Role of Rac1 in fibronectin-induced adhesion and motility of human corneal epithelial cells.
The fibronectin-integrin system plays an important role in adhesion and migration of corneal epithelial cells and thereby contributes to epithelial wound healing. The role of Rac1, a member of the Rho family of GTPases, in the intracellular signaling responsible for regulation of the adhesion and motility of corneal epithelial cells by fibronectin was examined. Simian virus 40-transformed human corneal epithelial (HCE) cells were plated on fibronectin or on bovine serum albumin as a control. Cell motility was monitored by time-lapse video microscopy. The actin cytoskeleton and focal adhesions were detected by staining of cells with rhodamine-phalloidin and antibodies to phosphotyrosine, respectively. The activation of Rac1 and phosphorylation of its effector PAK were evaluated with a pull-down assay and immunoblot analysis, respectively. The effects of mutant forms of Rac1 were determined by cell transfection. HCE cells plated on fibronectin manifested greater levels of cell adhesion and motility than did those plated on bovine serum albumin. Fibronectin also induced the accumulation of F-actin and the formation of focal adhesions at the cell periphery as well as the activation of Rac1 and the phosphorylation of PAK. Expression of the dominant negative mutant Asn17Rac1 inhibited the effects of fibronectin on cell adhesion and motility, the actin cytoskeleton, and focal adhesions. Expression of the constitutive active mutant Val12Rac1 mimicked the effects of fibronectin on F-actin and focal adhesions. Rac1 is necessary for the promotion of HCE cell adhesion and motility by fibronectin. It therefore probably plays an important role in corneal wound healing.


Glutathione Metabolism, Mitochondria Activity, and Nitrosative Stress in Patients Treated for Mandible Fractures.
The aim of the study was to evaluate the effect of titanium bone fixations on mitochondrial activity, reactive oxygen species (ROS) production, glutathione metabolism, and selected markers of oxidative/nitrosative stress in the periosteum-like tissue of patients treated with mandible fractures. The study group consisted of 30 patients with bilateral fractures of the mandible body eligible for surgical treatment. Our study is the first one that indicates disturbances of mitochondrial activity as well as a higher production of ROS in the periosteum-like tissue covering titanium fixations of the mandible. We also found significantly higher levels of reduced glutathione and enhanced activity of glutathione reductase in the periosteum homogenates of patients in the study group compared to the control group. Levels of nitrosative (S-nitrosothiols, peroxynitrite, nitrotyrosine) and oxidative stress biomarkers (malondialdehyde, protein carbonyls, dityrosine, kynurenine, and N-formylkynurenine) were statistically elevated in periosteum-like tissue covering titanium fixations. Although exposure to titanium fixations induces local antioxidant mechanisms, patients suffer oxidative damage, and in the periosteum-like tissue the phenomenon of metallosis was observed. Titanium implants cause oxidative/nitrosative stress as well as disturbances in mitochondrial activity.


Regenerative Rehabilitation: An Innovative and Multifactorial Approach to Recovery From Stroke and Brain Injury.
There is currently a dearth of treatment options for stroke or traumatic brain injury that can restore cognitive and motor function. Regenerative and translational medicine have ushered forth promising new methods for mediating recovery in the central nervous system, the most salient of which are rehabilitation and stem cell therapies that, when combined, result in more pronounced recovery than one approach alone.


Intracellular and extracellular renin have opposite effects on the regulation of heart cell volume. Implications for myocardial ischaemia.
The influence of intracellular renin plus angiotensinogen (Ao) as well as angiotensin (Ang) II on cell volume was investigated in myocytes isolated from the heart of four-month-old cardiomyopathic hamsters (TO-2) and normal hamsters (F1B). Measurements of cell width and cell length were performed on quiescent cells using a Px-it imaging and computer system. The cell volume was calculated assuming the cells as elliptical cylinders and taking the cell depth equal to one third of cell width. For measurements of sodium pump current, the cells were voltage clamped (holding potential -40 mV) using the whole cell configuration. Cells were exposed to K-free solution to inhibit the pump and then to normal Krebs solution to reactivate the pump. In other experiments the cells were voltage clamped (holding potential -40 mV) and changes in the background current elicited by renin plus Ao or by Ang II were monitored. The results indicated that: a) intracellular dialysis of renin (128 pmol Ang I/ml) plus Ao (110 pmol Ang I generated by renin by exhaustion) decreased the cell volume concurrently with the activation of the sodium pump; b) intracellular losartan (10(-)8 M) or extracellular ouabain (10(-8) M) abolished the effect of renin plus Ao on cell volume; c) intracellular Ang II (10(-8) M), by itself, reduced cell volume and increased the pump current density; d) extracellular administration of renin plus Ao, at the same concentration used intracellularly, increased cell volume and inhibited the sodium pump. This increase of cell volume elicited by extracellular renin plus Ao was related to the activation of the Na-K-2Cl cotransporter; e) intracellular Ang II (10(-8) M) reversed cell swelling induced by hypotonic solutions. Intracellular and extracellular renin plus Ao have opposite effects on sodium pump and cell volume regulation in the failing heart. Both effects of renin plus Ao are dependent upon the formation of Ang II. Since intracellular Ang II counteracted the cell swelling induced by hypotonic solution, it is reasonable to think that the activation of the intracrine renin-angiotensin system might play a protective role during myocardial ischaemia by reducing cell volume.


Application effect of single balloon catheters in labor induction of pregnant women in late-term pregnancy and their influences on stress and inflammatory responses.
This study was designed to evaluate the application effect of single balloon catheters and dinoprostone on promoting cervical ripening of pregnant women in late-term pregnancy and their influences on stress and inflammatory responses. A total of 160 pregnant women with indications of labor induction were included and randomly divided into the control (n=80) and observation (n=80) groups. Patients in the control group received labor induction by administration of dinoprostone at the vaginal vault, while those in the observation group received labor induction by domestic single balloon catheters. Cervical ripening (Bishop score), means of pregnancy, the total stage of labor, maternal and child complications, and Apgar scores of newborn infants at 1 min after delivery between the two groups were compared. At the prenatal and postpartum 12, 24 and 48 h, the levels of cortisol (COR), norepinephrine (NE) and β-endorphin (β-EP), were detected using radioimmunoassay, and those of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), were measured using enzyme-linked immunosorbent assay (ELISA). Cervical Bishop scores in the two groups after intervention were significantly higher than those before intervention, and the score of the observation group was significantly higher than that of the control group. The difference was statistically significant (P<0.05). In the observation group, the total stage of labor was significantly shortened, the Apgar score of the newborn infant at 1 min after delivery was increased compared with those in the control group, and the differences were statistically significant (P<0.05). The delivery rate of cesarean section in the observation group was lower than that in the control group, the overall incidence rate of perinatal complications was decreased, and the differences were statistically significant (P<0.05). The levels of stress and inflammatory response markers at 12 h after delivery in the two groups reached the peak, and then declined (P<0.05). The levels of stress and inflammatory response markers at each time-point after delivery in the observation group were significantly lower than those in the control group, and the difference was statistically significant (P<0.05). The results showed that the single balloon catheter promotes cervical ripening, improves pregnancy outcomes and reduces the stress and inflammatory responses of pregnant women in late-term pregnancy, and is better than dinoprostone and has better application and promotion values.


Impaired circadian rhythmicity of nociceptive reflex threshold in cluster headache.
Alteration of circadian rhythmicity involving several endocrinologic and autonomic parameters has been observed in cluster headache. To explore whether circadian failure of the pain control system may exist in cluster headache. The nociceptive flexion reflex threshold was studied in 25 patients with episodic cluster headache (14 active, 11 in remission) and 6 patients with chronic cluster headache, along with 10 normal volunteers throughout a 24-hour period. The reflex response was evoked at the level of the biceps femoris by stimulating the sural nerve at the ankle. Single and population mean cosinor methods were used to detect the circadian rhythmicity. In the patients with episodic cluster headache, a significant reduction in the nociceptive flexion reflex threshold was observed in both the active subgroup and the subgroup in remission (P < .05). In these patients, persistence of a significant 24-hour rhythm during both the active period and remission was observed, but a shift of the phase was observed during clinical activity when compared with the remission period. A lack of circadian nociceptive flexion reflex threshold rhythmicity was found in the patients with chronic cluster headache. Our findings suggest that in cluster headache there may be impairment of the pain control system that is associated with periodic failure of the mechanisms involved in the organization of biological rhythms.


An assessment of serum acid and alkaline phosphatase determinations in prostatic cancer with a clinical validation of an acid phosphatase assay utilizing adenosine 3'-monophosphate as substrate.
Serum acid phosphatase (AcPase) was measured by a colorimetric method utilizing adenosine 3' -monophosphate as substrate in 389 patients. In about half the cases blood was taken shortly after a rectal examination. The upper reference limit (mean + 2SD) for 116 cases with miscellaneous illness after eliminating outliers was 4.1 International Units per litre (U/I) at 37 degrees C, and no correlation existed between AcPase activity and age in these subjects (r = 0.040). Eight of 18 patients with untreated carcinoma confined within the prostate gland had AcPase activities below 4.1 U/l, and all of 27 cases with extension to pelvic soft tissues or to bone exceeded this value. AcPase activities above 4.1 U/l were found in 6% of cases with benign hypertrophy of the prostate, in 5% of cases with non-prostatic cancer, and in none of 22 cases with other urological illness. Raised serum alkaline phosphatase (APase) activity was found in 60% of patients with untreated prostatic cancer and in only 6% of patients free of prostatic cancer, in most of whom there was a clinical explanation for the elevation. The correlation between the two phosphatase activities was not significant (r = 0.294). While APase activity does not reflect the stage of the disease as closely as AcPase activity, and is not so frequently elevated, it provided useful confirmation of the diagnosis in five patients of the present series whose AcPase levels were normal or only minimally elevated.


Obsessional and Eating Disorder-related Intrusive Thoughts: Differences and Similarities Within and Between Individuals Vulnerable to OCD or to EDs.
Unwanted intrusive cognitions constitute the normal variant of clinically significant intrusive cognitions found in disorders such as obsessive-compulsive disorder (OCD) and eating disorders (EDs). This study investigates whether individuals who are vulnerable to OCD or EDs experience more intrusions than people with no vulnerability to these disorders, and it examines the consequences of obsessional (OITs) and eating disorder (EDITs) intrusions in the same individuals, taking into account their susceptibility to OCD, EDs or neither of the two. From a sample of 922 participants, three groups were formed: risk of OCD (n = 92), risk of EDs (n = 41) and a no-risk group (n = 100). EDITs were more frequent than OITs in the two risk groups. Within-group comparisons showed that in the OCD-risk group, the OIT had more negative consequences (interference, emotional distress, dysfunctional appraisals and neutralizing strategies) than the EDIT, whereas in the ED-risk group, the OIT and the EDIT instigated similar negative consequences. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association.


Fin field-effect-transistor engineered sensor for detection of MDA-MB-231 breast cancer cells: A switching-ratio-based sensitivity analysis.
The present study describes the utilization of a gallium-arsenide gate-stack gate-all-around (GaAs-GS-GAA) fin field-effect transistor (FinFET) to accomplish the electrical identification of the breast cancer cell MDA-MB-231 by monitoring the device switching ratio. The proposed sensor uses four nanocavities carved beneath the gate electrodes for enhanced detection sensitivity. MDA-MB-231 (cancerous) and MCF-10A (healthy) breast cells have a distinct dielectric constant, and it changes when exposed to microwave frequencies spanning across 200 MHz and 13.6 GHz, which modifies the electrical characteristics, allowing for early diagnosis. First, a percentage shift in the primary DC characteristics is presented to demonstrate the advantage of GS-GAA FinFET over conventional FinFET. The sensor measures the switching-ratio-based sensitivity, which comes out to be 99.72% for MDA-MB-231 and 47.78% for MCF-10A. The sensor was tested for stability and reproducibility and found to be repeatable and sufficiently stable with settling times of 55.51, 60.80, and 71.58 ps for MDA-MB-231 cells, MCF-10A cells, and air, respectively. It can distinguish between viable and nonviable cells based on electrical response alterations. The possibility of early detection of cancerous breast cells using Bruggeman's model is also discussed. Further, the impact of biomolecule occupancy and frequency variations on the device sensitivity is carried out. This study also explains how to maximize the sensing performance by adjusting the fin height, fin width, work function, channel doping, temperature, and drain voltage. Lastly, this article compared the proposed breast cancer cell detectors to existing literature to evaluate their performance and found considerable improvement. The findings of this research have the potential to establish GaAs-GS-GAA FinFET as a promising contender for MDA-MB-231 breast cancer cell detection.


The current status of hematopoietic stem cell transplantation for multiple myeloma.
Multiple myeloma is often successfully controlled with conventional chemotherapy, but complete remissions are uncommon and cure is rare. High-dose therapy followed by autologous or allogeneic stem cells, employed for the treatment of multiple myeloma in the past 20 years, is promising as a means to increase remission rates and improve survival. Autologous transplants have not always demonstrated survival benefits in randomized studies because most of the patients transplanted relapse, while patients given conventional therapy can receive salvage transplants when they relapse. Efforts to improve the results of autologous transplant include targeted radiation, cytoprotective agents, tandem transplants, or post-transplant immunotherapy. Only allogeneic hematopoietic stem cell transplantation is potentially curative, due to a graft-versus-myeloma effect. While patients who receive either allogeneic or autologous stem cell transplants for multiple myeloma have similar 3-5 year survival, only allograft recipients appear to enjoy long-term disease-free survival. High transplant-related mortality associated with allogeneic stem cell transplantation is currently the major limitation to wider use of this potentially curative modality. Strategies designed to improve the therapeutic index of allografts include the use of nonablative conditioning regimens, peripheral blood cells rather than bone marrow, graft engineering, and targeted conditioning therapies such as bone-seeking radioisotopes.


Clinical potential of SLAMF7 antibodies - focus on elotuzumab in multiple myeloma.
Elotuzumab is one of the first monoclonal antibodies to be approved for the treatment of multiple myeloma. It is a humanized immunoglobulin G kappa (IgGκ) antibody that targets signaling lymphocytic activation molecule family member 7 (SLAMF7), a surface marker that is highly expressed on normal and malignant plasma cells. This review summarizes the preclinical and clinical data that led to the approval of elotuzumab, along with a discussion on the ongoing and future clinical investigations.


Experiences of Gamified and Automated Virtual Reality Exposure Therapy for Spider Phobia: Qualitative Study.
Virtual reality exposure therapy is an efficacious treatment of anxiety disorders, and recent research suggests that such treatments can be automated, relying on gamification elements instead of a real-life therapist directing treatment. Such automated, gamified treatments could be disseminated without restrictions, helping to close the treatment gap for anxiety disorders. Despite initial findings suggesting high efficacy, very is little is known about how users experience this type of intervention. The aim of this study was to examine user experiences of automated, gamified virtual reality exposure therapy using in-depth qualitative methods. Seven participants were recruited from a parallel clinical trial comparing automated, gamified virtual reality exposure therapy for spider phobia against an in vivo exposure equivalent. Participants received the same virtual reality treatment as in the trial and completed a semistructured interview afterward. The transcribed material was analyzed using thematic analysis. Many of the uncovered themes pertained directly or indirectly to a sense of presence in the virtual environment, both positive and negative. The automated format was perceived as natural and the gamification elements appear to have been successful in framing the experience not as psychotherapy devoid of a therapist but rather as a serious game with a psychotherapeutic goal. Automated, gamified virtual reality exposure therapy appears to be an appealing treatment modality and to work by the intended mechanisms. Findings from the current study may guide the next generation of interventions and inform dissemination efforts and future qualitative research into user experiences.


miRIAD-integrating microRNA inter- and intragenic data.
MicroRNAs (miRNAs) are a class of small (∼22 nucleotides) non-coding RNAs that post-transcriptionally regulate gene expression by interacting with target mRNAs. A majority of miRNAs is located within intronic or exonic regions of protein-coding genes (host genes), and increasing evidence suggests a functional relationship between these miRNAs and their host genes. Here, we introduce miRIAD, a web-service to facilitate the analysis of genomic and structural features of intragenic miRNAs and their host genes for five species (human, rhesus monkey, mouse, chicken and opossum). miRIAD contains the genomic classification of all miRNAs (inter- and intragenic), as well as classification of all protein-coding genes into host or non-host genes (depending on whether they contain an intragenic miRNA or not). We collected and processed public data from several sources to provide a clear visualization of relevant knowledge related to intragenic miRNAs, such as host gene function, genomic context, names of and references to intragenic miRNAs, miRNA binding sites, clusters of intragenic miRNAs, miRNA and host gene expression across different tissues and expression correlation for intragenic miRNAs and their host genes. Protein-protein interaction data are also presented for functional network analysis of host genes. In summary, miRIAD was designed to help the research community to explore, in a user-friendly environment, intragenic miRNAs, their host genes and functional annotations with minimal effort, facilitating hypothesis generation and in-silico validations. Database URL: http://www.miriad-database.org.


[Anesthesic management of a patient with Stickler's syndrome].
Stickler's syndrome is a connective-tissue disease of autosome dominant inheritance. This report concerns a 3-year-old girl with Stickler's syndrome who underwent arthroplasty under general anesthesia. After slow induction of anesthesia with an inhalation anesthetic, neither a oropharyngeal airway nor a laryngeal mask airway fitted her, and mask ventilation and endotracheal intubation became difficult. Endotracheal intubation was performed not with a muscle relaxant but under deep anesthesia. Care should be taken when planning anesthesia for a case of this syndrome because airway management is often difficult and emergency surgery for detached retinas might be required.


Continuous-wave operation of an electrically pumped single microribbon based Fabry-Perot microlaser.
Fabry-Perot (FP) mode microlasers have been popularized and applied widely in on-chip coherent light sources because of the unique advantages of directional output emission. In this work, a heterojunction light-emitting diode (LED) made of a Ga-doped ZnO (ZnO:Ga) microribbon and p-GaAs template is fabricated. And its electroluminescence characteristics of strong coupling of exciton-photon and polariton lasing, in the blue-violet spectrum, were demonstrated under continuous-wave operation of an electrical injection. In the device structure, a single microribbon with a rectangular-shaped cross section can achieve the FP-mode lasing action by the optical oscillation between the two lateral sides of the microcrystals in the ultraviolet spectrum. As the reverse-current is below the threshold value, the device can have radiative polaritonic lighting directly from bilateral sides of the microribbon, yielding strong coupling between excitons and FP-mode microresonator. And the exciton-polariton coupling strengths characterized by a Rabi splitting energy were extracted to be 500 meV. Further, when the input current increased more than a certain value, strong laser illuminating developed as two sharp peaks at the lower energy shoulder of the spontaneous emission peak, and these oscillating modes can dominate the waveguide EL spectra. The experimental results can provide us with further unambiguous evidence that the lasing is originated from the polariton resonances for the microribbon with strong exciton-polariton coupling. Since single microribbon based optical FP-mode microresonators do not require additional feedback mirrors, their compact size and resulting low thresholds make them a powerful candidate to construct on-chip coherent light sources for future integrated nanophotonic and optoelectronic circuitry.


Antispermatogenic and androgenic activities of various extracts of Hibiscus rosa sinesis in albino mice.
The benzene chloroform and alcoholic extracts of the flowers of H.r.sinensis were administered (i.p.) at two different dose levels of 125 and 250 mg/kg body weight to adult male albino mice for 20 days. The results have shown decrease in the spermatogenic elements of testis and epididymal sperm count. High content of testicular cholesterol may be due to lowered androgen synthesis. The increase in the weight of accessory reproductive organs indicates the androgenicity of the plant extract itself, which is proved in the present study by testing the benzene extract in immature mice.


In vitro studies of chicken egg yolk antibody (IgY) against Salmonella enteritidis and Salmonella typhimurium.
Chicken egg yolk antibody (IgY) raised against Salmonella enteritidis or Salmonella typhimurium was found in highly specific activity levels by ELISA. S. enteritidis- and S. typhimurium-specific IgY powder, prepared by freeze-drying the egg yolk water-soluble fraction, contained 15.5 and 10.0% of specific IgY, respectively. Anti-S. enteritidis IgY cross-reacted 55.3% with S. typhimurium. The cross-reactivity of anti-S. typhimurium IgY with S. enteritidis was 42.4%. Salmonella-specific IgY was demonstrated to inhibit Salmonella growth in liquid medium. The growth rate of S. enteritidis incubated with S. enteritidis-specific IgY was fourfold less than that of the control group during a 4-to-6-h incubation. Cell counts of S. typhimurium incubated with S. typhimurium-specific IgY were reduced by 1.6 log cfu/mL in comparison to that of the control group after 6 h of incubation. The specific binding activity of IgY was further evaluated by using immunofluorescence and immunoelectron microscopy. It was found that Salmonella-specific IgY could bind to the antigens expressed on the Salmonella surface, resulting in structural alterations of the bacterial surface.


The ERβ4 variant induces transformation of the normal breast mammary epithelial cell line MCF-10A; the ERβ variants ERβ2 and ERβ5 increase aggressiveness of TNBC by regulation of hypoxic signaling.
Triple negative breast cancer (TNBC) still remains a challenge to treat in the clinic due to a lack of good targets for treatment. Although TNBC lacks expression of ERα, the expression of ERβ and its variants are detected quite frequently in this cancer type and can represent an avenue for treatment. We show that two of the variants of ERβ, namely ERβ2 and ERβ5, control aggressiveness of TNBC by regulating hypoxic signaling through stabilization of HIF-1α. RNA-seq of patient derived xenografts (PDX) from TNBC shows expression of ERβ2, ERβ4 and ERβ5 variants in more than half of the samples. Furthermore, expression of ERβ4 in the immortalized, normal mammary epithelial cell line MCF-10A that is resistant to tumorsphere formation caused transformation and development of tumorspheres. By contrast, ERβ1, ERβ2 or ERβ5 were unable to support tumorsphere formation. We have previously shown that all variants except ERβ1 stabilize HIF-1α but only ERβ4 appears to have the ability to transform normal mammary epithelial cells, pointing towards a unique property of ERβ4. We propose that ERβ variants may be good diagnostic tools and also serve as novel targets for treatment of breast cancer.


Can early interventions alter the course of autism?
Interventions for autism have come a long way since the condition was described by Kanner in the 1940s. At that time, autism was considered to be closely linked to schizophrenia, and inadequate parenting was viewed as the principal cause. Psychoanalysis was often the therapy of choice, but there was also widespread use of the drugs and even electroconvulsive treatments that had been developed for use in schizophrenia. Over the years, as autism has come to be recognized as a developmental disorder, interventions have focused instead on enhancing developmental skills and on ways of ameliorating behavioural difficulties. Recognition of the role that language deficits in particular play in causing behaviour problems has led to a focus on the teaching of more effective communication skills. The need for early support for families and appropriate education is also widely acknowledged. Nevertheless, follow-up studies indicate that the prognosis for the majority of individuals with autism remains poor. And despite claims to the contrary, there is little evidence that very early, intensive interventions can significantly alter the long-term course of the disorder. The paper discusses findings from follow-up studies over the years and assess the impact of different intervention procedures on outcome.


Hyperoxia-induced converting enzyme insufficiency in conscious rat: cardiovascular effects.
The effects of exposing rats to hyperoxia (100 percent O2) at normal atmospheric pressure for periods of 24-48 hours on components of the renin-angiotensin system and on blood pressure control were examined. Intrapulmonary conversion of angiotensin I (AI) to angiotensin (AII) was assessed using an isolated lung preparation perfused at constant flow. Exposure of rats to hyperoxia for 44-48 hours reduced single pass conversion of AI to AII in the pulmonary circulation from control levels of 82 +/- 4 to 29 +/- 5 percent (p less than 0.001). AII levels in trunk blood of 44-48 hour O2 exposed animals were 5.2 +/- 1.9 pg/ml, compared to 37.9 +/- 10.0 pg/ml in controls (p less than 0.001). Mean arterial pressure decreased significantly from 117 +/- 4.3 to 103 +/- 6.7 mmHg (p less than 0.05) in the O2 exposed group despite a threefold increase in plasma renin activity. The pressor response to exogenous AI was significantly diminished by O2 exposure, while the pressor response to exogenous AII remained unchanged from control. Pulmonary angiotensin-converting enzyme activity fell to approximately 50 percent of control in O2 exposed animals, but circulating converting enzyme activity was not change in this group. None of these alterations was apparent following 24 hours of hyperoxic exposure. These data suggest that O2 induced impairment in activity of angiotensin-converting enzyme at the endothelial membrane level has functionally significant effects on cardiovascular homeostasis, probably via reduced generation of endogenous AII.


Lipoic acid as a novel treatment for Alzheimer's disease and related dementias.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that destroys patient memory and cognition, communication ability with the social environment and the ability to carry out daily activities. Despite extensive research into the pathogenesis of AD, a neuroprotective treatment - particularly for the early stages of disease - remains unavailable for clinical use. In this review, we advance the suggestion that lipoic acid (LA) may fulfil this therapeutic need. A naturally occurring precursor of an essential cofactor for mitochondrial enzymes, including pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH), LA has been shown to have a variety of properties which can interfere with pathogenic principles of AD. For example, LA increases acetylcholine (ACh) production by activation of choline acetyltransferase and increases glucose uptake, thus supplying more acetyl-CoA for the production of ACh. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals and also scavenges reactive oxygen species (ROS), thereby increasing the levels of reduced glutathione. Via the same mechanisms, downregulation redox-sensitive inflammatory processes is also achieved. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein. The reduced form of LA, dihydrolipoic acid (DHLA), is the active compound responsible for most of these beneficial effects. R-alpha-LA can be applied instead of DHLA, as it is reduced by mitochondrial lipoamide dehydrogenase, a part of the PDH complex. In this review, the properties of LA are explored with particular emphasis on how this agent, particularly the R-alpha-enantiomer, may be effective to treat AD and related dementias.


Island Sign Predicts Hematoma Expansion and Poor Outcome After Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis.
Background: Early hematoma expansion (HE) occurs in patients with intracerebral hemorrhage (ICH) within the first few hours from ICH onset. Hematoma expansion has been considered as an independent predictor of poor clinical outcome and mortality after ICH. Island sign (IS) on the non-contrast computed tomography (NCCT) appears to increase the rate of detection of HE. However, there is insufficient evidence to declare that IS is an independent predictor for ICH patients prognosis and classification. Objectives: To investigate whether IS on NCCT could predict HE and functional outcome following ICH. Methods: Major databases were systematically searched, including PubMed, EMBASE, Cochrane library, and the Chinese database (CNKI, VIP, and Wanfang databases). Studies about the associations between IS and HE or IS and clinical outcome were included. The pooled result used the odds ratio (OR) with a 95% confidence interval (CI) as effect size. Heterogeneity and publication bias were assessed. Subgroup analysis and meta-regression were applied to detect potential factors of heterogeneity. Results: Eleven studies with 4,310 patients were included in the final analysis. The average incidence rate of IS and HE were 21.58 and 33%, respectively. The ideal timing for assessing HE was also not uniform or standardized. We separately performed two meta-analyses. First, 10 studies were included to estimate the association between IS and HE. The pooled OR was statistically significant (OR = 7.61, 95% CI = 3.10-18.67, P < 0.001). Second, four studies were included in the meta-analysis, and the pooled result showed that IS had a significantly positive relationship with poor outcome (OR = 3.83, 95% CI = 2.51-5.85, P < 0.001). Conclusions: This meta-analysis showed that NCCT IS is of great importance and value for evaluation of HE and poor outcome in patients with ICH. Future studies should focus on developing consensus guidelines, and more studies with large sample size and longitudinal design are needed to validate the conclusions.


Aurora-A identifies early recurrence and poor prognosis and promises a potential therapeutic target in triple negative breast cancer.
Triple negative breast cancer (TNBC) acquires an unfavorable prognosis, emerging as a major challenge for the treatment of breast cancer. In the present study, 122 TNBC patients were subjected to analysis of Aurora-A (Aur-A) expression and survival prognosis. We found that Aur-A high expression was positively associated with initial clinical stage (P = 0.025), the proliferation marker Ki-67 (P = 0.001), and the recurrence rate of TNBC patients (P<0.001). In TNBC patients with Aur-A high expression, the risk of distant recurrence peaked at the first 3 years and declined rapidly thereafter, whereas patients with Aur-A low expression showed a relatively constant risk of recurrence during the entire follow-up period. Univariate and multivariate analysis showed that overexpression of Aur-A predicted poor overall survival (P = 0.002) and progression-free survival (P = 0.012) in TNBC. Furthermore, overexpression of Aur-A, associated with high Ki-67, predicted an inferior prognosis compared with low expression of both Aur-A and Ki-67. Importantly, we further found that Aur-A was overexpressed in TNBC cells, and inhibition of this kinase inhibited cell proliferation and prevented cell migration in TNBC. Our findings demonstrated that Aur-A was a potential therapeutic target for TNBC and inhibition of Aur-A kinase was a promising regimen for TNBC cancer therapy.


Linear IgA bullous disease in a patient with Crohn's disease.
Linear IgA bullous disease is a rare autoimmune subepidermal blistering disease characterized by linear deposition of IgA along the basement membrane zone. We report a clinical case of a rare association of Linear IgA bullous disease and Crohn's disease. Parallel clinical improvement of both cutaneous and intestinal disease was observed with dapsone treatment.


Anomalous DC Hall response in noncentrosymmetric tilted Weyl semimetals.
Weyl nodes come in pairs of opposite chirality. For broken time reversal symmetry (TR) they are displaced in momentum space by [Formula: see text] and the anomalous DC Hall conductivity [Formula: see text] is proportional to [Formula: see text] at charge neutrality. For finite doping there are additive corrections to [Formula: see text] which depend on the chemical potential as well as on the tilt ([Formula: see text]) of the Dirac cones and on their relative orientation. If inversion symmetry (I) is also broken the Weyl nodes are shifted in energy by an amount [Formula: see text]. This introduces further changes in [Formula: see text] and we provide simple analytic formulas for these modifications for both type I ([Formula: see text]) and type II ([Formula: see text], overtilted) Weyl. For type I when the Weyl nodes have equal magnitude but oppositely directed tilts, the correction to [Formula: see text] is proportional to the chemical potential μ and completely independent of the energy shift [Formula: see text]. When instead the tilts are parallel, the correction is linear in [Formula: see text] and μ drops out. For type II the corrections involve both μ and [Formula: see text], are nonlinear and also involve a momentum cut off. We discuss the implied changes to the Nernst coefficient and to the thermal Hall effect of a finite [Formula: see text].


Calcium binding by chick calretinin and rat calbindin D28k synthesised in bacteria.
Calretinin is a member of the EF-hand calcium-binding protein family, with a high similarity with calbindin D28k. The chick calretinin cDNA sequence was reconstructed in a M13 vector and transferred into an expression plasmid derived from the pET series. The calretinin gene was expressed in Escherichia coli and produced immunoreactive calretinin of the expected size. Bacterially expressed calretinin was purified with successive ammonium-sulfate precipitation, DEAE chromatography, hydroxyapatite chromatography, Sephadex G-75 chromatography and Mono-Q chromatography. Normally, 1.0-1.5 mg calretinin was obtained from 1 l bacterial culture with a protein recovery of 0.5-1.5%. Calbindin D28k was purified similarly from bacteria using an expression plasmid provided by W. Hunziker. Calcium-binding activity of purified proteins was measured by equilibrium dialysis in calcium/EGTA mixtures with 45Ca as tracer. Both calretinin and calbindin D28k bound 3-4 Ca2+/molecule (calretinin, 4.0 +/- 0.5; calbindin D28k, 3.5 +/- 0.4), implying that at least one of the canonical EF-hand domains does not bind calcium. The Kd was 0.3-0.5 microM with little difference between the values for the two proteins.


SH2 domain protein E (SHE) and ABL signaling regulate blood vessel size.
Blood vessels in different vascular beds vary in lumen diameter, which is essential for their function and fluid flow along the vascular network. Molecular mechanisms involved in the formation of a vascular lumen of appropriate size, or tubulogenesis, are still only partially understood. Src homology 2 domain containing E (She) protein was previously identified in a screen for proteins that interact with Abelson (Abl)-kinase. However, its biological role has remained unknown. Here we demonstrate that She and Abl signaling regulate vascular lumen size in zebrafish embryos and human endothelial cell culture. Zebrafish she mutants displayed increased endothelial cell number and enlarged lumen size of the dorsal aorta (DA) and defects in blood flow. Vascular endothelial specific overexpression of she resulted in a reduced diameter of the DA lumen, which correlated with the reduced arterial cell number and lower endothelial cell proliferation. Chemical inhibition of Abl signaling in zebrafish embryos caused a similar reduction in the DA diameter and alleviated the she mutant phenotype, suggesting that She acts as a negative regulator of Abl signaling. Enlargement of the DA lumen in she mutants correlated with an increased endothelial expression of claudin 5a and 5b (cldn5a / cldn5b), which encode proteins enriched in tight junctions. Inhibition of cldn5a expression partially rescued the enlarged DA in she mutants, suggesting that She regulates DA lumen size, in part, by promoting cldn5a expression. SHE knockdown in human endothelial umbilical vein cells resulted in a similar increase in the diameter of vascular tubes, and also increased phosphorylation of a known ABL downstream effector CRKL. These results argue that SHE functions as an evolutionarily conserved inhibitor of ABL signaling and regulates lumen size during vascular tubulogenesis.


Neurotrophin3 promotes hepatocellular carcinoma apoptosis through the JNK and P38 MAPK pathways.
Although liver cancer is a malignant tumor with the highest mortality across the world, its pathogenesis and therapeutic targets remain unclear. Apoptosis, a natural cell death mechanism, is an important target of anticancer therapy. The discovery of effective apoptotic regulators can lead to the identification of novel therapeutic targets for treating cancer. Neurotrophin 3 (NTF3) is a member of the nerve growth factor (NGF) family that is involved in the progression of various cancers, including medulloblastoma, primitive neuroectodermal brain tumors, and breast cancer. NTF3 is under-expressed in human hepatocellular carcinoma (HCC), albeit its specific effects and the action mechanism have not been elucidated. Here, we confirmed that NTF3 expression was significantly low in HCC with reference to the GSEA database. By collecting patient data from our center and performing qRT-PCR analysis, we found that NTF3 expression was significantly downregulated in 74 patients with HCC. Low NTF3 expression was associated with a shorter overall survival (OS), recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). Both in vivo and in vitro experiments revealed that NTF3 considerably inhibited the progression of HCC cells. We found that the ligand NTF3 is regulated by c-Jun and binds to the p75 neurotrophin receptor (p75NTR) and then activates the JNK and P38 MAPK pathways to induce apoptosis. Entinostat (the target of HDAC1/HDAC3) can activate the NTF3/p75NTR pathway. These results indicate that NTF3 is a tumor suppressor, and that its low expression can help in predict poor clinical outcomes in HCC. Therefore, NTF3 can be used as a potential treatment molecule for HCC.


Upscaling the effect of traits in response to drought: The relative importance of safety-efficiency and acquisitive-conservation functional axes.
We tested the idea that functional trade-offs that underlie species tolerance to drought-driven shifts in community composition via their effects on demographic processes and subsequently on shifts in species' abundance. Using data from 298 tree species from tropical dry forests during the extreme ENSO-2015, we scaled-up the effects of trait trade-offs from individuals to communities. Conservative wood and leaf traits favoured slow tree growth, increased tree survival and positively impacted species abundance and dominance at the community-level. Safe hydraulic traits, on the other hand, were related to demography but did not affect species abundance and communities. The persistent effects of the conservative-acquisitive trade-off across organizational levels is promising for generalization and predictability of tree communities. However, the safety-efficient trade-off showed more intricate effects on performance. Our results demonstrated the complex pathways in which traits scale up to communities, highlighting the importance of considering a wide range of traits and performance processes.


Activity and mRNA Levels of Enzymes Involved in Hepatic Fatty Acid Synthesis in Rats Fed Naringenin.
We investigated the physiological activity of naringenin in affecting hepatic lipogenesis and serum and liver lipid levels in rats. Rats were fed diets containing 0, 1, or 2.5 g/kg naringenin for 15 d. Naringenin at a dietary level of 2.5 g/kg significantly decreased the activities and the mRNA levels of various lipogenic enzymes and sterol regulatory element binding protein-1c (SREBP-1c) mRNA level. The activities and the mRNA levels were also 9-22% and 12-38% lower, respectively, in rats fed a 1 g/kg naringenin diet than in the animals fed a naringenin-free diet, although the differences were not significant in many cases. Naringenin at 2.5 g/kg significantly lowered serum triacylglycerol, cholesterol, and phospholipid and hepatic triacylglycerol and cholesterol. This flavonoid at 1.0 g/kg also significantly lowered these parameters except for serum triacylglycerol. Naringenin levels in serum and liver dose-dependently increased, and hepatic concentrations reached levels that can affect various signaling pathways.


Efficient gene knockout in primary human and murine myeloid cells by non-viral delivery of CRISPR-Cas9.
Myeloid cells play critical and diverse roles in mammalian physiology, including tissue development and repair, innate defense against pathogens, and generation of adaptive immunity. As cells that show prolonged recruitment to sites of injury or pathology, myeloid cells represent therapeutic targets for a broad range of diseases. However, few approaches have been developed for gene editing of these cell types, likely owing to their sensitivity to foreign genetic material or virus-based manipulation. Here we describe optimized strategies for gene disruption in primary myeloid cells of human and murine origin. Using nucleofection-based delivery of Cas9-ribonuclear proteins (RNPs), we achieved near population-level genetic knockout of single and multiple targets in a range of cell types without selection or enrichment. Importantly, we show that cellular fitness and response to immunological stimuli is not significantly impacted by the gene editing process. This provides a significant advance in the study of myeloid cell biology, thus enabling pathway discovery and drug target validation across species in the field of innate immunity.


Low-cost fiber specklegram sensor for noncontact continuous patient monitoring.
Different low-cost approaches based on fiber specklegram sensors are employed to measure the physiological activity of patients lying in bed. This study is conducted over 20 volunteers to measure the movement and heart rate (HR) using two different sensor designs placed at two different bed locations. Three different processing methods are developed and tested in order to extract useful information from the measured data. The results suggest that a stretched fiber optic configuration under the head of the person lying in bed is the optimal configuration to detect HR and motion, nonetheless the other tested possibilities also exhibit remarkably good performances. On the other hand, the three proposed processing methods also achieve a good precision in the HR detection. The sensor implementation is simple, not requiring any special conditions, and it provides robust performance. This leads to the conclusion that fiber specklegram technology is a feasible method to be used in real situations for heartbeat and movement monitoring.


Quantification of santonin in eight species of Artemisia from Kazakhstan by means of HPLC-UV: Method development and validation.
Santonin, a powerful anthelmintic drug that was formely used to treat worms, is Artemisia cina's main constituent. However, due to its toxicity to humans, it is no longer in use. Kazakhstan is looking to introduce this plant as an anthelmintic drug for veterinary purposes, despite the known toxic properties of the santonin. The objective of this study was to develop a fast and specific method for the identification of santonin and its precise quantitation using HPLC-UV in order to avoid unnecessary intoxication, which is paramount for the development of veterinary medicines. The results obtained showed that santonin appears at around 5.7 minutes in this very reliable HPLC method. The validation of the method was performed by the investigation of parameters such as precision, accuracy, reproducibility and recovery. The method was used to identify and quantify santonin in leaves of A. scoparia, A. foetida, A. gmelinni, A. schrenkiana, A. frigida, A. sublesingiana, A terra-albae, and A. absinthium from Kazakhstan as well as in three different extracts of leaves of A. cina. This study has provided a faster and simpler method for the identification and quantification of this compound in other species of Artemisia of economic importance.


High-resolution genomic analysis of the 11q13 amplicon in breast cancers identifies synergy with 8p12 amplification, involving the mTOR targets S6K2 and 4EBP1.
The chromosomal region 11q13 is amplified in 15-20% of breast cancers; an event not only associated with estrogen receptor (ER) expression but also implicated in resistance to endocrine therapy. Coamplifications of the 11q13 and 8p12 regions are common, suggesting synergy between the amplicons. The aim was to identify candidate oncogenes in the 11q13 region based on recurrent amplification patterns and correlations to mRNA expression levels. Furthermore, the 11q13/8p12 coamplification and its prognostic value, was evaluated at the DNA and the mRNA levels. Affymetrix 250K NspI arrays were used for whole-genome screening of DNA copy number changes in 29 breast tumors. To identify amplicon cores at 11q13 and 8p12, genomic identification of significant targets in cancer (GISTIC) was applied. The mRNA expression levels of candidate oncogenes in the amplicons [RAD9A, RPS6KB2 (S6K2), CCND1, FGF19, FGF4, FGF3, PAK1, GAB2 (11q13); EIF4EBP1 (4EBP1), PPAPDC1B, and FGFR1 (8p12)] were evaluated using real-time PCR. Resulting data revealed three main amplification cores at 11q13. ER expression was associated with the central 11q13 amplification core, encompassing CCND1, whereas 8p12 amplification/gene expression correlated to S6K2 in a proximal 11q13 core. Amplification of 8p12 and high expression of 4EBP1 or FGFR1 was associated with a poor outcome in the group. In conclusion, single nucleotide polymorphism arrays have enabled mapping of the 11q13 amplicon in breast tumors with high resolution. A proximal 11q13 core including S6K2 was identified as involved in the coamplification/coexpression with 8p12, suggesting synergy between the mTOR targets S6K2 and 4EBP1 in breast cancer development and progression.


Statistical Approaches for the Study of Cognitive and Brain Aging.
Neuroimaging studies of cognitive and brain aging often yield massive datasets that create many analytic and statistical challenges. In this paper, we discuss and address several limitations in the existing work. (1) Linear models are often used to model the age effects on neuroimaging markers, which may be inadequate in capturing the potential nonlinear age effects. (2) Marginal correlations are often used in brain network analysis, which are not efficient in characterizing a complex brain network. (3) Due to the challenge of high-dimensionality, only a small subset of the regional neuroimaging markers is considered in a prediction model, which could miss important regional markers. To overcome those obstacles, we introduce several advanced statistical methods for analyzing data from cognitive and brain aging studies. Specifically, we introduce semiparametric models for modeling age effects, graphical models for brain network analysis, and penalized regression methods for selecting the most important markers in predicting cognitive outcomes. We illustrate these methods using the healthy aging data from the Active Brain Study.


The contrasting effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in hyperdynamic sepsis.
To compare the effects of dopamine and norepinephrine on systemic and splanchnic oxygen utilization in patients with hyperdynamic sepsis. A randomized short-term, interventional study. An intensive care unit of a university hospital. Twenty septic patients with a cardiac index greater than 3.2 L-min-1.m-2 and either a mean arterial pressure (MAP) less than 60 mm Hg or a systemic vascular resistance index less than 1200 dyne.s.cm-5.m-2. Patients were randomized to receive an infusion of either dopamine or norepinephrine titrated to increase the MAP to greater than 75 mm Hg. The hemodynamic profile, oxygen delivery, oxygen consumption (determined by indirect calorimetry), and gastric intramucosal pH (pHi) (determined by gastric tonometry) were determined at baseline and after 3 hours of achieving the target MAP. Dopamine increased the MAP largely by increasing the cardiac index whereas norepinephrine increased the MAP by increasing the systemic vascular resistance index while maintaining the cardiac index. Although oxygen delivery and oxygen consumption increased in both groups of patients, the pHi increased significantly in those patients treated with norepinephrine whereas the pHi decreased significantly in those patients receiving dopamine (P < .001, for corrected 3-hour value). This study suggests that dopamine may cause an uncompensated increase in splanchnic oxygen requirements in septic patients. Norepinephrine, however, may have a more favorable hemodynamic profile and improve splanchnic tissue oxygen utilization in sepsis.


Locomotion and chemotaxis of lymphocytes.
The behaviour of locomotor T and B lymphocytes and the chemoattractants to which they respond in vitro are reviewed. Following activation, T cells respond by locomotion and chemotaxis to cytokine attractants including IL-15 and IL-2 and several chemokines. In activated B cells chemotaxis may be signalled through the antigen receptor. Conversely resting lymphocytes respond poorly to the above signals though their locomotion is activated by contact with high endothelial venular cells. These differences in locomotion between resting and activated lymphocytes, together with differences in adhesion, may explain why activated lymphocytes migrate preferentially into inflammatory sites while resting cells recirculate.


Footwear recommendations and patterns among orthopaedic foot and ankle surgeons: a survey.
Foot and ankle surgeons are in a unique position to educate patients about the importance of proper footwear. Neither their recommendations regarding shoe selection nor their own footwear patterns have previously been reported. A total of 866 members of the American Orthopaedic Foot & Ankle Society (AOFAS) were asked to complete a survey via the Internet. Topics included specific shoe brands recommended to patients, how attributes of footwear are communicated, and respondents' footwear habits. In all, 276 (32%) surgeons responded, and 64% recommended New Balance athletic shoes to patients; 26% did not recommend specific brands. It was found that 50% wear New Balance athletic shoes; 25% wear Nike. Rockport (27%) and SAS (27%) were the most recommended dress shoes. In all, 76% are familiar with AOFAS guidelines for proper shoe fit, but only 56% educated their patients about the guidelines; 43% do not consider what patients might think of their shoes when selecting what to wear in the clinical setting. Despite the multitude of different brands, several were commonly recommended. Respondents seem to be aware of the impact of their own shoe selection on patients' perspectives of footwear, but many do not consider themselves role models for proper footwear.


Examining the comorbidity of language disorders and ADHD.
In the companion papers this issue we presented the value of research on comorbidity, particularly in complex developmental disorders where the identification of etiology is challenging. As we will document below, Language Impairment (SLI) and Attention Deficit Hyperactivity Disorder (ADHD) have been shown to co-occur in a number of studies, and this phenomenon is commonplace in the experience of many clinicians. Given this, we must ask whether the overlap between SLI and ADHD can aid our understanding of these disorders, particularly with regard to the basis for comorbidity. As we review the literature, we will consider the models of comorbidity that were outlined in the Introduction to this issue. Finally, we present original data on SLI and ADHD from a population-based sample of children that have studied over the last two decades in the State of Iowa.


Gallbladder volvulus: a case of mimicry.
Torsion of the gallbladder resulting in a volvulus is a rare clinical finding that poses a diagnostic challenge preoperatively to both surgeons and radiologists. It is thought to occur secondary to a redundant mesentery where rotation of the gallbladder occurs along the axis of the cystic duct and cystic artery. Gallbladder volvulus commonly presents as acute cholecystitis and is rarely diagnosed preoperatively. An early emergency laparoscopic cholecystectomy is the preferred treatment. Early consideration of this diagnosis enables prompt surgical intervention and quick postoperative recovery periods.


A phylogenetic study of Drosophila splicing assembly chaperone RNP-4F associated U4-/U6-snRNA secondary structure.
The rnp-4f gene in Drosophila melanogaster encodes nuclear protein RNP-4F. This encoded protein is represented by homologs in other eukaryotic species, where it has been shown to function as an intron splicing assembly factor. Here, RNP-4F is believed to initially bind to a recognition sequence on U6-snRNA, serving as a chaperone to facilitate its association with U4-snRNA by intermolecular hydrogen bonding. RNA conformations are a key factor in spliceosome function, so that elucidation of changing secondary structures for interacting snRNAs is a subject of considerable interest and importance. Among the five snRNAs which participate in removal of spliceosomal introns, there is a growing consensus that U6-snRNA is the most structurally dynamic and may constitute the catalytic core. Previous studies by others have generated potential secondary structures for free U4- and U6-snRNAs, including the Y-shaped U4-/U6-snRNA model. These models were based on study of RNAs from relatively few species, and the popular Y-shaped model remains to be systematically re-examined with reference to the many new sequences generated by recent genomic sequencing projects. We have utilized a comparative phylogenetic approach on 60 diverse eukaryotic species, which resulted in a revised and improved U4-/U6-snRNA secondary structure. This general model is supported by observation of abundant compensatory base mutations in every stem, and incorporates more of the nucleotides into base-paired associations than in previous models, thus being more energetically stable. We have extensively sampled the eukaryotic phylogenetic tree to its deepest roots, but did not find genes potentially encoding either U4- or U6-snRNA in the Giardia and Trichomonas data-bases. Our results support the hypothesis that nuclear introns in these most deeply rooted eukaryotes may represent evolutionary intermediates, sharing characteristics of both group II and spliceosomal introns. An unexpected result of this study was discovery of a potential competitive binding site for Drosophila splicing assembly factor RNP-4F to a 5'-UTR regulatory region within its own premRNA, which may play a role in negative feedback control.


Music therapy and the effects on laboring women.
Wiand's (1997) study supported the use of music therapy to decrease pain and anxiety. The results of this study could be used to support a research utilization project to educate nurses on the potential benefits of music therapy among laboring women. Nurses and physicians could collaborate together to educate clients on music therapy to decrease pain and anxiety. Feasibility issues would include education of the nurses to use music therapy and the cost of developing different types of music. Future research could be done to study a larger sample size. Other research is needed to determine what type of music works best with laboring women.


Psychometric evaluation of the German version of the Brief Reflective Functioning Interview.
To measure mentalization in a feasible manner, various instruments have been designed in recent years. The Brief Reflective Functioning Interview (BRFI) is a short interview that is based on the Adult Attachment Interview (AAI). The aim of both studies was to examine the psychometric properties of the German version of the BRFI and to compare them to those of the AAI. In Study 1, we examined 60 students using the BRFI and the AAI. In Study 2, the validity of the BRFI was examined using a mixed sample of students and patients (N = 149). Trained coders evaluated the Reflective Functioning Scale (RFS) for the BRFI and the AAI. We found a significant positive correlation between the RFS total scores of the BRFI and those of the AAI. In addition, both interviews showed excellent internal consistency. We could also show that persons with mental disorders exhibit lower levels of RF score than mentally stable individuals. Women had higher RF scores in the BRFI than men in both samples. Persons whose mentalization capacity was rated below average in either the BRFI or the AAI also reported significantly lower mentalization ability in the self-assessment (p < .01). Our results revealed that the RFS scores measured by the BRFI are highly comparable to those measured by the AAI. Our findings support the results of previous studies, suggesting that the BRFI is a reliable, valid and easy-to-administer alternative to the AAI. The German version of the Brief Reflective Functioning Interview (BRFI) proved to be a reliable and valid instrument for the assessment of reflective functioning that is shorter in terms of time to complete and the evaluation process than the measurement via the Adult Attachment Interview (AAI). Reflective functioning is negatively associated with psychopathology.


The IS10 antisense RNA blocks ribosome binding at the transposase translation initiation site.
Transposase (tnp) expression from insertion sequence IS10 is controlled, in part, by an antisense RNA, RNA-OUT, which pairs to the translation initiation region of the tnp mRNA, RNA-IN. Genetic experiments suggest that control occurs post-transcriptionally. Here, we present evidence that bears on the control mechanism. Specific ribosome binding at the tnp translation initiation site is demonstrated in vitro. Two mutations that alter tnp translation in vivo are shown to have corresponding effects in vitro. Most importantly, RNA-OUT/RNA-IN pairing is shown to block ribosome binding. In conjunction with the work described in the accompanying paper, we propose that inhibition of ribosome binding also occurs in vivo, and that it is sufficient to account for control. Implications for translational control in analogous systems are discussed.


The circadian gene, Per2, influences methamphetamine sensitization and reward through the dopaminergic system in the striatum of mice.
Drug addiction is a chronic and relapsing brain disorder, influenced by complex interactions between endogenous and exogenous factors. Per2, a circadian gene, plays a role in drug addiction. Previous studies using Per2-knockout mice have shown a role for Per2 in cocaine, morphine and alcohol addiction. In the present study, we investigated the role of Per2 in methamphetamine (METH) addiction using Per2-overexpression and knockout mice. We observed locomotor sensitization responses to METH administration, and rewarding effects using a conditioned place preference test. In addition, we measured expression levels of dopamine and dopamine-related genes (monoamine oxidase A, DA receptor 1, DA receptor 2, DA active transporter, tyrosine hydroxylase and cAMP response element-binding protein 1) in the striatum of the mice after repeated METH treatments, using qRT-PCR. Per2-overexpressed mice showed decreased locomotor sensitization and rewarding effects of METH compared to the wildtype mice, whereas the opposite was observed in Per2 knockout mice. Both types of transgenic mice showed altered expression levels of dopamine-related genes after repeated METH administration. Specifically, we observed lower dopamine levels in Per2-overexpressed mice and higher levels in Per2-knockout mice. Taken together, Per2 expression levels may influence the addictive effects of METH through the dopaminergic system in the striatum of mice.


The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases.
The accumulation of misfolded proteins in the human brain is one of the critical features of many neurodegenerative diseases, including Alzheimer's disease (AD). Assembles of beta-amyloid (Aβ) peptide-either soluble (oligomers) or insoluble (plaques) and of tau protein, which form neurofibrillary tangles, are the major hallmarks of AD. Chaperones and co-chaperones regulate protein folding and client maturation, but they also target misfolded or aggregated proteins for refolding or for degradation, mostly by the proteasome. They form an important line of defense against misfolded proteins and are part of the cellular quality control system. The heat shock protein (Hsp) family, particularly Hsp70 and Hsp90, plays a major part in this process and it is well-known to regulate protein misfolding in a variety of diseases, including tau levels and toxicity in AD. However, the role of Hsp90 in regulating protein misfolding is not yet fully understood. For example, knockdown of Hsp90 and its co-chaperones in a Caenorhabditis elegans model of Aβ misfolding leads to increased toxicity. On the other hand, the use of Hsp90 inhibitors in AD mouse models reduces Aβ toxicity, and normalizes synaptic function. Stress-inducible phosphoprotein 1 (STI1), an intracellular co-chaperone, mediates the transfer of clients from Hsp70 to Hsp90. Importantly, STI1 has been shown to regulate aggregation of amyloid-like proteins in yeast. In addition to its intracellular function, STI1 can be secreted by diverse cell types, including astrocytes and microglia and function as a neurotrophic ligand by triggering signaling via the cellular prion protein (PrPC). Extracellular STI1 can prevent Aβ toxic signaling by (i) interfering with Aβ binding to PrPC and (ii) triggering pro-survival signaling cascades. Interestingly, decreased levels of STI1 in C. elegans can also increase toxicity in an amyloid model. In this review, we will discuss the role of intracellular and extracellular STI1 and the Hsp70/Hsp90 chaperone network in mechanisms underlying protein misfolding in neurodegenerative diseases, with particular focus on AD.


Thermoelectric performance of restacked MoS2 nanosheets thin-film.
MoS2 has been predicted to be an excellent thermoelectric material due to its large intrinsic band gap and high carrier mobility. In this work, we exfoliated bulk MoS2 by the assistance of lithium intercalation and fabricated the restacked MoS2 thin-film using a simple filtration technique. These MoS2 thin-films with different thickness showed different thermoelectric performance. It was found that with the increase of thickness, carrier concentration, electrical conductivity and Seebeck coefficient all showed an increasing trend. In particular, the maximum Seebeck coefficient was able to reach 93.5 μV K(-1). This high thermopower indicates that MoS2 will have ideal thermoelectric performance in the future through optimizing its structure. The highest figure of merit (ZT = 0.01) is calculated in this experiment.


Are melanocortin peptides future therapeutics for cutaneous wound healing?
Cutaneous wound healing is a complex process divided into different phases, that is an inflammatory, proliferative and remodelling phase. During these phases, a variety of resident skin cell types but also cells of the immune system orchestrate the healing process. In the last year, it has been shown that the majority of cutaneous cell types express the melanocortin 1 receptor (MC1R) that binds α-melanocyte-stimulating hormone (α-MSH) with high affinity and elicits pleiotropic biological effects, for example modulation of inflammation and immune responses, cytoprotection, antioxidative defense and collagen turnover. Truncated α-MSH peptides such as Lys-Pro-Val (KPV) as well as derivatives like Lys-d-Pro-Thr (KdPT), the latter containing the amino acid sequence 193-195 of interleukin-1β, have been found to possess anti-inflammatory effects but to lack the pigment-inducing activity of α-MSH. We propose here that such peptides are promising future candidates for the treatment of cutaneous wounds and skin ulcers. Experimental approaches in silico, in vitro, ex vivo and in animal models are outlined. This is followed by an unbiased discussion of the pro and contra arguments of such peptides as future candidates for the therapeutic management of cutaneous wounds and a review of the so-far available data on melanocortin peptides and derivatives in wound healing.


Comparison of 25-hydroxyvitamin D and metabolic parameters between women with and without polycystic ovarian syndrome.
Background There is increasing evidence that supports the contribution of vitamin D deficiency in metabolic disturbances among women with polycystic ovarian syndrome (PCOS). The aim of this study was to compare 25-hydroxyvitamin D level and the prevalence of metabolic syndrome in the PCOS and normal women. Materials and methods A case-controlled study was conducted in a teaching hospital over a 6-month duration from June 2015 to January 2016. A total of 90 women, who consisted of 45 women with PCOS (study group) and 45 women without PCOS (control group), were recruited. Results The final analysis was of 80 women only and the prevalence of vitamin D deficiency (<20 ng/mL) was high between both groups, i.e. 93.7% but there was no significant difference (p = 0.874). Nevertheless, the prevalence of metabolic syndrome was significantly higher in the study group as compared to the control group (27.5% vs. 5.0%, p = 0.013). There was no statistically significant correlation between vitamin D level with clinical [age, weight, body mass index (BMI), waist and hip circumference, systolic and diastolic blood pressure (SBP and DPB, respectively)] and metabolic parameters (fasting glucose, triglycerides, cholesterol, high-density lipoprotein and low-density lipoprotein) among women with PCOS. However, height was positively correlated (r = 0.338, p = 0.033) and the contrary waist-hip ratio was negatively correlated with vitamin D level (r = -0.605, p = 0.048). Conclusion The prevalence of vitamin D deficiency was high in our study population. Nevertheless, the prevalence of metabolic syndrome was higher among women with PCOS as compared to women without PCOS.


Peripheral optogenetic stimulation induces whisker movement and sensory perception in head-fixed mice.
We discovered that optical stimulation of the mystacial pad in Emx1-Cre;Ai27D transgenic mice induces whisker movements due to activation of ChR2 expressed in muscles controlling retraction and protraction. Using high-speed videography in anesthetized mice, we characterize the amplitude of whisker protractions evoked by varying the intensity, duration, and frequency of optogenetic stimulation. Recordings from primary somatosensory cortex (S1) in anesthetized mice indicated that optogenetic whisker pad stimulation evokes robust yet longer latency responses than mechanical whisker stimulation. In head-fixed mice trained to report optogenetic whisker pad stimulation, psychometric curves showed similar dependence on stimulus duration as evoked whisker movements and S1 activity. Furthermore, optogenetic stimulation of S1 in expert mice was sufficient to substitute for peripheral stimulation. We conclude that whisker protractions evoked by optogenetic activation of whisker pad muscles results in cortical activity and sensory perception, consistent with the coding of evoked whisker movements by reafferent sensory input.


Limbic system involvement in the increase in plasma prolactin following cortical spreading depression in gonadotropin-treated female rats.
Cortical spreading depression (SD) was induced by applying 25% KCl to the frontal cerebral cortex in female rats under continuous ether anesthesia. Three weeks previously the animals had been subjected to sham operation, bilateral surgical "deefferentation" of the amygdala or transection of the dorsal columns of the fornix. During the week prior to experiment the rats were made "pseudopregnant" by treatment with PMS and hCG. Plasma prolactin was measured by radioimmunoassay in blood samples obtained from the peripheral circulation at 20 min intervals. After two control samples had been taken, KCl was applied to the cortex and sampling continued for another 100 min; In the sham-operated group prolactin levels increased with time following the application of KCl. Fornix-cut animals showed a similar, although briefer, increase with values significantly lower than those found in sham-operated animals at 80 min. The increase in plasma prolactin observed in sham-operated and fornix groups was completely abolished in amygdala-cut animals. These results indicate that limbic structures play a significant role in the mechanisms by which cortical SD elevates plasma prolactin levels under the present experimental conditions.


Stability of housekeeping gene expression in the rat retina during exposure to cyclic hyperoxia.
Recent evidence suggests a genetic component to oxygen-induced retinopathy (OIR), a robust experimental model of human retinopathy of prematurity. OIR lends itself well to quantitative analysis of gene expression in rodents with well-defined genetic backgrounds. Such analysis by real-time reverse transcription polymerase chain reaction (RT-PCR) requires the use of reference genes as internal standards for purposes of normalization. We sought to identify housekeeping genes showing stable retinal expression across different rat strains and developmental stages, that were not regulated by oxygen tension. Real-time RT-PCR was used to examine in normal (control) neonatal rat retina the expression of five candidate reference genes: acidic ribosomal phosphoprotein (ARBP), cyclophilin A (CYCA), gamma 2 actin (ACTG2), hypoxanthine guanine phosphoribosyltransferase (HPRT), and RNA polymerase 2 (RNAP2). ACTG2 was poorly expressed, whereas quantification of CYCA was confounded by putative amplification of pseudogenes. Expression of ARBP, HPRT, and RNAP2 was then quantified in dissected retinas from neonatal rats of three inbred strains (Fischer 344, Sprague Dawley, and Dark Agouti) under two different conditions of exposure to inspired oxygen (exposure to room air for 14 days from birth; exposure to cyclic hyperoxia for 14 days from birth). The average variation in relative expression between each pair of these three genes within each of the six cDNA test samples was used to assess stability of gene expression, relative to a standard retinal cDNA pool. The relative expression values for ARBP and HPRT were more closely correlated (r2=0.80) than were those for either gene with RNAP2 (ARBP and RNAP2: r2=0.31; HPRT and RNAP2: r2=0.25). There was little variation among the six experimental groups for the normalized expression of ARBP or HPRT (p>0.05). In contrast, the normalized expression of RNAP2 varied significantly amongst experimental groups: Within each strain, expression was higher in the oxygen-exposed group than in the room air-exposed group (p<0.05). We conclude that ARBP and HPRT exhibit expression that is sufficiently stable under conditions of varying oxygen tension, to permit their use as housekeeping genes in at least one model of OIR in the neonatal rat.


Hormonal screening in impotent patients.
Of a total 260 impotent patients entered in a hormonal study, serum testosterone, prolactin and hormonal abnormalities were detected in 30 (11.5%) patients (18 with hypotestosteronemia and 12 with hyperprolactinemia). The 18 cases of hypotestosteronemia included: 8 cases of hypergonadotropic hypogonadism due to klinefelter's syndrome (1), orchitis (2), chronic alcoholism (1), and idiopathic primary gonadal failure (4) and 10 cases etiologically unknown hypotestosteronemia. Nine of the 18 patients also displayed other organic etiologies (6 vasculogenic and 3 diabetic impotence). After replacement of testosterone propionate by intramuscular injection, the improvement in impotence was significant in 12 patients (excellent in 1, good in 11) and insignificant in 6 (poor in 3, no response in 3). The positive response rate was 89% (8/9) for sole hypotestosteronemia and 44% (4/9) for hypotestosteronemia accompanied by other organic causes of impotence. In the 12 patients with hyperprolactinemia, 4 had prolactinomas. Of these, 3 were treated by surgery and 1 with bromocriptine. Three (excellent in 2, good in 1) of the 4 showed a positive erection response afterwards, but the other patient's response was poor because of postoperative residual tumor. Two patients had drug-induced hyperprolactinemia (haloperidol and methyldopa) and for one, impotence was improved after withdrawal of haloperidol. However, the other responded poorly due to vasculogenic impotence. Six patients with hyperprolactinemia of unknown etiology (2 accompanied by vasculogenic impotence, 2 by diabetic impotence and 2 by sole hyperprolactinemia) were treated with bromocriptine and improvement was noted in 3. The positive response rate was 71.4% (5/7) for sole hyperprolactinemia and 40% (2/5) for hyperprolactinemia accompanied by other organic causes of impotence. Good results were achieved in prolactinoma, sole hyperprolactinemia and hypotestosteronemia.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of ondansetron in preventing postoperative nausea and vomiting under different conditions of general anesthesia: a preliminary, randomized, controlled study.
Two hundred and forty patients were randomly allocated into six groups: Group I, anesthesia was maintained with sevoflurane; Group II, anesthesia was maintained with sevoflurane and 8 mg of ondansetron; Group III, anesthesia was maintained with propofol; Group IV, anesthesia was maintained with propofol and 8 mg of ondansetron; Group V, anesthesia was maintained with sevoflurane and propofol; Group VI, anesthesia was maintained with sevoflurane combined with propofol and 8 mg of ondansetron. We found that the incidence of vomiting was lower in group II (17.5%), group IV (7.5%), and group VI (10%) compared with group I (55%), group III (27.5%), and group V (30%), respectively (P < 0.05). The incidence of vomiting was also lower in group III (27.5%) and group V (30%) when compared with group I (55%) (P < 0.05). The incidence of nausea was 55% in group I, 42.5% in group II, 30% in group III, 27.5% in group IV, 30% in group V, and 30% in group VI. Groups III and V had a lower incidence of nausea than group I (P < 0.05). We conclude that compared with sevoflurane anesthesia alone, anesthesia with either propofol alone or propofol combined with sevoflurane resulted in a reduced incidence of vomiting and nausea during the first 24 h after surgery. Administration of ondansetron effectively reduced the incidence of vomiting but not that of nausea for all three types of general anesthesia.


Brain Network Dynamics Adhere to a Power Law.
The temporal dynamics of complex networks such as the Internet are characterized by a power scaling between the temporal mean and dispersion of signals at each network node. Here we tested the hypothesis that the temporal dynamics of the brain networks are characterized by a similar power law. This realization could be useful to assess the effects of randomness and external modulators on the brain network dynamics. Simulated data using a well-stablished random diffusion model allowed us to predict that the temporal dispersion of the amplitude of low frequency fluctuations (ALFF) and that of the local functional connectivity density (lFCD) scale with their temporal means. We tested this hypothesis in open-access resting-state functional magnetic resonance imaging datasets from 66 healthy subjects. A robust power law emerged from the temporal dynamics of ALFF and lFCD metrics, which was insensitive to the methods used for the computation of the metrics. The scaling exponents (ALFF: 0.8 ± 0.1; lFCD: 1.1 ± 0.1; mean ± SD) decreased with age and varied significantly across brain regions; multimodal cortical areas exhibited lower scaling exponents, consistent with a stronger influence of external inputs, than limbic and subcortical regions, which exhibited higher scaling exponents, consistent with a stronger influence of internal randomness. Findings are consistent with the notion that external inputs govern neuronal communication in the brain and that their relative influence differs between brain regions. Further studies will assess the potential of this metric as biomarker to characterize neuropathology.


Squaramide-tertiary amine catalyzed asymmetric cascade sulfa-Michael/Michael addition via dynamic kinetic resolution: access to highly functionalized chromans with three contiguous stereocenters.
An efficient asymmetric cascade sulfa-Michael/Michael addition reaction catalyzed by a chiral bifunctional squaramide-tertiary amine catalyst has been developed. This organocatalytic cascade reaction provides easy access to highly functionalized chromans with three contiguous stereocenters, including one quaternary center. In addition, a novel cascade sulfa Michael/retro-sulfa-Michael/sulfa-Michael/Michael reaction process, involving dynamic kinetic resolution, is described.


Prostate Cancer Burden at the Uganda Cancer Institute.
In Uganda, the incidence of prostate cancer is increasing at a rate of 5.2% annually. Data describing presentation and outcomes for patients with prostate cancer are lacking. A retrospective review of medical records for men with histologically confirmed prostate cancer at the Uganda Cancer Institute (UCI) from January 1 to December 17, 2012, was performed. Our sample included 182 men whose mean age was 69.5 years (standard deviation, 9.0 years). Patients who presented to the UCI had lower urinary tract symptoms (73%; n = 131), bone pain (18%; n = 32), increased prostate-specific antigen (PSA; 3%; n = 5), and other symptoms (6%; n = 11). Median baseline PSA was 91.3 ng/mL (interquartile range, 19.5-311.3 ng/mL), and 51.1% of the patients (n = 92) had a PSA value above 100 ng/mL. Gleason score was 9 or 10 in 66.7% of the patients (n = 120). Ninety percent (n = 136) had stage IV disease, and metastatic sites included bone (73%; n = 102), viscera (21%; n = 29), and lymph nodes (4%; n = 5). Spinal cord compression occurred in 30.9% (n = 55), and 5.6% (n = 10) experienced a fracture. A total of 14.9% (n = 27) underwent prostatectomy, and 17.7% (n = 32) received radiotherapy. Gonadotropin-releasing hormone agonist was given to 45.3% (n = 82), 29.2% (n = 53) received diethylstilbestrol, and 26% (n = 47) underwent orchiectomy. Chemotherapy was administered to 21.6% (n = 39), and 52.5% (n = 95) received bisphosphonates. During the 12 months of study, 23.8% of the men (n = 43) died, and 54.4% (n = 98) were lost to follow-up. UCI patients commonly present with high PSA, aggressive Gleason scores, and stage IV disease. The primary treatments are hormonal manipulation and chemotherapy. Almost 25% of patients succumb within a year of presentation, and a large number of patients are lost to follow-up.


Orbital Fracture Repair.
Orbital fractures are very common after facial trauma. The assessment of a patient with a suspected orbital wall injury includes a detailed oculofacial examination as well as radiologic imaging. Surgical repair with or without an implant may be indicated for diplopia, enophthalmos, or both. Cicatricial eyelid malposition is an iatrogenic complication commonly due to poor orbitotomy technique. Optimal repair involves direct exposure of the perimeter of the fractures' site through surgical planes that minimally scar the eyelids. A wide variety of implant options exist; however, thin, pliable, nonadherent materials such as nylon foil may offer several advantages. The authors describe the evaluation and management of orbital wall fractures.


Influence of patient head definition on induced E-fields during MR examination.
Radiofrequency (RF) exposure during MR examination is limited by IEC 60601-2-33 to prevent thermal hazards to patients. These limits are also the basis to derive the maximum induced field for the demonstration of MR safety of implants per ISO/TS 10974 (2018). One limit is the head-averaged specific absorption rate (SAR), for which the head extent is defined differently by MR and implant vendors. The purpose of this technical note is to inform MR safety stakeholders on the sensitivity of safety evaluations due to different head extent definitions. RF distributions from the validated MRIxViP exposure libraries of 12 high-resolution human anatomical models were scaled to the normative SAR limits for different definitions of the head extent to compare the corresponding induced SAR and electric (E-)field levels. The definitions of the head extent used by major implant vendors and defined in ISO/TS 10974 (2018) are larger than those introduced in IEC 60601-2-33 (2022), resulting in lower RF head exposure by up to 2.4 dB (factor 1.7). Other proposed definitions of the head result in intermediate values. The different head extents result in different maximum RF exposures affecting the risk assessment by up to a factor of 1.7. The results of this study can be used to estimate the additional uncertainty in safety assessments. Future revisions of MR standards should eliminate this inconsistency.


Cerebral Small Vessel Disease in Population-Based Research: What are We Looking at - and What not?
Cerebral small vessel disease (CSVD) is considered as one of the main causes of cognitive decline and dementia. However, despite extensive research, the pathogenesis of CSVD and the mechanisms through which CSVD leads to its clinical manifestations remain largely unclear. The challenging in vivo quantification of CSVD hampers progress in further unraveling the pathogenesis and pathophysiology of CSVD. Currently, markers of CSVD are mainly brain abnormalities attributed to CSVD, but these are limited in reflecting morphological and functional changes of the microvasculature. We describe aspects of CSVD that are reflected by currently used techniques and those that are still insufficiently captured.


Comparison of multichannel electrogastrograms obtained with the use of three different electrode types.
The goal of the study was to establish if the conductive area size of recording electrodes affects the quality of a multichannel electrogastrogram. In twelve volunteers (9F, 3M, median age 24 years, range 22-28) on three separate days fasted and postprandial four-channel electrogastrograms were registered in randomized order with Red Dot class Ag/AgCl electrodes of a type: ;2222' (conductive area/total area: 2.00/10.24 cm2, ;2271' 2.54/29.64 cm2, or ;2660' 11.64/11.64 cm2 (total surface conductive!), and subsequently analyzed with a dedicated software. In the case of type 2271 and 2660 the between-electrode electrical conductivity improved at the end of the recording relative to the basal measurement, whereas type 2222 yielded a stable between-electrode electrical conductivity throughout the examination. Despite the differences in either the conductive area size or its construction, the analysis of variance on parameters describing quantitatively the multichannel electrogastrogram did not reveal a superiority of any from among the electrodes tested. Type 2271 was, however, rated the less handy among the three electrodes. Multichannel surface electrogastrography seems to be technically feasible with any type of high quality electrodes, therefore small dimensions and easy handling may favor the choice of a particular type for this examination.


Combined supra-infrasellar approach for large pituitary tumors.
A combined supra- infrasellar approach for the resection of very large pituitary tumors is described. We think that it is superior to either the transsphenoidal or the intracranial approaches to these difficult tumors.


Isoform-specific regulation and localization of the coxsackie and adenovirus receptor in human airway epithelia.
Adenovirus is an important respiratory pathogen. Adenovirus fiber from most serotypes co-opts the Coxsackie-Adenovirus Receptor (CAR) to bind and enter cells. However, CAR is a cell adhesion molecule localized on the basolateral membrane of polarized epithelia. Separation from the lumen of the airways by tight junctions renders airway epithelia resistant to inhaled adenovirus infection. Although a role for CAR in viral spread and egress has been established, the mechanism of initial respiratory infection remains controversial. CAR exists in several protein isoforms including two transmembrane isoforms that differ only at the carboxy-terminus (CAR(Ex7) and CAR(Ex8)). We found low-level expression of the CAR(Ex8) isoform in well-differentiated human airway epithelia. Surprisingly, in contrast to CAR(Ex7), CAR(Ex8) localizes to the apical membrane of epithelia where it augments adenovirus infection. Interestingly, despite sharing a similar class of PDZ-binding domain with CAR(Ex7), CAR(Ex8) differentially interacts with PICK1, PSD-95, and MAGI-1b. MAGI-1b appears to stoichiometrically regulate the degradation of CAR(Ex8) providing a potential mechanism for the apical localization of CAR(Ex8) in airway epithelial. In summary, apical localization of CAR(Ex8) may be responsible for initiation of respiratory adenoviral infections and this localization appears to be regulated by interactions with PDZ-domain containing proteins.


A Biofabrication Strategy for a Custom-Shaped, Non-Synthetic Bone Graft Precursor with a Prevascularized Tissue Shell.
Critical-sized defects of irregular bones requiring bone grafting, such as in craniofacial reconstruction, are particularly challenging to repair. With bone-grafting procedures growing in number annually, there is a reciprocal growing interest in bone graft substitutes to meet the demand. Autogenous osteo(myo)cutaneous grafts harvested from a secondary surgical site are the gold standard for reconstruction but are associated with donor-site morbidity and are in limited supply. We developed a bone graft strategy for irregular bone-involved reconstruction that is customizable to defect geometry and patient anatomy, is free of synthetic materials, is cellularized, and has an outer pre-vascularized tissue layer to enhance engraftment and promote osteogenesis. The graft, comprised of bioprinted human-derived demineralized bone matrix blended with native matrix proteins containing human mesenchymal stromal cells and encased in a simple tissue shell containing isolated, human adipose microvessels, ossifies when implanted in rats. Ossification follows robust vascularization within and around the graft, including the formation of a vascular leash, and develops mechanical strength. These results demonstrate an early feasibility animal study of a biofabrication strategy to manufacture a 3D printed patient-matched, osteoconductive, tissue-banked, bone graft without synthetic materials for use in craniofacial reconstruction. The bone fabrication workflow is designed to be performed within the hospital near the Point of Care.


Jehovah's Witness and consent for blood transfusion in a child: The Indian scenario.
In India, the clinical guidelines and laws governing consent for blood transfusion in a minor are meager and vague. In an elective situation, whether the parents can make a decision for the child on his/her behalf or whether the doctor has the right to make the decision in the best interests of the child is not clear. We present the case scenario of a child belonging to Jehovah's Witness denomination diagnosed with Burkitt lymphoma. His parents were in a dilemma whether to opt for blood transfusion or not. In the absence of laws and guidelines in this context, and considering the complications that he developed during the treatment period, it was very challenging for us to manage the situation both medically and medico-legally. This situation highlights the need for framing consensus guidelines/laws regarding elective blood transfusion in a minor to make health-care delivery, smooth, transparent and flawless.


Parasites of domestic and wild animals in South Africa. XLVIII. Ticks (Acari: Ixodidae) infesting domestic cats and wild felids in southern Africa.
Ticks collected from domestic cats (Felis catus), cheetahs (Acinonyx jubatus),caracals (Caracal caracal), African wild cats (Felis lybica), black-footed cats (Felis nigripes), a serval (Leptailurus serval), lions(Panthera leo), and leopards (Panthera pardus) were identified and counted. Thirteen species of ixodid ticks and one argasid tick were identified from domestic cats and 17 species of ixodid ticks from wild felids. The domestic cats and wild felids harboured 11 ixodid species in common. The adults of Haemaphysalis elliptica, the most abundant tick species infesting cats and wild felids, were most numerous on a domestic cat in late winter and in mid-summer, during 2 consecutive years. The recorded geographic distribution of the recently described Haemaphysalis colesbergensis, a parasite of cats and caracals, was extended by 2 new locality records in the Northern Cape Province, South Africa.


Regression models for mixed discrete and continuous responses with potentially missing values.
In this paper a likelihood-based method for analyzing mixed discrete and continuous regression models is proposed. We focus on marginal regression models, that is, models in which the marginal expectation of the response vector is related to covariates by known link functions. The proposed model is based on an extension of the general location model of Olkin and Tate (1961, Annals of Mathematical Statistics 32, 448-465), and can accommodate missing responses. When there are no missing data, our particular choice of parameterization yields maximum likelihood estimates of the marginal mean parameters that are robust to misspecification of the association between the responses. This robustness property does not, in general, hold for the case of incomplete data. There are a number of potential benefits of a multivariate approach over separate analyses of the distinct responses. First, a multivariate analysis can exploit the correlation structure of the response vector to address intrinsically multivariate questions. Second, multivariate test statistics allow for control over the inflation of the type I error that results when separate analyses of the distinct responses are performed without accounting for multiple comparisons. Third, it is generally possible to obtain more precise parameter estimates by accounting for the association between the responses. Finally, separate analyses of the distinct responses may be difficult to interpret when there is nonresponse because different sets of individuals contribute to each analysis. Furthermore, separate analyses can introduce bias when the missing responses are missing at random (MAR). A multivariate analysis can circumvent both of these problems. The proposed methods are applied to two biomedical datasets.


Speech-language profiles in the context of cognitive and adaptive functioning in SATB2-associated syndrome.
SATB2-associated syndrome (SAS) is a neurodevelopmental disorder caused by heterozygous pathogenic variants in the SATB2 gene, and is typically characterized by intellectual disability and severely impaired communication skills. The goal of this study was to contribute to the understanding of speech and language impairments in SAS, in the context of general developmental skills and cognitive and adaptive functioning. We performed detailed oral motor, speech and language profiling in combination with neuropsychological assessments in 23 individuals with a molecularly confirmed SAS diagnosis: 11 primarily verbal individuals and 12 primarily nonverbal individuals, independent of their ages. All individuals had severe receptive language delays. For all verbal individuals, we were able to define underlying speech conditions. While childhood apraxia of speech was most prevalent, oral motor problems appeared frequent as well and were more present in the nonverbal group than in the verbal group. For seven individuals, age-appropriate Wechsler indices could be derived, showing that the level of intellectual functioning of these individuals varied from moderate-mild ID to mild ID-borderline intellectual functioning. Assessments of adaptive functioning with the Vineland Screener showed relatively high scores on the domain "daily functioning" and relatively low scores on the domain "communication" in most individuals. Altogether, this study provides a detailed delineation of oral motor, speech and language skills and neuropsychological functioning in individuals with SAS, and can provide families and caregivers with information to guide diagnosis, management and treatment approaches.


Impact of Diet, Body Mass Index, and Physical Activity on Cancer Survival.
With the increase in the number of cancer patients worldwide in the coming years, the need for knowledge on the influence of lifestyle factors on cancer survival is increasing. In this paper, the current knowledge on diet, body mass index, and physical activity in relation to cancer outcome is summarized. Also, challenges are identified to be addressed to provide evidence-based recommendations for cancer patients. Studies in patients with breast, colorectal, or prostate cancer show that the influence of dietary factors on survival remains to be determined. Adiposity and a lack of physical activity, however, appear to influence cancer outcome negatively. Subsequent studies should focus on more detailed aspects of these lifestyle factors, such as body composition and dose of exercise, and on the timing with respect to diagnosis and treatment. Research should be directed toward investigating diet and physical activity simultaneously and on how changes in health behavior can be established.