Regulation of exocytosis and mitochondrial relocalization by Alpha-synuclein in a mammalian cell model.
We characterized phenotypes in RBL-2H3 mast cells transfected with human alpha synuclein (a-syn) using stimulated exocytosis of recycling endosomes as a proxy for similar activities of synaptic vesicles in neurons. We found that low expression of a-syn inhibits stimulated exocytosis and that higher expression causes slight enhancement. NMR measurements of membrane interactions correlate with these functional effects: they are eliminated differentially by mutants that perturb helical structure in the helix 1 (A30P) or NAC/helix-2 (V70P) regions of membrane-bound a-syn, but not by other PD-associated mutants or C-terminal truncation. We further found that a-syn (but not A30P or V70P mutants) associates weakly with mitochondria, but this association increases markedly under conditions of cellular stress. These results highlight the importance of specific structural features of a-syn in regulating vesicle release, and point to a potential role for a-syn in perturbing mitochondrial function under pathological conditions.


Effects of repeated sampling on the properties of the cervical mucus during one day at midcycle.
Midcycle cervical secretions were collected every hour from 08.00 to 12.00 h in 12 normal women. There was a significant decrease in gram wet weight of mucus in the first four samples followed by an increase in the fifth specimen (trend analysis). Spinnbarkeit decreased significantly during repeated sample collection. Albumin concentration in cervical secretion increased significantly during repeated sample collection, but there was no statistically significant difference in the total amount of albumin recovered during repeated sample collection. The possibility of a hormonal regulation of the water content in the cervical mucus is discussed.


Accuracy of transcutaneous bilirubin measurement in newborns after phototherapy.
We tested the accuracy of transcutaneous bilirubin (TcB) measure in newborns undergoing phototherapy. In a prospective study of 150 term Caucasian neonates, 255 measurements of total serum bilirubin (TSB) and TcB concentration were obtained 2 h after discontinuing phototherapy. TcB measurements obtained on the forehead, sternum, abdomen and covered lower abdomen were statistically compared with the corresponding TSB. TcB consistently underestimated TSB levels significantly. The smallest but significant difference between TSB and TcB was found on the lower abdomen. The correlation between TSB and TcB was found to be moderately close (r=0.4 to 0.5). TcB measurements were inaccurate, regardless of phototherapy technique (Bilibed, conventional phototherapy). Phototherapy significantly interferes with the accuracy of transcutaneous bilirubinometry. TcB measurements performed 2 h after stopping phototherapy were not reliable, even if they were carried out on the unexposed body area. TSB assessment remains necessary, if treatment of hyperbilirubinemia is being considered.


Characterization and expression of two avirulence genes cloned from Pseudomonas syringae pv. glycinea.
Two avirulence genes, avrB and avrC, from race 0 of Pseudomonas syringae pv. glycinea, were sequenced and found to encode single protein products of 36 and 39 kilodaltons, respectively. The proteins had neither recognizable signal peptide sequences nor significant stretches of hydrophobic amino acids that might indicate membrane association. Both avrB and avrC had relatively low position 3 and overall G+C contents, which suggests that they may have been recently introduced into P. syringae pv. glycinea. The deduced amino acid sequences of the proteins encoded by avrB and avrC shared 42% identical amino acids. However, when introduced into race 4 of P. syringae pv. glycinea, each gene directed a unique pattern of hypersensitive reactions on several differential soybean cultivars. The avrC protein was overproduced in Escherichia coli cells and deposited as insoluble inclusion bodies in the cell cytoplasm. The avrC protein could be solubilized with urea-octyl glucoside treatment, but neither the solubilized protein nor the intact inclusion bodies elicited a hypersensitive reaction in soybean leaves.


Absence of protein kinase C in nuclei of EL4 mouse thymoma cells.
Since evidence indicates that phorbol ester-induced production of interleukin 2 requires transcription, we investigated the possibility that the phorbol ester receptor acts directly in the nuclei of EL4 thymoma cells. Using a procedure that minimized plasma membrane contamination (as measured by 5'-nucleotidase activity) and maintained the integrity of the double nuclear membrane, we were unable to detect specific binding of [3H]phorbol 12,13-dibutyrate in nuclei of unstimulated cells. Treatment of cells with phorbol 12,13-dibutyrate (100 nM, 37 degrees C) for up to 6 h did not cause appearance of phorbol ester binding capacity in nuclei (4 +/- 8% of homogenate value; 5'-nucleotidase activity = 10 +/- 3%) despite translocation of 40% of the cytosolic binding capacity to the plasma membrane fraction. The failure to detect nuclear binding capacity in treated cells was not due to occupation of nuclear sites with unlabeled ligand; effective exchange binding was demonstrated by recovery of total homogenate binding capacity in treated cells of 82 +/- 13% of that in untreated cells. Treatment of isolated nuclei with DNase to liberate DNA binding proteins also failed to reveal any nuclear phorbol ester binding capacity. Assay of nuclei for protein kinase C enzymatic activity gave similar negative results. These data argue strongly against a direct action of the intact phorbol ester receptor (or the phorbol ester binding fragment) in the transcriptional activation of interleukin 2 in EL4 cells but cannot rule out the possibility of a role for the catalytic fragment.


What lessons can be learned from telemedicine programmes in other countries?
Reviews of telemedicine literature have shown that about half of the published studies come from the USA. This suggests that there is a large potentially useful stock of research outside the USA that could be used to guide telemedicine decision-making in the USA. In the present study, a request was sent to eight international experts in telemedicine asking about successful telemedicine programmes that have been assessed and could potentially be implemented in the US health-care system. We also conducted a focused review of a few key publications in the field to identify examples of successful telemedicine programmes. The review found that in some specific areas, such as teleradiology, telemental health, telegeriatric applications, e-referrals and discharge letters, and integration of health-care organizations with telemedicine networks, applications successfully implemented in international settings would be suitable for implementation in the USA. If telemedicine programmes from other countries are disseminated to the USA, differences in health-care systems, and technological infrastructure will probably affect their chances of success.


Calculating Protein Content of Expressed Breast Milk to Optimize Protein Supplementation in Very Low Birth Weight Infants with Minimal Effort-A Secondary Analysis.
Breast milk does not meet the nutritional needs of preterm infants, necessitating fortification. Breast milk is particularly variable in protein content, hence standardized (fixed dosage) supplementation results in inadequate supply. This was a secondary analysis of 589 breast milk protein content measurements of 51 mothers determined by mid-infrared spectroscopy during a clinical trial of higher versus lower protein supplementation in very low birth weight infants. Mothers (and breast milk samples) were divided into a test (41 mothers) and a validation cohort (10 mothers). In the test cohort, the decrease in protein content by day of lactation was modeled resulting in the breast milk-equation (BME)). In the validation cohort, five supplementation strategies to optimize protein supply were compared: standardized supplementation (adding 1.0 g (S1) or 1.42 g protein/100 mL (S2)) was compared with 'adapted' supplementation, considering variation in protein content (protein content according to Gidrewicz and Fenton (A1), to BME (A2) and to BME with adjustments at days 12 and 26 (A3)). S1 and S2 achieved 5% and 24% of adequate protein supply, while the corresponding values for A1-A3 were 89%, 96% and 95%. Adapted protein supplementation based on calculated breast milk protein content is easy, non-invasive, inexpensive and improves protein supply compared to standardized supplementation.


The vibrotactile threshold (VT) at the fingertips of chain saw operators.
The vibration sensitivity of the skin at the ten fingertips was tested with 72 chain saw operators examined due to VWF-disease and compared with controls. The vibrotactile perception threshold (frequency f = 125 Hz, load p = 1.3 N) proved to be 3 to 5 times as high for the exposed group compared to controls. There was no correlation between vibration sensitivity and peripheral circulation found in cold provocation test. Two different testing instruments (pallaesthesiometer = vibrotactometer) showed significant differences in results probably due to different technical details of the methods. It may be concluded that a standardization of the instrumentation and method is necessary for testing the vibrotactile perception threshold as a part of the nervous function in a comparable manner.


Dependence of phonation threshold pressure and frequency on vocal fold geometry and biomechanics.
Previous studies show that phonation onset occurs as two eigenmodes of the vocal folds are synchronized by the interaction between the vocal folds and the glottal flow. This study examines the influence of the geometrical and biomechanical properties of the vocal folds on this eigenmode-synchronization process, with a focus on phonation threshold pressure and frequency. The analysis showed that phonation threshold pressure was determined by the frequency spacing and coupling strength between the two natural modes that were synchronized by the fluid-structure interaction. The phonation frequency at onset was the root mean square value of the two natural frequencies plus a correction due to the added stiffness of the glottal flow. When higher-order modes of the vocal fold structure were included, more than one group of eigenmodes was synchronized as the system moved toward phonation onset. Changes in vocal fold biomechanics may change the relative dominance between different groups and cause phonation onset to occur at a different eigenmode, which was often accompanied by an abrupt change in onset frequency. Due to the synchronization of multiple pairs of eigenmodes and the mode-switching possibility, a complete and accurate description of vocal fold biomechanical properties is needed to determine the final synchronization pattern and obtain a reliable calculation of the dependence of phonation threshold pressure and frequency on vocal fold geometry and other biomechanical properties.


Curriculum Revision: Student Stress and Lessons Learned.
Curricular revision and engaging students in learning are important aspects of preparing students for a complex health care environment. The purpose of this study was to identify student perceptions of active learning practices incorporated into the junior year of a new curriculum. A descriptive qualitative design using focus group interviews for data collection was used to explore student perceptions of stress, engagement, and self-directed learning in an active learning environment. Three themes emerged from the data, including Feeling Stressed and Overwhelmed, Coping With Stress, and Being Prepared. The results of this study highlight how students responded to the increased stress of junior-year nursing courses and the lessons learned by both the students and the faculty teaching junior-year nursing students after a curricular revision and subsequent change in teaching strategies. [J Nurs Educ. 2017;56(6):337-342.].


Potential adjuvants for the development of a SARS-CoV-2 vaccine based on experimental results from similar coronaviruses.
The extensive efforts around the globe are being made to develop a suitable vaccine against COVID-19 (Coronavirus Disease-19) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2). An effective vaccine should be able to induce high titers of neutralizing antibodies to prevent the virus from attaching to the host cell receptors. However, to elicit the protective levels of antibodies, a vaccine may require multiple doses or assistance from other immunostimulatory molecules. Further, the vaccine should be able to induce protective levels of antibodies rapidly with the least amount of antigen used. This decreases the cost of a vaccine and makes it affordable. As the pandemic has hit most countries across the globe, there will be an overwhelming demand for the vaccine in a quick time. Incorporating a suitable adjuvant in a SARS-CoV-2 vaccine may address these requirements. This review paper will discuss the experimental results of the adjuvanted vaccine studies with similar coronaviruses (CoVs) which might be useful to select an appropriate adjuvant for a vaccine against rapidly emergingSARS-CoV-2. We also discuss the current progress in the development of adjuvanted vaccines against the disease.


Quickly Screening for Potential α-Glucosidase Inhibitors from Guava Leaves Tea by Bioaffinity Ultrafiltration Coupled with HPLC-ESI-TOF/MS Method.
Guava leaves tea (GLT) has a potential antihyperglycemic effect. Nevertheless, it is unclear which compound plays a key role in reducing blood sugar. In this study, GLT extract (IC50 = 19.37 ± 0.21 μg/mL) exhibited a stronger inhibitory potency against α-glucosidase than did acarbose (positive control) at IC50 = 178.52 ± 1.37 μg/mL. To rapidly identify the specific α-glucosidase inhibitor components from GLT, an approach based on bioaffinity ultrafiltration combined with high performance liquid chromatography coupled to electrospray ionization-time-of-flight-mass spectrometry (BAUF-HPLC-ESI-TOF/MS) was developed. Under the optimal bioaffinity ultrafiltration conditions, 11 corresponding potential α-glucosidase inhibitors with high affinity degrees (ADs) were screened and identified from the GLT extract. Quercetin (IC50 = 4.51 ± 0.71 μg/mL) and procyanidin B3 (IC50 = 28.67 ± 5.81 μg/mL) were determined to be primarily responsible for the antihyperglycemic effect, which further verified the established screening method. Moreover, structure-activity relationships were discussed. In conclusion, the BAUF-HPLC-ESI-TOF/MS method could be applied to determine the potential α-glucosidase inhibitors from complex natural products quickly.


The scientific rationale and development of an optimized dentifrice for the treatment of dentin hypersensitivity.
To describe the development of a new dentin hypersensitivity treatment, Colgate Sensitive Maximum Strength dentifrice, containing 5% potassium nitrate as the anti-hypersensitivity active agent. The objective was to develop a home-use hypersensitivity dentifrice that would be superior to the market leader, improving on what is available, which also contains 5% potassium nitrate as the anti-hypersensitivity active agent. In vivo (clinicals, taste evaluation and rat caries), in vitro (potassium flux) and analytical (rheology, dispensed volume, scanning electron microscopy, electron scanning chemical analysis and radioactive dentin abrasion) methods were performed. The objective was accomplished with the development of a new activated silica technology that resulted in enhanced potassium ion activity. In vitro documentation, supported by clinical studies, demonstrated that the resulting formula is more effective than the market leader for relief of hypersensitivity pain. Fast pain relief in less than 2 weeks and long-lasting protection against pain with regular use have also been clinically documented. Furthermore, FDA-required in vivo and in vitro studies indicate that this formula, which contains 0.45% stannous fluoride (1100 ppm fluoride) as the anti-caries active agent, is effective against caries. Good taste, acceptable rheology, acceptable abrasivity, and cosmetic and chemical stability have all been engineered into this unique dentin hypersensitivity treatment. In summary, a highly efficacious consumer friendly treatment for dentin hypersensitivity has been developed.


Salmeterol with fluticasone enhances the suppression of IL-8 release and increases the translocation of glucocorticoid receptor by human neutrophils stimulated with cigarette smoke.
The combination of inhaled corticosteroids and long-acting beta2-adrenoceptor agonists is increasingly used in chronic obstructive pulmonary disease (COPD). Recently, we have demonstrated that combination of salmeterol and fluticasone propionate (FP) additionally suppress the production of IL-8 by human monocyte. In this study, the molecular mechanism behind the effectiveness of this combination therapy is investigated in human neutrophils. Human neutrophils were preincubated with salmeterol or FP or the combination. The amount of interleukin-8 (IL-8), elastase and matrix metalloproteinases (MMP)-2 and -9 releases, and reactive oxygen species (ROS) generation and expression of MAP kinase phosphatase (MKP-1) and glucocorticoid receptor (GR) were determined. Cigarette smoke medium (CSM) induces an increased expression of CXC receptors and the production of ROS that may explain the strong production of IL-8 by neutrophils. The expression of CXC receptors, the production of ROS, and the release of elastase and MMP-2 and -9 were not influenced by salmeterol, FP, or the combination. Interestingly, the combination therapy had an additive suppressive effect on the CSM-induced production of IL-8. The latter could be explained by an increased mRNA expression of MKP-1, the GR and an increased translocation of the GR to the nucleus. This leads eventually to suppression of both the NF-kappaB and MAPK pathways and, hence, to less IL-8 production by the neutrophil. These data are in support for the use of a combination therapy in COPD patients.


Portland Retail Druggists Association vs Abbott Laboratories et al, part 2.
The ruling of the U.S. Supreme Court in Abbot Laboratories et al vs Portland Retail Druggists Association is discussed as it relates to hospital pharmacy purchasing practices. Topics covered include: the applicability of the Robinson-Patman Act and its Section 13C exemption to various types of hospitals; definitions of "former patient" and "reasonable quantity"; and recordkeeping requirements. It is concluded that the Portland case should not deter expansion or innovation in health care delivery and ambulatory care services but must be accounted for in implementing new programs.


Common haplotypes in the beta-2 adrenergic receptor gene are not associated with acute mountain sickness susceptibility in Nepalese.
Acute Mountain Sickness (AMS), the most common and least serious of the altitude-related illnesses, is frequently experienced by sojourners traveling above 2500 m. Although altitude and rate of ascent are likely the most critical factors in determining whether the condition will develop in a person, interindividual variation and patterns of susceptibility suggest that there may be genetic risk factors as well. We hypothesized that variants in the gene that encodes the beta-2 adrenergic receptor (the principal catecholamine receptor in the lungs) are involved in the etiology of AMS and tested this hypothesis in cohorts of Nepalese individuals who developed or did not develop AMS when attending the Purnima Festival at Lake Gosain Kunda at 4380. Polymorphisms that could serve as markers for the common haplotypes encompassing the gene were chosen using the HapMap database. We found no association between any alleles at the seven highly informative polymorphic loci (tagSNPs) that we assayed and AMS status, suggesting that variants in, or near, the beta-2 adrenergic receptor gene do not contribute to AMS susceptibility in this population. This study is the first application of the HapMap database and associated haplotype mapping tools to the understanding of altitude-related pathologies.


Platelet-rich fibrin, "a faster healing aid" in the treatment of combined lesions: A report of two cases.
Anatomically the pulp and periodontium are connected through apical foramen, and the lateral, accessory, and furcal canals. Diseases of one tissue may affect the other. In the present case report with two cases, a primary periodontal lesion with secondary endodontic involvement is described. In both cases, root canal treatment was done followed by periodontal therapy with the use of platelet-rich fibrin (PRF) as the regenerative material of choice. PRF has been a breakthrough in the stimulation and acceleration of tissue healing. It is used to achieve faster healing of the intrabony defects. Absence of an intraradicular lesion, pain, and swelling, along with tooth stability and adequate radiographic bone fill at 9 months of follow-up indicated a successful outcome.


Effect of audio and virtual reality distraction on the dental anxiety of children with mild intellectual disability.
Intellectual disability, is a neurodevelopmental disorder that typically manifests early in childhood and consists of both intellectual and adaptive functioning deficits in conceptual, social, and practical domains. It can be categorized into mild, moderate, severe, and profound based on its severity. Cognitive impairment may be observed predominantly in children with intellectual disabilities. Marked deficits in areas of learning, planning, communication, social participation, and personal independence in children with mild intellectual disabilities make behavior guidance and communication a challenge during dental treatments. The aim was to evaluate and compare the use of two different distraction tools, audio, and virtual reality (VR) on the dental anxiety of children with mild intellectual disability during dental treatment. Twenty children diagnosed with mild intellectual disability were equally divided into two groups. A cross-over study design consisting of two appointments 1 month apart was employed. In the first appointment, audio and VR distractions were provided to participants in Groups 1 and 2, respectively, and the distraction tools provided to the participants were interchanged in the second appointment. A trained observer recorded physiological parameters (pulse rate and oxygen saturation) and observational parameters (Venham's anxiety rating scale) during both appointments at three-time intervals. Statistical intra-group and inter-group comparison analyses were performed using Friedman's and Mann-Whitney U tests. A decrease in pulse, increase in oxygen saturation levels, and a decrease in Venham's Anxiety Rating Scores (statistically significant p < .05 / highly significant p < .01) was observed on introducing the distraction techniques in Groups 1 and 2 in both appointments. A statistically non-significant difference (p > .05) in physiological and observational parameters was observed between Groups 1 and 2 in both appointments. Audio and VR distraction techniques can be employed for behavior guidance in children with mild intellectual disability during restorative dental procedures.


Effect of axillary lymph node dissection on prevalence and intensity of chronic and phantom pain after breast cancer surgery.
Chronic pain after breast cancer surgery is a major problem and is expected to increase in the coming years because of an increased prevalence of breast cancer coupled with better survival. Axillary lymph node dissection (ALND) in patients with breast cancer is associated with nerve damage. The present study investigated the effect of ALND on the prevalence and intensity of chronic pain after breast cancer surgery. Furthermore, we studied the effect of chemotherapy and radiotherapy on chronic pain and the quality of life after breast cancer surgery. We analyzed 317 questionnaires of patients who underwent surgery for breast cancer between 2002 and 2004. In the first part, questions were asked concerning the prevalence of chronic pain, its intensity (visual analog scale), and phantom breast pain. The second part covered quality of life and included the EORTC QLQ-C30/BR-23. The prevalence of chronic pain after breast cancer surgery with ALND is double that without ALND (51% vs 23%). Chronic pain intensity and prevalence of phantom breast pain were not influenced by ALND. Chemotherapy and radiotherapy in interaction with ALND were associated with increased prevalence of chronic pain. The quality of life in patients was mainly affected by chronic pain and to a lesser extent by type of surgery. Nerve injury is particularly efficient at producing central sensitization. ALND in conjunction with breast cancer surgery is associated with a doubled prevalence of chronic pain, which has not been described to date. ALND and nerve injury may play a major role in pain chronification after breast cancer surgery.


Color Doppler indexes in early phase after kidney transplantation and their association with kidney function on six month follow up.
Doppler ultrasonography (DU) and measurement of its indexes, resistive index (RI) and pulsatility index (PI), is used to investigate transplanted kidney hemodynamic status and function. The aim of this study was to determine the correlation between Doppler indexes in the early phase after transplantation with long-term transplanted kidney function. In this cross-sectional study on 38 newly kidney transplant patients, we performed DU with assessment of its indexes within 48 hours, 1 week, and 6 months after kidney transplantation. Serum creatinine after stability and 6 months after kidney transplantation were assessed. Cyclosporine level was measured 1 week after kidney transplantation and compared with DU indexes. About 71% of kidney transplanted patients reached their normal initial creatinine level(cr<1.5 mg/ dl) and 28% of all patients were involved in kidney dysfunction after 6 months (increase in basic creatinine level more than 25%).There was no significant difference between mean RI and PI in patients with normal and disturbed kidney function based on creatinine level in early posttransplantation period but there was linear correlation between mean RI and PI within 48 hours and 1 week with kidney function after 6 months. Also no association between cyclosporine level and RI and PI was shown. There was a direct association between age and the levels of RI and PI 6 months after transplantation. This study suggests assessment of RI and PI in early period after transplantation and can be used as predictive parameters for long-term function of transplanted kidney and RI more than 0.80 in early phase after transplantation has an acceptable sensitivity and specificity to predict long-term kidney dysfunction.


Fast Hydrolysis Polyesters with a Rigid Cyclic Diol from Camphor.
2,2:3,3-Bis(4'-hydroxymethylethylenedioxy)-1,7,7-trimethylbicyclo[2.2.1]heptane, abbreviated as CaG, is a compound obtained by transforming a ketone group to a ketal group with camphorquinone and glycerol. The CaG diol has a complex and rigid structure and two primary hydroxyl groups. A polyester series was synthesized with the CaG diol, ethylene glycol, and dimethyl terephthalate. The polyesters exhibited adequate thermal stability up to nearly 330 °C and had a high Tg, which steadily increased from 78 to 129 °C as the content of CaG increased. A high proportion of the CaG moiety led to an amorphous region that is susceptible to hydrolysis and promoted degradation of the polyester in acidic conditions. Depending on the proportion of CaG in the polymer, the hydrolytic degradation of the polyesters was adjustable.


Age-related changes in upper body adaptation to walking speed in human locomotion.
Assessments of changes in gait stability due to aging and disease are predominantly based on lower extremity kinematic and kinetic data. These gait changes are also often based on comparisons at preferred speed only. The purpose of this experiment was to: (1) examine age-related changes in range of motion and coordination of segments of the upper body during locomotion; and (2) investigate the effects of a systematic walking velocity manipulation on rotational motion and coordination. Participants (n=30) walked on a motor driven treadmill at speeds ranging from 0.2 to 1.8m/s and were divided into three groups with mean ages of 23.3, 49.3 and 72.6 years, respectively. Seven high-speed infrared cameras were used to record three-dimensional kinematics of the pelvis, trunk and head. Dependent variables were amplitude of segmental and joint rotations, as well as relative phase to assess coordination between segments. Although no differences in stride parameters were found between the groups, age-related changes in movement amplitude in response to speed manipulations were observed for all segments and joints. Pelvic rotations in sagittal, frontal and transverse planes of motion were systematically reduced with age. Older individuals showed reduced trunk flexion-extension in the sagittal plane and increased trunk axial rotation in the transverse plane. Coordination analysis showed reduced compensatory movement between pelvis and trunk in older individuals. These findings support the importance of systematic manipulation of walking velocity and three-dimensional upper body kinematics in assessing age-related changes in locomotor stability and adaptability.


Bolus Detection in the Proximal Esophagus Using Pulse-Echo Ultrasound: A Feasibility Study.
Here, the feasibility of using nonimaging pulse-echo ultrasound as a method of noninvasively detecting a bolus in the proximal esophagus was demonstrated. To accomplish this, patient swallows were recorded on a clinical ultrasound device with research interface that allowed for collection of the pulse-echo data. These ultrasound data of the proximal esophagus were processed with a series of signal processing techniques in both the temporal and spectral domains, which revealed characteristic signatures that were unique for both liquid and food boluses compared to the normal collapsed esophageal state. Since substantial amounts of laryngopharyngeal reflux are gaseous in nature, future work will revolve around expanding the data set to include boluses of gaseous refluxate, a standardized methodology for capturing bolus events; developing automated detection tools for identifying laryngopharyngeal reflux for an extended duration; and assessing technology limitations due to user error.


Dietary carbohydrate, fibre, glycaemic index, glycaemic load and the risk of postmenopausal breast cancer.
Evidence that the insulin pathway may be involved in breast carcinogenesis has increased the interest in dietary factors that influence insulin secretion and resistance. We investigated dietary carbohydrate, fibre, glycaemic index (GI) and glycaemic load (GL) in a prospective study of 324 breast cancers diagnosed in 12,273 post-menopausal women. Although an increase of 1 standard deviation in carbohydrate was marginally associated with risk of breast cancer, relative risk (RR) 1.31 (95% CI, 0.98, 1.75), there were no significant associations with fibre, 1.08 (0.92, 1.26), GI, 0.98 (0.88, 1.10) or GL, 1.19 (0.93, 1.52) or with carbohydrate foods (bread, rice, pasta). The RR for carbohydrate and localized disease was elevated, 1.40 (1.02, 1.92), but like those for fibre, GI and GL did not differ significantly between localized and non-localized disease. RRs for grade I, but not grade II or III, tumours were elevated for fibre, 1.38 (1.08, 1.75), carbohydrate, 1.56 (1.08, 2.25) and GL, 1.41 (1.01, 1.98) but not for GI, 0.84 (0.65, 1.09). The RRs for fibre and oestrogen receptor (ER) positive (+) and progesterone receptor (PR) positive (+) tumours, 1.36 (1.10, 1.67), differed significantly from those for ER positive (+) and PR negative (-) tumours, 1.01 (0.61, 1.69) and ER-/PR- tumours, 0.65 (0.43, 0.99), p = 0.005. Our data do not support a strong role for GI and GL in breast carcinogenesis but suggest that increased intake of fibre and carbohydrate may be associated with the diagnosis of cancers of more favourable prognosis.


Role of histamine in the hypotensive action of d-tubocurarine in humans.
The administration of d-tubocurarine (dTc) to animals and humans has been reported to produce hypotension. Experiments in animals suggest that the hypotension is a result of both ganglionic blockade and histamine release. In order to determine the role of histamine release in dTc-induced hypotension in humans, the authors developed a sensitive radioenzymatic assay for plasma histamine and measured plasma histamine following dTc administration (0.25-0.75 mg/kg) to 21 surgical patients. While neither fentanyl (3 microgram/kg) nor thiopental (6 mg/kg) produced a significant change in plasma histamine, dTc caused a dose-dependent increase in plasma [dose dTc vs. log (plasma histamine), r = 0.62 P less than 0.003]. The log (plasma histamine) correlated with the dTc-induced hypotension (r= 0.61, P less than 0.005). The data suggest that histamine release is an important factor in the hypotension accompanying dTc administration in humans.


Autophagy-Src Regulates Connexin43-Mediated Gap Junction Intercellular Communication in Irradiated HepG2 Cells.
Connexin molecules are an important component of the gap junction, with connexin43 (Cx43) being the most abundantly expressed type. Src is a nonreceptor tyrosine-protein kinase that affects Cx43 activity by multiple mechanisms. However, it is not clear how Src regulates Cx43 to influence radiation-induced bystander effects (RIBEs). In this study, we demonstrated that Cx43 on Tyr265 was phosphorylated by activated Src in α-irradiated HepG2 cells, with the total expression of Cx43 unchanged. After inhibition of Cx43 phosphorylation in irradiated cells, the frequency of γ-H2AX foci formation in adjacent nonirradiated bystander cells was significantly enhanced. Furthermore, this study showed that autophagy regulated the activity of Src and phosphorylation of Cx43, and the level of autophagy was correlated with the radiation-induced reactive oxygen species (ROS). These results suggest that ROS and autophagy play an important role in regulating the Src-Cx43 axis to affect the RIBEs. Our findings provide new insights into the Cx43-mediated gap junction intercellular communication, as well as the underlying mechanism of RIBEs.


Defining Episodes of Care in Children's Mental Health Using Administrative Data.
Criteria to define an episode of care in children's mental health services are needed. Various criteria were applied to 5 years of visit data from children 4-11 years (N = 5,206) at their first visit to 1 of 3 children's mental health agencies. A minimum of 3 visits with 180 days between episodes optimized agreement with other dates (e.g., telephone intake assessment) marking the start and end of an episode, and clinician-rated number of episodes. Grouping visits into episodes provides a clearer representation of how services are distributed over extended periods of time, facilitating research and enhancing accuracy in service planning.


Neuronal Subset-Specific Migration and Axonal Wiring Mechanisms in the Developing Midbrain Dopamine System.
The midbrain dopamine (mDA) system is involved in the control of cognitive and motor behaviors, and is associated with several psychiatric and neurodegenerative diseases. mDA neurons receive diverse afferent inputs and establish efferent connections with many brain areas. Recent studies have unveiled a high level of molecular and cellular heterogeneity within the mDA system with specific subsets of mDA neurons displaying select molecular profiles and connectivity patterns. During mDA neuron development, molecular differences between mDA neuron subsets allow the establishment of subset-specific afferent and efferent connections and functional roles. In this review, we summarize and discuss recent work defining novel mDA neuron subsets based on specific molecular signatures. Then, molecular cues are highlighted that control mDA neuron migration during embryonic development and that facilitate the formation of selective patterns of efferent connections. The review focuses largely on studies that show differences in these mechanisms between different subsets of mDA neurons and for which in vivo data is available, and is concluded by a section that discusses open questions and provides directions for further research.


Differential requirement for p56lck in fetal and adult thymopoiesis.
The protein tyrosine kinase p56lck is critical for the generation of mature thymocytes in adult mice. However its requirement during the maturation of thymocytes from the fetal to the adult stage has not been clearly defined. We analyzed prenatal and postnatal thymocyte maturation in mice deficient for p56lck (lck[-/-]). Before birth, lck appears to play a crucial role in the expansion and proliferation of CD4+CD8+ double positive thymocytes, whereas proliferation and absolute numbers of CD4-CD8- double negative thymocyte precursors remained within the normal range until the end of the second week postnatal. Three weeks after birth, the total numbers of double negative and immature single positive thymocytes underwent a dramatic reduction that correlated with a decrease in the double positive population. This ontogenic defect was associated with a significant decrease in the proliferation rates of thymocyte precursors. Our data suggest that signaling via p56lck kinase is differentially required within a given phenotypically defined thymocyte subpopulation, depending on its stage of thymocyte maturation.


Intellectual freedom and editorial responsibilities within the context of controversial research.
The primary purpose of this article is to explore the limits that an agent, such as the government or the American Psychological Association, may place on one's right to pursue a program of research or to share the findings of a research project. The primary argument that evolves here is that researchers' rights to pursue an interesting hypothesis, and their freedom of expression, are conditional. The author examines the potential pragmatic and epistemological barriers to a program of research and the responsibilities that researchers bear to address epistemological and nonepistemological matters while reviewing the implications of their work.


Secoiridoids from Dogwood (Cornus officinalis) Potentiate Progesterone Signaling.
The use of botanical dietary supplements for the alleviation of conditions such as hot flashes, premenstrual syndrome, and fertility is prolific worldwide. Estrogen and progesterone receptors (ER and PR) and their corresponding steroid hormones are critical for the relief of hot flashes and the treatment of patients who develop endometriosis, and these pathways can influence the development of endometrial, ovarian, and breast cancers. However, few studies have investigated or identified the natural product components in herbal supplements that act on the PR. In the current study, a new secoiridoid, demethoxy-cornuside (1), along with six known secoiridoids (2-7) were isolated from the twigs of dogwood (Cornus officinalis) by bioassay-guided isolation with a progesterone response element (PRE)/luciferase (Luc) reporter assay in Ishikawa cells. Four phytoprogestins (1, 2, 6, 7) potentiated the effect of progesterone in the PRE/Luc assay. This study demonstrates that C. officinalis components might potentiate progesterone signaling in the presence of progesterone, which could modify progesterone receptor action in hormone-responsive tissues such as the uterus and mammary gland.


High-dose subchronic imipramine treatment: effects on anxiety-like (conflict) behavior in rats.
In the management of both anxiety and depression, agents such as imipramine (IMI) are noted for their 3-5 week delay to onset of clinical effect. A similar delay to onset has been reported for the anxiolytic-like (i.e., anticonflict) effect of chronic IMI treatment (2.5 mg/kg, BID for 5 weeks) in the Conditioned Suppression of Drinking (CSD) conflict paradigm; similar effects have been reported with other antidepressants and in other conflict procedures. In contrast, in the Forced Swim Test (FST) model of depression, antidepressant-like effects are reported immediately following subchronic treatment with relatively high doses of these agents (e.g., 30 mg/kg IMI, 3 times in 24 hr). The present study examined the effects of this high-dose, subchronic treatment with IMI on CSD conflict behavior. Conflict-trained female Sprague Dawley rats were divided into three groups with comparable pretreatment baselines for shocks received. Treatments (0, 15, and 30 mg/kg IMI) were administered intraperitoneally (IP) at 23, 5, and 1 hr prior to CSD conflict testing on day 1; CSD conflict behavior was then monitored daily (Mon-Fri) for 5 weeks following treatment. IMI treatment (30 and, to a lesser extent, 15 mg/kg) significantly reduced shocks received (punished responding) and water intake (unpunished responding) on day 1; although water intake was also slightly reduced in both IMI treatment groups for the remainder of test week 1, there was no difference in shocks received between the various treatments for this period. Subjects receiving 30 mg/kg IMI (but not those receiving 15 mg/kg IMI or vehicle) accepted significantly more shocks than controls on weeks 2-4 (maximal increase at week 3) and returned to pretreatment baseline levels by week 5. Thus, subchronic high-dose treatment with IMI (and perhaps other antidepressants) produces anxiolytic-like effects which are delayed in nature and persist for several weeks after treatment.


Is the effect of prenatal paracetamol exposure on wheezing in preschool children modified by asthma in the mother?
There seems to be an association between paracetamol consumption during late pregnancy and the prevalence of wheezing in infancy and childhood. The aim of the present study is to determine whether the aforementioned association is modified by the presence of asthma in the mother. A total of 1,741 children aged 3-5 years from an epidemiological survey performed in the province of Murcia (Spain) were included in the analysis. Data on paracetamol consumption (never, at least once during pregnancy or at least once per month during pregnancy), wheezing symptoms in the offspring (according to the International Study of Asthma and Allergies in Childhood protocol) and the presence of asthma in the mother, together with other known risk factors for asthma, were obtained by means of a questionnaire. The mean age of the children was 4.08 +/- 0.8 years and 51.1% were males. The overall prevalence of current wheezing was 20.2%. The frequency of paracetamol usage was similar among asthmatic and non-asthmatic mothers, and only a small proportion of them took this drug at least once a month (13.8% of asthmatics and 11.0% of non-asthmatics). Compared to the mothers who never took paracetamol, there was a significant association between the mother having taken paracetamol at least once per month during pregnancy and the offspring suffering from wheezing at preschool age, but only among non-asthmatic mothers (odds ratio 1.94, 95% confidence interval 1.34-2.79 vs. odds ratio 1.05, 95% confidence interval 0.21-5.08). This association was maintained after controlling for potential confounders (odds ratio 1.74, 95% confidence interval 1.15-2.61). The frequent usage of paracetamol during pregnancy is associated with the prevalence of wheezing in offspring during preschool years. Asthma in the mother might modify this association.


Effects of dietary supplements on athletic performance in elite soccer players: a systematic review.
Dietary supplements are widely used among athletes, and soccer players are no exception. Nevertheless, evidence supporting the use of dietary supplements aiming to enhance performance in soccer is somewhat contradictory, scarce, or even nonexistent. Thus, the present study aimed to systematically review and synthesize the effects of dietary supplements on athletic performance (e.g. distance covered, sprinting, jump performance) in elite soccer players. Studies enrolling highly trained, elite, and world-class soccer players using dietary supplements were searched in MEDLINE/PubMed, Web of Science, Scopus, and EBSCO databases in June 2022. In total, 1043 studies were identified, and 18 met the eligibility criteria. The studies evaluated the impacts on athletic performance of several dietary supplements, including caffeine, creatine, protein, beverages with carbohydrates and electrolytes, tart cherry juice, nitrate-rich beetroot juice, sodium bicarbonate with minerals, yohimbine, and a proprietary nutraceutical blend. Caffeine supplementation in doses between 3 and 6 mg/kg of body mass may improve jump height and sprint ability, particularly in female players, but individual response to caffeine must be considered. Creatine may improve sprint, agility, and in female players, jump performance. Protein supplementation can improve sprint and jump performance between matches, especially if protein ingested from food is not up to recommendations. Beverages containing carbohydrates and electrolytes can be used as part of the strategies to achieve carbohydrate intake during training and match-days but used alone do not benefit athletic performance. Tart cherry juice might be useful for maintaining athletic performance after matches that produce higher force loss and exercise-induced muscle damage, although polyphenols from the diet might attenuate the effects of tart cherry supplementation. Nitrate-rich beetroot concentrate can attenuate performance decrease in the days following matches. Further investigation with sodium bicarbonate alone is necessary, as supplementation protocols with elite players included other substances. Finally, the available data does not support yohimbine supplementation or the use of Resurgex Plus® to improve athletic performance in elite soccer players. Still, more well-designed research with elite soccer players is needed to improve support and advice regarding the use of dietary supplements for athletic performance enhancement.


The Effects of Yoga Exercise on Pelvic Floor Rehabilitation of Postpartum Women.
Rehabilitation of the pelvic floor after delivery is very important for women. Pelvic floor rehabilitation can speed up the recovery of the postpartum vagina and pelvic floor muscle tension and elasticity and have a good effect on the prevention and treatment of postpartum vaginal prolapse and relaxation, urinary incontinence and other pelvic floor disorders. Thus, this article focuses on yoga exercise to explore its impact on postpartum pelvic floor rehabilitation. This article uses electrical stimulation and the treatment of pelvic floor muscles combined with the posture recognition algorithm, the yoga rehabilitation training program that has the best effect on the parturient is obtained, and the yoga myoelectric stimulation combined method and the traditional myoelectric stimulation method are designed for comparison experiments. The experimental results show that the parturients who have undergone the combined method of yoga myoelectric stimulation, in the resting state, contraction state, and Valsalva state, the position of the bladder meridian, the position of the uterus, and the position of the rectal ampulla of the parturient have a significant recovery compared those who have undergone the traditional electromyography treatment. In addition, the average area of hiatus in the pelvic floor ultrasound examination in the control group 42 days postpartum was 12.2605 cm2, while the average area of the hiatus in the pelvic floor ultrasound examination in the experimental group 42 days postpartum was 10.788 cm2; the average area of hiatus in the pelvic floor ultrasound examination in the control group at 3 months postpartum was 11.4805 cm2, and the average area of hiatus in the pelvic floor ultrasound examination in the experimental group at 3 months postpartum was 8.9475 cm2. To sum up, yoga had a very significant improvement on the physical indicators and mental health of postpartum women.


Genetic mapping of Foxb1-cell lineage shows migration from caudal diencephalon to telencephalon and lateral hypothalamus.
The hypothalamus is a brain region with vital functions, and alterations in its development can cause human disease. However, we still do not have a complete description of how this complex structure is put together during embryonic and early postnatal stages. Radially oriented, outside-in migration of cells is prevalent in the developing hypothalamus. In spite of this, cell contingents from outside the hypothalamus as well as tangential hypothalamic migrations also have an important role. Here we study migrations in the hypothalamic primordium by genetically labeling the Foxb1 diencephalic lineage. Foxb1 is a transcription factor gene expressed in the neuroepithelium of the developing neural tube with a rostral expression boundary between caudal and rostral diencephalon, and therefore appropriate for marking migrations from caudal levels into the hypothalamus. We have found a large, longitudinally oriented migration stream apparently originating in the thalamic region and following an axonal bundle to end in the anterior portion of the lateral hypothalamic area. Additionally, we have mapped a specific expansion of the neuroepithelium into the rostral diencephalon. The expanded neuroepithelium generates abundant neurons for the medial hypothalamus at the tuberal level. Finally, we have uncovered novel diencephalon-to-telencephalon migrations into septum, piriform cortex and amygdala.


Prospective validation of a novel renal activity index of lupus nephritis.
Objectives The renal activity index for lupus (RAIL) score was developed in children with lupus nephritis as a weighted sum of six urine biomarkers (UBMs) (neutrophil gelatinase-associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin and kidney injury molecule 1) measured in a random urine sample. We aimed at prospectively validating the RAIL in adults with lupus nephritis. Methods Urine from 79 adults was collected at the time of kidney biopsy to assay the RAIL UBMs. Using receiver operating characteristic curve analysis, we evaluated the accuracy of the RAIL to discriminate high lupus nephritis activity status (National Institutes of Health activity index (NIH-AI) score >10), from low/moderate lupus nephritis activity status (NIH-AI score ≤10). Results In this mixed racial cohort, high lupus nephritis activity was present in 15 patients (19%), and 71% had proliferative lupus nephritis. Use of the identical RAIL algorithm developed in children resulted in only fair prediction of lupus nephritis activity status of adults (area under the receiver operating characteristic curve (AUC) 0.62). Alternative weightings of the six RAIL UBMs as suggested by logistic regression yielded excellent accuracy to predict lupus nephritis activity status (AUC 0.88). Accuracy of the model did not improve with adjustment of the UBMs for urine creatinine or albumin, and was little influenced by concurrent kidney damage. Conclusions The RAIL UBMs provide excellent prediction of lupus nephritis activity in adults. Age adaption of the RAIL is warranted to optimize its discriminative validity to predict high lupus nephritis activity status non-invasively.


Inhaled corticosteroids in the long-term management of patients with chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a major problem in the elderly population, with approximately 10% of the population affected. Since COPD is an inflammatory disorder of the pulmonary system, corticosteroids might be expected to improve clinical outcomes of the disease. Data from large, well designed randomised clinical trials in which approximately one third of patients were > or =65 years of age indicate that inhaled corticosteroids do not modify the natural history of COPD, as measured by the rate of decline in forced expiratory volume in 1 second (FEV1). However, these same studies also suggest that corticosteroids reduce the frequency of clinical exacerbations by nearly a third (compared with placebo). This beneficial effect is particularly pronounced among those with an FEV1 less than 50% of the predicted value. Withdrawal of inhaled corticosteroids, on the other hand, leads to increased symptoms and elevates the risk of exacerbations by 50% above baseline levels. Patients' health-related quality of life is also improved by the use of inhaled corticosteroids. It is clear that inhaled corticosteroids elevate the risk of thrush, dysphonia and skin bruising by 2-fold compared with placebo. In addition, the sum of evidence suggests a modest deleterious effect for inhaled corticosteroids on bone mineral density, especially for formulations that have an increased rate of systemic absorption. However, the clinical evidence of this observation is uncertain. The effect of inhaled corticosteroids on fracture risk is controversial with some observational studies suggesting a possible association. Whether inhaled corticosteroids increase the risk of ophthalmic complications (cataracts and glaucoma) is also uncertain. In conclusion, the current evidence indicates that inhaled corticosteroid therapy produces short- and long-term clinical benefits in COPD patients with moderate-to-severe disease and should be used as adjunctive therapy for elderly patients with COPD who experience frequent exacerbations or have moderately reduced lung function.


Hepatoprotective Effect of Corm of Ensete ventricosum (Welw.) Cheesman Extract against Isoniazid and Rifampicin Induced Hepatotoxicity in Swiss Albino Mice.
Drug-induced liver injury (DILI) is one of the cumbersome health-related problems which render approximately 50% of liver failure and patients to receiving liver transplantation every year. Antituberculosis drugs such as isoniazid and rifampicin are potentially rendering hepatotoxicity. Ensete ventricosum (Welw.) Cheesman is an herbaceous perennial plant that contributes to the indigenous ethnomedicinal values for the society. This study aimed to investigate the hepatoprotective effect of corm of Ensete ventricosum (Welw.) Cheesman extracts against isoniazid and rifampicin induced hepatotoxicity in Swiss albino mice. The study was conducted on 30 Swiss albino mice randomly allocated into five groups. Group I, group II, group III, group IV, and group V were the groups in which mice were given distilled water, only isoniazid and rifampicin, isoniazid and rifampicin along with 200 mg/kg corm of Ensete ventricosum (Welw.) Cheesman extract, isoniazid and rifampicin along with 400 mg/kg corm of Ensete ventricosum (Welw.) Cheesman extract, and isoniazid and rifampicin along with silymarin per oral per day, respectively. On the 30th day of the experiment, mice were sacrificed after anesthetized, and blood was drawn for the liver function test, and the liver was also taken from each experimental mouse for histopathological evaluation. Data were entered into EpiData version 3.1 subsequently exported to SPSS version 25 for analysis by using one-way ANOVA. Plasma alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBIL) of group II mice were significantly (p < 0.05) elevated as compared to group I. The group of mice treated with a corm of Ensete ventricosum (Welw.) Cheesman at a dose of 400 mg/kg (group IV) and silymarin100 mg/kg (group V) showed a significant (p < 0.05) decrease in ALT, AST, ALP, and TBIL as compared to the group II. The liver section of group II showed a change in liver architecture; however, these deformities were not noticed in group IV mice. The result showed corm of Ensete ventricosum (Welw.) Cheesman extract has a very promising hepatoprotective potential against isoniazid and rifampicin induced liver injury.


Obstructive sleep apnea syndrome caused by uncommon tumors of the upper aerodigestive tract.
Obstructive sleep apnea syndrome (OSAS) is always caused by anatomic abnormalities, including nasal cavity, pharynx, and neuromuscular dysfunctions, leading to airway narrowing. OSAS associated with a mass in the aerodigestive tract is rare. In the present study, we report OSAS caused by 9 cases of preoperative uncommon tumors in the aerodigestive tract. Two tumors in the parapharyngeal space were pleomorphic adenoma, one oropharyngeal tumor was mucoepidermoid carcinoma, one tumor in the right tonsil was schwannoma, and five tumors were non-Hodgkin's lymphoma (NHL). Of the five NHL cases, one in the nasopharynx was diffuse large B-cell lymphoma, two were mantle cell lymphoma, one was chronic lymphocytic leukemia/small lymphocytic lymphoma, and one was NHL. Tumors in the aerodigestive tract should be considered in the differential diagnosis of OSAS upon exacerbation of snoring or sudden gasping. Further examinations should be performed, including a routine workup (computed tomography (CT) and magnetic resonance imaging) and positron emission tomography/CT.


Antinociceptive synergism of MD-354 and clonidine. Part II. The alpha-adrenoceptor component.
Previously, we reported that antinociceptive synergism of a 5-HT(3)/alpha(2)-adrenoceptor ligand MD-354 (m-chlorophenylguanidine) and clonidine combination occurs, in part, through a 5-HT(3) receptor antagonist mechanism. In the present investigation, a possible role for alpha(2)-adrenoceptors was examined. Mechanistic studies using yohimbine (a subtype non-selective alpha(2)-adrenoceptor antagonist), BRL 44408 (a preferential alpha(2A)-adrenoceptor antagonist) and imiloxan (a preferential alpha(2B/C)-adrenoceptor antagonist) on the antinociceptive actions of a MD-354/clonidine combination were conducted. Subcutaneous pre-treatment with all three antagonists inhibited the antinociceptive synergism of MD-354 and clonidine in the mouse tail-flick assay in a dose-dependent manner (AD(50) = 0.33, 2.1, and 0.17 mg/kg, respectively). Enhancement of clonidine antinociception by MD-354 did not potentiate clonidine's locomotor suppressant activity in a mouse locomotor assay. When [ethyl-3H]RS-79948-197 was used as radioligand, MD-354 displayed almost equal affinity to alpha(2A)- and alpha(2B)-adrenoceptors (K(i) = 110 and 220 nM) and showed lower affinity at alpha(2C)-adrenoceptors (K(i) = 4,700 nM). MD-354 had no subtype-selectivity for the alpha(2)-adrenoceptor subtypes as an antagonist in functional [35S]GTPgammaS binding assays. MD-354 was a weak partial agonist at alpha(2A)-adrenoceptors. Overall, in addition to the 5-HT(3) receptor component, the present investigation found MD-354 to be a weak partial alpha(2A)-adrenoceptor agonist that enhances clonidine's thermal antinociceptive actions through an alpha(2)-adrenoceptor-mediated mechanism without augmenting sedation.


Detection of gamma interferon in the sera of patients with Behçet's disease.
The serum levels of interferon (IFN) in 58 patients with Behçet's disease were significantly higher than those in 79 normal controls (P less than 0.0001). The average IFN titer was 51.4 +/- 9.3 IU/ml in the patients and 5.9 +/- 1.1 IU/ml in the controls. The patients were then divided into two groups according to the stage of ocular disease. Forty-six patients in the ocular convalescent stage had higher IFN levels (61.3 +/- 11.2 IU/ml) than did 12 patients in the exacerbation stage (13.2 +/- 3.0 IU/ml). Moreover, the kinetics of the IFN level in the circulation of seven patients showed a significant decrease of IFN in the exacerbation stage. IFN activity in sera from patients was destroyed by acid treatment and heating at 56 degrees C for 30 min and was not neutralized with anti-human IFN-alpha and -beta sera. In addition, it was demonstrated that vesicular stomatitis virus inhibitors detected in sera from both the patients and the controls had no effect on our IFN assay. Therefore, antiviral activity detected in sera of patients seems to be due to gamma interferon (IFN-gamma). IFN-gamma may play a significant role in the pathophysiology of Behçet's disease.


The refined crystal structure of hexon, the major coat protein of adenovirus type 2, at 2.9 A resolution.
The crystal structure of hexon, the major coat protein from adenovirus type 2, has been refined at 2.9 A resolution. Hexon is a homo-trimer (molecular mass 3 x 109,077 Da) and crystallizes in the cubic space group P2(1)3, with a cell edge of 150.5 A. There are four molecules in the unit cell so that the crystallographic asymmetric unit contains one subunit of the trimer. The electron density in most regions is well-defined and 880 amino acid residues, of the 967 in this unusually long polypeptide chain, have been located and fitted. The N terminus (1 to 43) and three internal stretches (192 to 203, 270 to 291 and 444 to 453) are not defined, and a stretch (168 to 207) with unclear side-chain density is modelled as poly(Ala/Gly). The current refined model, consisting of 6943 non-hydrogen protein atoms and 85 water molecules, yields an R-factor of 19.9% for 18,176 reflections in the resolution range 5.0 to 2.9 A. The model has reasonable geometry with root-mean-square deviations from ideal bond lengths of 0.022 A and angle-related 1-3 distances of 0.056 A. The overall shape of the trimeric hexon molecule is unusual and may be divided into a pseudo-hexagonal base rich in beta-structure, and a triangular top formed from three long loops containing some secondary structure. The base contains two similar pedestal domains, P1 and P2, each of which is a flattened eight-stranded beta-barrel with the "jelly-roll greek key" topology characteristic of other viral coat proteins. P1 and P2 are related by an approximate 6-fold operation about the molecular 3-fold axis so that six barrels form the walls of the tubular hexon base. The hexon bases form close-packed p3 arrays on each facet of the icosahedral adenovirus virion. Unlike other viral capsids, the barrel axes are almost perpendicular to rather than parallel with the capsid surface. The hexon top, which consists of intimately interacting loops emerging from P1 and P2 in the base, has a triangular outline and so does not exhibit the pseudo-symmetry of the base. The structure of the hexon trimer shows how economically it meets the demands of its function as a stable protective viral coat, reveals the significance of the special features in its unusual amino acid sequence, and explains its biochemical and immunological properties. The molecule is hollow, with a large central cavity, and so has a high effective volume for its mass.(ABSTRACT TRUNCATED AT 400 WORDS)


A hybrid rule and machine learning based generic alerting platform for smart environments.
Existing smart environment based alert solutions have adopted a relatively complex and tailored approach to supporting individuals. These solutions have involved sensor based monitoring, activity recognition and assistance provisioning. Traditionally they have suffered from a number of issues, rooted in scalability and performance, associated with complex activity recognition processes. This paper introduces a generic approach to realizing an alerting platform within a smart environment. The core concept of this approach is presented and placed within the context of related work. A description of the approach is provided, followed by an evaluation. This evaluation shows the approach offers reasonable accuracy, future work will increase accuracy.


Combination Therapy for Bacterial Pathogens: Naturally Derived Antimicrobial Drugs Combined with Ulva lactuca Extract.
With the growing incidence of microbial pathogenesis, several alternative strategies have been developed. The number of treatments using naturally (e.g., plants, algae, fungi, bacteria, and animals) derived compounds has increased. Importantly, marine-derived products have become a promising and effective approach to combat the antibiotic resistance properties developed by bacterial pathogens. Furthermore, augmenting the sub-inhibitory concentration of the naturally-derived antimicrobial compounds (e.g., hydroxycinnamic acids, terpenes, marine-derived polysaccharides, phenolic compounds) into the naturally derived extracts as a combination therapy to treat the bacterial infection has not been well studied. The present study was aimed to prepare green algae Ulva lactuca extract and evaluate its antibacterial activity towards Gram-positive and Gram-negative human pathogenic bacteria. Also, revitalize the antibacterial efficiency of the naturally-derived antimicrobial drugs and conventional antibiotics by mixing their sub-MIC to the U. lactuca extracts. Extraction was done using a different organic solvent, and its antibacterial activity was tested towards Gram-positive and Gram-negative pathogens. The minimum inhibitory concentration (MIC) of U. lactuca extracts has been determined towards pathogenic bacteria using the micro broth dilution method. The viable cell counting method was used to determine the minimum bactericidal concentration (MBC). The fractional inhibitory concentration (FIC) assay was utilized to examine the combinatorial impact of sub-MIC of two antibacterial drugs using the micro broth dilution method. The chemical components of the extract were analyzed by GC-MS analysis. Among all the extracts, n-hexane extract was found to show effective antibacterial activity towards tested pathogens with the lowest MIC and MBC value. Furthermore, the n-hexane extracts have also been used to enhance the efficacy of the naturally-derived (derived from plants and marine organisms) compounds and conventional antibiotics at their sub-inhibitory concentrations. Most of the tested antibiotics and natural drugs at their sub-MIC were found to exhibit synergistic and additive antibacterial activity towards the tested bacterial pathogens. The combining of U. lactuca n-hexane extracts with natural drugs resulted in synergistic and additive bactericidal effects on Gram-positive and Gram-negative human pathogenic bacteria. The present study shows a new alternative strategy to revitalize the antimicrobial activity of naturally derived compounds for treating human bacterial pathogens.


Characterization of VPS41, a gene required for vacuolar trafficking and high-affinity iron transport in yeast.
Mutations in the yeast gene VPS41 give rise to poor growth on low iron medium, severe alterations in vacuolar morphology, and cause the missorting of membranous and soluble vacuolar proteins. Our studies predict that VPS41 encodes a hydrophilic protein of 992 amino acids that contains no obvious signal sequence or hydrophobic domains. The deduced Vps41p sequence contains a domain rich in glutamic and aspartic residues, as well as a domain with resemblance to a region of clathrin heavy chain. We have also identified and sequenced putative VPS41 homologues from Caenorhabditis elegans, plants, and humans. The VPS41 homologues (but not the yeast VPS41 itself) contain a conserved cysteine-rich RING-H2 zinc finger at their COOH termini. Biochemical experiments suggest that VPS41 functions in post-Golgi protein processing: the deletion mutant exhibits defective high affinity transport due to impaired Fet3p activity and also exhibits defects in the processing and sorting of multiple vacuolar hydrolases.


Serial vagus nerve stimulation functional MRI in treatment-resistant depression.
Vagus nerve stimulation (VNS) therapy has shown antidepressant effects in open acute and long-term studies of treatment-resistant major depression. Mechanisms of action are not fully understood, although clinical data suggest slower onset therapeutic benefit than conventional psychotropic interventions. We set out to map brain systems activated by VNS and to identify serial brain functional correlates of antidepressant treatment and symptomatic response. Nine adults, satisfying DSM-IV criteria for unipolar or bipolar disorder, severe depressed type, were implanted with adjunctive VNS therapy (MRI-compatible technique) and enrolled in a 3-month, double-blind, placebo-controlled, serial-interleaved VNS/functional MRI (fMRI) study and open 20-month follow-up. A multiple regression mixed model with blood oxygenation level dependent (BOLD) signal as the dependent variable revealed that over time, VNS therapy was associated with ventro-medial prefrontal cortex deactivation. Controlling for other variables, acute VNS produced greater right insula activation among the participants with a greater degree of depression. These results suggest that similar to other antidepressant treatments, BOLD deactivation in the ventro-medial prefrontal cortex correlates with the antidepressant response to VNS therapy. The increased acute VNS insula effects among actively depressed participants may also account for the lower dosing observed in VNS clinical trials of depression compared with epilepsy. Future interleaved VNS/fMRI studies to confirm these findings and further clarify the regional neurobiological effects of VNS.


HCV knowledge among a sample of HCV positive Aboriginal Australians residing in New South Wales.
Australian Aboriginal and Torres Strait Islanders are overrepresented in both the prevalence and incidence of the hepatitis C (HCV). HCV knowledge has been associated with a range of positive health behaviours. HCV knowledge has previously been investigated as a single construct; however examining different knowledge domains (i.e. transmission, risk of complications, testing and treatment) separately may be beneficial. This study investigated whether having greater HCV knowledge in different domains is associated with self-reported positive health behaviours. 203 Aboriginal people living with HCV completed a survey assessing HCV knowledge, testing and care, lifestyle changes since diagnosis and treatment intent. Respondents' knowledge was relatively high. Greater knowledge of risk of health complications was associated with undertaking more positive lifestyle changes since diagnosis. Respondents testing and treatment knowledge was significantly associated with incarceration, lifestyle changes since diagnosis and future treatment intentions. This study illustrates the importance of ensuring that knowledge is high across different HCV domains to optimise a range of positive health behaviours of Aboriginal people living with HCV. Future health promotion campaigns targeted at Aboriginal people living with HCV could benefit from broadening their focus from prevention to other domains such as testing and treatment.


Storage and Diffusion of Carbon Dioxide in the Metal Organic Framework MOF-5─A Semi-empirical Molecular Dynamics Study.
Metal-organic frameworks (MOFs) have attracted increasing attention due to their high porosity for exceptional gas storage applications. MOF-5 belongs to the family of isoreticular MOFs (IRMOFs) and consists of Zn4O6+ clusters linked by 1,4-benzenedicarboxylate. Due to the large number of atoms in the unit cell, molecular dynamics simulation based on density functional theory has proved to be too demanding, while force field models are often inadequate to model complex host-guest interactions. To overcome this limitation, an alternative semi-empirical approach using a set of approximations and extensive parametrization of interactions called density functional tight binding (DFTB) was applied in this work to study CO2 in the MOF-5 host. Calculations of pristine MOF-5 yield very good agreement with experimental data in terms of X-ray diffraction patterns as well as mechanical properties, such as the negative thermal expansion coefficient and the bulk modulus. In addition, different loadings of CO2 were introduced, and the associated self-diffusion coefficients and activation energies were investigated. The results show very good agreement with those of other experimental and theoretical investigations. This study provides detailed insights into the capability of semi-empirical DFTB-based molecular dynamics simulations of these challenging guest@host systems. Based on the comparison of the guest-guest pair distributions observed inside the MOF host and the corresponding gas-phase reference, a liquid-like structure of CO2 can be deduced upon storage in the host material.


Enhanced antiscrapie effect using combination drug treatment.
Combination treatment with pentosan polysulfate and Fe(III)meso-tetra(4-sulfonatophenyl)porphine in mice beginning 14 or 28 days after scrapie inoculation significantly increased survival times. This increase may be synergistic, implying that the compounds act cooperatively in vivo. Combination therapy may therefore be more effective for treatment of transmissible spongiform encephalopathies and other protein-misfolding diseases.


Comparison of 5-year oncological outcomes of breast cancer based on surgery type.
A standardized classification system for breast surgery that incorporates oncoplastic techniques is needed. We classified the surgical techniques for breast cancer treatment into five groups according to the extent of surgery and reconstructive methods, i.e. conventional breast-conserving surgery, partial mastectomy with volume displacement, partial mastectomy with volume replacement, simple mastectomy and total mastectomy with immediate reconstruction. We then evaluated the oncological outcomes for each of the five groups. We analysed clinical data and 5-year oncological results from patients with breast cancer who underwent breast surgery with reconstruction between 2008 and 2013. Local recurrence, distant metastasis and overall survival were investigated. In total, 1469 patients had 1504 breast surgeries performed with a mean follow-up of 72.40 ± 16.76 months. There were 35 cases (2.3%) of locoregional recurrence and 85 cases (5.7%) of distant metastasis, and the 5-year overall survival rate was 98.6%. No statistically significant differences were observed in local recurrence, distant metastasis or death among the five surgical technique groups (P = 0.218, 0.518 and 0.450, respectively). Oncological outcomes among all patients and within each surgical technique group were excellent during the 5-year follow-up period. No significant differences in oncological results were observed among the five surgical technique groups.


Relationship between hyperglycemia and retinopathy of prematurity in very low birth weight infants.
Retinopathy of prematurity (ROP) is a multifactorial vasoproliferative retinal disorder that increases in incidence with decreasing gestational age. Recently, an association between hyperglycemia and severe ROP was found in extremely low birth weight infants (ELBWI). The purpose of this study was to evaluate the possible relation between hyperglycemia and ROP at any stage in very low birth weight infants (VLBWI). We analyzed the data of 201 VLBWI. The incidence of ROP and hyperglycemia was detected and the chi2 test was applied to investigate the association between the two variables. The Clinical Risk Index for Babies (CRIB) score was attributed as a marker of illness severity. The incidence of ROP and hyperglycemia in VLBWI was 35.3 and 19.4%, respectively. ROP developed more frequently in hyperglycemic infants (p < 0.001). The gestational age, birth weight, and Apgar scores were significantly lower, the CRIB score was higher in ROP patients. In hyperglycemic ROP patients the CRIB score was significantly higher compared to euglycemic ROP patients (mean (SD) 8.1 (4.2) vs. 5.5 (3.3); p < 0.01). A logistic regression model revealed that gestational age (OR 0.59; 95% CI 0.46-0.76; p < 0.001) and hyperglycemia (OR 3.15; 95% CI 1.12-8.84; p < 0.05) are independent risk factors in ROP development. When ELBWI were analyzed separately, gestational age (OR 0.38; 95% CI 0.20-0.72; p < 0.01) and CRIB score (OR 1.58; 95% CI 1.02-2.45; p < 0.05) were found as significant contributors. Further studies are needed to elucidate the pathophysiological role of hyperglycemia in the development of vasoproliferative retinal disorder.


Synthesis of nanoparticles-deposited double-walled TiO₂-B nanotubes with enhanced performance for lithium-ion batteries.
A one-step hydrothermal method, followed by calcination at 300 °C in an argon atmosphere, has been developed to synthesize TiO2-B nanoparticles/double-walled nanotubes (NP/DWNT) and TiO2-B nanoparticles/multiple-walled nanotubes (NP/MWNT). To the best of our knowledge, this is the first synthesis of TiO2-B NP/NT hierarchical structures. Both NP/DWNT and NP/MWNT show high performance as anode materials for lithium-ion batteries, superior to their counterparts of DWNT and MWNT, respectively. Among all the four materials studied herein, NP/DWNT demonstrates the highest discharge-charge capacity, rate capability, and cycling stability. The enhancement due to the NP loading results from the increased surface areas, the improved kinetics, and the decreased transport distance for both electrons and Li ions. The charge capacity at high rates lies in the intercalation pseudocapacitance originating from fast Li-ion transport through the infinite channels in TiO2-B. The superiority of DWNT materials versus MWNT materials is ascribed to the thinner walls, which provide a shorter distance for Li-ion transport through the radial direction.


The Potential of Astrocytes as Immune Modulators in Brain Tumors.
The neuro-immune axis has emerged as a key aspect to understand the normal function of the Central Nervous System (CNS) as well as the pathophysiology of many brain disorders. As such, it may represent a promising source for novel therapeutic targets. Glial cells, and in particular the extensively studied microglia, play important roles in brain disorders. Astrocytes, in their reactive state, have been shown to positively and negatively modulate the progression of multiple CNS disorders. These seemingly opposing effects, might stem from their underlying heterogeneity, an aspect that has recently come to light. In this article we will discuss the link between reactive astrocytes and the neuro-immune axis with a perspective on their potential importance in brain tumors. Based on the gained knowledge from studies in other CNS disorders, reactive astrocytes are undoubtfully emerging as a key component of the neuro-immune axis, with ability to modulate both the innate and adaptive branches of the immune system. Lastly, we will discuss how we can exploit our improved understanding of the basic biology of astrocytes to further enhance the efficacy of emerging immune-based therapies in primary brain tumors and brain metastasis.


Do vaccines modify the prevalence of asthma and allergies?
Epidemiological studies suggest the hypothesis that the increase in asthma and allergies in the industrialized world can be explained by a decline in the number of infectious diseases occurring during childhood. In the context of this 'hygiene hypothesis', is immunization in early life a risk factor for promoting allergic diseases? The majority of studies, especially those conducted with more extensive populations, have not found an increased risk, and although 'not finding an increased risk' is not the same as 'the non-existence of any risk at all', it seems that the evidence is tipped in favor of the absence of risk. Conversely, although some surveys have described a protective effect of vaccination, the majority refuted this result. If there is any effect, it is probably a weak one.


Elevated erythropoietin levels in cord blood of newborns with Down's syndrome.
Plasma erythropoietin (Ep) was determined in umbilical cord blood in 18 infants with Down's syndrome. The 16 infants with Down's syndrome who were delivered after labor had significantly elevated plasma Ep levels compared to 36 control infants born after labor (p < 0.001). Six of the ten infants with Down's syndrome who had their packed cell volume (PCV) measured in the first 24 h of life were polycythemic based on a PCV of > or = 0.65. The presence of congenital heart disease in 9 of the 18 infants with Down's syndrome was not associated with a higher plasma Ep or PCV levels. Plasma Ep was correlated with neonatal PCV in the combined group of control and Down's syndrome infants (p = 0.003). Increased plasma Ep levels observed in infants with Down's syndrome suggested chronic fetal hypoxemia as a likely explanation for the high incidence of neonatal polycythemia observed in this group.


A four-part working bibliography of neuroethics: Part 4 - Ethical issues in clinical and social applications of neuroscience.
As a discipline, neuroethics addresses a range of questions and issues generated by basic neuroscientific research (inclusive of studies of putative neurobiological processes involved in moral and ethical cognition and behavior), and its use and meanings in the clinical and social spheres. Here, we present Part 4 of a four-part bibliography of the neuroethics literature focusing on clinical and social applications of neuroscience, to include: the treatment-enhancement discourse; issues arising in neurology, psychiatry, and pain care; neuroethics education and training; neuroethics and the law; neuroethics and policy and political issues; international neuroethics; and discourses addressing "trans-" and "post-" humanity. To complete a systematic survey of the literature, 19 databases and 4 individual open-access journals were employed. Searches were conducted using the indexing language of the U.S. National Library of Medicine (NLM). A Python code was used to eliminate duplications in the final bibliography. When taken with Parts 1-3, this bibliography aims to provide a listing of international peerreviewed papers, books, and book chapters published from 2002 through 2016. While seeking to be as comprehensive as possible, it may be that some works were inadvertently and unintentionally not included. We therefore invite commentary from the field to afford completeness and contribute to this bibliography as a participatory work-in-progress.


Life is three-dimensional, and it begins with molecules.
The iconic image of the DNA double helix embodies the central role that three-dimensional structures play in understanding biological processes, which, in turn, impact health and well-being. Here, that role is explored through the eyes of one scientist, who has been lucky enough to have over 150 talented people pass through his laboratory. Each contributed to that understanding. What follows is a small fraction of their story, with an emphasis on basic research outcomes of importance to society at large.


Hydrogen Tunneling above Room Temperature Evidenced by Infrared Ion Spectroscopy.
While hydrogen tunneling at elevated temperatures has, for instance, often been postulated in biochemical processes, spectroscopic proof is thus far limited to cryogenic conditions, under which thermal reactivity is negligible. We report spectroscopic evidence for H-tunneling in the gas phase at temperatures around 320-350 K observed in the isomerization reaction of a hydroxycarbene into an aldehyde. The charge-tagged carbene was generated in situ in a tandem mass spectrometer by decarboxylation of oxo[4-(trimethylammonio)phenyl]acetic acid upon collision induced dissociation. All ion structures involved are characterized by infrared ion spectroscopy and quantum chemical calculations. The charge-tagged phenylhydroxycarbene undergoes a 1,2-H-shift to the corresponding aldehyde with an half-life of about 10 s, evidenced by isomer-selective two-color (IR-IR) spectroscopy. In contrast, the deuterated (OD) carbene analogue showed much reduced 1,2-D-shift reactivity with an estimated half-life of at least 200 s under the experimental conditions, and provides clear evidence for hydrogen atom tunneling in the H-isotopologue. This is the first spectroscopic confirmation of hydrogen atom tunneling governing 1,2-H-shift reactions at noncryogenic temperatures, which is of broad significance for a range of (bio)chemical processes, including enzymatic transformations and organocatalysis.


Role of gravity in prism ballasting.
One of the techniques commonly used in stabilizing the rotation of a contact lens is prism ballasting. The idea is to gain stabilization by the action of gravity pulling on the base of the prism. The determination of just how much prism is necessary in any particular case is usually made empirically, gradually increasing prism amount when more stability is required. This paper will present the results of a mathematical investigation which demonstrates that gravity forces alone do not play the major role in the stabilization of prism ballasted lenses. It is hoped that this preliminary analysis will stimulate further theoretical work of a similar nature, in the growing field of contact lenses.


Expression of c-Myc and Fas correlates with perineural invasion of pancreatic cancer.
Lymph node metastasis (LNM) and perineural invasion (PNI) are regarded as two important prognostic factors in pancreatic cancer. The aim of this study was to identify the LNM-associated and PNI-associated markers in pancreatic cancer. We have constructed a formalin-fixed paraffin embedded pancreatic tissue microarrays containing 324 cylindrical tissue cores of human pancreatic cancer and its paracancerous nonmalignant pancreatic specimens (NMPs) from 162 patients. Among those patients, there were 83 of 162 with PNI, and 65 of 162 with LNM. The protein products of 2 genes encompassing a variety of functional classes, such as oncogenes (c-Myc), apoptosis (Fas), were analyzed by immunohistochemistry on the tissue microarray. There was marked increase in cancer tissues cytoplasmic c-Myc expression level in pancreatic cancer compared with the NMPs (P < 0.0001). Additionally, the expression level of c-Myc was also significant increase in pancreatic cancer with PNI compared with cancer without PNI (P < 0.01). In contrast, cytoplasmic Fas, low expressed in pancreatic cancer (P < 0.0001) was negatively correlated with PNI (P < 0.05). Logistic regression analysis showed that the c-Myc expression in the cancer tissues cytoplasm acted as a potential and independently predictive factor for PNI. However, there were no significant association between the expression of these two genes and LNM (P > 0.05). This study for the first time described expression levels of c-Myc and Fas played an important role in PNI of pancreatic cancer. Combined detection can be used as predictive factors, especially c-Myc.


Cyclic AMP regulation of early gene expression in Dictyostelium discoideum: mediation via the cell surface cyclic AMP receptor.
We examined two sets of genes expressed early in the developmental cycle of Dictyostelium discoideum that appear to be regulated by cyclic AMP (cAMP). The transcripts of both sets of genes were not detectable in vegetative cells. During normal development on filter pads, RNA complementary to these genes could be detected at about 2 h, peaked around 6 to 8 h, and decreased gradually thereafter. Expression of these genes upon starvation in shaking culture was stimulated by pulsing the cells with nanomolar levels of cAMP, a condition that mimics the in vivo pulsing during normal aggregation. Expression was inhibited by caffeine or by continuous levels of cAMP, a condition found later in development when in vivo expression of these genes decreased. The inhibition of caffeine could be overcome by pulsing cells with cAMP. These results suggest that the expression is mediated via the cell surface cAMP receptor, but does not require a rise in intracellular cAMP. mRNA from a gene of the second class was induced upon starvation, peaked by 2.5 h of development, and then declined. In contrast to the other genes, its expression was maintained by continuous levels of cAMP and repressed by cAMP pulses. These and other results on a number of classes of developmentally regulated genes indicates that changing levels of cAMP, acting via the cell surface cAMP receptor, are involved in controlling these groups of genes. We also examined the structure and partial sequence of the cAMP pulse-induced genes. The two tandemly duplicated M3 genes were almost continuously homologous over the sequenced portion of the protein-coding region except for a region near the N-terminal end. The two M3 genes had regions of homology in the 5' flanking sequence and showed slight homology to the same regions in gene D2, another cAMP pulse-induced gene. D2 showed extremely significant homology over its entire sequenced length to an acetylcholinesterase. The results presented here and by others suggest that expression of many early genes in D. discoideum is regulated via the cell surface cAMP receptor. We expect that many of these genes may play essential roles in early Dictyostelium development and could code for elements of the cAMP signal transduction pathway involved in aggregation.


Spermatogenesis in testis xenografts grafted from pre-pubertal Holstein bulls is re-established by stem cell or early spermatogonia.
Xenografting of testis explants into recipient mice has resulted in successful restoration of spermatogenesis in several species. Most studies have utilized neonatal donor tissue, although a few have used prepubertal testes. In Holstein bulls, prepubertal development of the testis occurs between 16 and 32 weeks of age. The purpose of the present study was to determine the optimal age during prepubertal development of Holstein bulls for testis grafting. Explants of testis tissue from Holstein bulls between 12 and 32 weeks of age (2 bulls/age; 6 ages) were subcutaneously grafted into castrated or intact immunocompromised mice (n=8/age), then recovered after 75 and 173 days (n=4 mice/grafting period) and evaluated histologically for spermatogenic progression. Seminiferous tubules were assigned a score based on the most advanced type of germ cell present within the tubule and the average for all tubules scored (n=25) within an explant was calculated. Scores for all explants per mouse (n=6) were averaged to give a single spermatogenic progression score per mouse. No difference in spermatogenic progression of grafts between intact and castrated recipients was observed. Spermatocytes were observed in testis grafts from bulls of all ages 75 days post-grafting. At 173 days, the spermatogenic progression score for explants derived from 20 weeks bulls was greater than all ages except 12 weeks donors (p<0.05), with 8% of tubules containing spermatids. Donor material from bulls older than 20 weeks had lesser spermatogenic progression scores largely attributed to the greater number of atrophic tubules in grafts from older donors. Grafts from 28 and 32 weeks donors showed signs of degeneration by 75 days post-grafting, with 30 and 55% atrophic tubules, respectively, and lesser spermatogenic efficiency scores. By 173 days post-grafting, 72% of tubules in explants from 32 weeks donors were atrophic. The results of the present study suggest that the early stages of prepubertal development are optimal for testis grafting while advanced spermatogenesis in the donor tissue prior to grafting had a negative effect on graft development. Spermatogenesis within the grafts apparently needs to be re-established by spermatogonial stem cells or early spermatogonia.


Enhanced Methodologies to Enumerate Persons Experiencing Homelessness in a Large Urban Area.
Homelessness is a public health problem, and persons experiencing homelessness are a vulnerable population. Estimates of the number of persons experiencing homelessness inform funding allocations and services planning and directly determine the ability of a community to intervene effectively in homelessness. The point-in-time (PIT) count presents a logistical problem in large urban areas, particularly those covering a vast geographical area. Working together, academia, local government, and community organizations improved the methodology for the count. Specific enhancements include use of incident command system (ICS), increased number of staging areas/teams, specialized outreach and Special Weapons and Tactics teams, and day-after surveying to collect demographic information. This collaboration and enhanced methodology resulted in a more accurate estimate of the number of persons experiencing homelessness and allowed comparison of findings for 4 years. While initial results showed an increase due to improved counting, the number of persons experiencing homelessness counted for the subsequent years showed significant decrease during the same time period as a "housing first" campaign was implemented. The collaboration also built capacity in each sector: The health department used ICS as a training opportunity; the academics enhanced their community health efforts; the service sector was taught and implemented more rigorous quantitative methods; and the community was exposed to public health as a pragmatic and effective discipline. Improvements made to increase the reliability of the PIT count can be adapted for use in other jurisdictions, leading to improved counts and better evaluation of progress in ending homelessness.


Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms.
Cenani-Lenz syndactyly syndrome (CLSS; MIM-212780) is a rare autosomal recessive limb malformation characterized by complete osseous fusion of all fingers and toes, disorganization of phalangeal elements and severe shortening of the radius and ulna. It is occasionally associated with renal hypoplasia, oro-facial defects, scoliosis of the thoracic spine, hearing loss, and genital anomalies. Here we describe a consanguineous Pakistani kindred with a severe form of CLSS characterized by complete syndactyly and disorganization of fingers, oligo-syndactyly of toes, shortening of limbs, frontal bossing, and hypoplasia/agenesis of left kidney. The affected individuals were additionally presented with short stature, cleft-lip and hypoplastic shoulder joint with restricted upper limb movement. A novel splice variant in LRP4 (c.316+1G > A) segregated with the phenotype in a five generations family. The mutation is predicted to add 29 non-native amino acids with a premature termination, resulting in approximately 90% length reduction of the wild-type transcript. These findings not only further expand the phenotypic variability of CLSS but also indicate that early truncated and loss-of-function mutations in LRP4 lead to a more severe CLSS phenotype.


Incorporation of nonadiabatic transition into wave-packet dynamics.
Nonadiabatic wave-packet dynamics is factorized into purely adiabatic propagation and instantaneous localized nonadiabatic transition. A general formula is derived for the quantum-mechanical local nonadiabatic operator which is implemented within the framework of the R-matrix method. The operator can be used for incorporating the nonadiabatic transition in semiclassical wave-packet dynamics.


[Color Doppler echography of the cavernous bodies after F.I.C. in the study of erectile impotence of vascular origin].
Study with the Doppler method has been associated with "cavernometrics" and "cavernography" in erection pathologies for some time. But this enquiry is burdened not only be technical inaccuracies such as the lack of knowledge of the angle of incidence of the doppler wave and the diameter of the explored vessel etc, but also by intrinsic difficulty method itself. Therefore, the authors have used a color Doppler to individuate and study the cavernous arteries, and present the results obtained from a group of 21 patients, all affected by erectile deficits, who were selected on the basis of anamnestica and clinical criteria. They individualized 21 patients in whom the vasculogenic nature of their affection appeared probable, out of the 125 who were under their observation for their sexual inadequacy. In three patients the clinical suspicion of a venous incompetency was confirmed by dynamic "cavernometrics with cavernography". The study of the four phases of erection (flaccidity, tumescence, erection, detumescence) was carried out after an intracavernous injection of 20 micrograms of PGE/1. The parameters considered were: systolic velocity of the hematic wave, diastolic speed, the index of resistance and range. In cases of vasculogenic impotence with an arterial base the systolic wave in the 2nd and 3rd phases presented a speed inferior to the norm of standard values, the resistance index altered by the lacking of physiological increment due in the erectile beyond the closing of venous "polsters", also to the rigidity of the albuginea.(ABSTRACT TRUNCATED AT 250 WORDS)


Fenretinide-polyethylene glycol (PEG) conjugate with improved solubility enhanced cytotoxicity to cancer cell and potent in vivo efficacy.
Fenretinide (4-HPR), a synthetic retinoid, has shown its antitumor activity in many tumor types with low cytotoxicity to normal cells and high clinical safety. However, the low water solubility limits its further biological applications. To increase solubility, 4-HPR was conjugated with methoxy polyethylene glycol carboxylic acid (mPEG2K-COOH) by an ester linkage between the phenol hydroxyl of 4-HPR and the carboxyl of mPEG2K-COOH. The 4-HPR-PEG2K conjugate micelles had mean size of 76.70 ± 1.248 nm with a narrow distribution and a low critical micelle concentration. In vitro cytotoxicity studies showed the micelles have higher cytotoxicity to A2780s and MCF-7 cells. Its IC50 was 4.7 and 4.1-fold lower than the free 4-HPR, respectively. Importantly, in vivo pharmacokinetic studies, the AUC of 4-HPR was found to be 2.3-fold higher in 4-HPR-PEG2K micelles compared to free 4-HPR. And the 4-HPR-PEG2K micelles had higher antitumor activity. Meanwhile, the histopathology analysis exhibited that the micellar treatment decreased the viability of A2780s cells and increased the level of induced apoptosis. Therefore, the enhanced activity of 4-HPR by the method of conjugation with mPEG2K-COOH could hopefully provide new insights into the matter of ovarian cancer and breast cancer treatment.