A Next-Generation Single-Port Robotic Surgical System for Transoral Robotic Surgery: Results From Prospective Nonrandomized Clinical Trials.
Transoral endoscopic head and neck surgery now plays an important role in the multidisciplinary management of oropharyngeal carcinoma. Previous generations of robotic surgical systems used a multiport system with a rigid stereo-endoscope and 2 wristed instruments that facilitated transoral robotic surgery. To evaluate a new single-port robotic surgical system in head and neck surgery prospectively through concurrent nonrandomized clinical trials. Two prospective clinical trials were conducted from December 16, 2016, to December 26, 2017, to assess the safety, feasibility, and performance of a flexible single-port robotic surgical system in 4 institutions, including 3 in the United States and 1 in Hong Kong. A total of 47 patients with tumors of the oropharynx were enrolled and underwent surgery. All patients were classified as having American Society of Anesthesiologists class I to III status and Eastern Cooperative Oncology Group status 0 to 1. An initial cohort of 7 patients underwent staging and endoscopic procedures for benign disease. The remaining 40 patients all had malignant tumors of the oropharynx. Safety was measured by the incidence of device-related serious adverse events. Feasibility and performance were measured by the conversion rate from the use of the single-port robotic surgical system to either open surgery or the use of any other transoral technology required to complete the planned procedure. Secondary end points of swallowing function and surgical margins were also measured. All 47 patients (8 women and 39 men; mean [SD] age, 61 [8] years) safely underwent transoral resection with the single-port robotic surgical system without conversion to open surgery, laser surgery, or multiport robotic surgery. There were no intraoperative complications or device-related serious adverse events. Mean (SD) estimated intraoperative blood loss per procedure was 15.4 (23.9) mL; no patients received a transfusion. Two patients underwent a planned tracheotomy owing to medical comorbidity (previous chemoradiotherapy; obesity and severe sleep apnea). Two patients (4%) had grade III or IV postoperative hemorrhage, requiring a return to the operating room; however, both patients had medical comorbidities requiring the use of antithrombotic medication. The incidence of positive margins for patients with oropharyngeal malignancy was 3% (1 of 40). Within 30 days, 45 patients (96%) were eating by mouth and without the need for a percutaneous endoscopic gastrostomy tube. This study describes the results of phase 2 clinical testing of a next-generation, robotic surgical system using a single-port architecture. The use of the device appears to be feasible, safe, and effective for transoral robotic surgery of oropharyngeal tumors. ClinicalTrials.gov identifiers: NCT03010813 and NCT03049280.


Calcitriol Analogues Decrease Lung Metastasis but Impair Bone Metabolism in Aged Ovariectomized Mice Bearing 4T1 Mammary Gland Tumours.
Calcitriol and its analogues are considered drugs supporting the anticancer treatment of breast cancer and preventing the osteoporosis that results from the development of cancer or from chemotherapy or hormone therapy. Following the orthotopic implantation of 4T1 mammary carcinoma cells into aged ovariectomized (OVX) mice, we evaluated the effects of calcitriol and its two analogues, PRI-2191 and PRI-2205, on metastatic spread and bone homeostasis. Calcitriol and its analogues temporarily inhibited the formation of metastases in the lungs. Unexpectedly, only mice treated with calcitriol analogues showed a deterioration of bone-related parameters, such as bone column density, marrow column density and the CaPO4 coefficient. These findings correlated with an increased number of active osteoclasts differentiated from bone marrow-derived macrophages in mice treated with the analogues. Interestingly, in the tumours from mice treated with PRI-2191 and PRI-2205, the expression of Tnfsf11 (RANKL) was increased. On the other hand, osteopontin (OPN) levels in plasma and tumour tissue, as well as TRAC5b levels in tumours, were diminished by calcitriol and its analogues. Despite a similar action of both analogues towards bone metabolism, their impact on vitamin D metabolism differed. In particular, PRI-2191 and calcitriol, not PRI-2205 treatment significantly diminished the levels of both 25(OH)D3 and 24,25(OH)2D3. In conclusion, though there is evident antimetastatic activity in old OVX mice, signs of increased bone metabolism and deterioration of bone mineralization during therapy with calcitriol analogues were observed.


Persistence of asthmatic response after ammonium persulfate-induced occupational asthma in mice.
Since persulfate salts are an important cause of occupational asthma (OA), we aimed to study the persistence of respiratory symptoms after a single exposure to ammonium persulfate (AP) in AP-sensitized mice. BALB/c mice received dermal applications of AP or dimethylsulfoxide (DMSO) on days 1 and 8. On day 15, they received a single nasal instillation of AP or saline. Airway hyperresponsiveness (AHR) was assessed using methacholine provocation, while pulmonary inflammation was evaluated in bronchoalveolar lavage (BAL), and total serum immunoglobulin E (IgE), IgG1 and IgG2a were measured in blood at 1, 4, 8, 24 hours and 4, 8, 15 days after the single exposure to the causal agent. Histological studies of lungs were assessed. AP-treated mice showed a sustained increase in AHR, lasting up to 4 days after the challenge. There was a significant increase in the percentage of neutrophils 8 hours after the challenge, which persisted for 24 hours in AP-treated mice. The extent of airway inflammation was also seen in the histological analysis of the lungs from challenged mice. Slight increases in total serum IgE 4 days after the challenge were found, while IgG gradually increased further 4 to 15 days after the AP challenge in AP-sensitized mice. In AP-sensitized mice, an Ig-independent response is induced after AP challenge. AHR appears immediately, but airway neutrophil inflammation appears later. This response decreases in time; at early stages only respiratory and inflammatory responses decrease, but later on immunological response decreases as well.


Effect of food and tablet-dissolution characteristics on the bioavailability of linagliptin fixed-dose combination with metformin: evidence from two randomized trials.
The objectives of the studies reported here were to determine the relative bioavailability of linagliptin and metformin when administered in a fixed-dose combination (FDC) tablet with and without food, and to investigate the relative bioavailability of linagliptin and metformin FDC tablets from two treatment batches with different dissolution behavior. These studies were open-label, single-dose, randomized, two-way crossover trials. After an overnight fast, healthy volunteers received an FDC tablet once (with/without food in the food-effect study; or from one of two batches with differing dissolution behavior in the tablet-dissolution study). On a separate visit, following a washout period of 35 days, participants received the alternative treatment. In the food-effect study the primary endpoints were maximum measured concentration in plasma (C(max)) for linagliptin and metformin, area under the plasma concentration-time curve from 0 to 72 hours (AUC(0-72)) for linagliptin and from 0 to infinity (AUC(0-inf)) for metformin. In the tablet-dissolution study the primary endpoints were Cmax for both analytes, AUC(0-72) for linagliptin, and from 0 to the time of the last quantifiable data point (AUC(0-t)) for metformin. The administration of the FDC tablet with food had no influence on the relative bioavailability of linagliptin and metformin with regard to the extent of exposure as determined by AUC(0-72) (linagliptin) and AUC(0-inf) (metformin) compared with FDC tablet administration while fasting. After food intake, peak plasma concentrations of linagliptin were slightly lowered (from 4.99 to 4.56 nmol L⁻¹), but the 90% confidence interval (CI) of the geometric mean test/reference ratio was still located within the generally applied bioequivalence acceptance limits of 80 - 125%. The median time from dosing to the maximum concentration of linagliptin in plasma (t(max)) was similar under both conditions. Administration with food reduced the rate of absorption of metformin indicated by a prolongation in median tmax (from 2 to 4 hours) and a decrease in Cmax by ~ 18%. There were no notable differences between the two treatment groups with respect to safety and tolerability. In the tablet-dissolution study, bioequivalence was demonstrated between linagliptin/metformin FDC tablets with normal and slower dissolution characteristics. For both linagliptin and metformin, the 90% CI of all pharmacokinetic (PK) parameters were well within the bioequivalence acceptance limits of 80 - 125%. Tablets from both batches were well tolerated with no unexpected adverse events. Food did not have a relevant impact on the bioavailability of linagliptin from the FDC tablet. The effect of food on the metformin component was comparable to that previously demonstrated. Furthermore, differences in tablet-dissolution characteristics did not have an impact on the bioavailability of linagliptin or metformin from the FDC tablet.


Context memory in Alzheimer's disease.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by a gradual loss of memory. Specifically, context aspects of memory are impaired in AD. Our review sheds light on the neurocognitive mechanisms of this memory component that forms the core of episodic memory function. Context recall, an element of episodic memory, refers to remembering the context in which an event has occurred, such as from whom or to whom information has been transmitted. Our review raises crucial questions. For example, (1) which context element is more prone to being forgotten in the disease? (2) How do AD patients fail to bind context features together? (3) May distinctiveness heuristic or decisions based on metacognitive expectations improve context retrieval in these patients? (4) How does cueing at retrieval enhance reinstating of encoding context in AD? By addressing these questions, our work contributes to the understanding of the memory deficits in AD.


Levodopa/dopamine replacement strategies in Parkinson's disease--future directions.
After 40 years, levodopa remains the most effective therapy for the treatment of PD. However, long-term therapy is complicated by motor fluctuations and dyskinesia that can represent a source of significant disability for some patients. Other medical therapies that are currently available for the treatment of PD primarily represent an attempt to prevent or treat motor complications. Surgical therapies improve motor complications in appropriate candidates, but do not provide antiparkinsonian benefits that are superior to levodopa, and are themselves associated with potentially serious side effects. Increasing information suggests that levodopa-induced motor complications relate to pulsatile, nonphysiologic dopamine replacement. A therapeutic strategy that could deliver levodopa/dopamine to the brain in a more continuous and physiologic manner might be expected to provide all of the benefits of standard levodopa with reduced motor complications. Such a levodopa formulation might replace all current dopaminergic antiparkinsonian medications and avoid the need for surgery in most PD patients. However, problems of continuous dopaminergic stimulation must be addressed and avoided, and the issue of nondopaminergic features remains to be addressed.


Nonverbal Communication and Psychopathology in Kidney Transplant Recipients.
Transplant recipients have difficulty expressing, identifying, and describing their emotional experiences. The Machover human figure test allows us to bring out the deepest contents of a patient's personality, which are normally hidden and not explained to structured quantitative tests. The study analyzed possible situations of distress and possible symptoms of psychopathology in kidney transplant recipients, emerged from the projective test of the human figure and not easily verbalized to the common standardized tests. The sample included 80 kidney transplant patients (51 men and 29 women; mean age, 47.74 [SD, 12.39] years) during follow-up visits at 12 months after transplant. The Machover test was used to evaluate body image, affective aspects, and personality variables by projective method; the Symptom Checklist-90-R was used for the evaluation of possible psychopathology, and the 36-Item Short Form Health Survey was used for the assessment of perceived quality of life. RESULTS: showed that the more anxiety there is in the human figure test, the less somatization dimensions (ANX/SOM R = -331, P < .05), depression (ANX/DEP R = -326, P < .05), and the global index of psychic symptomatology (ANX/GSI R = -367, P < .05) of the Symptom Checklist-90-R are present. This research has confirmed the hypothesis that the spontaneous graphic production of the recipients, through the projective methods, allows them to identify and deepen their psychological contents and to activate and maintain a good psychophysical balance post transplant.


IL-17-producing T cells can augment autoantibody-induced arthritis.
Rheumatoid arthritis is a T lymphocyte-mediated disorder, but the precise nature of T cell involvement remains unclear. In the K/BxN mouse model of inflammatory arthritis, T cells initiate disease by providing help to B cells to produce arthritogenic autoantibodies. Here, we have characterized an additional, nonhumoral role for T cells in promoting autoantibody-induced arthritis. Autoreactive KRN T cells introduced either by direct transfer or bone marrow transplantation into B-cell-deficient hosts enhanced K/BxN serum-transferred arthritis, an effect that was dependent on expression of the cognate MHC-molecule/peptide complex. The T cell influence was dependent on interleukin (IL)-17; in contrast, standard serum-transferred arthritis, unenhanced by the addition of T cells, was unaffected by IL-17 neutralization. An IL-17-producing population of transferred KRN T cells was identified and found to be supported by the cotransfer of arthritogenic autoantibodies. IL-17-producing KRN T cells were enriched in inflamed joints of K/BxN mice, suggesting either selective recruitment or preferential differentiation. These results demonstrate the potential for autoreactive T cells to play two roles in the development of arthritis, both driving the production of pathogenic autoantibodies and bolstering the subsequent inflammatory cascade dependent on the innate immune system.


Obstructive lung diseases and allergic bronchopulmonary aspergillosis.
Allergic bronchopulmonary aspergillosis (ABPA) is a disease frequently complicating asthma and cystic fibrosis. ABPA is increasingly recognized in other obstructive lung diseases (OLDs), including chronic obstructive pulmonary disease (COPD) and noncystic fibrosis bronchiectasis. Herein, we summarize the recent developments in ABPA complicating OLDs. Recent research has described the clinical features and natural history of ABPA complicating asthma in children and the elderly. We have gained insights into the pathophysiology of ABPA, especially the role of eosinophil extracellular trap cell death and mucus plugs. The utility of recombinant fungal antigens in the diagnosis of ABPA has been established. Newer, more sensitive criteria for the diagnosis of ABPA have been proposed. Although ABPA is uncommon in COPD and noncystic fibrosis bronchiectasis, aspergillus sensitization is more common and is associated with a higher exacerbation rate. Several advances have occurred in the diagnosis and treatment of ABPA in recent years. However, there is an unmet need for research into the genetic predisposition, pathophysiology, and treatment of ABPA. Apart from asthma and cystic fibrosis, patients with other OLDs also require evaluation for Aspergillus sensitization and ABPA.


Long term risks of stroke, myocardial infarction, and vascular death in "low risk" patients with a non-recent transient ischaemic attack.
Previous studies of prognosis after a transient ischaemic attack (TIA) have recruited patients soon after the event, when the risk of stroke is very high. However, the majority of patients survive for many years after a TIA, and the need for continued preventive treatment to lower vascular risk will need to be reassessed at a later date. To determine the long term risks of stroke and other vascular events in patients with TIA who survive the initial high risk period. 290 patients were studied who had initially been followed up after a TIA in the Oxford community stroke project and in a contemporaneous hospital based cohort study, and who were alive and stroke-free at the end of planned follow up in 1988. All patients were followed for a further 10 years, and the risks of major vascular events (stroke, myocardial infarction, vascular death) were determined. Standardised mortality ratios (SMR) were calculated from the observed numbers of fatal events and the number expected on the basis of age and sex in the general population. Median time since last TIA was 3.8 years (interquartile range, 2.2 to 5.8 years). The risk of major vascular events was constant through time. The 10 year risk of first stroke was 18.8% (95% confidence interval (CI), 13.6 to 23.7; 45 events). The 10 year risk of myocardial infarction or death from coronary heart disease was 27.8% (95% CI, 21.8 to 33.3; 67 events) and there was a significant excess of fatal coronary events compared with that expected in the general population (SMR = 1.47; 95% CI, 1.10 to 1.93; p = 0.009). A total of 114 patients had at least one major vascular event, with a 10 year risk of any first stroke, myocardial infarction, or vascular death of 42.8% (95% CI, 36.4 to 48.5). The overall risk of major vascular events remains high for 10 to 15 years after a TIA. It is important therefore that preventive treatments are continued in the long term, even in apparently "low risk" patients who have already survived free of stroke for several years.


Effects of the fruit essential oil of Cuminum cyminum Linn. (Apiaceae) on acquisition and expression of morphine tolerance and dependence in mice.
The problem of morphine tolerance and dependence is a universal phenomenon threatening social health everywhere the world. The major objective of this paper was to investigate the effects of fruit essential oil (FEO) of Cuminum cyminum on acquisition and expression of morphine tolerance and dependence in mice. Animals were rendered dependent on morphine using the well-established method in which was morphine (50, 50, 75 mg/kg; s.c.) injected three times daily for 3 days. In experimental groups, administration of FEO (0.001, 0.01, 0.1, 0.5, 1 and 2%; 5 ml/kg; i.p.) or Tween-80 (5 ml/kg; i.p.) was performed 60 min prior to each morphine injection (for acquisition) or the last injection of morphine on test day (for expression). Morphine tolerance was measured by tail-flick before and after administration of a single dose of morphine (50 mg/kg; s.c.) in test day (4th day). Morphine dependence was also evaluated by counting the number of jumps after injection of naloxone (5 mg/kg; i.p.) on the test day. The results showed that Cumin FEO, only at the dose of 2%, significantly attenuated the development of morphine tolerance (P<0.01) and dependence (P<0.05) while it could be significantly effective on expression of morphine tolerance (1 and 2%) and dependence (0.5, 1 and 2%) in a dose-dependent manner. Solely Cumin FEO injection (0.001-2%) did not show any analgesic effect. In conclusion, the essential oil of Cuminum cyminum seems to ameliorate the morphine tolerance and dependence in mice.


Effects of nucleoside analogues on liver regeneration 70% partially hepatectomized rats.
The alternatives for prophlaxis and treatment of recurrent hepatitis B virus infection have increased since new oral nucleoside analogues have become available. We conducted this experimental study to investigate the effect in the liver of these agents on the expression of transforming growth factor alpha (TGF-alpha) and on proliferation index, estimated by Ki-67. Thirty male Wistar albino rats were randomized into three groups: group A (n = 10) received adefovir dipivoxil (40 mg/kg/d per gavage); group B (n = 10), lamivudine (L; 30 mg/kg/d per gavage); and group C (n = 10) did not receive any treatment and were the control group. Groups A and B were treated for 3 days. Animal treatment began on day -1. After performing 70% partial hepatectomy on day 0, all rats were sacrificed on postoperative day 2 to harvest liver tissues for histopathological examination. We stained and indexed Ki-67 and TGF-alpha immunohistochemically on the hepatectomy surface and in the parenchyma, Ki-67 and TGF-alpha indices were significantly higher in group A compared with group B (P = .001 and P = .004, respectively, and P = .003 and P = .001, respectively). When the L group was compared with the control group for results on the hepatectomy surface and the parenchyma, Ki-67 and TGF-alpha indexes were insignificantly different (P = .6 and P = .3, respectively, and P = .1 and P = .6, respectively). Based on the results of this experimental study, we concluded that Adefovir dipivoxil has greater proliferative effect on liver parenchyma and in the cut surface than does lamivudine.


WEB 2.0 AS A NEW SUPPORT FOR BREASTFEEDING: PERCEPTION OF MOTHERS AND PROFESSIONALS THROUGH A QUALITATIVE APPROACH.
The objective of this paper is to explore the influence of Web 2.0 as a complementary support network to traditional networks for the promotion of breastfeeding (BF). Qualitative and exploratory study carried out from September 8 to December 31, 2022, at the Las Vegas Health Centre (Corvera), Health Service of the Principality of Asturias (SESPA). The participants were 5 professional experts in BF and 7 breastfeeding mothers, who made up two focus groups, selected by convenience sampling. The analysis consisted of transcription of data, in-depth reading, analysis by grouping concepts and classification of the information into categories. After the final analysis, seven categories were identified, organised according to the proximity of the topic and the proposed objective, based on the most significant discourses of the study: Difficulties during BF, Importance of receiving help: First support networks, Other support networks, A health system with deficiencies, Pandemic and BF 2.0, Health 2.0 and apps in BF: new form of support and Characteristics of an "ideal" app on BF. Web 2.0 has revolutionised the way mothers access information and support on BF, creating an online support network connecting mothers and professionals around the world, providing up-to-date information and enabling a source of emotional support through the creation of peer groups. This positive influence of Web 2.0 has had a significant impact on promoting BF and empowering mothers to make informed decisions about their breastfeeding process.


First Clinical Trial of a Newly Developed, Low Menaquinone-7, Fermented Soybean Natto in Warfarin-Dependent Patients.
Bacillus subtilis fermented soybeans (natto) contain high vitamin K2 levels, mostly as menaquinone-7 (MK-7), and must be avoided by warfarin-dependent patients. This is the first report which demonstrates the characteristics and clinical relevance of a low MK-7 natto for such patients. We generated a novel, mutant B. subtilis strain TTCC2051 with short-term fermentation and reduced MK-7 production, yielding 19-24% of the normal MK-7 content. After functional assessments and a preclinical trial, 10 warfarin-dependent patients underwent a clinical trial with a 7-day ingestion test of the low MK-7 natto. Functional assessments were satisfactory, and the preclinical trial showed no increases in plasma MK-7 levels after 7 days of ingestion. In the clinical trial, 20 g/day of the low MK-7 natto significantly increased plasma MK-7 levels while 10 g/day did not. However, neither dose of low MK-7 natto changed international normalized ratio of prothrombin time (PT-INR) values in either group. The low MK-7 natto neither changed PT-INR values nor precipitated adverse events if ingested with a once-daily maximum of 20 g (46 μg of MK-7). Thus, this novel food product has potential for consumption by warfarin-dependent patients.


Information and perception of meaningful patterns.
The visual system needs to extract the most important elements of the external world from a large flux of information in a short time for survival purposes. It is widely believed that in performing this task, it operates a strong data reduction at an early stage, by creating a compact summary of relevant information that can be handled by further levels of processing. In this work we formulate a model of early vision based on a pattern-filtering architecture, partly inspired by high-speed digital data reduction in experimental high-energy physics (HEP). This allows a much stronger data reduction than models based just on redundancy reduction. We show that optimizing this model for best information preservation under tight constraints on computational resources yields surprisingly specific a-priori predictions for the shape of biologically plausible features, and for experimental observations on fast extraction of salient visual features by human observers. Interestingly, applying the same optimized model to HEP data acquisition systems based on pattern-filtering architectures leads to specific a-priori predictions for the relevant data patterns that these devices extract from their inputs. These results suggest that the limitedness of computing resources can play an important role in shaping the nature of perception, by determining what is perceived as "meaningful features" in the input data.


Optimum Cell Pathlength or Volume for Absorbance Detection in Liquid Chromatography: Transforming Longer Cell Results to Virtual Shorter Cells.
The cell volume permissible for a specified degree of loss of efficiency can be computed from response volume considerations. For an open tubular column, the permissible illuminated length can be computed for the unretained peak. Similar estimations can be made for the maximum permissible cell volume with a packed column for a given column efficiency and flow rate. The packed column case does require an assumption on the degree to which the cell behaves as a mixer. An altogether different question is if the data from a long cell, with its considerable advantage in S/N, can be used and the associated dispersion mathematically removed. Experimental data for a variable path length (0-60 mm) HPLC detection cell indicate that an exponential model fits the observed dispersion. Once fit parameters are determined, the same can be applied to a peak, not part of the original training set, obtained in a longer path cell and the effects of dispersion mathematically reversed without major loss of S/N. Results with shorter path cell dispersion characteristics are then obtained with much higher S/N. A comparison is made with Fourier transform-inverse Fourier transform based deconvolution that can be used to achieve the same ends.


Application of QbD principles for the evaluation of empty hard capsules as an input parameter in formulation development and manufacturing.
Understanding the product and process variable on the final product performance is an essential part of the quality-by-design (QbD) principles in pharmaceutical development. The hard capsule is an established pharmaceutical dosage form used worldwide in development and manufacturing. The empty hard capsules are supplied as an excipient that is filled by pharmaceutical manufacturers with a variety of different formulations and products. To understand the potential variations of the empty hard capsules as an input parameter and its potential impact on the finished product quality, a study was performed investigating the critical quality parameters within and in between different batches of empty hard gelatin capsules. The variability of the hard capsules showed high consistency within the specification of the critical quality parameters. This also accounts for the disintegration times, when automatic endpoint detection was used. Based on these data, hard capsules can be considered as a suitable excipient for product development using QbD principles.


Decreased hatchability of turkeys eggs caused by experimental infection with Mycoplasma meleagridis.
Turkey eggs experimentally infected with Mycoplasma meleagridis (MM) showed a significant (p less than 0.05) decrease in production of first-quality poults of approximately 20% when compared with uninoculated controls and a placebo group of eggs. Embryo mortality was highest between the time the eggs were transferred from incubator to hatcher (25 days of incubation) and the time the embryos hatched. Risk of embryo mortality associated with infection in this late incubation period for the MM-infected embryo was more than double the risk for uninfected embryos. The number of dead-in-shell and pipped embryos was almost 10% higher than the number found in either control or placebo groups. There appeared to be a stress due to the inoculation of both the placebo and the organism, increasing embryo mortality between 9 and 24 days of incubation. However, this effect was not evident after transfer. Total economic loss associated with decreased hatchability caused by MM and the cost of a control program were estimated to be $9.4 million per year in the United States.


Sepsis and septic shock.
Sepsis and septic shock remain all too frequent syndromes in modern medicine with unacceptably high mortality rates. Physicians must be aware of the many ways in which sepsis and septic shock may present and the multiple differential diagnoses. Early recognition and prompt institution of empiric therapy are of utmost importance. Our current limited understanding of the pathophysiology of sepsis and septic shock significantly limits our ability to treat this syndrome effectively and thus substantively alter mortality. New developments in immunology and metabolism seem promising in furthering our understanding and improving our therapy of this complex multisystem disorder.


Mobile-bearing prosthesis did not improve mid-term clinical results of total knee arthroplasty.
A prospective study was performed to compare the clinical and radiological results of mobile- and fixed-bearing total knee arthroplasty with specific attention to rotational alignment and range of motion. Sixty-one knees were assigned to total knee arthroplasty with either the NexGen LPS Flex fixed-bearing or with the NexGen LPS Flex mobile-bearing prosthesis. Postoperatively, knees were compared with regard to range of motion, clinical score, and radiographic findings. Rotational alignment of the femoral and tibial components was evaluated by computed tomography. The median follow-up period was 5.9 years (range 2.1-8.8 years). Median postoperative Knee Society scores were 99 points (68-100) for the fixed-bearing group and 100 points (66-100) for the mobile-bearing group (n.s.). The median postoperative flexion angles of 120° (90°-150°) for the fixed-bearing group and 125° (90°-145°) for the mobile-bearing group were not significantly different from each other (n.s.). No knee required revision surgery due to wear of polyethylene or loosening of the component in either group. Computed tomography showed that 11 knees had rotational mismatches of more than 10° between the femoral and tibial components, but no significant difference was found in the postoperative extension and flexion angles or in the clinical score between the two treatment groups. Using the identical design for both fixed- and mobile-bearing prostheses, this prospective, randomized study did not show any clinical advantages of the mobile-bearing knee. Analysis of rotational alignment by CT scan did not reveal a particular advantage of the self-aligning mechanism of mobile-bearing implants.


[Spiral comb filter].
The paper is concerned with some considerations on ridge filters used for proton beam therapy. Such filters are able to transform the beam energy spectrum and the corresponding Bragg curve defining proton beam depth dose distribution. Some difficulties in the manufacture of ridge filters are discussed. The authors describe a ridge filter design which is simple and fit for continuous production. An account of a calculation method and production process is given.


Improving stroke risk stratification in atrial fibrillation.
Risk factors for stroke and thromboembolism in patients with atrial fibrillation used in current risk stratification schema are derived largely from analyses of clinical trial cohorts, and the available data depend on the comprehensiveness of trial reports and whether specific risk factors were sought. The most commonly used schema is the Cardiac failure, Hypertension, Age, Diabetes, Stroke [Doubled] (CHADS(2)) score. Although simple and well validated, some limitations of CHADS(2) this schema are apparent. A more recent approach to risk stratification of patients with nonvalvular atrial fibrillation defines "major (definitive)" risk factors (eg, previous stroke/transient ischemic attack and age> or =75 years) and "clinically relevant non-major" risk factors (eg, heart failure, hypertension, diabetes, female gender, age 65-75 years, and atherosclerotic vascular disease). This scheme can be expressed as an acronym, CHA(2)DS(2)-VASc, denoting Cardiac failure or dysfunction, Hypertension, Age> or =75 [Doubled], Diabetes, Stroke [Doubled]-Vascular disease, Age 65-74, and Sex category [Female]), whereby 2 points are assigned for a history of stroke or age 75 years or more and 1 point each is assigned for age 65 to 74 years, a history of hypertension, diabetes, cardiac failure, and vascular disease. Patients with 1 definitive risk factor or a patient with a CHA(2)DS(2)-VASc score of 1 or more could be considered for oral anticoagulation, but a patient with a CHA(2)DS(2)-VASc score of 0 is truly low risk and could be managed with no antithrombotic therapy. This would simplify our approach to thromboprophylaxis in patients with atrial fibrillation.


Mechanics and energetics of muscle contraction in normal and dystrophic chickens.
Energy liberation and isometric force generation were compared at 25 degrees C in isolated normal (n = 15) and dystrophic (n = 18) posterior latissimus dorsi muscles (PLD) from 16- to 33-day-old chickens. Twitch-energy liberation in dystrophic muscle decreased by 27 +/- 6%, and force per cross-sectional area decreased by 26 +/- 11%. Tetanic energy liberation in dystrophic PLD was depressed by 32 +/- 10% compared with a 22 +/- 9% reduction in peak force per cross-sectional area plus a 26 +/- 3% reduction in ability to maintain force. Normalizing results using the force-time integral demonstrates an unaltered force generation per unit energy liberation in dystrophic PLD (7 +/- 11% difference from normal). Kinetic properties of the mechanical responses were not significantly different in normal compared with dystrophic PLD. Dystrophic PLD demonstrated hyperexcitability to nerve transection and electrical stimulation. Although force-generating capacity is reduced in dystrophic PLD, coupling of force production to energy utilization appears unaltered.


Effects of acute intermittent hypoxia on hand use after spinal cord trauma: A preliminary study.
To test the hypothesis that daily acute intermittent hypoxia (AIH) combined with hand opening practice improves hand dexterity, function, and maximum hand opening in persons with chronic, motor-incomplete, cervical spinal cord injury. Six participants completed the double-blind, crossover study. Participants received daily (5 consecutive days) AIH (15 episodes per day: 1.5 minutes of fraction of inspired oxygen [FIo2] = 0.09, 1-minute normoxic intervals) followed by 20 repetitions of hand opening practice and normoxia (sham, FIo2 = 0.21) + hand opening practice. Hand dexterity and function were quantified with Box and Block and Jebsen-Taylor hand function tests. We also recorded maximum hand opening using motion analyses and coactivity of extensor digitorum and flexor digitorum superficialis muscles using surface EMG. Daily AIH + hand opening practice improved hand dexterity, function, and maximum hand opening in all participants. AIH + hand opening practice improved Box and Block Test scores vs baseline in 5 participants (p = 0.057) and vs sham + hand opening practice in all 6 participants (p = 0.016). All participants reduced Jebsen-Taylor Hand Function Test (JTHF) time after daily AIH + hand opening practice (-7.2 ± 1.4 seconds) vs baseline; 4 of 6 reduced JTHF time vs sham + hand opening practice (p = 0.078). AIH + hand opening practice improved maximum hand aperture in 5 of 6 participants (8.1 ± 2.7 mm) vs baseline (p = 0.018) and sham + hand opening practice (p = 0.030). In 5 participants, daily AIH-induced changes in hand opening were accompanied by improved EMG coactivity (p = 0.029). This report suggests the need for further study of AIH as a plasticity "primer" for task-specific training in spinal cord injury rehabilitation. Important clinical questions remain concerning optimal AIH dosage, patient screening, safety, and effect persistence. NCT01272336.


Translation in astrocyte distal processes sets molecular heterogeneity at the gliovascular interface.
Astrocytes send out long processes that are terminated by endfeet at the vascular surface and regulate vascular functions as well as homeostasis at the vascular interface. To date, the astroglial mechanisms underlying these functions have been poorly addressed. Here we demonstrate that a subset of messenger RNAs is distributed in astrocyte endfeet. We identified, among this transcriptome, a pool of messenger RNAs bound to ribosomes, the endfeetome, that primarily encodes for secreted and membrane proteins. We detected nascent protein synthesis in astrocyte endfeet. Finally, we determined the presence of smooth and rough endoplasmic reticulum and the Golgi apparatus in astrocyte perivascular processes and endfeet, suggesting for local maturation of membrane and secreted proteins. These results demonstrate for the first time that protein synthesis occurs in astrocyte perivascular distal processes that may sustain their structural and functional polarization at the vascular interface.


Contribution of CYP3A isoforms to dealkylation of PDE5 inhibitors: a comparison between sildenafil N-demethylation and tadalafil demethylenation.
The aim of this study was to characterize the kinetics of metabolite formation of the phosphodiesterase type-5 (PDE5) inhibitors sildenafil and tadalafil by CYP3A4, CYP3A5, and CYP3A7 isoforms. The formations of N-desmethyl sildenafil and desmethylene tadalafil were examined using CYP3A supersomes co-expressing human P450 oxidoreductase and cytochrome b5. Both sildenafil N-demethylation and tadalafil demethylenation were catalyzed by CYP3A4, CYP3A5, and to a lesser extent by CYP3A7. The kinetics of desalkyl metabolite formation of the two drugs were well fitted to the Hill equation; however, the Hill coefficients (n) suggested CYP3A-mediated negative cooperativity. Next, we analyzed the kinetics with a two binding sites model assuming two reaction steps: reaction 1 with high-affinity and low-capacity metabolism and reaction 2 with low-affinity and high-capacity metabolism. The kinetics of desalkyl metabolite formation were also fitted to the two binding sites model. The intrinsic clearance (CLint) values of reactions 1 and 2 for sildenafil N-demethylation were 0.733 and 0.033 µL/min/pmol P450 for CYP3A4, 0.788 and 0.019 µL/min/pmol P450 for CYP3A5, and 0.079 and 0.004 µL/min/pmol P450 for CYP3A7, respectively. The CLint values of reactions 1 and 2 for tadalafil demethylenation were 0.187 and 0.014 µL/min/pmol P450 for CYP3A4, 0.050 and <0.001 µL/min/pmol P450 for CYP3A5, and 0.004 and <0.001 µL/min/pmol P450 for CYP3A7, respectively. These results may provide the basis not only for understanding the metabolic properties of the two PDE5 inhibitors, but also for one possible explanation of the mechanisms of CYP3A-mediated negative cooperativity.


Clinical Evaluation of the Athlete's Shoulder.
To describe the history and physical examination of the athlete's shoulder. The complex, highly mobile shoulder joint is very susceptible to athletic injury. A comprehensive history and physical examination lay the groundwork for accurate decision making about the nature of the injury and the appropriate treatment plan. In taking the history,inquire about the patient's lifestyle (dominant hand, occupation, sports, activity level) and then focus on the specific complaint. Ask about the location, quality, and nature of the pain and activities that provoke the pain. If stiffness is a factor, a review of systems and the patient's past medical history are important. Discuss any previously undertaken interventions and their effects. The physical examination consists of inspection, range of motion, palpation, manual muscle testing, and provocative tests. Once the clinical evaluation has been completed, the nature of the injury will, in most cases, be apparent. If necessary, appropriate diagnostic tests are ordered, and then a treatment plan tailored to the athlete and the injury is instituted.


Ranking Saliency.
Most existing bottom-up algorithms measure the foreground saliency of a pixel or region based on its contrast within a local context or the entire image, whereas a few methods focus on segmenting out background regions and thereby salient objects. Instead of only considering the contrast between salient objects and their surrounding regions, we consider both foreground and background cues in this work. We rank the similarity of image elements with foreground or background cues via graph-based manifold ranking. The saliency of image elements is defined based on their relevances to the given seeds or queries. We represent an image as a multi-scale graph with fine superpixels and coarse regions as nodes. These nodes are ranked based on the similarity to background and foreground queries using affinity matrices. Saliency detection is carried out in a cascade scheme to extract background regions and foreground salient objects efficiently. Experimental results demonstrate the proposed method performs well against the state-of-the-art methods in terms of accuracy and speed. We also propose a new benchmark dataset containing 5,168 images for large-scale performance evaluation of saliency detection methods.


Two-Dimensional Antifouling Fluidic Channels on Nanopapers for Biosensing.
Two-dimensional (hydrophilic) channels were patterned on films prepared from cellulose nanofibrils (CNF) using photolithography and inkjet printing. Such processes included UV-activated thiol-yne click coupling and inkjet-printed designs with polystyrene. The microfluidic channels were characterized (SEM, wetting, and fluid flow) and applied as platforms for biosensing. Compared to results from the click method, a better feature fidelity and flow properties were achieved with the simpler inkjet-printed channels. Human immunoglobulin G (hIgG) was used as target protein after surface modification with either bovine serum albumin (BSA), fibrinogen, or block copolymers of poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) and poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) (PDMAEMA- block-POEGMA copolymers). Surface plasmon resonance (SPR) and AFM imaging were used to determine their antifouling effect to prevent nonspecific hIgG binding. Confocal laser scanning microscopy revealed diffusion and adsorption traces in the channels. The results confirm an effective surface passivation of the microfluidic channels (95% reduction of hIgG adsorption and binding). The inexpensive and disposable systems proposed here allow designs with space-resolved blocking efficiency that offer a great potential in biosensing.


Kaiso overexpression promotes intestinal inflammation and potentiates intestinal tumorigenesis in Apc(Min/+) mice.
Constitutive Wnt/β-catenin signaling is a key contributor to colorectal cancer (CRC). Although inactivation of the tumor suppressor adenomatous polyposis coli (APC) is recognized as an early event in CRC development, it is the accumulation of multiple subsequent oncogenic insults facilitates malignant transformation. One potential contributor to colorectal carcinogenesis is the POZ-ZF transcription factor Kaiso, whose depletion extends lifespan and delays polyp onset in the widely used Apc(Min/+) mouse model of intestinal cancer. These findings suggested that Kaiso potentiates intestinal tumorigenesis, but this was paradoxical as Kaiso was previously implicated as a negative regulator of Wnt/β-catenin signaling. To resolve Kaiso's role in intestinal tumorigenesis and canonical Wnt signaling, we generated a transgenic mouse model (Kaiso(Tg/+)) expressing an intestinal-specific myc-tagged Kaiso transgene. We then mated Kaiso(Tg/+) and Apc(Min/+) mice to generate Kaiso(Tg/+):Apc(Min/+) mice for further characterization. Kaiso(Tg/+):Apc(Min/+) mice exhibited reduced lifespan and increased polyp multiplicity compared to Apc(Min/+) mice. Consistent with this murine phenotype, we found increased Kaiso expression in human CRC tissue, supporting a role for Kaiso in human CRC. Interestingly, Wnt target gene expression was increased in Kaiso(Tg/+):Apc(Min/+) mice, suggesting that Kaiso's function as a negative regulator of canonical Wnt signaling, as seen in Xenopus, is not maintained in this context. Notably, Kaiso(Tg/+):Apc(Min/+) mice exhibited increased inflammation and activation of NFκB signaling compared to their Apc(Min/+) counterparts. This phenotype was consistent with our previous report that Kaiso(Tg/+) mice exhibit chronic intestinal inflammation. Together our findings highlight a role for Kaiso in promoting Wnt signaling, inflammation and tumorigenesis in the mammalian intestine.


Actinomycotic Osteomyelitis of the Mandible - A Rare Case Report.
Actinomycetes are a relatively sporadic cause of infection of the head-and-neck region and their appearance is usually uncharacteristic, and hence pose a challenge for the diagnosis. The present article intends to exhibit this rarity afflicting mandible and highlight its management. The present report describes a case of a 55-year-old countryside female who presented with pain and swelling affecting the left side of the mandible. Orthopantomograph and cone-beam computed tomography imaging showed multiple ill-defined radiolucencies and perforations of the buccal and lingual cortical plates. Fine-needle aspiration microbiology was used to ascertain the microbial organism and the patient was treated with amoxicillin + clavulanic acid with curettage of the infected site. The patient responded well to prompt systemic antibiotics and local surgical measures with complete resolution of the infection and spontaneous bone regeneration. Although rare actinomycosis of the mandible is curable and should be included in the differential diagnosis of osteomyelitis of the jaw. Early and accurate diagnosis and prompt intervention confirm better outcomes.


Pharmacotherapy of systolic heart failure: a review of recent literature and practical applications.
Since the publication of the Agency for Health Care Policy and Research Guidelines for treatment of heart failure, a number of new agents have been investigated for this indication. beta-Blockers have now been shown to improve outcomes in mild to moderate heart failure when added to standard therapy. Angiotensin II receptor antagonists have also been investigated and show promise. In general, calcium channel blockers are second- or third-line agents in patients refractory to other therapy. Investigational agents including spironolactone may also hold promise for future therapy.


Angiogenic and tissue remodeling factors in the prostate of elderly rats submitted to hormonal replacement.
The influence of senescence and hormone replacement on the onset of pathologic processes in the prostate is not yet fully understood. The aim was to identify the immunoreactivity and protein levels of molecules involved in cell proliferation, tissue remodeling and angiogenesis in the ventral prostate of elderly rodents following hormonal replacement. Male Sprague-Dawley rats were separated into one Young group (4-months old), treated with peanut oil (5 mL kg(-1) , s.c.), and six Senile groups. The senile rats (10-months old) were subdivided into: Senile group (SEN) (5 mL kg(-1) peanut oil, s.c.); Testosterone group (TEST) (5 mg kg(-1) testosterone cipionate, s.c.); Estrogen group (EST) (25 µg kg(-1) 17β-estradiol, s.c.); castrated group (CAS) (surgical castration); castrated-testosterone group (CT) (same treatment as CAS and TEST groups); and castrated-estrogen group (CE) (same treatment as CAS and EST groups). After 30 days, samples of the ventral prostate were harvested for analyses of insulin-like growth factor-1 receptor (IGFR-1), matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF) and endostatin features. IGFR-1 and MMP-9 showed increased protein levels and epithelial immunolabeling both after hormonal replacement and castration. Increased VEGF levels and reduced endostatin were verified in the SEN group. Hormonal therapy and castration led to a higher increase of VEGF, especially in the EST, CAS, and CE groups. Endostatin increased mainly in the TEST and CT groups. Hormonal therapy in senescence generated a reactive microenvironment characterized by the increase of mitogenic and tissue remodeling factors and by the imbalance of angiogenesis, which possibly compromised organ function and predisposed toward glandular disorders.


Peak expiratory flow rate in Nigerian school children.
Peak expiratory flow rate (PEFR) was measured using the Wright's peak flow meter in 263 school boys and 275 school girls living in Lagos, Nigeria. Their ages ranged from 6.0 years to 19.0 years (mean 11.9 +/- 3.8 yrs. for boys and 11.8 +/- 3.9 yrs. for girls). Mean PEFR was 359.2 +/- 102.0 L/min (range 160.0-610.0 L/min) in boys and 327.7 +/- 81.3 L/min (range 160.0-500.0 L/min) in girls. Apart from ages 17, 18 and 19, peak expiratory flow rates were similar in both boys and girls. In both sexes, PEFR correlated positively and significantly with age, height, weight and body surface area. Also in both sexes and in all age groups studied, PEFR was significantly higher than predicted values obtained from previous Nigerian and caucasian prediction equations. When compared with values obtained from a second caucasian prediction equation, observed values were significantly higher in the 6-10 years and 16-19 years age groups in boys and 11-15 years and 16-19 years age groups in girls. New prediction equations for calculating PEFR in Nigerian boys and girls are presented. Observed PEFR may be due to enhanced stature in Nigerian children resulting from improved environment and genetic factors.


Association of interleukin-1 α (-889) gene polymorphism in patients with generalized aggressive and chronic periodontitis.
There is a strong evidence that genetic as well as environmental factors affect the age of onset, severity and lifetime risk of developing periodontitis. The objective of the present study was to compare and to evaluate the association between interleukin (IL)-1α(-889) and gene polymorphisms in patients with generalized aggressive periodontitis, chronic periodontitis and healthy controls. A total of 60 Indian patients, with 20 aggressive periodontitis, 20 chronic periodontitis and 20 healthy controls were recruited for this study. From each patient, a volume of 2 ml of blood was collected by venipuncture in the ante-cubital fossa and was stored in sodium EDTA vacutainers and was used for genotyping assays with the polymerase chain reaction restriction fragment length polymorphism technique. Clinical parameters such as oral hygiene index, gingival index and clinical attachment loss (CAL) were evaluated for each patient. Genotype distribution between different groups were analyzed using Chi-square test. A P = 0.05 or less was set for significance. The mean oral hygiene index was 3.7 ± 0.86 and 3.25 ± 0.30 for chronic and aggressive periodontitis cases respectively. The CAL was 4.29 ± 0.63 mm for chronic periodontitis and 6.44 ± 0.57 mm for aggressive periodontitis. Homozygous genotype 2,2 was more predominant in cases of aggressive periodontitis whereas in chronic periodontitis, heterozygous genotype 1,2 was more predominant when compared with others (P < 0.001). Odds ratio for aggressive versus chronic periodontitis was calculated as 6.2 (95% confidence interval 6.019-7.892). The results of the present study support a positive association between aggressive periodontitis and the presence of the IL-1α-889, allele 2 polymorphism in Indian patients.


Signal transduction mechanism of biased ligands at histamine H2 receptors.
7TMRs (seven-transmembrane receptors) exist as conformational collections in which different conformations would lead to differential downstream behaviours such as receptor phosphorylation, G-protein activation and receptor internalization. In this context, a ligand may cause differential activation of some, but not all, of the signalling events, which are associated to a particular receptor, and it would lead to biased agonism. The aim of the present study was to investigate whether H2R (histamine H2 receptor) ligands, described as inverse agonists because of their negative efficacy at modulating adenylate cyclase, could display some positive efficacy concerning receptor desensitization, internalization or even signalling through an adenylate-cyclase-independent pathway. Our present findings indicate that treatment with H2R inverse agonists leads to receptor internalization in HEK (human embryonic kidney)-293T transfected cells, by a mechanism mediated by arrestin and dynamin, but independent of GRK2 (G-protein-coupled receptor kinase 2)-mediated phosphorylation. On the other hand, we prove that two of the H2R inverse agonists tested, ranitidine and tiotidine, also induce receptor desensitization. Finally, we show that these ligands are able to display positive efficacy towards the ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway by a mechanism that involves Gβγ and PI3K (phosphoinositide 3-kinase)-mediated signalling in both transfected HEK-293T cells and human gastric adenocarcinoma cells. These results point to the aspect of pluridimensional efficacy at H2R as a phenomenon that could be extended to naïve cells, and challenge previous classification of pharmacologically relevant histaminergic ligands.


Zinc/Imidazole procedure for visualization of proteins in gels by negative staining.
INTRODUCTIONThe zinc/imidazole staining procedure for visualizing proteins in acrylamide gels is based on differential salt binding. Because protein-bound salts (e.g., dodecyl sulfate or the heavy cation zinc) are chemically less active than free zinc ions in the gel, precipitation of an insoluble salt is much slower in those regions of the gel occupied by proteins than in the gel background where zinc dodecyl sulfate precipitates. The result is a "negative stain," with translucent proteins and an opaque gel background, due to zinc dodecyl sulfate precipitation. The sensitivity of the method has been markedly improved by altering the composition of the precipitated salt to a complex of zinc and imidazole. This protocol provides two methods: reverse stain using imidazole, SDS, and zinc, and double-staining using Coomassie blue stain followed by zinc/imidazole.


Effects of the Spouse's Aromatherapy Massage on Labor Pain, Anxiety and Childbirth Satisfaction for Laboring Women.
The purpose of this study was to determine the effects of the spouse's aromatherapy massage on labor pain, anxiety during labor and childbirth satisfaction for laboring women. The subjects of this study were laboring women who didn't have any complication during pregnancy and who have admitted for childbirth with their spouse to E. hospital in D city. This study was carried out from June to November in 2007. The subjects were allocated into three groups: spouse's aromatherapy massage group, spouse's carrier oil massage group and control group. Aromatherapy massage and carrier oil massage was applied for ten minutes every hour after the cervix dilated 5cm. The subjects in the control group were with their spouse during labor. The labor pain by VAS was significantly different among the three groups (Kruskal-Wallis chi2=7.09 p=.029) in the deceleration phase. The anxiety during labor by VAS were significantly different among the three groups (Kruskal-Wallis chi2=6.77 p=.034) in the deceleration phase. There was no significant difference in childbirth satisfaction among the three groups. The spouse's aromatherapy massage using Lavender, Clary sage, Frankincense and Neroli could be effective in decreasing labor pain and decreasing anxiety level during labor.


Mutagenicity and cytotoxicity of two regioisomeric mercapturic acids and cysteine S-conjugates of trichloroethylene.
The mutagenicity, cytotoxicity and metabolism of two regioisomic L-cysteine- and N-acetyl-L-cysteine-S-conjugates of trichloroethylene were studied. The 1,2-dichlorovinyl(1,2-DCV) isomers of both the cysteine conjugate and the mercapturate were much stronger mutagens in the Ames test with Salmonella typhimurium TA2638 when compared to the corresponding 2,2-dichlorovinyl (2,2-DCV) isomers. Similarly, the 1,2-DCV isomers were more cytotoxic towards isolated rat kidney proximal tubular cells, as assessed by inhibition of alpha-methylglucose uptake, than the 2,2-DCV isomers. The 3-4-fold higher rate of beta-lyase-dependent activation of S-(1,2-dichlorovinyl)-L-cysteine (1,2-DCV-Cys) when compared to S-(1,2-dichlorovinyl)-L-cysteine (2,2-DCV-Cys) as well as the different nature of the reactive intermediates formed is probably responsible for these structure-dependent effects. The cytotoxicity of N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (1,2-DCV-NAc) toward isolated kidney cells showed a delayed time course as compared to that of 1,2-DCV-Cys, probably due to the relatively low rate of deacetylation of 1,2-DCV-NAc. The time course of cytotoxicity of N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine (2,2-DCV-NAc), however, parallelled that of 2,2-DCV-Cys. Due to the relatively high rate of N-acetylation and low rate of beta-lyase activation, for 2,2-DCV-Nac the beta-lyase activation step may be rate limiting. Different rates of cellular uptake also may play a role in time course of toxicity of the cysteine conjugates and the mercapturic acids in the renal cells.


Reversible myocardial dysfunction after traumatic brain injury: mechanisms and implications for heart transplantation.
Reversible myocardial dysfunction is known to occur in patients with cerebrovascular accidents and brain death. Several mechanisms for transient myocardial dysfunction have been proposed, including increased sympathetic activity, hormone depletion, and a reduction in coronary perfusion pressure. The relative importance of each of these mechanisms remains controversial. We report the case of a 19-year-old man who suffered traumatic brain death associated with reversible myocardial dysfunction despite elevated cardiac enzymes. Myocardial recovery occurred after correcting his hemodynamic instability and hypothermia emphasizing the importance of normalization of coronary perfusion pressure and core body temperature. The mechanisms for reversible myocardial dysfunction and their implications for heart transplantation following traumatic brain death are reviewed. A diagnostic strategy is proposed that would allow early recognition of reversible myocardial dysfunction in brain-dead patients.


Pharmacokinetics of liposomal amphotericin B (Ambisome) in critically ill patients.
The liposomal formulation of amphotericin B (AmBisome) greatly reduces the acute and chronic side effects of the parent drug. The present study describes the pharmacokinetic characteristics of AmBisome applied to 10 patients at a dose of 2.8 to 3.0 mg/kg of body weight and compares them to the pharmacokinetics observed in 6 patients treated with amphotericin B deoxycholate at the standard dose of 1.0 mg/kg. Interpatient variabilities of amphotericin B peak concentrations (Cmax) and areas under concentration-time curves (AUC) were 8- to 10-fold greater for patients treated with AmBisome than for patients treated with amphotericin B deoxycholate. At the threefold greater dose of AmBisome, median Cmaxs were 8.4-fold higher (14.4 versus 1.7 microg/ml) and median AUCs exceeded those observed with amphotericin B deoxycholate by 9-fold. This was in part explained by a 5.7-fold lower volume of distribution (0.42 liters/kg) in AmBisome-treated patients. The elimination of amphotericin B from serum was biphasic for both formulations. However, the apparent half-life of elimination was twofold shorter for AmBisome (P = 0.03). Neither hemodialysis nor hemofiltration had a significant impact on AmBisome pharmacokinetics as analyzed in one patient. In conclusion, the liposomal formulation of amphotericin B significantly (P = 0.001) reduces the volume of drug distribution, thereby allowing for greater drug concentrations in serum. The low toxicity of AmBisome therefore cannot readily be explained by its serum pharmacokinetics.


The well-being and personal wellness promotion strategies of medical oncologists in the North Central Cancer Treatment Group.
The well-being of oncologists is important to the well-being of their patients. While much is known about oncologist distress, little is known about oncologist well-being. We set out to evaluate oncologist well-being and the personal wellness promotion strategies used by oncologists. We performed a cross-sectional survey of medical oncologists in the North Central Cancer Treatment Group using a validated instrument to measure quality of life. Study-specific questions explored stressors, wellness promotion strategies and career satisfaction. Of 241 responding oncologists (response rate 61%), 121 (50%) reported high overall well-being. Being age 50 or younger (57 vs. 41%; p = 0.01), male (53 vs. 31%; p = 0.01) and working 60 h or less per week (50 vs. 33%; p = 0.005) were associated with increased overall well-being on bivariate analysis. Ratings of the importance of a number of personal wellness promotion strategies differed for oncologists with high well-being compared with those without high well-being. Developing an approach/philosophy to dealing with death and end-of-life care, using recreation/hobbies/exercise, taking a positive outlook and incorporating a philosophy of balance between personal and professional life were all rated as substantially more important wellness strategies by oncologists with high well-being (p values <0.001). Oncologists with high overall well-being also reported greater career satisfaction. Half of medical oncologists experience high overall well-being. Use of specific personal wellness promotion strategies appears to be associated with oncologist well-being. Further investigations of the prevalence, promotion, causes, inequities and clinical impact of physician well-being are needed. .


Diurnal oscillation of SBE expression in sorghum endosperm.
Spatial and temporal expression patterns of the sorghum SBEI, SBEIIA and SBEIIB genes, encoding, respectively, starch branching enzyme (SBE) I, IIA and IIB, in the developing endosperm of sorghum (Sorghum bicolor) were studied. Full-length genomic and cDNA clones for sorghum were cloned, and the SBEIIA cDNA was used together with gene-specific probes for sorghum SBEIIB and SBEI. In contrast to sorghum SBEIIB, which was expressed primarily in endosperm and embryo, SBEIIA was also expressed in vegetative tissues. All three genes shared a similar temporal expression profile during endosperm development, with a maximum activity at 15-24 d after pollination. This differed from barley and maize, in which SBEI gene activity showed a significantly later onset compared to that of SBEIIA and SBEIIB. Expression of the three SBE genes in the sorghum endosperm exhibited a diurnal rhythm during a 24-h cycle.


The Conserved ASCL1/MASH-1 Ortholog HLH-3 Specifies Sex-Specific Ventral Cord Motor Neuron Fate in Caenorhabditis elegans.
Neural specification is regulated by one or many transcription factors that control expression of effector genes that mediate function and determine neuronal type. Here we identify a novel role for one conserved proneural factor, the bHLH protein HLH-3, implicated in the specification of sex-specific ventral cord motor neurons in C. elegans Proneural genes act in early stages of neurogenesis in early progenitors, but here, we demonstrate a later role for hlh-3 First, we document that differentiation of the ventral cord type C motor neuron class (VC) within their neuron class, is dynamic in time and space. Expression of VC class-specific and subclass-specific identity genes is distinct through development and is dependent on the VC position along the A-P axis and their proximity to the vulva. Our characterization of the expression of VC class and VC subclass-specific differentiation markers in the absence of hlh-3 function reveals that VC fate specification, differentiation, and morphology requires hlh-3 function. Finally, we conclude that hlh-3 cell-autonomously specifies VC cell fate.


Use of Cumulative Assessments in U.S. Schools and Colleges of Pharmacy.
The Accreditation Council of Pharmacy Education (ACPE) has taken a strong stance on assessment in pharmacy education. One available assessment tool is cumulative assessments, which may be administered at various points in the curriculum. This article presents the results of a survey of U.S. schools of pharmacy regarding the use of cumulative assessments within their curriculum. A 20-question survey tool was emailed to 125 schools of pharmacy. A total of 105 out of 125 schools participated (response rate 84%). Of these, 52 schools currently have a cumulative assessment program; 18 have one cumulative exam prior to advanced pharmacy practice experiences (APPEs); 19 have a cumulative exam every didactic year; and seven have accumulative exams every semester, except during APPEs (n = 44). Increased faculty workload emerged as the top challenge faced by schools that have implemented a cumulative assessment program. Eighteen schools indicated that no outcomes are measured to determine the utility of the cumulative assessment. From these results, it appears that almost half of participating U.S. schools have implemented a cumulative assessment plan. However, it is apparent that more research needs to be done to determine which outcomes are expected to improve with the implementation of such an assessment plan.


A comparative study of pain, sleep quality and pain responsiveness in fibrositis and myofascial pain syndrome.
Twenty patients with fibrositis and 19 patients with myofascial pain syndrome were compared with regard to pain levels, sleep quality, general pain threshold and localized pain responsiveness at fibrositic tender points. Patients with fibrositis had significantly lower pain responsiveness (p less than 0.01), lower pain threshold (p less than 0.05) and higher pain levels (p less than 0.05) than patients with myofascial pain syndrome when differences in age between the groups were controlled. No significant difference was found for sleep quality. Regional pain levels influenced local measures of pain sensitivity. A discriminant function, developed on the 4 main study variables, resulted in an almost 80% correct classification to groups.


Epigenetic aging of mammalian gametes.
The process of aging refers to physiological changes that occur to an organism as time progresses and involves changes to DNA, proteins, metabolism, cells, and organs. Like the rest of the cells in the body, gametes age, and it is well established that there is a decline in reproductive capabilities in females and males with aging. One of the major pathways known to be involved in aging is epigenetic changes. The epigenome is the multitude of chemical modifications performed on DNA and chromatin that affect the ability of chromatin to be transcribed. In this review, we explore the effects of aging on female and male gametes with a focus on the epigenetic changes that occur in gametes throughout aging. Quality decline in oocytes occurs at a relatively early age. Epigenetic changes constitute an important part of oocyte aging. DNA methylation is reduced with age, along with reduced expression of DNA methyltransferases (DNMTs). Histone deacetylases (HDAC) expression is also reduced, and a loss of heterochromatin marks occurs with age. As a consequence of heterochromatin loss, retrotransposon expression is elevated, and aged oocytes suffer from DNA damage. In sperm, aging affects sperm number, motility and fecundity, and epigenetic changes may constitute a part of this process. 5 methyl-cytosine (5mC) methylation is elevated in sperm from aged men, but methylation on Long interspersed nuclear elements (LINE) elements is reduced. Di and trimethylation of histone 3 lysine 9 (H3K9me2/3) is reduced in sperm from aged men and trimethylation of histone 3 lysine 27 (H3K27me3) is elevated. The protamine makeup of sperm from aged men is also changed, with reduced protamine expression and a misbalanced ratio between protamine proteins protamine P1 and protamine P2. The study of epigenetic reproductive aging is recently gaining interest. The current status of the field suggests that many aspects of gamete epigenetic aging are still open for investigation. The clinical applications of these investigations have far-reaching consequences for fertility and sociological human behavior.


EnlightenGAN: Deep Light Enhancement Without Paired Supervision.
Deep learning-based methods have achieved remarkable success in image restoration and enhancement, but are they still competitive when there is a lack of paired training data? As one such example, this paper explores the low-light image enhancement problem, where in practice it is extremely challenging to simultaneously take a low-light and a normal-light photo of the same visual scene. We propose a highly effective unsupervised generative adversarial network, dubbed EnlightenGAN, that can be trained without low/normal-light image pairs, yet proves to generalize very well on various real-world test images. Instead of supervising the learning using ground truth data, we propose to regularize the unpaired training using the information extracted from the input itself, and benchmark a series of innovations for the low-light image enhancement problem, including a global-local discriminator structure, a self-regularized perceptual loss fusion, and the attention mechanism. Through extensive experiments, our proposed approach outperforms recent methods under a variety of metrics in terms of visual quality and subjective user study. Thanks to the great flexibility brought by unpaired training, EnlightenGAN is demonstrated to be easily adaptable to enhancing real-world images from various domains. Our codes and pre-trained models are available at: https://github.com/VITA-Group/EnlightenGAN.


Characterization of human anti-factor VIII antibodies purified by immune complex formation.
Anti-factor VIII antibodies from three hemophilia A patients were selectively isolated by immune complex formation and secondary precipitation with polyethylene glycol. These antibodies were characterized as IgG, with only one type of light chains (kappa) and a mixture of IgG3 and IgG4 heavy chains. This finding indicated that stable complexes of factor VIII and homologous anti-factor VIII antibodies could be obtained, and that the immunologic response to the infusion of homologous factor VIII was oligoclonal rather than monoclonal in these patients.


Immunocytochemical studies of endothelial cells in vivo. I. The presence of desmin only, or of desmin plus vimentin, or vimentin only, in the endothelial cells of different capillaries of the adult chicken.
It is currently believed that the intermediate filaments of endothelial cells contain vimentin subunits exclusively. This inference, however, is derived from studies of only a few types of endothelial cells. By double indirect immunofluorescence and immunoelectron microscopy, we have now examined the endothelial cells of the micro- and macrovasculature of a variety of tissues and organs of adult chicken in vivo for their content of desmin and vimentin. Endothelial cells of the peritubular capillary in the renal cortex, the hepatic sinusoid, and the splenic sinusoid were found to contain only desmin; those of the exocrine pancreas capillary contained both desmin and vimentin; and the endothelial cells of the macrovasculatures and of all the other microvasculatures examined, including the vasa recta of the renal medulla, contained only vimentin. Such heterogeneity suggests that different types of adult chicken endothelial cells may have different embryological origins. To the extent that desmin and vimentin intermediate filaments may be functionally distinct, these results also suggest that different capillary endothelial cells may have different functional properties.


Adherence of Aeromonas caviae to human cell lines Hep-2 and Caco-2.
Adherence of Aeromonas caviae to HEp-2 and Caco-2 cell monolayers was investigated with 24 clinical isolates. Growth phase, temperature, multiplicity of infection and length of incubation affected adherence. Treatment of the bacteria with trypsin, sodium metaperiodate, mechanical shearing and the addition of cytochalasin B and cycloheximide to the monolayer significantly reduced the adherence capabilities of the strains investigated. The use of chloramphenicol to inhibit protein synthesis reduced the adhesive capabilities of bacteria grown in liquid medium and those subjected to mechanical shearing. Light microscopy, scanning and transmission electron microscopy were employed in the investigation of bacteria-bacteria and bacteria-monolayer interactions and indicated similarities with the aggregative adherence patterns of the Enterobacteriaceae. The presence of extracellular bacterial appendages and their correlation with increased adhesive capacity may indicate a role in the process of adherence.


Factors affecting the appearance of the hump charge movement component in frog cut twitch fibers.
Charge movement was measured in frog cut twitch fibers with the double Vaseline gap technique. Five manipulations listed below were applied to investigate their effects on the hump component (I gamma) in the ON segments of TEST minus CONTROL current traces. When external Cl-1 was replaced by MeSO3- to eliminate Cl current, I gamma peaked earlier due to a few millivolts shift of the voltage dependence of I gamma kinetics in the negative direction. The Q-V plots in the TEA.Cl and TEA.MeSO3 solutions were well fitted by a sum of two Boltzmann distribution functions. The more steeply voltage-dependent component (Q gamma) had a V approximately 6 mV more negative in the TEA.MeSO3 solution than in the TEA.Cl solution. These voltage shifts were partially reversible. When creatine phosphate in the end pool solution was removed, the I gamma hump disappeared slowly over the course of 20-30 min, partly due to a suppression of Q gamma. The hump reappeared when creatine phosphate was restored. When 0.2-1.0 mM Cd2+ was added to the center pool solution to block inward Ca current, the I gamma hump became less prominent due to a prolongation in the time course of I gamma but not to a suppression of Q gamma. When the holding potential was changed from -90 to -120 mV, the amplitude of I beta was increased, thereby obscuring the I gamma hump. Finally, when a cut fiber was stimulated repetitively, I gamma lost its hump appearance because its time course was prolonged. In an extreme case, a 5-min resting interval was insufficient for a complete recovery of the waveform. In general, a stimulation rate of once per minute had a negligible effect on the shape of I gamma. Of the five manipulations, MeSO3- has the least perturbation on the appearance of I gamma and is potentially a better substitute for Cl- than SO2-(4) in eliminating Cl current if the appearance of the I gamma hump is to be preserved.


Syntheses of beta,beta-difluorotryptamines.
Tryptamines disubstituted at the beta-position with fluorine have been synthesized as part of our research program to study the effects of fluorine substitution on the biological activities of neuroactive amines. Treatment of N-Boc-3-azidoacetyl indoles, prepared from readily available 2-chloracetylindoles, with dimethoxyethylamino sulfurtrifluoride produced the corresponding 3-(2-azido-1,1-difluoroethyl)indoles. Reduction of the azide to amine with hydrogen over Pd-C and careful removal of the N-Boc protecting group produced beta,beta-difluorotryptamines.


Current concepts. Serum osmolality. Uses and limitations.
The serum osmolality measurement has a clearly circumscribed use in clinical medicine. Comparison of the measured osmolality with the osmolality calculated from the concentrations of the major solutes in serum gives information about large deviations in the serum water content. In addition, comparison of the measured and calculated values of osmolality provides rapid screening information about the presence of foreign low-molecular-weight solutes in the blood. Taken at face value, the test cannot be used to determine whether abnormalities in tonicity homeostasis are present. A simple and direct way to assess whether tonicity is normal is to calculate the effective osmolality from the concentrations of sodium and glucose in serum. With rare exceptions, this calculation provides the information needed to make decisions about therapy.


Blood pressure and renal function responses in workers exposed to lead for up to six years.
The Study for Promotion of Health in Recycling Lead (SPHERL) assessed the blood pressure (BP) and renal function (RF) responses for up to 6 years in the workers without previous occupational lead exposure. BP was the average of five consecutive readings and the estimated glomerular filtration rate was derived from serum creatinine (eGFRcrt) and cystatin C (eGFRcys). Blood lead (BL) was measured by inductively coupled plasma mass spectrometry (detection limit 0.5 μg/dL). The statistical methods included multivariable-adjusted mixed models and interval-censored Cox regression analysis. The 234 workers analyzed were on average 28.5 years old and included 91.9% men. The baseline BL concentration was 4.35 μg/dL and increased 3.17-fold over follow-up (median: 2.03 years; range: 0.92-6.45 years). The changes in BP and RF were not significantly correlated with the follow-up-to-baseline BL ratio (p ≥ .51 and p ≥ .18, respectively). The fully-adjusted changes in systolic/diastolic BP associated with a doubling of BL were -0.25/-0.12 mm Hg (CI: -0.94 to 0.44/-0.66 to 0.42 mm Hg). Accordingly, the incidence of stage-1 or -2 hypertension was not associated with the BL change (p ≥ .063). Similarly, the changes in eGFRcrt and eGFRcys associated with a 3-fold BL increment were not significant, amounting to -0.70 mL/min/1.73 m2 (CI: -1.70 to 0.30 mL/min/1.73 m2 ) and -1.06 mL/min/1.73 m2 (-2.16 to 0.03 mL/min/1.73 m2 ). In conclusion, the BP and RF responses to an over 3-fold BL increment were small and not significant confirming the safety of modern lead-handing facilities operating under current safety rules.


The architecture of human kin detection.
Evolved mechanisms for assessing genetic relatedness have been found in many species, but their existence in humans has been a matter of controversy. Here we report three converging lines of evidence, drawn from siblings, that support the hypothesis that kin detection mechanisms exist in humans. These operate by computing, for each familiar individual, a unitary regulatory variable (the kinship index) that corresponds to a pairwise estimate of genetic relatedness between self and other. The cues that the system uses were identified by quantitatively matching individual exposure to potential cues of relatedness to variation in three outputs relevant to the system's evolved functions: sibling altruism, aversion to personally engaging in sibling incest, and moral opposition to third party sibling incest. As predicted, the kin detection system uses two distinct, ancestrally valid cues to compute relatedness: the familiar other's perinatal association with the individual's biological mother, and duration of sibling coresidence.


Evolutionarily conserved sites in yeast tropomyosin function in cell polarity, transport and contractile ring formation.
Tropomyosin is a coiled-coil protein that binds and regulates actin filaments. The tropomyosin gene in Schizosaccharomyces pombe, cdc8, is required for formation of actin cables, contractile rings, and polar localization of actin patches. The roles of conserved residues were investigated in gene replacement mutants. The work validates an evolution-based approach to identify tropomyosin functions in living cells and sites of potential interactions with other proteins. A cdc8 mutant with near-normal actin affinity affects patch polarization and vacuole fusion, possibly by affecting Myo52p, a class V myosin, function. The presence of labile residual cell attachments suggests a delay in completion of cell division and redistribution of cell patches following cytokinesis. Another mutant with a mild phenotype is synthetic negative with GFP-fimbrin, inferring involvement of the mutated tropomyosin sites in interaction between the two proteins. Proteins that assemble in the contractile ring region before actin do so in a mutant cdc8 strain that cannot assemble condensed actin rings, yet some cells can divide. Of general significance, LifeAct-GFP negatively affects the actin cytoskeleton, indicating caution in its use as a biomarker for actin filaments.


[Atrial fibrillation in postoperative cardiac surgery. Prevalence and hospitalized period].
Atrial fibrillation is the most common heart rhythm disorder after cardiac surgery. In previous studies it has been associated with prolonged hospitalization, increased costs and mortality. This study aimed to determine the prevalence of postoperative atrial fibrillation in cardiac surgery and its impact on the hospitalization period. Medical records of consecutive patients undergoing cardiac surgery (coronary artery bypass graft, valvular, or both) between January 2006 and November 2008 were included and retrospectively analyzed. Primary outcome was the presence of postoperative atrial fibrillation. The sample was divided into two groups, with and without atrial fibrillation in the postoperative. The clinical variables and length of hospital stay were compared between both groups. A total of 172 patients underwent surgery in this period. Seven patients were excluded from analysis due to lack of data. The mean age was 64.2 +/- 9.5 years, and they were predominantly male. Atrial fibrillation was the most common complication (23.6%). The average length hospital stay was 6.7 +/- 4.6 days. There were no significant differences between both groups, with atrial fibrillation (7.5 +/- 4.1 days), and without (6.5 +/- 4.7 days), p = 0.21. The presence of atrial fibrillation did not prolong hospitalization. Probably, such strategy of prevention would not be cost-effective.


Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer.
Numerous components and pathways are involved in the complex interplay between cancer cells and their environment. The family of glycophosphoproteins comprising osteopontin, bone sialoprotein, dentin matrix protein 1, dentin sialophosphoprotein and matrix extracellular phosphoglycoprotein - small integrin-binding ligand N-linked glycoproteins (SIBLINGs) - are emerging as important players in many stages of cancer progression. From their detection in various human cancers to the demonstration of their key functional roles during malignant transformation, invasion and metastasis, the SIBLINGs are proteins with potential as diagnostic and prognostic tools, as well as new therapeutic targets.


Angiogenesis in endocrine tumors.
Angiogenesis is the process of new blood vessel development from preexisting vasculature. Although vascular endothelium is usually quiescent in the adult, active angiogenesis has been shown to be an important process for new vessel formation, tumor growth, progression, and spread. The angiogenic phenotype depends on the balance of proangiogenic growth factors such as vascular endothelial growth factor (VEGF) and inhibitors, as well as interactions with the extracellular matrix, allowing for endothelial migration. Endocrine glands are typically vascular organs, and their blood supply is essential for normal function and tight control of hormone feedback loops. In addition to metabolic factors such as hypoxia, the process of angiogenesis is also regulated by hormonal changes such as increased estrogen, IGF-I, and TSH levels. By measuring microvascular density, differences in angiogenesis have been related to differences in tumor behavior, and similar techniques have been applied to both benign and malignant endocrine tumors with the aim of identification of tumors that subsequently behave in an aggressive fashion. In contrast to other tumor types, pituitary tumors are less vascular than normal pituitary tissue, although the mechanism for this observation is not known. A relationship between angiogenesis and tumor size, tumor invasiveness, and aggressiveness has been shown in some pituitary tumor types, but not in others. There are few reports on the role of microvascular density or angiogenic factors in adrenal tumors. The mechanism of the vascular tumors, which include adrenomedullary tumors, found in patients with Von Hippel Lindau disease has been well characterized, and clinical trials of antiangiogenic therapy are currently being performed in patients with Von Hippel Lindau disease. Thyroid tumors are more vascular than normal thyroid tissue, and there is a clear correlation between increased VEGF expression and more aggressive thyroid tumor behavior and metastasis. Although parathyroid tissue induces angiogenesis when autotransplanted and PTH regulates both VEGF and MMP expression, there are few studies of angiogenesis and angiogenic factors in parathyroid tumors. An understanding of the balance of angiogenesis in these vascular tumors and mechanisms of vascular control may assist in therapeutic decisions and allow appropriately targeted treatment.


Detection of thyroglobulin, thyroid peroxidase, and RET/PTC1 mRNA transcripts in the peripheral blood of patients with thyroid disease.
Detection of mRNA transcripts for thyroglobulin (TG), thyroid peroxidase (TPO) and RET/PTC1 in the peripheral blood of patients with thyroid disease. TG, TPO, and RET/PTC1 mRNA were analyzed in 52 peripheral-blood samples from 44 patients diagnosed with thyroid carcinoma (24 patients), adenoma (five patients), and nodular hyperplasia (15 patients) by reverse transcription-polymerase chain reaction (RT-PCR). TG and TPO were identified in 13 patients (54.2%) with thyroid carcinoma, which includes five of eight patients with no clinical evidence of disease at the time of blood collection. Four of 5 patients had cervical lymph node metastases and/or extrathyroid extension at the time of the initial surgery. RET/PTC1 mRNA was detected in the peripheral blood of only one patient with papillary thyroid carcinoma. This sample was also positive for TG and TPO. TG and TPO were detected in two patients (10%) with benign thyroid nodules. All positive samples from patients with benign thyroid lesions were collected before surgery, whereas all samples collected after surgery were negative. RET/PTC1 mRNA was not detected in any of the patients with benign thyroid nodules. RT-PCR positivity for TG and TPO mRNA was higher in patients with carcinoma than in patients with benign lesions (P = .002). TG, TPO, and RET/PTC1 mRNA are detectable in the peripheral blood of patients with thyroid disease, which correlates with a diagnosis of carcinoma.


[The prognosis of the late results of vagotomy and dispensary care in patients with duodenal peptic ulcer].
The article studies the remote results of vagotomy in treatment of 212 servicemen with ulcer of duodenum. Laboratory, endoscopic, roentgenological, pH-metric, manometric, radioimmunological and morphological researches were used before and after operations. From the point of view of prognostication 30 important criteria were selected to forecast the results of vagometry, and also to determine the groups for control examination. These data made it possible to prognosticate the right outcomes of treatment in 84.7% of cases, and thus individualize the treatment and prophylaxis of the prior disease and postvagotomy syndromes reducing their frequency. In the results of these measures the cases of invalidity and disability retirement of servicemen were diminished.


Non-invasive Evaluation for Epilepsy Surgery.
Epilepsy surgery is aimed to remove the brain tissues that are indispensable for generating patient's epileptic seizures. There are two purposes in the pre-operative evaluation: localization of the epileptogenic zone and localization of function. Surgery is planned to remove possible epileptogenic zone while preserving functional area. Since no single diagnostic modality is superior to others in identifying and localizing the epileptogenic zone, multiple non-invasive evaluations are performed to estimate the location of the epileptogenic zone after concordance between evaluations. Essential components of non-invasive pre-surgical evaluation of epilepsy include detailed clinical history, long-term video-electroencephalography monitoring, epilepsy-protocol magnetic resonance imaging (MRI), and neuropsychological testing. However, a significant portion of drug-resistant epilepsy is associated with no or subtle MRI lesions or with ambiguous electro-clinical signs. Additional evaluations including fluoro-deoxy glucose positron emission tomography (FDG-PET), magnetoencephalography and ictal single photon emission computed tomography can play critical roles in planning surgery. FDG-PET should be registered on three-dimensional MRI for better detection of focal cortical dysplasia. All diagnostic tools are complementary to each other in defining the epileptogenic zone, so that it is always important to reassess the data based on other results to pick up or confirm subtle abnormalities.


Pivmecillinam plus pivampicillin in urinary tract infections: a randomized, open comparison with co-trimoxazole in hospitalized patients.
The efficacy and tolerance of a fixed-dose combination of 200 mg pivmecillinam and 250 mg pivampicllin was compared with that of co-trimoxazole (800 mg sulphamethoxazole plus 160 mg trimethoprim) in 42 hospital in-patients with complicated urinary tract infections. Patients received a 10-day course of tablets of either agent twice daily. The infecting organisms, which were Enterobacteriaceae (79%) and enterococci (21%), were eradicated in 17(89%) of the 19 patients given co-trimoxazole and in all 23 subjects who received pivmecillinam/pivampicillin. Sixteen (89%) of the 18 symptomatic patients responded clinically to co-trimoxazole. Pivmecillinam/pivampicillin was effective in 19 (95%) of 20 patients with symptomatic infections. There was a fairly good correlation between the bacteriological and clinical responses. No serious side-effects were recorded and all patients completed the prescribed course of treatment.


Low dose recombinant full-length circumsporozoite protein-based Plasmodium falciparum vaccine is well-tolerated and highly immunogenic in phase 1 first-in-human clinical testing.
Plasmodium falciparum circumsporozoite protein (CSP) is a major sporozoite surface protein and a key target of pre-erythrocytic malaria subunit vaccines. A full-length recombinant CSP (rCSP) based strategy could be advantageous, as this antigen includes a region critical to sporozoite cell attachment and hepatocyte invasion. The adjuvant Glucopyranosyl Lipid A-liposome Quillaja saponaria 21 (GLA-LSQ) functions as a TLR4 agonist, promotes antigen-specific TH1 responses and stimulates cytotoxic T cell production. To date, one study has reported the clinical acceptability of GLA-LSQ. We present interim results of a phase 1 first-in-human dose-escalation clinical trial of full-length rCSP vaccine given with or without GLA-LSQ adjuvant. Participants experienced only mild to moderate related solicited adverse events. The lowest adjuvanted vaccine dose achieved >90-fold rise in geometric mean anti-CSP IgG antibody titer. These favorable safety and immunogenicity results confirm the immunostimulatory capacity of this relatively new adjuvant and support next steps in clinical product development. Trial registration: ClinicalTrials.gov Identifier NCT03589794 (registered 18 July 2018).


Conversion from Intravenous Vitamin D Analogs to Oral Calcitriol in Patients Receiving Maintenance Hemodialysis.
In the United States, intravenous vitamin D analogs are the first-line therapy for management of secondary hyperparathyroidism in hemodialysis patients. Outside the United States, oral calcitriol (1,25-dihydroxyvitamin D3) is routinely used. We examined standard laboratory parameters of patients on in-center hemodialysis receiving intravenous vitamin D who switched to oral calcitriol. We conducted a retrospective cohort study of adult patients treated within Fresenius Kidney Care clinics. During a 6-month period (December 2013 to May 2014), we identified patients on an intravenous vitamin D analog (doxercalciferol or paricalcitol) who switched to oral calcitriol and matched them to patients receiving an intravenous vitamin D analog. Mean serum calcium, phosphate, and intact parathyroid hormone (iPTH) concentrations were examined for up to 12 months of follow-up. We used Poisson and Cox proportional hazards regression models to examine hospitalization and survival rates. The primary analysis was conducted as intention-to-treat; secondary analyses included an as-treated evaluation. A total of 2280 patients who switched to oral calcitriol were matched to 2280 patients receiving intravenous vitamin D. Compared with patients on intravenous vitamin D, mean calcium and phosphate levels in the oral calcitriol group were lower after the change to oral calcitriol. In contrast, iPTH levels were higher in the oral calcitriol group. At 12 months, the percentage of patients with composite laboratories in target range (calcium <10 mg/dl, phosphate 3.0-5.5 mg/dl, and iPTH 150-600 pg/ml) were comparable between groups (45% versus 45%; P=0.96). Hospital admissions, length of hospital stay, and survival were comparable between groups. An as-treated analysis and excluding those receiving cinacalcet did not reveal significant between-group differences. Among patients receiving in-center hemodialysis who were switched to oral calcitriol versus those on an intravenous vitamin D analog, the aggregate of all mineral and bone laboratory parameters in range was largely similar between groups.


Gd-DTPA-enhanced MR imaging of cryptococcal meningoencephalitis.
This report describes magnetic resonance (MR) imaging of biopsy-proved cryptococcal central nervous system (CNS) infection in a 31-year-old HIV negative man. Initial MR imaging revealed multi-focal Gd-DTPA enhancement and showed more lesions than contrast enhanced CT. The lesions regressed after antifungal therapy. MR imaging aids in diagnosis as well as helps to monitor the response to the pharmacological therapy of cryptococcal meningoencephalitis and possibly provides valuable insights into the pathophysiology of this condition.


Hydration, thermoregulation, and performance effects of two sport drinks during soccer training sessions.
In the present study, we aimed to compare the thermoregulatory response and soccer-specific training performance aspects of two commercially available sport drinks, both of similar carbohydrate concentration, but one containing 5.2% glycerol. Ten players participated in two similar outdoor training sessions and were randomly assigned to each of two drinks: a carbohydrate (C) beverage or a carbohydrate-glycerol (CG) beverage. Players consumed 500 mL of C or CG 30 minutes pre-exercise and at half-time. Pre- and postexercise body mass, core temperature (CT), and heart rate (HR) were recorded, and urine and blood samples were taken. No difference was observed between days for wet bulb globe temperature (session 1: 17.0 +/- 1.1 degrees C, session 2: 16.9 +/- 1.1 degrees C; P = 0.944). The degree of dehydration (% Delta BM) was greater after the C trial (P = 0.041). Similarly, percent change in plasma volume was greater in the C trial (P = 0.049). No overall main affect was observed between CT and mean exercise HRs during either training session (CT: P = 0.350; mean HR: P = 0.256), and there was no difference observed between groups in time to failure during the session-ending fatigue test (P = 0.547). Ingestion of a CG beverage provided players with better hydration than C alone. However, if training sessions are short (<75 minute), with adequate time for recovery, both drinks are sufficient for maintaining performance intensities during soccer-specific training.