method, and Cox multivariable Regression model was used to analyze trends. The median follow-up was 18 months and 27 months in surviving patients. The 3-year overall survival (OS) and LRC was 46% and 79%. The overall response for the entire cohort included a pathologic complete response (pCR) rate of 41.4%, 21.3% with microscopic residual disease (mRD) and 36.3% with gross residual disease (gRD). The 3-year OS of patients who achieved a pCR versus mRD versus gRD was 58%, 53%, and 29%. OS was significantly improved in patients with a pCR and mRD compared with gRD (P = 0.001). On multivariate analysis both pCR and mRD correlated with an improved OS. Squamous cell cancers (SCC) had a higher rate of pCR than adenocarcinomas (AC), 54% versus 34.8% (P = 0.01). The 3 year LRC for patients with SCC and AC was 100% and 71% (P = 0.03). Among SCC with recurrence, there were no local failures and all failed distantly (P = 0.001). Patients with microscopic residual disease following trimodality therapy had similar outcomes to patients achieving a pCR. Patients with SCC were more likely to achieve a pCR, and had a higher propensity to fail distantly when compared with patients with AC. This data should be considered in the design of future clinical trials.


Identification of five chronic obstructive pulmonary disease subgroups with different prognoses in the ECLIPSE cohort using cluster analysis.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease that likely includes clinically relevant subgroups. To identify subgroups of COPD in ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) subjects using cluster analysis and to assess clinically meaningful outcomes of the clusters during 3 years of longitudinal follow-up. Factor analysis was used to reduce 41 variables determined at recruitment in 2,164 patients with COPD to 13 main factors, and the variables with the highest loading were used for cluster analysis. Clusters were evaluated for their relationship with clinically meaningful outcomes during 3 years of follow-up. The relationships among clinical parameters were evaluated within clusters. Five subgroups were distinguished using cross-sectional clinical features. These groups differed regarding outcomes. Cluster A included patients with milder disease and had fewer deaths and hospitalizations. Cluster B had less systemic inflammation at baseline but had notable changes in health status and emphysema extent. Cluster C had many comorbidities, evidence of systemic inflammation, and the highest mortality. Cluster D had low FEV1, severe emphysema, and the highest exacerbation and COPD hospitalization rate. Cluster E was intermediate for most variables and may represent a mixed group that includes further clusters. The relationships among clinical variables within clusters differed from that in the entire COPD population. Cluster analysis using baseline data in ECLIPSE identified five COPD subgroups that differ in outcomes and inflammatory biomarkers and show different relationships between clinical parameters, suggesting the clusters represent clinically and biologically different subtypes of COPD.


Immune fingerprinting through repertoire similarity.
Immune repertoires provide a unique fingerprint reflecting the immune history of individuals, with potential applications in precision medicine. However, the question of how personal that information is and how it can be used to identify individuals has not been explored. Here, we show that individuals can be uniquely identified from repertoires of just a few thousands lymphocytes. We present "Immprint," a classifier using an information-theoretic measure of repertoire similarity to distinguish pairs of repertoire samples coming from the same versus different individuals. Using published T-cell receptor repertoires and statistical modeling, we tested its ability to identify individuals with great accuracy, including identical twins, by computing false positive and false negative rates < 10-6 from samples composed of 10,000 T-cells. We verified through longitudinal datasets that the method is robust to acute infections and that the immune fingerprint is stable for at least three years. These results emphasize the private and personal nature of repertoire data.


Proliferative state of blast cell progenitors in acute myeloblastic leukemia (AML).
Peripheral blood from patients with acute myeloblastic leukemia (AML) contains cells capable of giving rise to colonies in culture when stimulated by media conditioned by leukocytes (LCM) in the presence of phytohemagglutinin (PHA). Two types of colonies are recognized with high frequency: The first grows in the presence of low concentrations of PHA LCM, have a blast-like morphology, and are numerically correlated with morphologically identified blast cells. The second requires either high PHA LCM concentrations or PHA alone with or without 2-mercaptoethanol and consists of cells capable of forming rossettes with sheep erythrocytes and resembles. T-lymphocyte colonies from normal blood. Precursors of blast cell colonies from 15 leukemic patients were tested for cycle state, using either the 3H-thymidine or hydroxyurea techniques. All were found to have a high proportion of cells in the S phase of the cycle. In contrast, T lymphocyte precursors from three normal individual were quiescent. The data are consistent with the maintenance of the leukemic blast cell populations by the proliferative activity of a small subpopulation of blasts.


A rate-constrained fast full-search algorithm based on block sum pyramid.
This paper presents a fast full-search algorithm (FSA) for rate-constrained motion estimation. The proposed algorithm, which is based on the block sum pyramid frame structure, successively eliminates unnecessary search positions according to rate-constrained criterion. This algorithm provides the identical estimation performance to a conventional FSA having rate constraint, while achieving considerable reduction in computation.


Occupational gaps reported by proxies for persons with dementia residing in a nursing home.
In accordance with Swedish national dementia guidelines, persons with dementia residing in nursing homes should have the possibility to participate in everyday occupations. Securing choices and desires for participating in occupations is challenging due to the nature of dementia and is not evident in empirical studies regarding nursing home residents. to describe gaps in participation in everyday occupations among persons with dementia living in a nursing home, as reported by a proxy respondent. To record the congruence or discrepancy between doing and wanting to do, the Occupational Gaps Questionnaire was used. Results were analysed with descriptive statistics. The respondents scored that over half of the persons with dementia had two or more occupational gaps and one-fourth wanted to participate in minor shopping. However, less than two percent were deemed to do this activity. Persons with dementia living in nursing homes risk restrictions in participation. Securing valuable information regarding individuals' choices and desires, adhering to the persons' inherent rights to expression, can be the first step in promoting participation in everyday occupations. Occupational therapists with their unique theoretical knowledge can facilitate participation in occupations, supporting the citizenship of nursing home residents.


An exploration of how women in the UK perceive the provision of care received in an early pregnancy assessment unit: an interpretive phenomenological analysis.
The objective of the study was to explore how women experience care within an early pregnancy assessment unit (EPAU) and how they are helped to understand, reconcile and make sense of their loss and make informed decisions about how their care will be managed following a first trimester miscarriage. This was a single centre, prospective qualitative study. An interpretive phenomenological analysis approach was used to interpret the participants' meanings of their experiences. It is an ideographic approach that focuses in depth on a small set of cases to explore how individuals make sense of a similar experience. An EPAU in a large teaching hospital in the Midlands that provides care to women in their early pregnancy, including those experiencing pregnancy loss. A purposive sample of 10 women were recruited to this study. All of the women were either miscarrying at the time of this study or had miscarried within the previous few weeks. Six superordinate themes in relation to women's experiences of miscarriage were identified: (1) the waiting game, (2) searching for information, (3) management of miscarriage: no real choice, (4) the EPAU environment, (5) communication: some room for improvement and (6) moving on. This study found that improvements are required to ensure women and their partners receive a streamlined, informative, supportive and continuous package of care from the point they first see their general practitioner or midwife for support to being discharged from the EPAU. The provision of individualised care, respect for women's opinions and appropriate clinical information is imperative to those experiencing miscarriage to help them gain a degree of agency within an unfamiliar situation and one in which they feel is out of their control.


[The lipogenic role of leucine in animal skeletal muscles].
After incubation of rat, pig and cattle skeletal muscle homogenates with [U-14C]leucine, 80.4%, 37.0% and 57.0% of radioactivity was found in the proteins, 9.4%, 58.7% and 40.9% in the lipids, and 10.2%, 4.3% and 2.1% in 14CO2. This suggests that along-side with utilization in protein synthesis, leucine plays an essential role in lipid synthesis in muscle tissues of agricultural animals. The contribution of [U-14C]leucine to lipogenesis with substrates is greater than that of [U-14C]acetate and [U-14C]glucose in cattle skeletal muscles in vitro and greater than that of [U-14C]acetate in pig muscle. The CO2 production during oxidation of the [U-14C]leucine carbohydrate chain is higher than that during [U-14C]glucose and [U-14C]palmitate oxidation in skeletal muscles of rat and pig. In skeletal muscles of all animal species under study [U-14C]acetate is oxidized far more intensively than the other substrates tested.


The study of degradation mechanisms of glyco-engineered plant produced anti-rabies monoclonal antibodies E559 and 62-71-3.
Rabies is an ancient and neglected zoonotic disease caused by the rabies virus, a neurotropic RNA virus that belongs to the Rhabdoviridae family, genus Lyssavirus. It remains an important public health problem as there are cost and health concerns imposed by the current human post exposure prophylaxis therapy. The use of monoclonal antibodies (mAbs) is therefore an attractive alternative. Rabies mostly affects people that reside in resource-limited areas where there are occasional failures in the cold-chain. These environmental changes may upset the stability of the mAbs. This study focused on mAbs 62-71-3 and E559; their structures, responses to freeze/thaw (F/T) and exposure to reactive oxygen species were therefore studied with the aid of a wide range of biophysical and in silico techniques in order to elucidate their stability and identify aggregation prone regions. E559 was found to be less stable than 62-71-3. The complementarity determining regions (CDR) contributed the most to its instability, more specifically: peptides 99EIWD102 and 92ATSPYT97 found in CDR3, Trp33 found in CDR1 and the oxidised Met34. The constant region "158SWNSGALTGHTFPAVL175" was also flagged by the special aggregation propensity (SAP) tool and F/T experiments to be highly prone to aggregation. The E559 peptides "4LQESGSVL11 from the heavy chain and 4LTQSPSSL11 from the light chain, were also highly affected by F/T. These residues may serve as good candidates for mutation, in the aim to bring forward more stable therapeutic antibodies, thus paving a way to a more safe and efficacious antibody-based cocktail treatment against rabies.


Differential effects of dimethylsulfoxide on the activities of human DNA polymerases alpha and delta.
The effects of dimethylsulfoxide on the activities of purified human placental DNA polymerase alpha and DNA polymerase delta were examined. DNA polymerase alpha was inhibited by dimethylsulfoxide, whereas DNA polymerase delta was significantly activated, by as much as 6-fold. Kinetic data show that the effect of dimethylsulfoxide on DNA polymerase delta activity was due to a reduction in the apparent Km for its substrate, dTTP. This novel finding of the differential effects of dimethylsulfoxide on the activities of polymerases alpha and delta may be useful in their identification and differential assay.


Formation of nickel sulfide nanoframes from metal-organic frameworks with enhanced pseudocapacitive and electrocatalytic properties.
Nanoframe-like hollow structures with unique three-dimensional (3D) open architecture hold great promise for various applications. Current research efforts mainly focus on frame-like noble metals and metal oxides. However, metal sulfides with frame-like nanostructures have been rarely reported. Starting from metal-organic frameworks (MOFs), we demonstrate a novel structure-induced anisotropic chemical etching/anion exchange method to transform Ni-Co Prussian blue analogue (PBA) nanocubes into NiS nanoframes with tunable size. The reaction between Ni-Co PBA nanocube templates and Na2 S in solution leads to the formation of well-defined NiS nanoframes. The different reactivity between the edges and the plane surface of the Ni-Co PBA nanocubes is found to be the key factor for the formation of NiS nanoframes. Benefitting from their structural merits including 3D open structure, small size of primary nanoparticles, high specific surface area, and good structural robustness, the as-derived NiS nanoframes manifest excellent electrochemical performance for electrochemical capacitors and hydrogen evolution reaction in alkaline electrolyte.


SlideSort: all pairs similarity search for short reads.
Recent progress in DNA sequencing technologies calls for fast and accurate algorithms that can evaluate sequence similarity for a huge amount of short reads. Searching similar pairs from a string pool is a fundamental process of de novo genome assembly, genome-wide alignment and other important analyses. In this study, we designed and implemented an exact algorithm SlideSort that finds all similar pairs from a string pool in terms of edit distance. Using an efficient pattern growth algorithm, SlideSort discovers chains of common k-mers to narrow down the search. Compared to existing methods based on single k-mers, our method is more effective in reducing the number of edit distance calculations. In comparison to backtracking methods such as BWA, our method is much faster in finding remote matches, scaling easily to tens of millions of sequences. Our software has an additional function of single link clustering, which is useful in summarizing short reads for further processing. Executable binary files and C++ libraries are available at http://www.cbrc.jp/~shimizu/slidesort/ for Linux and Windows.