Remote nailing of intertrochanteric and subtrochanteric fractures of the femur.
Remote nailing of intertrochanteric and subtrochanteric fractures of the femur is a definite addition to the armamentarium in the management of these injuries. The advantages of the technique are too great to ignore. The surgeon should not be misled, however, into thinking that this is an easy operation or that it represents a panacea for difficult fracture situations. Considerable time must be spent learning the operative technique, its pitfalls and complications, and the postoperative management of patients. After the operation we allow our patients early weight bearing in the knee-extended position, this being maintained by the use of a Jones bandage. We believe that the prevention of knee flexion minimizes stresses across the fracture site and prevents the tendency toward external rotation. Early external rotation deformity in the patient lying in bed may cause concern, but this tendency toward external rotation disappears as soon as the patient begins to walk and bear weight. In the patient with the fracture anatomically reduced and fixed a significant external rotation will not be a problem. The use of remote nailing does not eliminate complications in the surgical treatment of intertrochanteric fractures but merely replaces one set of complications for another. It is our belief that the complications arising from remote nailing in intertrochanteric and subtrochanteric fractures are of less severity to the patient and more easily managed by the surgeon than the more traditional complications occurring as a result of direct attack on the fracture site with the implantation of various nail plate devices. Lower blood loss, shorter operating time, decreased incidence of infection, earlier walking, extremely high rate of union, and extremely low rate of implant failure are sufficient returns for occasional shortening and occasional external rotation deformity, the two complications most frequently mentioned in the literature. Excessive deformity, failure of fixation, and pin migration either proximally or distally are attributable to poor technique (with the system) and are not inherent defects of the method itself. As a relatively unbiased observer I find praise and fault with both techniques and am not in a position to recommend one over the other for any given surgeon or any given fracture. The concept advanced by both Ender and Harris, however, is sound and if used correctly can improve the overall care of the unfortunate patient who suffers an intertrochanteric fracture of the femur.


Time Spent in Practicing Dissection Correlated with Improvement in Anatomical Knowledge of Students: Experimental Study in an Integrated Learning Program.
Introduction and aim Cadaveric dissection has long been used as the main domain for teaching anatomy in medical schools. However, recently with a limited number of cadavers and time for practicing dissection, prosections and anatomical models are widely used and may replace traditional dissection. We aimed to explore the possible association between practicing dissection and test results among medical students and to determine whether there are differences in achievements between students who studied anatomy by cadaveric dissection and those who used prosections and anatomical models. Methods The study was conducted at the University of Bisha, College of Medicine, Saudi Arabia, during the period from March to August 2017. Students were randomly assigned to one of two groups (50 in each). The first group studied anatomy (upper limb course) by practicing dissection while the other studied it by using prosections and anatomical models. Both groups were subjected to the same final assessments. Scores of both groups were compared by using the Student's t-test. Correlation analysis between time spent in practicing dissection (carefully registered using a predesigned portfolio and an attendance logbook) and assessment grades was implemented using the rank-based Pearson correlation coefficient. Results Students practicing dissection achieved higher grades (169 ± 1.99) than those who studied anatomy by only using prosections and anatomical models (142 ± 1.78, p<0.001). There was an association between the time spent in practicing dissections and overall anatomy summative assessments (r2=0.841, p<0.001). Students expressed positive responses towards the effectiveness and value of practicing dissection. Conclusions We concluded that practicing dissection helps students to achieve higher results than learning using only models and prosections. Time spent in practicing dissection correlated with final assessment results. Further research is required to measure not only the statistical significance of results but also their educational effectiveness and long term learning outcomes.


Polyelectrolyte-induced reduction of exfoliated graphite oxide: a facile route to synthesis of soluble graphene nanosheets.
Here we report that poly(diallyldimethylammonium chloride) (PDDA) acts as both a reducing agent and a stabilizer to prepare soluble graphene nanosheets from graphite oxide. The results of transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, atomic force microscopy, and Fourier transform infrared indicated that graphite oxide was successfully reduced to graphene nanosheets which exhibited single-layer structure and high dispersion in various solvents. The reaction mechanism for PDDA-induced reduction of exfoliated graphite oxide was proposed. Furthermore, PDDA facilitated the in situ growth of highly dispersed Pt nanoparticles on the surface of graphene nanosheets to form Pt/graphene nanocomposites, which exhibited excellent catalytic activity toward formic acid oxidation. This work presents a facile and environmentally friendly approach to the synthesis of graphene nanosheets and opens up a new possibility for preparing graphene and graphene-based nanomaterials for large-scale applications.


Effect of 810 nm light on nerve regeneration after autograft repair of severely injured rat median nerve.
Destruction of large segments of peripheral nerves results in chronic loss of sensation and paralysis. For this type of severe injury, the defect can be bridged by nerve grafts. However, even with state-of-the-art microsurgical techniques, there is minimal recovery of sensation and motor function. Light therapy (LT) has been shown to improve functional outcome after surgical intervention to repair injured nerves using different techniques. Our objective was to investigate the effect of LT on peripheral nerve regeneration and function after severe median nerve injury and microsurgical autologous nerve graft repair using fibrin glue. Adult female Sprague Dawley rats were used for this study. A 6-7 mm segment of the median nerve was excised and sural nerve segments from the same animal were used to bridge the gap using fibrin-based sealant. There were three experimental groups: control, autograft (AG), and autograft + LT (AG + LT). The AG + LT group received LT at the surgery site for 14 consecutive days using an 810 nm wavelength diode laser. Functional recovery was assessed bi-weekly by the grip strength test. Compound muscle action potential (CMAP) measurements were taken pre-injury and at 16 weeks post-surgery. Optical density measurement of S-100 immunoreactivity was done on the transplanted segment of the nerve. The AG + LT group had faster functional recovery of grip strength (P < 0.05), shorter CMAP latency (P < 0.05), and higher S-100 immunoreactivity (P = 0.0213) when compared to the AG group. However, at 15 weeks, grip strength in both the AG and AG + LT groups, while significantly improved, were still below control levels. These results suggest that LT can accelerate functional recovery and improve the quality of nerve regeneration after autograft repair of severely injured peripheral nerves.


Hypoxia imaging with 18F-FAZA PET/CT predicts radiotherapy response in esophageal adenocarcinoma xenografts.
Esophageal cancer is an aggressive disease with poor survival rates. A more patient-tailored approach based on predictive biomarkers could improve outcome. We aimed to predict radiotherapy (RT) response by imaging tumor hypoxia with 18F-FAZA PET/CT in an esophageal adenocarcinoma (EAC) mouse model. Additionally, we investigated the radiosensitizing effect of the hypoxia modifier nimorazole in vitro and in vivo. In vitro MTS cell proliferation assays (OACM5 1.C SC1, human EAC cell line) were performed under normoxic and hypoxic (< 1%) conditions: control (100 μL PBS), nimorazole, irradiation (5, 10 or 20 Gy) with or without nimorazole. In vivo, subcutaneous xenografts were induced in nude mice (OACM5 1.C SC1). Treatment was given daily for 5 consecutive days: (A) control (600 μl NaCl 0.9% intraperitoneally (IP)) (N = 5, n = 7), (B) RT (5 Gy/d) (N = 11, n = 20), (C) combination (nimorazole (200 mg/kg/d IP) 30 min before RT) (N = 13, n = 21). N = number of mice, n = number of tumors. 18F-FAZA PET/CT was performed before treatment and tumor to background (T/B) ratios were calculated. Relative tumor growth was calculated and tumor sections were examined histologically (hypoxia, proliferation). A T/B ≥ 3.59 on pre-treatment 18F-FAZA PET/CT was predictive for worse RT response (sensitivity 92.3%, specificity 71.4%). Radiation was less effective in hypoxic tumors (T/B ≥ 3.59) compared to normoxic tumors (T/B < 3.59) (P = 0.0025). In vitro, pre-treatment with nimorazole significantly decreased hypoxic radioresistance (P < 0.01) while in vivo, nimorazole enhanced the efficacy of RT to suppress cancer cell proliferation in hypoxic tumor areas (Ki67, P = 0.064), but did not affect macroscopic tumor growth. Tumor tissue hypoxia as measured with 18F-FAZA PET/CT is predictive for RT response in an EAC xenograft model. The radiosensitizing effect of nimorazole was questionable and requires further investigation.


Posttransplantation bone marrow assessment by quantifying hematopoietic cell-derived mRNAs in plasma exosomes/microvesicles.
Bone marrow (BM) aspiration often can be a painful medical procedure. It is unavoidable, however, because hematopoietic precursor cells (HPC) exist only in BM and few escape to peripheral blood (PB). We hypothesized that HPCs might release exosomes and microvesicles (EMV) in BM, and the resulting EMV would penetrate into PB. Such BM-derived EMV might be identified in PB by measuring specific mRNAs produced by HPC. Human plasma was applied to an EMV-capture filter plate. After centrifugation, captured EMV were lysed on the filter plate. Resulting lysates were transferred to an oligo(dT)-immobilized microplate for mRNA isolation followed by reverse transcription PCR (RT-PCR). Using this system, myeloid-, erythroid-, and megakaryocyte-lineage-specific poly(A)(+) mRNAs were quantified in plasma obtained from 18 patients who had undergone hematopoietic stem cell transplantation (HSCT). When fluorescent liposomes were applied to the filter plate, more than 95% of applied liposomes were absorbed. When human plasma was applied, a scanning electron microscope showed EMV-like particles on the membrane of the filter plate. After RT-PCR, various HPC-specific mRNAs were detected, and the results were equivalent to those derived from the standard ultracentrifugation method. The levels of these mRNAs were undetectable after HSCT and became detectable 1-2 weeks after HSCT, a substantially earlier time point than with traditional hematological analysis. The recovery of EMV mRNA at day 15 corresponded to the final clinical outcome at day 180. HPC-derived mRNAs in plasma EMV may represent new biomarkers for the assessment of BM condition and could reduce the necessity for frequent BM aspiration.


Weight Loss-Independent Effect of Liraglutide on Insulin Sensitivity in Individuals with Obesity and Pre-Diabetes.
Metabolic effects of glucagon-like peptide-1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We tested the hypothesis that GLP-1 receptor (GLP-1R) agonists exert weight loss-independent, GLP-1Rdependent effects that differ from effects of increasing endogenous GLP-1. Individuals with obesity and pre-diabetes were randomized to 14 weeks of the GLP-1R agonist liraglutide, hypocaloric diet, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The GLP-1R antagonist exendin (9-39) and placebo were administered in a two-by-two crossover study during mixed meal tests. Liraglutide and diet, but not sitagliptin, caused weight loss. Liraglutide improved insulin sensitivity measured by HOMA-IR, HOMA2 and the Matsuda index after two weeks, prior to weight loss. Liraglutide decreased fasting and post-prandial glucose, decreased insulin and C-peptide, and decreased fasting glucagon. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not Matsuda index, and did not decrease glucose. Sitagliptin increased endogenous GLP-1 and GIP without altering insulin sensitivity or fasting glucose, but decreased post-prandial glucose and glucagon. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose in all groups, increased Matsuda index and fasting glucagon during liraglutide, and increased endogenous GLP-1 during liraglutide and sitagliptin. Thus, liraglutide exerts rapid, weight lossindependent, GLP-1R-dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1.


Proximal focal humeral deficiency in a large breed dog.
A 26-week-old female Boerboel was referred for evaluation of progressive left thoracic limb lameness. Computed tomography and radiographic evaluation revealed radiolucency of the caudal region of the proximal humeral metaphysis, absence of the humeral head, and gross distortion of the glenoid. Given the severe glenohumeral deformation, arthrodesis of the left shoulder was performed using orthogonal locking bone plates, lag screw fixation, and bone grafting. Despite late implant failure, arthrodesis was successful in this case, and satisfactory limb function was restored. To the author's knowledge, this is the first report of a case of a focal developmental deficiency of the proximal humerus reported in a dog.


Genotoxic activity of nitroarene-contaminated industrial sludge following large-scale treatment in aerated and non-aerated sacs.
An industrial sludge containing a complex mixture of nitroaromatic compounds was treated in industrial large-scale aerobic and anaerobic biodegradation processes, performed in compost sacs. The goal was to study changes in genotoxicity during the two different oxygen regimes using the umuC genotoxicity assay. The composting sac was actively aerated during 3 months and allowed to mature for another 3 months. The anaerobic sac was not aerated for 5 months and aerated during the last month in order to enhance degradation of remaining organic carbon. The sludge was obtained from the wastewater treatment plant at an industrial area in Karlskoga, Sweden. The biodegradation study was performed at a commercial waste treatment plant in Stockholm, according to the company routine procedure when treating household waste in sealed sacs. The material from the non-aerated system showed increased genotoxicity in the acetone-soluble fraction after treatment, as did the water-soluble fraction. The subsequent aeration period did not decrease the toxicity below the genotoxicity limit. The increase in the water-soluble genotoxic compounds may pose an environmental problem during secondary storage or use of sludge treated this way, since leakage of water-dissolved genotoxic compounds may occur. The composting process also generated genotoxicity, but this was restricted to acetone-soluble compounds, while the water-soluble compounds remained low in genotoxicity. The aerated process therefore seems more favorable in term of risk reduction of this industrial sludge, although it is necessary to optimize the aerated process in order to achieve non-toxic levels of potential genotoxic compounds extractable by organic solvents.


Neuronal mechanisms of respiratory rhythm generation: an approach using in vitro preparation.
The respiratory network in the ventrolateral medulla of the brainstem-spinal cord preparation from newborn rat involves pre-inspiratory (Pre-I) neurons, three types of inspiratory (Insp I, II, III) neurons and two types of expiratory (Exp-i, Exp-p-i) neurons as major subtypes, which were classified according to patterns of postsynaptic potentials. The neuronal respiratory-related membrane potential fluctuations of these cells indicate at least four distinguishable phases of the in vitro respiratory cycle: pre-inspiratory, inspiratory, post-inspiratory (E1), and late-expiratory (E2). A current hypothesis for the central pattern generator of respiration proposed by our group is that Pre-I neurons in the rostral ventrolateral medulla, with intrinsic burster properties, produce the primary respiration rhythm. This rhythm triggers an inspiratory pattern generator composed of Insp neurons in the rostral and caudal ventrolateral medulla. Respiratory neurons possess several types of ionic channels which are involved in the generation of rhythm and burst pattern. Particularly, P-type Ca2+ channels and TTX-sensitive persistent Na+ channels are postulated to contribute to the intrinsic burst generation of Pre-I neurons. N-type Ca2+ channels may be involved in the maintenance and termination of inspiratory burst activity via the activation of Ca2(+)-dependent K+ channels. Respiratory neuron networks in this preparation were compared with those of different in vitro preparations, like rhythmic slices or perfused brainstems and of adult mammals in vivo. Many types of synaptic connections among respiratory neurons in adult mammals were also found in the (rostral) ventrolateral medulla of a brainstem-spinal cord preparation from newborn rat. The characteristics of the inspiratory burst pattern and inspiratory off switch mechanisms in newborn rat preparations might be explained by insufficient inhibitory (or excitatory) synaptic inputs to the inspiratory pattern generator due to an immature neuron network and/or deafferentiation.


Case-based considerations in the treatment of actinic keratoses: utilizing combination or sequential therapy with 5-fluorouracil cream and destructive treatments.
Dermatologic conditions associated with prolonged sun exposure represent a substantial portion of visits to the dermatologist's office, particularly among elderly populations. Actinic keratoses are premalignant lesions that increase in frequency with each decade of life and have the potential to progress to squamous cell carcinoma. Non-melanoma skin cancers, such as squamous cell carcinoma and basal cell carcinoma, also represent sun-related conditions that require early and aggressive treatment. Therapeutic options for these conditions are abundant and range from topical field-directed therapies to destructive, lesion-directed procedures. Choice of therapy depends on the types and extent of lesions with which a patient presents; often, a combination of treatments provides the optimal means for successful outcomes. The following case-based review represents typical situations where multiple treatments were combined to manage actinic keratosis, squamous cell carcinoma and basal cell carcinoma in patients over an extended treatment period.


Formation of taste-active amino acids, amino acid derivatives and peptides in food fermentations - A review.
Fermented foods are valued for their rich and complex odour and taste. The metabolic activity of food-fermenting microorganisms determines food quality and generates odour and taste compounds. This communication reviews the formation of taste-active amino acids, amino acid derivatives and peptides in food fermentations. Pathways of the generation of taste compounds are presented for soy sauce, cheese, fermented meats, and bread. Proteolysis or autolysis during food fermentations generates taste-active amino acids and peptides; peptides derived from proteolysis particularly impart umami taste (e.g. α-glutamyl peptides) or bitter taste (e.g. hydrophobic peptides containing proline). Taste active peptide derivatives include pyroglutamyl peptides, γ-glutamyl peptides, and succinyl- or lactoyl amino acids. The influence of fermentation microbiota on proteolysis, and peptide hydrolysis, and the metabolism of glutamate and arginine is well understood, however, the understanding of microbial metabolic activities related to the formation of taste-active peptide derivatives is incomplete. Improved knowledge of the interactions between taste-active compounds will enable the development of novel fermentation strategies to develop tastier, less bitter, and low-salt food products, and may provide novel and "clean label" ingredients to improve the taste of other food products.


Tandem mass spectrometry determined maternal cortisone to cortisol ratio and psychiatric morbidity during pregnancy-interaction with birth weight.
Maternal serum cortisol has been suggested to be influenced by psychiatric morbidity, and may also influence fetal growth. However, several studies found equal cortisol levels in depressed and healthy pregnant women. Placental 11-β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) shields the fetus from maternal cortisol by conversion to cortisone, a function that may be compromised by maternal stress. We aimed to compare the serum ratio of cortisone to cortisol, in women with and without psychiatric morbidity during pregnancy. A secondary aim was to investigate whether fetal growth, approximated by infant birth weight, was associated with the cortisone to cortisol ratio. We performed tandem mass spectrometry analysis of serum cortisol and cortisone in late pregnancy in 94 women with antenatal psychiatric morbidity and 122 controls (cohort 1). We also compared the placental gene expression of HSD11B1 and 2 in another group of 69 women with psychiatric morbidity and 47 controls (cohort 2). There were no group differences in cortisol to cortisone ratio, absolute levels of cortisone and cortisol (cohort 1), or expression of HSD11B1 or 2 (cohort 2). However, cortisone to cortisol ratio was positively associated with birth weight in women with psychiatric morbidity, also after adjustment for gestational length, fetal sex, maternal height, smoking, SSRI use, and time of blood sampling (standardized β=0.35, p<0.001), with no association in the healthy controls Thus, the maternal serum cortisone to cortisol ratio does not seem to be affected by psychiatric morbidity, but psychiatric morbidity may increase fetal exposure to cortisol or other metabolic factors influencing fetal growth.


Regional cerebral blood flow during tinnitus: a PET case study with lidocaine and auditory stimulation.
Brain imaging of tinnitus has suggested central correlates of tinnitus perception. This study presents positron emission tomographic (PET) measurements of regional cerebral blood flow (rCBF) in a female tinnitus patient with bilateral left dominant tinnitus. Lidocaine infusion (75 mg during 5 min (0.2 mg/kg/min)) resulted in a 75% reduction of tinnitus and a temporary abolition of the dominant tinnitus in her left ear. Regional CBF was measured in four conditions: i) at rest while concentrating on tinnitus, ii) following maximum effect of lidocaine, iii) during sound stimulation, and iv) the following day at rest while concentrating on tinnitus. Subtraction analyses showed that tinnitus was associated with increased rCBF in the left parieto-temporal auditory cortex, including the primary and secondary auditory cortex with a focus in the parietal cortex (Brodmann areas 39, 41, 42, 21, 22). Activations were also found in right frontal paralimbic areas (Brodmann areas 47, 49 and 15). Sound stimulation resulted in bilateral activation of auditory areas. It is suggested that tinnitus is processed in primary, secondary and integrative auditory cortical areas. Tinnitus perception may involve areas related to auditory attention, while emotional processing relates to temporofrontal paralimbic areas.


[Sarcoidosis and sarcoid-like granulomas in the liver].
Based on examination of 2450 liver biopsy specimens it has been shown that different granulomas occur in 4% of all the biopsy specimens. Of these, sarcoid-like granulomas are detectable in 13.5% of cases. Diagnosis of liver sarcoidosis is always based on the clinicomorphological findings with regard to an injury to at least of one more organ or tissue characteristic for such a disease. Sarcoid impairment of the liver is not infrequently coupled with chronic liver disease. The greatest difficulties may occur in differential diagnosis between primary biliary cirrhosis and sarcoidosis.


Unexpected Infant Death Due to Undiagnosed Biliary Atresia: A Case of Fatal Neglect.
Biliary atresia (BA) is a fatal condition resulting in the lack of effective biliary drainage leading invariably to liver failure and cirrhosis within a year, and it is often lethal within a few months in the absence of corrective surgery or liver transplantation. In fact, BA is the most common indication for pediatric liver transplantation.Herein, we present a rare case of unexpected infant death due to BA diagnosed only postmortem in a context of child neglect and carelessness on the part of the parents. It emerged from the clinical history that after a few months, the parents no longer took their daughter to any medical checkups despite the indications and express recommendations for follow-up. The autopsy revealed agenesis of the gallbladder with BA and complete disruption of the hepatic architecture and parenchyma from biliary cirrhosis. Histological examinations documented severe biliary cirrhosis from hypoplasia of the biliary ducts.The child neglect in this case proved fatal inasmuch as an early diagnosis by a pediatrician would have likely allowed appropriate surgical treatment, thus avoiding the untimely death of the child. We highlight the importance of educating and informing parents (especially the disadvantaged) in matters of health. At the same time, primary care physicians should closely monitor the conditions and development of infants so as to recognize the early warning signs and symptoms of BA, bearing in mind that a timely diagnosis and proper surgical treatment can save the lives of most of these children.


Point-of-care diagnostics: needs of African health care workers and their role combating global antimicrobial resistance.
Point-of-care tests (POCTs) offer the opportunity for increased diagnostic capacity in resource-limited settings, where there is lack of electricity, technical capacity, reagents, and infrastructure. Understanding how POCTs are currently used and determining what health care workers (HCWs) need is key to development of appropriate tests. In 2016, we undertook an email survey of 7584 HCWs who had received training at the Infectious Diseases Institute, Uganda, in a wide variety of courses. HCWs were contacted up to three times and asked to complete the survey using Qualtrics software. Of 555 participants answering the survey (7.3% response rate), 62% completed. Ninety-one percent were from Uganda and 50.3% were male. The most commonly-used POCTs were pregnancy tests (74%), urine dipstick (71%), syphilis rapid test (66%), and Gram stain (41%). The majority (74%) practiced syndromic diagnosis for sexually transmitted infections/HIV. Lack of availability of POCTs, increased patient wait time, and lack of training were the leading barriers for POCT use. Increasing POCT availability and training could improve uptake of POCTs for sexually transmitted infections in Africa and decrease syndromic management. This could reduce overtreatment and slow the emergence of antibiotic resistance. This is the first published email survey of HCWs in Uganda; mechanisms to increase the response rate should be evaluated.


The Effect of Code-Switching Experience on the Neural Response Elicited to a Sentential Code Switch.
Switching between languages, or codeswitching, is a cognitive ability that multilinguals can perform with ease. This study investigates whether codeswitching during sentence reading affects early access to meaning, as indexed by the robust brain response called the N400. We hypothesize that the brain prioritizes the meaning of the word during comprehension with codeswitching costs emerging at a different stage of processing. Event-related potentials (ERPs) were recorded while Spanish-English balanced bilinguals (n = 24) read Spanish sentences containing a target noun that could create a semantic violation, codeswitch or both. Self-reported frequency of daily codeswitching was used as a regressor to determine if the cost of reading a switch is modulated by codeswitching experience. A robust N400 to semantic violations was followed by a late positive component (LPC). Codeswitches modulated the left anterior negativity (LAN) and LPC, but not the N400, with codeswitched semantic violations resulting in a sub-additive interaction. Codeswitching experience modulated the LPC, but not the N400. The results suggest that early access to semantic memory during comprehension happens independent of the language in which the words are presented. Codeswitching affects a separate stage of comprehension with switching experience modulating the brain's response to experiencing a language switch.


Innate immunity in HIV-1 infection: epithelial and non-specific host factors of mucosal immunity- a workshop report.
The interplay between HIV-1 and epithelial cells represents a critical aspect in mucosal HIV-1 transmission. Epithelial cells lining the oral cavity cover subepithelial tissues, which contain virus-susceptible host cells including CD4(+) T lymphocytes, monocytes/macrophages, and dendritic cells. Oral epithelia are among the sites of first exposure to both cell-free and cell-associated virus HIV-1 through breast-feeding and oral-genital contact. However, oral mucosa is considered to be naturally resistant to HIV-1 transmission. Oral epithelial cells have been shown to play a crucial role in innate host defense. Nevertheless, it is not clear to what degree these local innate immune factors contribute to HIV-1 resistance of the oral mucosa. This review paper addressed the following issues that were discussed at the 7th World Workshop on Oral Health and Disease in AIDS held in Hyderabad, India, during November 6-9, 2014: (i) What is the fate of HIV-1 after interactions with oral epithelial cells?; (ii) What are the keratinocyte and other anti-HIV effector oral factors, and how do they contribute to mucosal protection?; (iii) How can HIV-1 interactions with oral epithelium affect activation and populations of local immune cells?; (iv) How can HIV-1 interactions alter functions of oral epithelial cells?


Stilbene compound trans-3,4,5,4´-tetramethoxystilbene, a potential anticancer drug, regulates constitutive androstane receptor (Car) target genes, but does not possess proliferative activity in mouse liver.
The constitutive androstane receptor(CAR) activation is connected with mitogenic effects leading to liver hyperplasia and tumorigenesis in rodents. CAR activators, including phenobarbital, are considered rodent non-genotoxic carcinogens. Recently, trans-3,4,5,4´-tetramethoxystilbene(TMS), a potential anticancer drug (DMU-212), have been shown to alleviate N-nitrosodiethylamine/phenobarbital-induced liver carcinogenesis. We studied whether TMS inhibits mouse Car to protect from the PB-induced tumorigenesis. Unexpectedly, we identified TMS as a murine CAR agonist in reporter gene experiments, in mouse hepatocytes, and in C57BL/6 mice in vivo. TMS up-regulated Car target genes Cyp2b10, Cyp2c29 and Cyp2c55 mRNAs, but down-regulated expression of genes involved in gluconeogenesis and lipogenesis. TMS did not change or down-regulate genes involved in liver proliferation or apoptosis such as Mki67, Foxm1, Myc, Mcl1, Pcna, Bcl2, or Mdm2, which were up-regulated by another Car ligand TCPOBOP. TMS did not increase liver weight and had no significant effect on Ki67 and Pcna labeling indices in mouse liver in vivo. In murine hepatic AML12 cells, we confirmed a Car-independent proapoptotic effect of TMS. We conclude that TMS is a Car ligand with limited effects on hepatocyte proliferation, likely due to promoting apoptosis in mouse hepatic cells, while controlling Car target genes involved in xenobiotic and endobiotic metabolism.


Cranberry supplementation in the prevention of non-severe lower urinary tract infections: a pilot study.
Cranberry extracts have been tested as a nutritional supplementation in the prevention of recurrent lower-urinary tract infections (R-UTIs), with mixed results. This pilot, registry study evaluates the prophylactic effects of oral supplementation with a new well-standardized cranberry extract in patients with R-UTI, over a 2-month follow-up. All subjects were suggested to take one capsule containing a cranberry extract (Anthocran™) for 60 days and were also given lifestyle advice. Clinical outcomes were compared between patients on cranberry extracts and those who don't take this supplementation. In total, 22 subjects completed the study in each of the two groups. In the cranberry group, the reduction in the frequency of UTI episodes during the study period compared with the two months before the inclusion was 73.3% (p < 0.05). This figure was 15.4% in the control group (p < 0.05; p = 0.012 vs cranberry group). Seven (31.8%) subjects in the cranberry group were symptom-free; no patient was symptom-free in the control group (p < 0.05). The mean duration of UTI episodes was 2.5 ± 1.3 days in the cranberry group, compared with 3.6 ± 1.7 days in subjects not on cranberry (p < 0.05). Three subjects (13.6%) in the cranberry group and 8 (36.3%) in the control group required medical consultation for UTI symptoms (p < 0.05). Urine evaluation was completely negative in 20/22 subjects in the Cranberry group (90.9%) and in 11 control subjects (50.0%; p < 0.005). No adverse events were observed. These preliminary results, obtained in a field-practice setting, indicates the effectiveness and safety of a well-standardized cranberry extract in the prevention of R-UTI.


Changes in the incidence, pattern of presentation and clinical outcome of early chronic lymphocytic leukemia patients using the 2008 International Workshop on CLL guidelines.
Before 2008, diagnosis of chronic lymphocytic leukemia (CLL) relied on 1996 National Cancer Institute Working Group criteria which required an absolute lymphocyte count of 5.0 × 10(9)/l or higher. The up-dated 2008 International Workshop on CLL (IWCLL) guidelines recommend using the B-cell count as a basis for the diagnosis of CLL and indicate a B-cell threshold of 5.0 × 10(9)/l. The objective of this study was to assess the effects of these changes on the pattern of presentation and clinical outcome of early CLL. For this purpose we analysed 414 patients with previously untreated, Binet stage A CLL diagnosed between January 2006 and December 2010 and registered prospectively at a national database. After patients were reclassified according to updated 2008 IWCLL guidelines, 130 Rai stage 0 CLL patients were reclassifed as clinical monoclonal B-cell lymphocytosis, resulting in a 31.4% decrease (from 414 to 284) in the diagnosis of early stage CLL. Moreover, a shift towards a more advanced Rai clinical stage under 2008 IWCLL criteria was observed. Finally, the estimated 3-year time to first treatment decreased from 77.2 to 69.9% according to whether 1996 National Cancer Institute Working Group criteria or 2008 IWCLL criteria were used. In conclusion, the 2008 IWCLL guidelines modify the distribution of Rai stage at diagnosis and shorten the time to first treatment in early CLL patients. We expect that these changes might be considered in the interpretation of epidemiologic studies in CLL and in designing clinical trials of early therapeutic intervention in patients with asymptomatic CLL.


Folk Theories of Artifact Creation: How Intuitions About Human Labor Influence the Value of Artifacts.
What are the consequences of lay beliefs about how things are made? In this article, we describe a Western folk theory of artifact creation, highlighting how intuitive dualism regarding mental and physical labor (i.e., folk psychology) can lead to the perceived transmission of properties from makers to material artifacts (i.e., folk physics), and affect people's interactions with material artifacts. We show how this folk theory structures the conceptual domain of material artifacts by differentiating the contemporary lay concepts of art/craft and industrial production, and how it influences people's evaluations of different types of artifacts and their makers. We propose that the folk theory and lay concepts of art/craft and industrial production are best understood within a specific sociohistorical context, and review potential sources of cross-cultural and cross-temporal variation. We conclude by making recommendations for future research and examining the implications for promoting environmental sustainability and social justice in production systems.


Reducing Barriers to COVID-19 Vaccination Uptake: Community Ideas from Urban and Rural Kenya.
Following the rapid development of COVID-19 vaccines, addressing vaccine hesitancy and optimizing uptake have emerged as critical challenges, emphasizing the importance of reducing barriers toward COVID-19 vaccination. This study investigates ideas on ways to reduce barriers to COVID-19 vaccination uptake. It explores methods that can overcome COVID-19 vaccination barriers through qualitative research: interviews and group discussions involving healthcare providers, administration personnel, teachers, and individuals with chronic conditions across urban (Mombasa) and rural (Kilifi) Kenya. Audio-recorded discussions were transcribed and thematically analyzed across locations. Five themes emerged in our results regarding the reduction in barriers to COVID-19 vaccination in the context of Kenya, including awareness campaigns, engaging diverse stakeholders, using various communication techniques, capacity building to increase vaccination centers and trained staff, and lastly, revising relevant government health policies and guidelines. These results indicate the importance of adopting multiple approaches, as no single strategy can boost vaccine acceptance. Moreover, this study provides recommendations for conceiving actionable interventions to potentially boost vaccine demand and maintain routine immunization in Kenya.


A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels.
Minor variation in serum thyroid hormone (TH) levels can have important effects on various clinical endpoints. Although 45-65% of the inter-individual variation in serum TH levels is due to genetic factors, the causative genes are not well established. We therefore studied the effects of genetic variation in 68 TH pathway genes on serum TSH and free thyroxine (FT(4)) levels. Sixty-eight genes (1512 polymorphisms) were studied in relation to serum TSH and FT(4) levels in 1121 Caucasian subjects. Promising hits (P<0.01) were studied in three independent Caucasian populations (2656 subjects) for confirmation. A meta-analysis of all four studies was performed. For TSH, eight PDE8B polymorphisms (P=4×10(-17)) remained significant in the meta-analysis. For FT(4), two DIO1 (P=8×10(-12)) and one FOXE1 (P=0.0003) polymorphisms remained significant in the meta-analysis. Suggestive associations were detected for one FOXE1 (P=0.0028) and three THRB (P=0.0045) polymorphisms with TSH, and one SLC16A10 polymorphism (P=0.0110) with FT(4), but failed to reach the significant multiple-testing corrected P value (P<0.0022 and P<0.0033 respectively). Using a large-scale association analysis, we replicated previously reported associations with genetic variation in PDE8B, THRB, and DIO1. We demonstrate effects of genetic variation in FOXE1 on serum FT(4) levels, and borderline significant effects on serum TSH levels. A suggestive association of genetic variation in SLC16A10 with serum FT(4) levels was found. These data provide insight into the molecular basis of inter-individual variation in TH serum levels.


Practical use of the new American Urological Association interstitial cystitis guidelines.
The American Urological Association recently developed guidelines to assist clinicians who evaluate and treat interstitial cystitis/bladder pain syndrome. Knowledge in this area continues to advance, and some of the guideline statements differ from what clinicians may have been previously taught. This review includes the 27 guideline statements, which address both evaluation and treatment. This review lists the guideline statements and, when applicable, comments on their practical implementation and the most recent research. Practical information includes the following: key questions that help in the differential diagnosis, when to perform cystoscopy and urodynamics, how to recognize and treat Hunner lesions, useful practical resources for patients and clinicians, information on elimination diet and stress management, initial selection of oral and intravesical medications, and description of advanced treatment options (limited to dedicated, experienced clinicians).


Ankyloblepharon associated with systemic 5-fluorouracil treatment.
A 59-year-old man undergoing systemic 5-fluorouracil treatment for metastatic adenocarcinoma of the stomach developed ocular lesions consisting of bilateral conjunctival ulcers and ulcerative blepharitis leading to ankyloblepharon. Ophthalmologists should be cognizant of potential ocular side effects of chemotherapy, in order to institute appropriate changes in treatment.


Enhancing the magnetic coupling of oxalato-bridged Re(IV)2M(II) (M=Mn, Co, Ni, and Cu) trinuclear complexes via peripheral halide ligand effects.
Four heterotrinuclear Re(IV)(2)M(II) compounds of general formula (NBu(4))(2)[{Re(IV)Br(4)(μ-ox)}(2)M(II)(Him)(2)] [NBu(4)(+) = tetra-n-butylammonium cation, ox = oxalate, Him = imidazole; M = Mn (1), Co (2), Ni (3), and Cu (4)] have been synthesized by using the novel mononuclear complex [Re(IV)Br(4)(ox)](2-) as a ligand toward divalent first-row transition metal ions in the presence of imidazole. Compounds 1-4 are isostructural complexes whose structure contains discrete trinuclear [{Re(IV)Br(4)(μ-ox)}(2)M(II)(Him)(2)](2-) anions and bulky NBu(4)(+) cations. The Re and M atoms are six-coordinated: four peripheral bromo and two oxalate-oxygens (at Re), and two cis-coordinated imidazole molecules and four oxygen atoms from two oxalate ligands (at M), build distorted octahedral surroundings. Two peripheral [ReBr(4)(ox)](2-) units act as bidentate ligands through the oxalate group toward the central [M(II)(Him)(2)] fragment affording the trinuclear entities. The values of the intramolecular Re···M separation are 5.62(1) (1), 5.51(1) (2), 5.46(1) (3), and 5.55(1) Å (4). Magnetic susceptibility measurements on polycrystalline samples of 1-4 in the temperature range of 1.9-300 K show the occurrence of intramolecular antiferro- [J = -1.1 cm(-1) (1)] and ferromagnetic interactions [J = +3.9 (2), +19.7 (3), and +14.4 cm(-1) (4)], the Hamiltonian being defined as Ĥ = -J [Ŝ(M)(Ŝ(Re1) + Ŝ(Re2))]. The larger spin delocalization on the oxalato bridge in 1-4 when compared to the trinuclear Re(IV)(2)M(II) complexes with chloro instead of bromo as peripheral ligands (1'-4') accounts for the strengthening of the magnetic interactions in 1-4 [J = -0.35 (1'), +14.2 (3'), and +7.7 cm(-1) (4')]. An incipient frequency dependence of the out-of-phase ac signals of 3 at very low temperatures is reminiscent of a system with slow relaxation of the magnetization, a phenomenon characteristic of single-molecule magnet behavior.


S1PR2 Regulates Autophagy Through the AKT/mTOR Pathway to Promote Pathological Damage in Alzheimer's Disease.
Alzheimer's disease (AD) is a fatal and debilitating neurodegenerative disease. Sphingosine-1-phosphate receptor 2 (S1PR2), one of the receptors of S1P, is a key regulatory factor for various diseases. This study aimed to explore the role and possible mechanism of S1PR2 in AD. S1PR2 expression in the AD mice was detected, and after intervening S1PR2 expression with sh-S1PR2 in AD mice, the behavioral changes, pathological lesions of the hippocampus, autophagy level, and AKT/mTOR pathway activation were analyzed. Furthermore, SH-SY5Y cells were induced by Aβ25-35 to construct an AD cell model, and the effects of sh-S1PR2 on proliferation, apoptosis, autophagy, and AKT/mTOR pathway of AD cells were investigated. In addition, the effects of pathway inhibitor rapamycin on model cells were further analyzed. The expression of S1PR2 was significantly increased in AD mice, the sh-S1PR2 significantly improved behavioral dysfunction, alleviated pathological injury of the hippocampus, increased the number of neurons, and inhibited Aβ production and p-tau expression, showing a positive effect on the AD pathology. In addition, silencing of S1PR2 expression significantly promoted the autophagy level and inhibited the activation of the AKT/mTOR pathway in AD model mice. In vitro experiments further confirmed that sh-S1PR2 promoted cell proliferation, inhibited apoptosis, relieved cytopathology, promoted autophagy, and inhibited the activation of the AKT/mTOR pathway in the cell model. The use of rapamycin further confirmed the role of AKT/mTOR pathway-mediated autophagy in the regulation of AD by S1PR2. S1PR2 promoted AD pathogenesis by inhibiting autophagy through the activation of AKT/mTOR pathway.


Papillary fibroelastoma of the tricuspid valve.
A 50-year-old woman with a long-standing history of palpitations was found by echocardiography to have a 1.5 cm mass on the atrial surface of the anterior leaflet of the tricuspid valve. Surgical excision included a portion of surrounding leaflet tissue. The tumour was a papillary fibroelastoma. She remained asymptomatic with no recurrence in follow-up.


Evaluating and Improving an Outpatient Clinic Scheduling Template Using Secondary Electronic Health Record Data.
Improving the efficiency of outpatient clinics is challenging in the face of increased patient loads, decreased reimbursements and potential negative productivity impacts of using electronic health records (EHR). We modeled outpatient ophthalmology clinic workflow using discrete event simulation for testing new scheduling templates that decrease patient wait time and improve clinic efficiency. Despite challenges in implementing the new scheduling templates in one outpatient clinic, the new templates improved patient wait time and clinic session length when they were followed. Analyzing EHR data about these schedules and their adherence to the template provides insight into new policies that can better balance the competing priorities of filling the schedules, meeting patient demand and minimizing wait time.


Interactions of macromolecular crowding agents and cosolutes with small-molecule substrates: effect on horseradish peroxidase activity with two different substrates.
The importance of solution composition on enzymatic reactions is increasingly appreciated, particularly with respect to macromolecular cosolutes. Macromolecular crowding and its effect on enzymatic reactions has been studied for several enzymes and is often understood in terms of changes to enzyme conformation. Comparatively little attention has been paid to the chemical properties of small-molecule substrates for enzyme reactions in crowded solution. In this article, we studied the reaction of horseradish peroxidase (HRP) with two small-molecule substrates that differ in their hydrophobicity. Crowding agents and cosolutes had quite different effects on HRP activity when the substrate used was 3,3',5,5'-tetramethylbenzidine (TMB, which is hydrophobic) as compared to o-phenylenediamine (OPD, which is more hydrophilic). Reaction rates with TMB were much more sensitive to the presence of crowding agents and cosolutes than OPD, suggesting that the small-molecule substrates may themselves be interacting with crowders and cosolutes. At high polyethylene glycol (PEG) concentrations (25-30 wt/wt %), no reaction was observed for TMB. Even at lower concentrations, Michaelis constants (KM) for HRP with the more hydrophobic substrate increased in the presence of crowding agents and cosolutes, particularly with PEG. Diffusion of TMB and OPD in the PEG and dextran reaction media was evaluated using pulsed field gradient nuclear magnetic resonance (PFG-NMR). The diffusivity of the TMB decreased 3.9× in 10% PEG 8k compared to that in buffer and decreased only 1.7× for OPD. Together, these data suggest that weak attractive interactions between small-molecule substrates and crowders or cosolutes can reduce substrate chemical activity and consequently decrease enzyme activity and that these effects vary with the identity of the molecules involved. Because many enzymes can act on multiple substrates, it is important to consider substrate chemistry in understanding enzymatic reactions in complex media such as biological fluids.


A competitive ligand binding assay for detection of neutralizing antibodies against an insulin analog.
Biotherapeutics have the potential to trigger undesired immune responses in the patients. For therapeutic proteins, immunogenicity is manifested as anti-drug antibodies (ADA). Because ADA could compromise pharmacokinetics, efficacy, and safety, regulatory agencies require immunogenicity assessment during clinical development. A tiered bioanalytical approach is recommended to monitor clinical immunogenicity, and neutralizing antibodies (NAb) are studied in Tier 4 if the molecule is immunogenic. Although cell-based assays, which reflect the pharmacological mechanism of action, are in some cases the preferred assay format for detecting NAbs, they are associated with operational complexity and sometimes suboptimal assay performance. Alternatively, non-cell-based assays have also been developed and implemented. In our current study, a competitive ligand binding assay (CLBA) was developed to detect NAbs for insulin efsitora alfa (efsitora, basal insulin Fc, LY3209590), a novel fusion protein being studied for the treatment of Type 1 diabetes and Type 2 diabetes. The CLBA demonstrated acceptable sensitivity, drug tolerance, precision, and robustness, and thus provides a suitable approach for detecting NAbs against efsitora.


Individual preferences on the balancing of good and harm of cardiovascular disease screening.
Transition towards value-based healthcare requires insight into what makes value to the individual. The aim was to elicit individual preferences for cardiovascular disease screening with respect to the difficult balancing of good and harm as well as mode of delivery. A discrete choice experiment was conducted as a cross-sectional survey among 1231 male screening participants at three Danish hospitals between June and December 2017. Participants chose between hypothetical screening programmes characterised by varying levels of mortality risk reduction, avoidance of overtreatment, avoidance of regretting participation, screening duration and location. A multinomial mixed logit model was used to model the preferences and the willingness to trade mortality risk reduction for improvements on other characteristics. Respondents expressed preferences for improvements on all programme characteristics. They were willing to give up 0.09 (95% CI 0.08 to 0.09) lives saved per 1000 screened to avoid one individual being over treated. Similarly, respondents were willing to give up 1.22 (95% CI 0.90 to 1.55) or 5.21 (95% CI 4.78 to 5.67) lives saved per 1000 screened to upgrade the location from general practice to a hospital or to a high-tech hospital, respectively. Subgroup analysis revealed important preference heterogeneity with respect to smoking status, level of health literacy and self-perceived risk of cardiovascular disease. Individuals are able to express clear preferences about what makes value to them. Not only health benefit but also time with health professionals and access to specialised facilities were important. This information could guide the optimal programme design in search of value-based healthcare.


Lethal Gastric Mucosal Necrosis due to Administration of Oral Ferrous Bisglycinate Chelate to Suckling Piglets.
The oral application of a newly developed ferrous bisglycinate paste for suckling piglets at a dose of 180 mg/kg body weight led to increased death rates in 10% (n = 10) of Swiss test pig breeding farms (n = 100). Necropsy examination of suckling piglets (n = 12), selected randomly from the test farms with increased death rates, demonstrated severe gastric mucosal ulceration and necrosis. Due to the presence of crystalline iron surface coating within the gastric lesions, the iron was considered as the toxic principle and cause of death. To demonstrate the direct toxicity of ferrous bisglycinate, the paste was administered experimentally to a litter of suckling piglets (n = 11). Different time points (24, 48 and 72 h post partum) and doses (180 mg/kg and 360 mg/kg) were investigated. The manufacturer's recommended dose of 180 mg/kg corresponded to approximately 36 mg Fe/kg and to 6.4 % of the acute lethal dose50 of oral iron in rats. In all piglets the lesions were reproduced and most severe at the earliest time point (24 h post partum) and with the highest applied dose (360 mg/kg). The lesions were in accordance with those described from oral iron intoxication in man, suggesting pigs as an ideal animal model for oral iron toxicity studies.


QDs-based fluorescent lateral flow assays for Point-of-care testing of insulin.
Point-of-care testing (POCT) can be performed near the site of the patient to achieve results in a few minutes. Different POCT devices are available in the market, such as microfluidic chips and paper-based lateral flow assays (LFAs). The paper-based LFAs have certain advantages, such as being cheap and disposable, able to detect a wide range of biomolecules, and the fluid flows through them via capillary action eliminating the need for external forces. The LFAs can be optimized for the sensitive and rapid detection of biomolecules. In this study, paper-based fluorescent LFAs platforms using aptamers as the biorecognition molecules were developed for the POCT of insulin. Various parameters were optimized such as concentrations of aptamers, the type of reporter molecules, the volume of sample, and the assay time to quantify insulin levels using a standard LFA reader. The fluorescent LFAs exhibited a linear detection range of 0.1-4 ng.mL-1 with a limit of detection (LOD) 0.1 ng.mL-1. The developed LFAs will help to achieve insulin measurement in a few minutes and will be easy to perform by end-users without the requirement of sophisticated instruments, laboratory set-up, and trained personnel. The developed device will be useful for the measurement of insulin levels in biological samples without the need for pretreatment, reducing the overall cost and time of testing. Moreover, the POCT device were fabricated using paper which is a low-cost (approximately AUD 2 per strip) option and is disposable.Clinical Relevance- POCT monitoring of insulin can facilitate both disease diagnosis and management. The developed LFAs have the capability of rapidly testing insulin concentration within several minutes. It will benefit both patients for at-home daily insulin monitoring and clinicians for hospital rapid insulin testing.


Stocking activities for the Arctic charr in Lake Geneva: Genetic effects in space and time.
Artificial stocking practices are widely used by resource managers worldwide, in order to sustain fish populations exploited by both recreational and commercial activities, but their benefits are controversial. Former practices involved exotic strains, although current programs rather consider artificial breeding of local fishes (supportive breeding). Understanding the complex genetic effects of these management strategies is an important challenge with economic and conservation implications, especially in the context of population declines. In this study, we focus on the declining Arctic charr (Salvelinus alpinus) population from Lake Geneva (Switzerland and France), which has initially been restocked with allochtonous fishes in the early eighties, followed by supportive breeding. In this context, we conducted a genetic survey to document the evolution of the genetic diversity and structure throughout the last 50 years, before and after the initiation of hatchery supplementation, using contemporary and historical samples. We show that the introduction of exotic fishes was associated with a genetic bottleneck in the 1980-1990s, a break of Hardy-Weinberg Equilibrium (HWE), a reduction in genetic diversity, an increase in genetic structure among spawning sites, and a change in their genetic composition. Together with better environmental conditions, three decades of subsequent supportive breeding using local fishes allowed to re-establish HWE and the initial levels of genetic variation. However, current spawning sites have not fully recovered their original genetic composition and were extensively homogenized across the lake. Our study demonstrates the drastic genetic consequences of different restocking tactics in a comprehensive spatiotemporal framework and suggests that genetic alteration by nonlocal stocking may be partly reversible through supportive breeding. We recommend that conservation-based programs consider local diversity and implement adequate protocols to limit the genetic homogenization of this Arctic charr population.


Low LH Level on the Day of GnRH Agonist Trigger Is Associated With Reduced Ongoing Pregnancy and Live Birth Rates and Increased Early Miscarriage Rates Following IVF/ICSI Treatment and Fresh Embryo Transfer.
Objective: To examine the correlation between serum luteinizing hormone (LH) levels on the day of GnRH agonist (GnRH-a) trigger and reproductive outcomes following in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment and fresh embryo transfer, and to identify a pre-trigger serum LH threshold which would be compatible with the most optimal cycle outcome. Design: This study is based on data from a previously published randomized controlled trial conducted from 2014 to 2016. Patients: A total of 322 participants were enrolled. Setting: Private IVF center. Intervention(s): GnRH-antagonist-based IVF cycles triggered with GnRH-a. For the purpose of the study, patients were stratified according to preovulatory LH quartiles (Q1-Q4). Main Outcome Measure(s): Ongoing pregnancy rates (OP), live birth rates (LB) and early pregnancy loss (EPL) rates. Results: The results of the present study showed increasing OP as well as LB rates and decreasing EPL rates with increasing pre-trigger serum LH levels (P for trend < 0.06, 0.07, and 0.02), respectively. The absolute difference between the highest LH(Q4) and the lowest LH (Q1) group was 13.4%, 12.1%, and 12% in OP, LB, and EPL rates, respectively. In multivariate regression analysis, a pre-trigger serum LH level of 1.60 mIU/ml was identified as a threshold below which reproductive outcomes decreased. The ROC curve values were statistically significant for OP, LB, and EPL; the AUC (95% CI) = [0.57 (0.50-0.63) P < 0.04; 0.57 (0.50-0.63) P < 0.05, and 0.60 (0.51-0.70) P < 0.04], respectively. A significant positive correlation was found on the day of GnRH-a trigger between serum LH, the number of follicles, serum P4, and serum E2, p < 0.03; P < 0.03; and P < 0.001, respectively. Conclusion: Low serum LH levels on the day of GnRH-a trigger is associated with reduced ongoing pregnancy and live birth rates and increased early miscarriage rates. Our findings suggest a lower threshold of serum LH values on the day of GnRH-a trigger necessary to optimize reproductive outcomes in fresh embryo transfer cycles. Clinical Trial Registration: www.ClinicalTrials.gov, Number: 02053779.


Glucose deprivation triggers protein kinase C-dependent β-catenin proteasomal degradation.
Autophagy is a conserved process that contributes to cell homeostasis. It is well known that induction mainly occurs in response to nutrient starvation, such as starvation of amino acids and insulin, and its mechanisms have been extensively characterized. However, the mechanisms behind cellular glucose deprivation-induced autophagy are as of now poorly understood. In the present study, we determined a mechanism by which glucose deprivation induced the PKC-dependent proteasomal degradation of β-catenin, leading to autophagy. Glucose deprivation was shown to cause a sub-G1 transition and enhancement of the LC3-II protein levels, whereas β-catenin protein underwent degradation in a proteasome-dependent manner. Moreover, the inhibition of GSK3β was unable to abolish the glucose deprivation-mediated β-catenin degradation or up-regulation of LC3-II protein levels, which suggested GSK3β-independent protein degradation. Intriguingly, the inhibition of PKCα using a pharmacological inhibitor and transfection of siRNA for PKCα was observed to effectively block glucose deprivation-induced β-catenin degradation as well as the increase in LC3-II levels and the accumulation of a sub-G1 population. Together, our results demonstrated a molecular mechanism by which glucose deprivation can induce the GSK3β-independent protein degradation of β-catenin, leading to autophagy.


Gene duplication in Mimulus underlies parallel floral evolution via independent trans-regulatory changes.
Identifying the genetic basis of parallelism reveals the means by which evolution repeats itself and shows what aspects-if any-may be predictable. The recently tetraploid luteus group of Mimulus contains five species native to central Chile, three of which have evolved extensive red floral pigmentation using at least two distinct loci . Here we show that the parallel evolution of petal lobe anthocyanin (PLA) pigmentation in M. cupreus and M. luteus var. variegatus occurred via separate yet strikingly similar mechanisms. In each case, a dominant, single-locus gain of pigmentation maps to a genomic region (pla1 and pla2, respectively) containing adjacent, apparently recently duplicated paralogs of MYB anthocyanin-regulating transcription factors. Interestingly, candidate genes in pla1 and pla2 are themselves related by an older duplication. In both cases, pla genotype cosegregates with expression of multiple genes in the anthocyanin biosynthetic pathway, revealing a mechanism of coordinated trans-regulatory expression changes across functionally related enzyme-encoding genes. We conclude that in this instance, evolution has repeated itself with marked consistency. Duplication has enabled that repetition to occur using two physically independent but functionally similar loci, highlighting the importance of genomic complexity to the evolutionary process.


Stored Fas ligand, a mediator of rapid CTL-mediated killing, has a lower threshold for response than degranulation or newly synthesized Fas ligand.
CTL lyse target cells through the release of cytolytic granule mediators and expression of the death receptor ligand Fas ligand (FasL). We previously demonstrated that FasL is stored in vesicles distinct from cytolytic granules and is translocated to the cell surface within 15 min of TCR stimulation, followed by a later wave of newly synthesized FasL cell surface expression at 2 h poststimulation. Initial studies suggested that the two FasL responses had different signaling thresholds. To test this possibility directly, we titrated Ag presented to murine CTL to measure FasL and degranulation response thresholds. Stored FasL translocation to the cell surface required substantially lower concentrations of peptide than was required for de novo expression of FasL and degranulation. Furthermore, a low-affinity agonist peptide stimulated strong stored FasL translocation but only limited de novo FasL expression and degranulation. These data imply that the two FasL populations may have distinct functions. We examined bystander killing and found that the rapidly expressed FasL triggered highly specific lysis of target cells, as did degranulation. In contrast, the newly synthesized later wave of FasL mediated extensive Fas-dependent bystander killing. Our data indicate that stored FasL is mobilized in response to low concentrations of Ag to mediate rapid, highly specific lysis of target cells, whereas the later, newly synthesized FasL requires higher concentrations of Ag and mediates indiscriminate lysis. These findings suggest that early and late FasL and degranulation represent nonredundant lytic mechanisms that have been selected for distinct situations, possibly for optimal pathogen clearance.


In vitro effect of green tea and turmeric extracts on GLP-1 and CCK secretion: the effect of gastrointestinal digestion.
Plant extract activity can be modified by the digestion process. In order to assess the satiety effect of green tea and turmeric extracts, an in vitro gastrointestinal digestion process was performed and the STC-1 cell line was used. The enteroendocrine cell line was incubated (for 30, 60 and 120 minutes) with the digested and non-digested extracts measuring the secretion of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) by enzyme-linked immunosorbent assay (ELISA). The release of satiety hormones by the STC-1 cells showed similar or higher results for plant extracts compared to the positive controls reported as satiatogenic (proteins and short chain fatty acids). For the non-digested samples, the largest amount of CCK and GLP-1 was found for turmeric, with 379 ± 46 pg ml-1 (60 min) and 347 ± 125 pg ml-1 (120 min) respectively. For the digested samples, the highest level of CCK was found for turmeric at 30 minutes (43.3 ± 11) and for GLP-1 by green tea at 120 minutes (165.7 ± 52). The in vitro gastrointestinal digestion process affects the satiety of plant extracts, increasing for green tea and decreasing for turmeric. Green tea showed the most stable satiating capacity after the in vitro digestion process and this may be useful for using it as a stable food supplement to reduce hunger associated with overweight and obesity.


Methamphetamine-associated pulmonary arterial hypertension: data from the national biological sample and data repository for pulmonary arterial hypertension (PAH Biobank).
This study compares the clinical and haemodynamic severity of methamphetamine-associated pulmonary arterial hypertension (MA-PAH) with idiopathic pulmonary arterial hypertension (IPAH) and connective tissue-associated pulmonary arterial hypertension (CTD-PAH). It also examines sex differences in clinical and physiological parameters among those with MA-PAH. This is a cross-sectional study using clinically derived data from the National Biological Sample and Data Repository for Pulmonary Arterial Hypertension (PAH biobank), a US-based registry, to compare clinical and physiological characteristics between males and females with MA-PAH. The analysis included 1830 patients enrolled in the PAH biobank, with a diagnosis of MA-PAH (n=42), IPAH (n=1073), or CTD-PAH (n=715). The study assessed and compared the clinical and haemodynamic parameters of patients with MA-PAH, IPAH and CTD-PAH. Among the patients analysed, 42 had MA-PAH, with 69.1% being female. There were no statistically significant differences in functional class among patients with MA-PAH, IPAH and CTD-PAH. The per cent predicted 6-min walk distance (6MWD) was comparable between the three groups. Patients with MA-PAH had similar mean pulmonary artery pressure and pulmonary vascular resistance to patients with IPAH but higher compared with patients with CTD-PAH. Male patients with MA-PAH exhibited a worse functional class and lower per cent predicted 6MWD, but no significant differences in haemodynamic findings were observed between the sexes. There were no differences in haemodynamic between MA-PAH and IPAH but we found that MA-PAH differed from CTD-PAH. The study did not find evidence of sex differences in MA-PAH. Further research is necessary to identify risk factors and underlying mechanisms of MA-PAH, particularly considering the increasing prevalence of methamphetamine use. Such investigations will contribute to the development of effective prevention and treatment strategies for this condition.


Cytosolic and mitochondrial proteins as possible targets of cycloheximide effect on adrenal steroidogenesis.
It is well accepted that protein(s) with a short half-life are required in the pathway leading to steroid synthesis following stimulation by trophic hormones. A correlation between the disappearance of several proteins in different subcellular compartments and the inhibition of steroid synthesis produced by cycloheximide (CHx) has also been shown. In the present report we describe the effect of CHx in the stimulation of steroid synthesis using a cell-free assay. Mitochondrial progesterone (P4) production was studied by recombination of the different subcellular fractions of adrenal zona fasciculata and determined by radioimmunoassay. Soluble factors from ACTH-treated adrenals produced a four-fold stimulation of mitochondrial steroidogenesis (3.0 +/- 0.6 vs. 13.3 +/- 0.5 ng P4/tube for control and ACTH-treated adrenals respectively). Mitochondria obtained from CHx-ACTH-treated adrenals fail to respond to soluble ACTH-dependent factors. A permeable analogue of cholesterol (22(R)-OH cholesterol) could overcome the inhibition imposed by CHx, confirming the role of mitochondrial proteins in intramitochondrial cholesterol transport. The treatment of the adrenals with CHx 10 minutes before ACTH administration abolished also the stimulation induced by the cytosol on control mitochondria (2.6 +/- 0.5 vs. 13.0 +/- 1.0 ng P4/tube for CHx-ACTH-treated cytosol vs. ACTH-treated cytosol). Arachidonic acid (AA) added to CHx-ACTH-treated cytosol subdued this inhibition (10.3 +/- 1.2 ng P4/tube). CHx treatment had no effect on the stimulation by ACTH of the cAMP-dependent protein kinase. These results indicate the involvement of a cycloheximide-sensitive protein in the release of AA in adrenal steroidogenesis.


An 8-Week Self-Administered At-Home Behavioral Skills-Based Virtual Reality Program for Chronic Low Back Pain: Double-Blind, Randomized, Placebo-Controlled Trial Conducted During COVID-19.
Chronic low back pain is the most prevalent chronic pain condition worldwide and access to behavioral pain treatment is limited. Virtual reality (VR) is an immersive technology that may provide effective behavioral therapeutics for chronic pain. We aimed to conduct a double-blind, parallel-arm, single-cohort, remote, randomized placebo-controlled trial for a self-administered behavioral skills-based VR program in community-based individuals with self-reported chronic low back pain during the COVID-19 pandemic. A national online convenience sample of individuals with self-reported nonmalignant low back pain with duration of 6 months or more and with average pain intensity of 4 or more/10 was enrolled and randomized 1:1 to 1 of 2 daily (56-day) VR programs: (1) EaseVRx (immersive pain relief skills VR program); or (2) Sham VR (2D nature content delivered in a VR headset). Objective device use data and self-reported data were collected. The primary outcomes were the between-group effect of EaseVRx versus Sham VR across time points, and the between-within interaction effect representing the change in average pain intensity and pain-related interference with activity, stress, mood, and sleep over time (baseline to end-of-treatment at day 56). Secondary outcomes were global impression of change and change in physical function, sleep disturbance, pain self-efficacy, pain catastrophizing, pain acceptance, pain medication use, and user satisfaction. Analytic methods included intention-to-treat and a mixed-model framework. The study sample was 179 adults (female: 76.5%, 137/179; Caucasian: 90.5%, 162/179; at least some college education: 91.1%, 163/179; mean age: 51.5 years [SD 13.1]; average pain intensity: 5/10 [SD 1.2]; back pain duration ≥5 years: 67%, 120/179). No group differences were found for any baseline variable or treatment engagement. User satisfaction ratings were higher for EaseVRx versus Sham VR (P<.001). For the between-groups factor, EaseVRx was superior to Sham VR for all primary outcomes (highest P value=.009), and between-groups Cohen d effect sizes ranged from 0.40 to 0.49, indicating superiority was moderately clinically meaningful. For EaseVRx, large pre-post effect sizes ranged from 1.17 to 1.3 and met moderate to substantial clinical importance for reduced pain intensity and pain-related interference with activity, mood, and stress. Between-group comparisons for Physical Function and Sleep Disturbance showed superiority for the EaseVRx group versus the Sham VR group (P=.022 and .013, respectively). Pain catastrophizing, pain self-efficacy, pain acceptance, prescription opioid use (morphine milligram equivalent) did not reach statistical significance for either group. Use of over-the-counter analgesic use was reduced for EaseVRx (P<.01) but not for Sham VR. EaseVRx had high user satisfaction and superior and clinically meaningful symptom reduction for average pain intensity and pain-related interference with activity, mood, and stress compared to sham VR. Additional research is needed to determine durability of treatment effects and to characterize mechanisms of treatment effects. Home-based VR may expand access to effective and on-demand nonpharmacologic treatment for chronic low back pain. ClinicalTrials.gov NCT04415177; https://clinicaltrials.gov/ct2/show/NCT04415177. RR2-10.2196/25291.


Onset of action of antipsychotics in the treatment of mania.
An important consideration in treating acute mania is the promptness with which a chosen therapy can bring symptom amelioration. This article reviews the available published data from controlled, blinded studies regarding the latency of responses to antipsychotics in patients with acute mania. Articles for this review were obtained from a search of the Medline database (1966- 1999), using the following keywords and phrases: antipsychotic, atypical, bipolar disorder, mania, neuroleptic, typical. The bibliographic sections of articles gleaned from this search were used to direct further inquiries. Although information regarding the onset of action of antipsychotics is limited, we discovered data for four typical and three atypical antipsychotics. Drugs with the fastest onsets include haloperidol, risperidone, and olanzapine, with onsets appearing in 2 6 days. Chlorpromazine and thiothixene were at the slowest end of the continuum, with onsets of 2 weeks or longer. Data regarding pimozide are mixed, with some studies showing an onset equivalent to that of the 'fast' compounds and others showing one similar to that of the 'slow' compounds. Choice of therapy should consider not only efficacy and safety, but also onset speed. Atypical antipsychotics appear to offer safer, faster, and more effective therapies.


Exclusion of context knowledge in the development of prehospital guidelines: results produced by realistic evaluation.
Prehospital work is accomplished using guidelines and protocols, but there is evidence suggesting that compliance with guidelines is sometimes low in the prehospital setting. The reason for the poor compliance is not known. The objective of this study was to describe how guidelines and protocols are used in the prehospital context. This was a single-case study with realistic evaluation as a methodological framework. The study took place in an ambulance organization in Sweden. The data collection was divided into four phases, where phase one consisted of a literature screening and selection of a theoretical framework. In phase two, semi-structured interviews with the ambulance organization's stakeholders, responsible for the development and implementation of guidelines, were performed. The third phase, observations, comprised 30 participants from both a rural and an urban ambulance station. In the last phase, two focus group interviews were performed. A template analysis style of documents, interviews and observation protocols was used. The development of guidelines took place using an informal consensus approach, where no party from the end users was represented. The development process resulted in guidelines with an insufficiently adapted format for the prehospital context. At local level, there was a conscious implementation strategy with lectures and manikin simulation. The physical format of the guidelines was the main obstacle to explicit use. Due to the format, the ambulance personnel feel they have to learn the content of the guidelines by heart. Explicit use of the guidelines in the assessment of patients was uncommon. Many ambulance personnel developed homemade guidelines in both electronic and paper format. The ambulance personnel in the study generally took a positive view of working with guidelines and protocols and they regarded them as indispensable in prehospital care, but an improved format was requested by both representatives of the organization and the ambulance personnel. The personnel take a positive view of the use of guidelines and protocols in prehospital work. The main obstacle to the use of guidelines and protocols in this organization is the format, due to the exclusion of context knowledge in the development process.


The tumor microenvironment in non-small-cell lung cancer.
The tumor microenvironment (TME) of NSCLC is heterogeneous with variable blood flow through leaky immature vessels resulting in regions of acidosis and hypoxia. Hypoxia has been documented in NSCLC directly by polarographic needle electrodes and indirectly by assessing tissue and plasma hypoxia markers. In general, elevated expression of these markers portends poorer outcomes in NSCLC. Impaired vascularity and hypoxia can lead to increased metastasis and treatment resistance. Compounds that directly target hypoxic cells such as tirapazamine have been tested in clinical trials for NSCLC with mixed results. Preclinical data, however, suggest other ways of exploiting the abnormal TME in NSCLC for therapeutic gain. The inhibition of hypoxia-inducible factor-1alpha or vascular endothelial growth factor may increase local control after radiation. Inhibitors of the epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K)/Akt pathway, such as erlotinib or PI-103, may "normalize" tumor vessels, allowing for increased chemotherapy delivery or improved oxygenation and radiation response. To select patients who may respond to these therapies and to evaluate the effects of these agents, a noninvasive means of imaging the TME is critical. Presently, there are several promising modalities to image hypoxia and the tumor vasculature; these include dynamic perfusion imaging and positron emission tomography scanning with radiolabled nitroimidazoles.


The mouse atlas and graphical gene-expression database
The large amounts of gene-expression data on mouse development are now too extensive to be stored in any format other than that of a database. Furthermore, as this data is intrinsically graphical and as, in the early developmental stages at least, its boundaries do not map directly to those of anatomical tissues, the natural way to store it is in graphical format. We are therefore constructing a database able to handle such graphical gene-expression data by mapping it onto 3-D reconstructions of mouse embryos whose tissues have been delineated. This article reviews the progress that has been made in this project and describes its two major components, CD-ROMs of the 3-D reconstructions to be held on the user's computer and a gene-expression database that will be maintained at a host site, the two being linked over the internet by a complex Java-based interface for submitting data and querying the database.Copyright 1997 Academic Press Limited Copyright 1997Academic Press Limited


Hydrogenophaga borbori sp. nov., isolated from activated sludge.
A novel Gram-stain-negative, yellowish-pigmented bacterial strain, designated LA-38T, was isolated from activated sludge of wastewater treatment plants in Hanam city, South Korea. Cell of LA-38T were rod-shaped, aerobic, motile and non-spore-forming. In phylogenetic analyses based on 16S rRNA genes, LA-38T clustered with species of the genus Hydrogenophaga and appeared closely related to Hydrogenophaga intermedia DSM 5680T (99.2 % similarity), Hydrogenophaga palleronii DSM 63T (98.2 %), Hydrogrenophaga laconesensis KCTC 42478T (98.1 %), Hydrogenophaga. atypica DSM 15342T (98.1 %), Hydrogenophaga defluvii DSM 15341T (98.0 %) and Hydrogenophaga taeniospiralis DSM 2082T (97.2 %). The average nucleotide identities between LA-38T and the closely related strains were 79.3-88.5 %, indicating that LA-38T represents a novel species of the genus Hydrogenophaga. The DNA G+C content of the genomic DNA was 69.9 mol% and ubiquinone Q-8 was the predominant respiratory quinone. The major cellular fatty acids (>5 %) were C16 : 0, cyclo-C19 : 0, C16 : 1ω7c and/or C16 : 1ω6c (summed feature 3), and C18 : 1ω7c and/or C18 : 1ω6c (summed feature 8). The major polar lipids consisted of phosphatidylglycerol, diphosphatidylglycerol and phosphatidylethanolamine, the major polyamines were 2-hydroxyputrescine and putrescine. ANI calculation, physiological and biochemical characteristics indicated that LA-38T represents a novel species of the genus Hydrogenophaga, for which the name Hydrogenophaga borbori sp. nov. is proposed. The type strain is LA-38T (=KACC 19730T=LMG 30805T).


The nonpeptide NK-1 receptor antagonists LY303870 and LY306740 block the responses of spinal dorsal horn neurons to substance P and to peripheral noxious stimuli.
The effects of novel substance P (NK-1) receptor antagonists LY303870 and LY306740, as well as LY306155, the enantiomer of LY303870, were tested on the responses of nociceptive spinal dorsal horn neurons to iontophoretically applied substance P and to peripheral noxious stimuli. The peripheral stimuli included noxious thermal and pinch stimuli applied to the cutaneous receptive field in the hind paw and stimulation of the superficial peroneal nerve with a train of high-intensity electrical stimuli. Extracellular recordings were obtained using multi-barrel electrodes from L4-L7 segments of the spinal cord in cats anaesthetized with alpha-chloralose and spinalized at the L1 level. The antagonists were given i.v. (0.5-4.0 mg/kg). Responses to substance P were inhibited by LY303870 and by LY306740 in a dose-related manner, but were not affected by LY306155. Responses to peripheral noxious thermal stimulation were inhibited in a dose-related manner by LY303870 and LY306740, and only at higher doses (2 mg/kg or more) by LY306155. Responses to pinch stimuli were inhibited by LY303870 and LY306740. LY306155 lacked consistent effects on pinch responses. LY303870 selectively inhibited the late component of the response to electrical stimulation of the superficial peroneal nerve. When these three drugs were tested against the responses of dorsal horn neurons to the excitatory amino acid, N-methyl-D-aspartate, the responses were unaffected. These data suggest that LY303870 and LY306740 pass from the circulation into the spinal cord where they antagonize dorsal horn neuronal responses to substance P and nociceptive inputs.


Region of interest reconstruction in x-ray fluorescence computed tomography for negligible attenuation.
X-ray fluorescence computed tomography (XFCT) is a synchrotron-based imaging modality employed for mapping the distribution of elements within slices or volumes of intact specimens. A pencil beam of external radiation is used to stimulate emission of characteristic X-rays from within a sample, which is scanned and rotated through the pencil beam in a first-generation tomographic geometry. One limitation of XFCT is the long image acquisition time required to acquire a complete set of line integrals one-by-one. Typically, even if only a portion of a slice through the object is of interest, measurement lines are acquired spanning the entire object at every projection view over 180 degrees to avoid reconstructing images with so-called truncation artifacts. In this work, we show that when attenuation is negligible, recent developments in tomographic reconstruction theory can be used to reduce the scanning effort required to reconstruct regions of interest within the slice. The new theory provides explicit guidance as to which line integrals must be measured for a given ROI and also provides a backprojection-filtration reconstruction algorithm that averts the truncation artifacts that typically plague filtered backprojection reconstructions from truncated data. This is demonstrated through simulation studies and with real synchrotron-based XFCT data.


Nucleic acid amplification tests for diagnosis of Neisseria gonorrhoeae oropharyngeal infections.
The optimal methods for the diagnosis of pharyngeal Neisseria gonorrhoeae infection are uncertain. The objective of this study was to define the performance of culture and nucleic acid amplification tests (NAATs) for the diagnosis of pharyngeal N. gonorrhoeae. In this cross-sectional study, males and females >15 years old who acknowledged performing fellatio or cunnilingus (in the previous 2 months) were recruited from three clinics (two human immunodeficiency virus clinics and one sexually transmitted diseases clinic) located in Birmingham, AL. The test performance of culture for N. gonorrhoeae, the Gen-Probe Aptima Combo 2 transcription-mediated amplification assay (TMA), the BD ProbeTec ET amplified DNA strand displacement assay (SDA), and the Roche Cobas Amplicor PCR was defined by using a rotating "gold standard" of any positive results by two or three of the three tests that excluded the test being evaluated. A total of 961 evaluable test sets were collected. On the basis of a rotating gold standard of positive results by two of three comparator tests, the sensitivity and the specificity were as follows: culture for N. gonorrhoeae, 50.0% and 99.4%, respectively; PCR, 80.3% and 73.0%, respectively; TMA, 83.6% and 98.6%, respectively; and SDA, 93.2% and 96.3%, respectively. On the basis of a rotating gold standard of positive results by three of three comparator tests, the sensitivity and specificity were as follows: culture for N. gonorrhoeae, 65.4% and 99.0%, respectively; PCR, 91.9% and 71.8%, respectively; TMA, 100% and 96.2%, respectively; and SDA, 97.1% and 94.2%, respectively. In conclusion, currently available NAATs are more sensitive than culture for the detection of pharyngeal gonorrhea in at-risk patients. PCR is substantially less specific than culture, TMA, or SDA and should not be used for the detection of pharyngeal gonorrhea.


Inflammation markers in the serum of salt miners.
The inflammation markers alpha-1-antitrypsin (AAT), Clara cell protein (CC-16), soluble interleukin-2-receptor (IL-R) and the soluble adhesion molecule E-selectin, the intercellular adhesion molecule (ICAM-1) and the vascular adhesion molecule (VCAM-1) were determined in the serum of 195 salt-exposed miners to analyse dose-response relationships between markers and potash dust. Alpha-1-antitrypsin, Clara-cell protein, IL2-R, E-selectin and VCAM-1 were not changed by salt exposure, however the ICAM-1 level in the serum fell slightly as the salt exposure increased. This effect was strongest in the group of smokers, still visible in the group of ex-smokers, no effect was seen in non-smokers. Markers, with the exception of VCAM-1, were influenced by tobacco exposure. Since markers were not elevated in relation to salt dust exposure, the results do not support an inflammatory effect of potash dust on the respiratory system.


Properties and regulation of high-affinity pituitary receptors for corticotropin-releasing factor.
Specific receptors for corticotropin-releasing factor (CRF) were identified in the rat anterior pituitary gland by binding studies with 125I-Tyr-CRF. Binding of the labeled CRF analog to pituitary particles was rapid and temperature-dependent, and reached steady state within 45 min at 22 degrees C. The CRF binding sites were saturable and of high affinity, with dissociation constant (Kd) of 0.76 X 10(-9) M. Pituitary binding of 125I-Tyr-CRF was inhibited by CRF, Tyr-CRF and the active 15-41 fragment of CRF, but not by the inactive 21-41 CRF fragment and unrelated peptides. The binding-inhibition potencies of the CRF peptides were similar to their activities as stimuli of adrenocorticotropic hormone (ACTH) release. The high-affinity CRF sites were markedly reduced in adrenalectomized rats, and this change was reversed by dexamethasone treatment. These data indicate that the high-affinity CRF sites demonstrated in the anterior pituitary are the functional receptors which mediate the stimulatory action of the peptide on ACTH release, and that CRF receptors are down-regulated during increased secretion of the hypothalamic hormone.


THE PHARMACOTHERAPY OF THE DEPRESSIVE SYNDROME.
THREE THERAPEUTIC MODALITIES HAVE PROVED EFFECTIVE IN THE TREATMENT OF DEPRESSIVE SYNDROMES: electroconvulsive therapy (ECT), pharmacotherapy and psychotherapy. ECT gives the most reliable and most rapid results but may be contraindicated in certain cases. Psychotherapy is limited in its application to the reactive aspects of a depression. Pharmacotherapy is currently the most widely applied treatment of depression. Two classes of drugs are available which are effective in about 60% of depressed patients: the monoamine oxidase inhibitors and tricyclic compounds. Their mechanism of action is probably related to the regulation of the biogenic amine balance in the brain. The distinction between antipsychotic and antidepressant drugs is not as sharp as was formerly assumed. Maintenance pharmacotherapy has been shown to have prophylactic value in preventing relapses.


Cyclist's travel distances and risk of falls in snowy and icy conditions in German cities.
So far, no studies are known that estimate distance-based risks for cyclist falls in snowy/icy conditions compared to other conditions to account for differences in cycling levels in the different weather situations. The number of cyclist falls was gathered from retrospective surveys in Germany. Cycling distances were obtained from the German Household Travel Survey "Mobility in cities - SrV," assigned to meteorological data, and validated against counts and own surveys. The number of falls per distance cycled and Risk Ratios for snowy/icy versus other weather conditions were estimated. An average decrease of 53% in the distance travelled per person and day is estimated for snowy/icy days versus other days. This decrease is lower in regions with higher general cycling mode shares. We find average risks of falls from 9.5 to 16 (field surveys) up to 76.5 falls per 10,000 km (online survey) and average Risk Ratios for cycling in snowy/icy conditions of 20 (field survey conducted in times of other weather) to 36 (field survey conducted in times of snow/ice) and 38 (online survey conducted in times of snow/ice). The risk of suffering an injury in the event of a fall is lower in snowy/icy compared to other weather conditions. Seeing the current trend of growing general cycling levels in Germany, we expect more cycling in winter and, in case of unchanged winter weather and maintenance, a substantial increase of cyclist falls. The reduced risk of being injured in the event of a fall in snowy/icy conditions does not outweigh the higher risk of falling in the first place. Improved winter maintenance on cycling facilities can help increase winter cycling and reduce the risk of falls at the same time.


Cerebrovascular blood flow in patients with tetralogy of fallot: prediction for early surgical intervention.
Children with tetralogy of Fallot (TOF) require initial intervention at varying times reflecting a spectrum of obstruction to pulmonary blood flow. In utero, fetal patients with right sided obstructive lesions demonstrate increased middle cerebral artery (MCA) pulsatility index (PI). We sought to determine whether MCA flow patterns are associated with the degree of pulmonary obstruction and the consequential need for early surgical intervention (ESI). We performed a multi-center retrospective study evaluating patients with a prenatal diagnosis of TOF. All echocardiographic fetal studies performed from 16 weeks' gestational age through delivery were reviewed between 2001 and 2015 with subsequent postnatal medical chart review. 82 patients met inclusion criteria. Patients who ultimately required ESI (n=30) demonstrated an increased MCA PI z-score (-0.68 vs -1.32, p=0.02) compared to those who did not (n=52). An elevated MCA PI in patients with TOF was associated with ESI after 24 weeks' gestational age (-0.36 vs -1.22, p=0.02). Fetal patients with TOF demonstrate altered MCA flow that correlates with need for ESI. This effect is blunted earlier in gestation which may reflect cerebral autoregulation. MCA PI may be a beneficial tool in helping determine perinatal management and counseling for patients with TOF.


Description of Hyphopichia buzzinii f.a., sp. nov. and Hyphopichia homilentoma comb. nov., the teleomorph of Candida homilentoma.
During studies of the yeast diversity associated with rotting wood in Brazil and fruits, plants and insects in French Guiana, three strains of a new species were isolated. Analysis of the sequences of the internal transcribed spacer (ITS)-5.8S and D1/D2 domains of the large subunit of the rRNA gene showed that this species belongs to the genus Hyphopichia and its closest relative is Candida homilentoma. These species differ by 44 nucleotide substitutions in D1/D2 sequences. A new species Hyphopichia buzzinii f. a., sp. nov., is proposed to accommodate these isolates. The type strain of Hyphopichia buzzinii sp. nov. is CLIB 1739T (=CBS 14300T = UFMG-CM-Y6121T; MycoBank number is MB 815609). In addition, we isolated 11 strains of C. homilentoma from rotting wood, leaf surfaces, and water bodies in Brazil, and these strains when crossed among one another and with the type strain (CBS 6312T) of this species, produced hat-shaped ascospores typical of the genus Hyphopichia. We describe the teleomorph of C. homilentoma as a new combination, Hyphopichia homilentoma comb. nov. (type strain CBS 6312T; MycoBank number is MB 820009). We also propose to transfer the other six Candida species of the Hyphopichia clade to this genus as new combinations. Hyphopichia homilentoma produced ethanol and xylitol from D-xylose whereas H. buzzinii was only able to convert this pentose to xylitol.


Cytochemical evidence of an organized microtubular cytoskeleton in Xenopus laevis oocytes: involvement in the segregation of mitochondrial populations.
An organized microtubular cytoskeleton was discovered in the cytoplasm of Xenopus laevis oocytes. The microtubules were observed in 10- to 30-micron cryostat sections by indirect immunoperoxidase labeling using an antibody to tubulin. A gradual extraction of cells with a nonionic detergent was essential for good penetration of the antibody into the cells. In the cytoplasm of all previtellogenic oocytes, a dense network of criss-crossed long microtubules was associated in a basket-like structure surrounding the mitochondrial mass. At the beginning of vitellogenesis, the network meshes enlarged, while clusters of mitochondria migrated, in close association with microtubule bundles. At the beginning of vitellogenesis, the reorganization of the microtubular network, mostly in the vegetal hemisphere, occurred during the segregation of the mitochondrial populations. Reorganization is characterized by (1) a temporary enlargement of the network and close association of mitochondrial clusters with microtubular bundles, and (2) a progressive organization of a ring-shaped microtubular structure in the crown elaboration area. It is hypothesized that these modifications of the microtubular cytoskeleton contribute to the maintenance of cell shape and the polarized organization of the cell.


The relationship between clinical and MRI findings in patients with unilateral temporomandibular joint pain.
With the advent of magnetic resonance imaging, or MRI, clinicians and researchers have sophisticated techniques by which to assess the anatomy of the temporomandibular joint, or TMJ. Imaging is indicated when the results will affect the patient's care beyond that which can be gained from a complete clinical assessment. One of the primary indications for treatment of patients with temporomandibular disorders, or TMDs, is jaw pain, including TMJ pain. Therefore, it is necessary to assess whether MRI-depicted TMJ findings are associated with TMJ pain. This study assessed the relationship between TMJ pain and clinical and MRI findings. Subjects consisted of 85 patients with unilateral jaw pain in the area of the TMJ. The contralateral, nonpainful TMJ served as the matched control. All patients underwent a complete stomatognathic examination that included palpation of both TMJs. No care was given and no anti-inflammatory medications were prescribed until bilateral MRIs were obtained within one week. The authors found significant relationships between the side of reported jaw pain and the patient's report that palpation of the TMJ was painful and between the side of reported pain and the presence of MRI-detected effusions. The authors found no relationship between the side of reported pain and the presence of a disk displacement, or DD, or between the presence of effusions and DD on either side of the jaw. Although MRI-depicted effusions of the TMJ were associated with reports of TMJ pain, there was a high level of false-positive and false-negative findings. The results indicate that palpation of the TMJ is more accurate than MRI-depicted effusions in identifying the TMJ as the source of pain for patients with unilateral jaw pain. The results of this study suggest that palpation of the TMJ is superior to MRI in identifying the joint as the source of pain. Therefore, the most cost-effective and valid test to determine if the TMJ is a source of jaw pain is a complete clinical assessment.