Correlation of clot imaging with endovascular recanalization in internal carotid artery terminus occlusion.
In a swine stroke model we have previously demonstrated a high-intensity fluid attenuated inversion recovery (FLAIR) signal representing the erythrocyte component of the clot. We hypothesized that the intensity of the FLAIR clot signal in patients with acute stroke may predict the efficacy of recanalization by thrombectomy devices. In this study we compared the pretreatment FLAIR signal intensity of the clots in the distal internal carotid artery (ICA) and the degree of angiographic recanalization rate after mechanical thrombectomy. 25 consecutive acute stroke patients with ICA terminus (ICA-T) occlusion diagnosed with MRI at the UCLA Medical Center between 2002 and 2013 were retrospectively reviewed. The intensity of the FLAIR clot signal at the distal ICA was blindly compared with the angiographic recanalization status (successful recanalization defined as Thrombolysis In Cerebral Infarction (TICI) score of 2b-3) and non-successful recanalization as TICI score 0-2a) after endovascular treatment. Multivariate logistic regression analysis for successful recanalization was performed. Successful recanalization was achieved in 40% of patients (10/25) and showed a significantly higher FLAIR intensity (p=0.014). The cut-off value for clot intensity on the FLAIR sequence to predict recanalization was 0.7952, with 70% sensitivity and 80% specificity (95% CI 0.59 to 0.96) using a receiver operating characteristic curve. In multivariate logistic regression analysis, only a high FLAIR clot intensity (>0.7952) was associated with successful recanalization (OR 16.79; 95% CI 1.29 to 218.92; p=0.031). High signal intensity on FLAIR clot imaging may predict successful recanalization after endovascular therapy for ICA-T occlusion.


Adjudicative Competence in the Context of a Defendant's Absence from Trial after a Suicide Attempt.
Defendants who are facing criminal charges in the United States have a constitutional right to be present at trial. This right can be voluntarily waived; for such a waiver to be valid, the defendant must be competent to waive the right to be present at trial. There have been several cases where a defendant is absent from trial because of a suicide attempt, and in these cases the courts must determine whether it is necessary to pause the criminal trial to allow for a competence hearing to take place. The U.S. Supreme Court offered guidance on this matter in its ruling in Drope v. Missouri; however, the Court did not clearly define the threshold for requiring a competence hearing when defendants attempt suicide during trial. Subsequent judicial rulings have provided insights into how courts might proceed when a criminal defendant is absent from trial following a suicide attempt. This topic has relevance to forensic psychiatry, as forensic psychiatrists may be called upon to participate in evaluations of adjudicative competence in these scenarios.


Assessment of Knowledge and Awareness Regarding Oro-systemic Link among General Population: A Cross-sectional Survey.
Various surveys aimed at gathering the knowledge and awareness of health practitioners as well as students, both medical and dental, regarding the link between oral health and systemic diseases have been published. However, relatively few studies have attempted to examine the awareness of such knowledge among the general population. Therefore, the current study aimed to explore the public perception regarding the oro-systemic link. The present study was designed as a cross-sectional survey to be carried out in the Department of Periodontology and Oral Implantology, PGIDS, Rohtak. All survey participants were provided with a written questionnaire which was required to be completed by each participant independently. The study questionnaire was designed to collect demographic data followed by specific questions targeting the awareness and knowledge of the participants regarding the relationship between oral and systemic health. A total of 240 completed questionnaires were available for analysis. Only about a quarter of the total participants (27.5 %) believed that oral health status has any effect on the rest of the body. A positive response (YES) of 25% was observed for effect of diabetes and physician prescribed medicines on systemic health. Regarding the effect of pregnancy, smoking, stress, and obesity on systemic health, less than 20% positive response was recorded. The findings indicate a very poor awareness regarding the impact of systemic conditions on oral status and vice versa, among the studied population. Pedodontists should lay emphasis on imparting knowledge about oro-systemic connections to their patients as well accompanying guardians. This would go a long way in spreading much needed awareness among the general population as well as ensuring that children adopt healthy lifestyle habits right from childhood. Sangwan A, Sangwan P, Kaur M, et al. Assessment of Knowledge and Awareness Regarding Oro-systemic Link among General Population: A Cross-sectional Survey. Int J Clin Pediatr Dent 2023;16(S-2):S202-S205.


Personal growth initiative and posttraumatic stress among survivors of transportation accidents: Mixture modeling indicating changes in group membership over time.
The current study explored subgroups in reported personal growth initiative (PGI) and posttraumatic stress symptoms (PTSS) and examined the changes in class memberships among survivors of a transportation accident. Participants at Time 1 were 602 adults who reported directly experiencing a transportation accident within the past year (Mmonths = 6.36; SDmonths = 3.20). Of these participants, 171 adults completed the follow-up survey after 3 months (Time 2). Finite mixture modeling was conducted to identify the heterogeneity of PTSS in relation with PGI at each time point. At Time 1, a four-class model was the best-fitting model, and at Time 2, a three-class model was the best-fitting model. As hypothesized, when examined cross-sectionally, various subgroups were identified at each time point, finding subgroups with moderate to high levels of PGI but differing in their PTSS. However, when examining the longitudinal changes in class membership from Time 1 to Time 2, members of subgroups with higher PGI skills at Time 1 were more likely to be assigned to subgroups with lower PTSS at Time 2. The current study suggests a potential application of PGI skills in alleviating PTSS after a transportation accident and having a critical role in adjustment after hardship.


Microbial Diversity and Antibiotic Susceptibility Pattern of Bacteria Associated with Motorcycle Helmets.
Motorcycle helmets can serve as a potential vehicle for the transmission of pathogenic bacteria and fungi with serious health implications. The main aim of this study was to explore the microbial diversity associated with the motorcycle helmets and determine the antibiotic susceptibility profile of the bacterial isolates. A descriptive cross-sectional study was carried out among the teaching staffs of Birendra Multiple Campus, Bharatpur, Nepal. A total of 130 motorcycle helmets worn by the teaching staffs of the Birendra Multiple Campus, Bharatpur, were included in the study for microbiological investigations. Of the total 130 motorcycle helmets analyzed, 392 bacteria and 346 fungi belonging to seven different genera were recovered. Staphylococcus aureus 89 (22.7%) was the predominant bacteria followed by S. epidermidis 77 (19.6%) and E. coli 54 (13.8%), whereas Aspergillus niger 67 (19.4%) was the predominant fungi followed by A. fumigatus 49 (14.2%). Antibiotic susceptibility test was performed by the disc diffusion method for all the bacterial isolates. Tetracycline, gentamycin, and cotrimoxazole were the most effective antibiotics for Gram-positive isolates, whereas Gram-negative isolates were sensitive towards imipenem and ciprofloxacin. Of the total bacterial isolates, 153 (39.0%) were multidrug-resistant (MDR), 10.4% were extended-spectrum beta-lactamase (ESBL) producers, and 4.3% were metallo-beta-lactamase (MBL) producers and, out of 89 isolates of Staphylococcus aureus, 30 (33.7%) were detected as methicillin-resistant Staphylococcus aureus (MRSA). The findings suggest that motorcycle riders should follow good hygiene practices and regularly clean their helmets with suitable sterilants to avoid the risk of microbial contamination and reduce the associated risks.


Effects of stereo-regularity on the single-chain mechanics of polylactic acid and its implications on the physical properties of bulk materials.
The material properties of polylactic acid (PLA) are largely determined by its stereo-regularity (tacticity). To find out the origin at the molecular level, the single-chain mechanics of poly-l-lactic acid (PLLA) and poly-d,l-lactide (PDLLA) were comparatively investigated by single-molecule atomic force microscopy (AFM). At a low concentration, PLLA adopted a random-coil conformation in a good solvent. At a high concentration, however, the PLLA chain can be induced into a helix, which consumed additional energy during unfolding by further stretching. Due to the random arrangement of l- and d-repeating units in the PDLLA chain, PDLLA adopts a random-coil conformation at all concentrations. The difference in single-chain mechanics of PLLA and PDLLA at high concentrations may be the cause of their different macroscopic properties. This is the first report to reveal the stereo-regularity-dependent mechanics of a polymer at the single-molecule level, which may help to bridge the gap between understanding single-molecule and materials properties.


Micromodular implants to provide electrical stimulation of paralyzed muscles and limbs.
We describe the design, fabrication, and output capabilities of a microminiature electrical stimulator that can be injected in or near nerves and muscles. Each single-channel microstimulator consists of a cylindrical glass capsule with hermetically sealed electrodes in either end (2-mm diameter x 13-mm overall length). Power and digital control data can be transmitted to multiple implants (256 unique addresses) via a 2-MHz RF field created by an external AM oscillator and inductive coil. In vitro testing demonstrated accurate control of output pulsewidth (3-258 microseconds in 1-microseconds steps) and current (0-30 mA in two linear ranges of 16 steps each, up to 8.5 V available compliance voltage). Microstimulators were used successfully for chronic stimulation in hindlimb muscles of cats. Design and fabrication issues affecting yield and reliability of the packaging and electronics are discussed.


Inconsistent sodium current records derived on Ranvier nodes with a commercially available potential clamp device according to Nonner.
We tried to reproduce some basic implications of the Hodgkin-Huxley-Frankenhaeuser formalism by measuring sodium currents in single myelinated nerve fibres with a commercially available version of the potential clamp device according to Nonner. The following contradictory observations were made: 1. The potential dependence of the time to peak sodium currents showed a discontinuity around the sodium equilibrium potential. 2. Defining the sodium permeability PNa by the constant field equation and fitting the peak PNa-voltage relation by a sigmoid function we obtained unbelievable high values of PNa at rest. 3. Testing PNa as calculated by the constant field equation by so-called "sodium tail current" experiments we obtained instantaneous changes of PNa. Summing up, neither the kinetics of sodium currents nor the constant field concept as tested with the equipment used seem to agree satisfactorily with the standard data of sodium currents in Ranvier nodes.


OnTARi: an ontology for factors influencing therapy adherence to rehabilitation.
Adherence and motivation are key factors for successful treatment of patients with chronic diseases, especially in long-term care processes like rehabilitation. However, only a few patients achieve good treatment adherence. The causes are manifold. Adherence-influencing factors vary depending on indications, therapies, and individuals. Positive and negative effects are rarely confirmed or even contradictory. An ontology seems to be convenient to represent existing knowledge in this domain and to make it available for information retrieval. First, a manual data extraction of current knowledge in the domain of treatment adherence in rehabilitation was conducted. Data was retrieved from various sources, including basic literature, scientific publications, and health behavior models. Second, all adherence and motivation factors identified were formalized according to the ontology development methodology METHONTOLOGY. This comprises the specification, conceptualization, formalization, and implementation of the ontology "Ontology for factors influencing therapy adherence to rehabilitation" (OnTARi) in Protégé. A taxonomy-oriented evaluation was conducted by two domain experts. OnTARi includes 281 classes implemented in ontology web language, ten object properties, 22 data properties, 1440 logical axioms, 244 individuals, and 1023 annotations. Six higher-level classes are differentiated: (1) Adherence, (2) AdherenceFactors, (3) AdherenceFactorCategory, (4) Rehabilitation, (5) RehabilitationForm, and (6) RehabilitationType. By means of the class AdherenceFactors 227 adherence factors, thereof 49 hard factors, are represented. Each factor involves a proper description, synonyms, possibly existing acronyms, and a German translation. OnTARi illustrates links between adherence factors through 160 influences-relations. Description logic queries implemented in Protégé allow multiple targeted requests, e.g., for the extraction of adherence factors in a specific rehabilitation area. With OnTARi, a generic reference model was built to represent potential adherence and motivation factors and their interrelations in rehabilitation of patients with chronic diseases. In terms of information retrieval, this formalization can serve as a basis for implementation and adaptation of conventional rehabilitative measures, taking into account (patient-specific) adherence factors. OnTARi also enables the development of medical assistance systems to increase motivation and adherence in rehabilitation processes.


Analysis of prognostic factors for the indication of central lymphadenectomy in papillary thyroid carcinomas.
In this study we examined whether it was possible following preoperative parameters statistically significant correlation with the presence of metastatic lymph nodes in the papillary thyroid carcinoma. We conducted a retrospective study in a group of patients with a preoperative diagnosis of papillary carcinoma who underwent total thyroidectomy associated with routine lymphadenectomy of the central compartment (level VI). The study group consisted of patients whose definitive histological lymph node examination was positive for metastasis (N1), and the control group comprised patients found negative for metastasis (N0). Tumour diameter had a significance at 10% level [Pr(>|z|): 0.056], thus indicating that increased tumour size results in a higher probability of being in group N1. The logistic regression revealed that variables with a significance at 5% level for the presence of metastatic lymph nodes in the central compartment (N1) were: sex [Pr(>|z|): 0.019], overall patient age [Pr(>|z|): 0.012] and age >45 [Pr(>|z|): 0.022]. We performed a statistical analysis with the association of three preoperative variables (presence of ultrasound-revealed microcalcifications, presence of solid hypoechogenic nodule and type III vascularisation on echocolour-Doppler); this was found to result in a highly significant probability of entering into group N1. We found variables statistically significant for the presence of metastatic central compartment lymph nodes, including female sex, age >45 yrs and tumour diameter >1.5 cm. The association of papillary carcinoma with microcalcifications, solid hypoechogenic nodule structure and type III vascularisation on echocolour-Doppler also resulted in a statistically significant increase in the probability of positive level VI lymph nodes.


Measurement of HVL on Fluoroscopy Units.
The total filtration of a fluoroscopy x-ray tube assembly may be deduced from the half value layer (HVL) of the x-ray beam at a specified tube voltage using published data tables. The HVL is usually measured by placing increasing thicknesses of Al plates between the focus and a dosimeter, and measuring the output while keeping the kV constant. However, on many of the newer fluoroscopy units, it is not possible to set the tube potential manually. This can create difficulties when measuring the HVL since the increasing thicknesses of aluminum trigger the automatic brightness control to adjust the kV and mA automatically, thus altering the tube output and HVL. This communication describes a simple but effective method to measure the amount of filtration on such units, which has the advantage of not requiring any extra equipment.


Na+ transport properties of isolated rat parotid acini.
The effect of carbachol stimulation on the Na+ transport properties of rat parotid acini was characterized. Upon stimulation, the acinar Na+ concentration increased from 20 to 70 mM within 25 s, whereafter a backregulation toward the prestimulatory level was observed, mediated by the Na(+)-K+ pump. The transport mechanisms responsible for the net Na+ uptake observed between 10 and 20 s after carbachol stimulation in a Krebs-Ringer-bicarbonate medium (KRB) consisted of a dimethylamiloride-sensitive Na(+)-H+ exchange system (3.5 mmol.liter cell water-1.s-1 or approximately 75% of the total Na+ influx) and a bumetanide-sensitive cotransport system (of approximately 15%). The data are consistent with the residual influx being mediated by amiloride-sensitive Na+ channels. In unstimulated acini acidified by a NH4+ prepulse technique, the relationship between intracellular pH (pHi) and the rate of acinar Na(+)-H+ exchange was determined. At pHi 6.5 the rate of Na(+)-H+ exchange in a KRB medium amounted to 1.2 mmol.liter cell water-1.s-1 and ceased when pHi had recovered to 7.2. It was concluded that under physiological conditions carbachol stimulation activates Na(+)-H+ exchange, an effect that is responsible for the major part of the Na+ gain after stimulation. The role of cotransport in mediating net Cl- uptake against an electrochemical gradient was investigated. It was found that when the Na+ gradient is strongly reduced (in a 20 mM Na+ medium) a Cl(-)-HCO3- exchange system can mediate a net Cl- uptake at a rate similar to the rate observed in a medium containing high Na+. The results are compatible with both Cl(-)-HCO3- exchange and cotransport keeping an intracellular Cl- concentration above the electrochemical equilibrium under physiological conditions.


Postremission chemotherapy for adults with acute myelogenous leukemia: improved survival with high-dose cytarabine and daunorubicin consolidation treatment.
Results of postremission chemotherapy for adults with acute myelogenous leukemia (AML) were assessed in two sequential prospective studies involving similar induction therapy and two courses of intensive consolidation treatment. Fifty-six patients achieving remission on the acute leukemia protocol (ALP3) study received high-dose cytarabine and daunorubicin as course one and standard-dose cytarabine and daunorubicin as course two. Results are compared with forty-six patients achieving remission on the ALP2 study who received azacitidine and doxorubicin as consolidation course one and standard-dose cytarabine, daunorubicin, and thioguanine as course two. The ALP3 regimen resulted in a significantly improved 5-year disease-free survival of 32% +/- 19% versus 20% +/- 11% for the ALP2 study (P = .03). Survival from remission was also improved, 40% +/- 14% versus 24% +/- 12% (P less than .01). Favorable prognostic factors for disease-free survival included receiving the ALP3 treatment regimen, absence of a prior preleukemic syndrome, and female sex. These factors and younger patient age were significant for survival following first chemotherapy and survival after achieving remission. Six of 34 patients who relapsed after receiving the ALP3 regimen successfully achieved prolonged second remissions with high-dose cytarabine-based chemotherapy and/or allogeneic bone marrow transplantation (BMT). Overall survival for adults less than or equal to 45 years of age was 58% +/- 19% with the ALP3 postremission chemotherapy regimen, comparable to most studies of BMT for AML in first remission. Actuarial 5-year survival for ALP3 patients greater than 60 years of age was 18% +/- 20% with no improvement compared with ALP2.


Extending resection and preserving function: modern concepts of glioma surgery.
Recent studies have demonstrated that the improved prognosis derived from resection of gliomas largely depends on the extent and quality of the resection, making maximum but safe resection the ultimate goal. Simultaneously, technical innovations and refined neurosurgical methods have rapidly improved efficacy and safety. Because gliomas derive from intrinsic brain cells, they often cannot be visually distinguished from the surrounding brain tissue during surgery. In order to appreciate the full extent of their solid compartment, various technologies have recently been introduced. However, radical resection of infiltrative glioma puts neurological function at risk, with potential detrimental consequences for patients' survival and quality of life. The allocation of various neurological functions within the brain varies in each patient and may undergo additional changes in the presence of a tumour (brain plasticity), making intra-operative localisation of eloquent areas mandatory for preservation of essential brain functions. Combining methods that visually distinguish tumour tissue and detect tissues responsible for critical functions now enables resection of tumours in brain regions that were previously considered off-limits, and benefits patients by enabling a more radical resection, while simultaneously lowering the risk of neurological deficits. Here we review recent and expected developments in microsurgery for glioma and their respective benefits.


Observation of CP violation in K(L)-->pi(+)pi(-)e(+)e(-) decays
We report the first observation of a manifestly CP violating effect in the K(L)-->pi(+)pi(-)e(+)e(-) decay mode. A large asymmetry was observed in the distribution of these decays in the CP-odd and T-odd angle straight phi between the decay planes of the e(+)e(-) and pi(+)pi(-) pairs in the K(L) center of mass system. After acceptance corrections, the overall asymmetry is found to be [13.6+/-2. 5(stat)+/-1.2(syst)]%. This is the largest CP-violating effect yet observed when integrating over the entire phase space of a mode and the first such effect observed in an angular variable.


Assessment of the ovarian reserve with anti-Müllerian hormone in women who underwent allogeneic hematopoietic stem cell transplantation using reduced-intensity conditioning regimens or myeloablative regimens with ovarian shielding.
Conditioning regimens that include cyclophosphamide (CY) and total body irradiation (TBI) induce severe gonadal toxicity and permanent infertility in approximately 90 % of female patients who undergo hematopoietic stem cell transplantation (HSCT). However, the use of ovarian shielding or non-myeloablative regimens may preserve ovarian function. To evaluate the ovarian reserve, serum anti-Müllerian hormone (AMH) levels were retrospectively measured in 11 female HSCT recipients aged less than 40 years, including seven with acute leukemia (AL) and four with aplastic anemia (AA), who received a myeloablative conditioning regimen with ovarian shielding or a reduced-intensity conditioning regimen. In most patients, menstruation had stopped and AMH level had decreased to an undetectable level (<0.1 ng/ml) after HSCT. Most patients showed a recovery of regular menstruation, but AMH levels did not increase immediately after the resumption of menstruation. However, in three AL patients and two AA patients who were evaluable for long-term recovery, AMH level increased gradually beyond 1 year after HSCT. In conclusion, recovery of the serum AMH level may be delayed after HSCT, and the AMH level early after HSCT may not accurately reflect ovarian reserve. A prospective study is required to address the usefulness of measuring the AMH level in HSCT recipients.


BDNF overexpression prevents cognitive deficit elicited by adolescent cannabis exposure and host susceptibility interaction.
Cannabis abuse in adolescence is associated with increased risk of psychotic disorders. Δ-9-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. Disrupted-In-Schizophrenia-1 (DISC1) protein is a driver for major mental illness by influencing neurodevelopmental processes. Here, utilizing a unique mouse model based on host (DISC1) X environment (THC administration) interaction, we aimed at studying the pathobiological basis through which THC exposure elicits psychiatric manifestations. Wild-Type and dominant-negative-DISC1 (DN-DISC1) mice were injected with THC (10 mg/kg) or vehicle for 10 days during mid-adolescence-equivalent period. Behavioral tests were conducted to assess exploratory activity (open field test, light-dark box test) and cognitive function (novel object recognition test). Electrophysiological effect of THC was evaluated using acute hippocampal slices, and hippocampal cannabinoid receptor type 1 and brain-derived neurotrophic factor (BDNF) protein levels were measured. Our results indicate that THC exposure elicits deficits in exploratory activity and recognition memory, together with reduced short-term synaptic facilitation and loss of BDNF surge in the hippocampus of DN-DISC mice, but not in wild-type mice. Over-expression of BDNF in the hippocampus of THC-treated DN-DISC1 mice prevented the impairment in recognition memory. The results of this study imply that induction of BDNF following adolescence THC exposure may serve as a homeostatic response geared to maintain proper cognitive function against exogenous insult. The BDNF surge in response to THC is perturbed in the presence of mutant DISC1, suggesting DISC1 may be a useful probe to identify biological cascades involved in the neurochemical, electrophysiological, and behavioral effects of cannabis related psychiatric manifestations.


Synaptic Involvement of the Human Amygdala in Parkinson's Disease.
α-Synuclein, a protein mostly present in presynaptic terminals, accumulates neuropathologically in Parkinson's disease in a 6-stage sequence and propagates in the nervous system in a prion-like manner through neurons and glia. In stage 3, the substantia nigra are affected, provoking motor symptoms and the amygdaloid complex, leading to different nonmotor symptoms; from here, synucleinopathy spreads to the temporal cortex and beyond. The expected increase in Parkinson's disease incidence accelerates the need for detection biomarkers; however, the heterogeneity of this disease, including pathological aggregates and pathophysiological pathways, poses a challenge in the search for new therapeutic targets and biomarkers. Proteomic analyses are lacking, and the literature regarding synucleinopathy, neural and glial involvement, and volume of the human amygdaloid complex is controversial. Therefore, the present study combines both proteomic and stereological probes. Data-independent acquisition-parallel accumulation of serial fragmentation proteomic analysis revealed a remarkable proteomic impact, especially at the synaptic level in the human amygdaloid complex in Parkinson's disease. Among the 199 differentially expressed proteins, guanine nucleotide-binding protein G(i) subunit alpha-1 (GNAI1), elongation factor 1-alpha 1 (EEF1A1), myelin proteolipid protein (PLP1), neuroplastin (NPTN), 14-3-3 protein eta (YWHAH), gene associated with retinoic and interferon-induced mortality 19 protein (GRIM19), and orosomucoid-2 (ORM2) stand out as potential biomarkers in Parkinson's disease. Stereological analysis, however, did not reveal alterations regarding synucleinopathy, neural or glial populations, or volume changes. To our knowledge, this is the first proteomic study of the human amygdaloid complex in Parkinson's disease, and it identified possible biomarkers of the disease. Lewy pathology could not be sufficient to cause neurodegeneration or alteration of microglial and astroglial populations in the human amygdaloid complex in Parkinson's disease. Nevertheless, damage at the proteomic level is manifest, showing up significant synaptic involvement.


Emergence of physiological oscillation frequencies in a computer model of neocortex.
Coordination of neocortical oscillations has been hypothesized to underlie the "binding" essential to cognitive function. However, the mechanisms that generate neocortical oscillations in physiological frequency bands remain unknown. We hypothesized that interlaminar relations in neocortex would provide multiple intermediate loops that would play particular roles in generating oscillations, adding different dynamics to the network. We simulated networks from sensory neocortex using nine columns of event-driven rule-based neurons wired according to anatomical data and driven with random white-noise synaptic inputs. We tuned the network to achieve realistic cell firing rates and to avoid population spikes. A physiological frequency spectrum appeared as an emergent property, displaying dominant frequencies that were not present in the inputs or in the intrinsic or activated frequencies of any of the cell groups. We monitored spectral changes while using minimal dynamical perturbation as a methodology through gradual introduction of hubs into individual layers. We found that hubs in layer 2/3 excitatory cells had the greatest influence on overall network activity, suggesting that this subpopulation was a primary generator of theta/beta strength in the network. Similarly, layer 2/3 interneurons appeared largely responsible for gamma activation through preferential attenuation of the rest of the spectrum. The network showed evidence of frequency homeostasis: increased activation of supragranular layers increased firing rates in the network without altering the spectral profile, and alteration in synaptic delays did not significantly shift spectral peaks. Direct comparison of the power spectra with experimentally recorded local field potentials from prefrontal cortex of awake rat showed substantial similarities, including comparable patterns of cross-frequency coupling.


A temperature-sensitive Krp1 allows in vivo characterization of kexin activation.
Members of the kexin family of processing enzymes are responsible for the cleavage of many proproteins during their transport through the secretory pathway. The enzymes are themselves made as inactive precursors and we have investigated the activation of Krp1, a kexin from the fission yeast Schizosaccharomyces pombe. As Krp1 is essential for cell growth, we have used a krp1ts strain to investigate the role of the prosequence in the activation process. Mutations that reduce either the efficiency with which the prosequence is released or the rate at which the released prosegment is subsequently cleaved at an internal site are less active when assayed in vivo. We also show that prosegments lacking an internal dibasic motif can act as autoinhibitors and prevent activation of the catalytic fragment. Krp1 constructs containing prosequences based on these inhibitors do not become active in vitro. Surprisingly, the same constructs do become active in the intact cell and appear to suggest that alternative activation processes can be used by these enzymes.


Population-based cohort study assessing the efficacy of cervical cytology (Pap smear) and human papillomavirus (HPV) testing as modalities for cervical cancer screening.
In cervical cancer screening, several trials have shown that human papillomavirus (HPV) testing or combined HPV testing and cytology leads to earlier detection of cervical intraepithelial neoplasia Grade 3 or worse (CIN3+) compared with cytology alone. However, the availability of similar evidence in our country remains limited. In 2013, 34 local governments were selected to administer a cervical cancer screening program utilizing either cytology alone or in combination with HPV testing. We planned a cohort study to assess the effectiveness of HPV testing as a modality for cervical cancer screening. The primary outcome of this study was the incidence of CIN3+ in each group, as well as to assess the risks and benefits of receiving screening for women in both groups. These results will contribute to elucidating the details of the positive and negative impacts of introducing HPV testing into a population-based cervical cancer screening program in Japan.


Ciclosporin-induced accessory breast tissue: Dramatic improvement after dose adjustment.
Accessory breast tissue is a relatively common congenital condition in which abnormal accessory breast tissue is seen as a mass anywhere along the course of embryologic mammary streak in addition to the presence of normal breast tissue. Ciclosporin therapy has been associated with benign breast disease in women. However, to the best of our knowledge, there are no reported cases of accessory breast tissue growth associated with ciclosporin therapy and regression after adjusting the dose. A 48-year-old woman had renal transplantation in 2009 with her brother as the donor. Her transplant follow-up over eight years had been unremarkable. She presented to our transplant follow-up clinic with bilateral painful axillary masses approximately 3 cm × 3 cm in diameter, not attached to the skin or underlying structures with no skin changes and no lymphadenopathy. Breast examination did not reveal any abnormalities. Her ciclosporin levels over the previous three years ranged between 130 and 150 ng/mL. These levels were within the acceptable recommended level of 100-150 ng/mL at that time (currently reduced to 80-120 ng/ml). Ultrasound of both axilla showed well-defined hypoechoic smooth outline masses in both axillary regions 3 cm × 4 cm. Fine-needle aspiration showed lesions consisting of cohesive ductal cells. The findings were consistent with accessory breast tissue with no evidence of inflammatory infiltrate or malignant changes. Her ciclosporin dose was reduced with the subsequent follow-up visits levels ranging between 90 and 110 ng/mL. Clinical examination four months later showed dramatic reduction in the axillary masses on both sides. Ultrasound confirmed the regression in the size of both masses. We conclude that ciclosporin was probably responsible for the formation of accessory breast tissue and reduction in the dose of ciclosporin resulted in substantial reduction in the tissue size.


Possible method of identifying spotter practices in a health board in Northern Ireland.
We examined the notification of infectious diseases, including measles, by general practitioners over 18 months, which included a measles epidemic in the area covered by the Southern Health and Social Services Board in Northern Ireland. Of the 156 general practitioners who provided services in the area, 27 (17.3%) had a pattern of notification which might render them acceptable as "spotter" practices, a system which at present does not exist in Northern Ireland, although it is used in the rest of the United Kingdom. In future we hope to be able to; (i) predict impending epidemics of infectious disease; (ii) mobilise Health Service resources to minimise the effects of such epidemics; (iii) monitor the effects of improving the level of uptake of measles vaccine.


Effects of interadsorbate interactions on surface resistivity: oxygen on sulfur-predosed Cu(100).
Measurements of surface resistivity as a function of coverage for oxygen adsorbed on sulfur-predosed Cu(100) films reveal two types of interactions between sulfur and oxygen: S-O repulsion and short-range suppression of the surface resistivity change induced by oxygen adsorption. The repulsive interaction causes oxygen atoms to first occupy adsorption sites far from the sulfur atoms, beyond second-nearest-neighbor sites, where the oxygen-induced surface resistivity is unaffected by sulfur. As a result the low-coverage variation of surface resistivity with oxygen coverage is indistinguishable from the linear dependence observed for oxygen on clean Cu(100). As the oxygen coverage increases, oxygen begins to occupy sites close to sulfur. At the nearest-neighbor sites, the resistivity change due to added oxygen is completely suppressed, and the sample resistance levels off, remaining unchanged even as oxygen continues to adsorb. This resistivity suppression may involve both a reduction of oxygen's direct effect on the resistivity and an oxygen-induced reduction in the resistivity due to the already adsorbed sulfur. With increasing sulfur precoverage both the maximum resistivity change and the oxygen coverage at which the leveling occurs decrease, because the number of sites unaffected by sulfur is reduced. Both the sulfur-oxygen repulsion and the resistivity suppression presumably arise from a through-metal coupling involving adsorbate-induced modifications of the local electronic structure.


Effects of grab bar on utilized friction and dynamic stability when elderly people enter the bathtub.
The effect of the grab bar on dynamic stability when elderly people enter the bathtub remains unclear. The purpose of the present study is to examine the age-related effect of the grab bar on dynamic stability during lateral stepping over an obstacle when entering bathtub. Sixteen young, healthy adults and sixteen elderly adults participated. The subjects performed lateral stepping over an obstacle with and without vertical and horizontal bars. Displacement and velocity of the center of mass and utilized friction, which is the required coefficient of friction to avoid slipping, were simultaneously measured by a three-dimensional motion analysis system and two force plates. A post hoc test for two-way ANOVA revealed that velocity of the center of mass in the vertical direction (p<0.05) and peak-to-peak values of the center of mass in the lateral (p<0.05) and vertical directions (p<0.05) with each grab bar were significantly slower and smaller than those without the grab bar in young and elderly people. Moreover, the utilized friction at push off of the trailing leg with the vertical bar in elderly people was lower (p<0.05) than that in participants without the grab bar. The use of each grab bar while performing a lateral step over an obstacle may help maintaining balance in lateral and vertical directions. However, use of the vertical bar while lateral stepping over an object in elderly people may need low utilized friction to prevent slipping.


Can transcriptomics provide insight into the chemopreventive mechanisms of complex mixtures of phytochemicals in humans?
Blueberries contain relatively large amounts of different phytochemicals, which are suggested to have chemopreventive properties, but little information is available on the underlying molecular modes of action. This study investigates whole genome gene expression changes in lymphocytes of 143 humans after a 4-week blueberry-apple juice dietary intervention. Differentially expressed genes and genes correlating with the extent of antioxidant protection were identified in four subgroups. The magnitude of the preventive effect after the intervention differed between these four subgroups. Furthermore, subjects in two groups carried genetic polymorphisms that were previously found to influence the chemopreventive response. Pathway analysis of the identified genes showed strong but complex gene expression changes in pathways signaling for apoptosis, immune response, cell adhesion, and lipid metabolism. These pathways indicate increased apoptosis, upgraded growth control, induced immunity, reduced platelet aggregation and activation, blood glucose homeostasis, and regulation of fatty acid metabolism. Based on these observations, we hypothesize that combining transcriptomic data with phenotypic markers of oxidative stress may provide insight into the relevant cellular processes and genetic pathways, which contribute to the antioxidant response of complex mixtures of phytochemicals, such as found in blueberry-apple juice.


Acute Hepatopathy in a Dog Secondary to Hypothyroidism-Induced Atherosclerotic Infarction and Necrosis.
A 7 yr old male beagle was examined because of lethargy, anorexia, and cranial abdominal discomfort. Significant clinicopathologic abnormalities included severe liver enzyme elevations and hypercholesterolemia. Abdominal imaging identified vascular compromise of the left lateral liver lobe and a gallbladder mucocele. Following liver lobectomy and cholecystectomy, the dog's clinical signs resolved, and liver enzymes substantially improved. Diffuse hepatocellular infarction and necrosis secondary to multifocal atherosclerosis was present on histopathology of the liver. Hypothyroidism was subsequently diagnosed. Restoration of euthyroidism with oral levothyroxine therapy resolved the remaining liver enzyme elevations and hypercholesterolemia. To the author's knowledge, this is the first case report of hypothyroidism resulting in a clinically apparent and resolvable acute hepatopathy due to atherosclerosis. Clinicians should include atherosclerosis as a differential diagnosis for dogs with an acute hepatopathy and investigate dogs for hypothyroidism if atherosclerosis is diagnosed on liver biopsy.


TCR and Inflammatory Signals Tune Human MAIT Cells to Exert Specific Tissue Repair and Effector Functions.
MAIT cells are an unconventional T cell population that can be activated through both TCR-dependent and TCR-independent mechanisms. Here, we examined the impact of combinations of TCR-dependent and TCR-independent signals in human CD8+ MAIT cells. TCR-independent activation of these MAIT cells from blood and gut was maximized by extending the panel of cytokines to include TNF-superfamily member TL1A. RNA-seq experiments revealed that TCR-dependent and TCR-independent signals drive MAIT cells to exert overlapping and specific effector functions, affecting both host defense and tissue homeostasis. Although TCR triggering alone is insufficient to drive sustained activation, TCR-triggered MAIT cells showed specific enrichment of tissue-repair functions at the gene and protein levels and in in vitro assays. Altogether, these data indicate the blend of TCR-dependent and TCR-independent signaling to CD8+ MAIT cells may play a role in controlling the balance between healthy and pathological processes of tissue inflammation and repair.


Using the framework of corporate culture in "mergers" to support the development of a cultural basis for integrative medicine - guidance for building an integrative medicine department or service.
An increasing number of clinics offer complementary or integrative medicine services; however, clear guidance about how complementary medicine could be successfully and efficiently integrated into conventional health care settings is still lacking. Combining conventional and complementary medicine into integrative medicine can be regarded as a kind of merger. In a merger, two or more organizations - usually companies - are combined into one in order to strengthen the companies financially and strategically. The corporate culture of both merger partners has an important influence on the integration. The aim of this project was to transfer the concept of corporate culture in mergers to the merging of two medical systems. A two-step approach (literature analyses and expert consensus procedure) was used to develop practical guidance for the development of a cultural basis for integrative medicine, based on the framework of corporate culture in "mergers," which could be used to build an integrative medicine department or integrative medicine service. Results include recommendations for general strategic dimensions (definition of the medical model, motivation for integration, clarification of the available resources, development of the integration team, and development of a communication strategy), and recommendations to overcome cultural differences (the clinic environment, the professional language, the professional image, and the implementation of evidence-based medicine). The framework of mergers in corporate culture provides an understanding of the difficulties involved in integrative medicine projects. The specific recommendations provide a good basis for more efficient implementation.


Health Care Costs and Resource Utilization Among Patients With Crohn's Disease With and Without Perianal Fistula.
Perianal fistula (PAF), a complication of Crohn's disease (CD), is associated with substantial economic costs and poor prognosis. We determined prevalence of PAF CD in the United States and compared costs and health care resource utilization (HRU) of PAF CD patients with matched non-PAF CD patients. This was a retrospective cohort study of claims data from the IBM MarketScan Commercial Database from October 1, 2015, to September 30, 2018. Eligible patients were aged 18 to 89 years with ≥2 CD diagnoses. Patients with PAF CD had ≥1 PAF diagnosis or procedure code and were matched with non-PAF CD patients. Cumulative prevalence of PAF CD in the US population was calculated across total patients in MarketScan. All-cause and gastrointestinal (GI)-related costs and HRU were compared between groups using a generalized linear model (GLM). Cumulative 3-year prevalence of PAF was 7.70% of patients with CD (N = 81,862) and 0.01% of the US population. Among PAF CD (n = 1218) and matched non-PAF CD (n = 4095) patients, most all-cause costs and HRU were GI-related. Mean total all-cause and GI-related health care costs per patient and per year for PAF CD were $85,233 and $71,612, respectively, vs $40,526 and $29,458 for non-PAF CD (P < .0001). Among PAF CD vs non-PAF CD patients, GLM-adjusted proportions of patients with GI-related inpatient, outpatient, or pharmacy visits, mean GI-related inpatient length of stay, and mean GI-related surgeries were higher (P < .0001 for all comparisons). Costs and HRU are significantly higher for patients with PAF CD vs non-PAF CD patients, highlighting the economic burden of the disease.


The dynamics of interhemispheric compensatory processes in mental imagery.
The capacity to generate and analyze mental visual images is essential for many cognitive abilities. We combined triple-pulse transcranial magnetic stimulation (tpTMS) and repetitive TMS (rTMS) to determine which distinct aspect of mental imagery is carried out by the left and right parietal lobe and to reveal interhemispheric compensatory interactions. The left parietal lobe was predominant in generating mental images, whereas the right parietal lobe was specialized in the spatial comparison of the imagined content. Furthermore, in case of an rTMS-induced left parietal lesion, the right parietal cortex could immediately compensate such a left parietal disruption by taking over the specific function of the left hemisphere.


Staining- and aging-dependent changes in color and translucency of 3D-printed resin-modified ceramics.
To evaluate staining- and aging-dependent changes in the color and translucency of 3D-printed resin-modified ceramics (RMC). Specimens (n= 5 per condition and material) were fabricated from test materials: Permanent Crown Resin (PCR), Crowntec (CT), Vita Enamic (VE) and Tetric CAD (TC). Specimens were stained in wine, coffee, tea, and water (control) and exposed to artificial accelerated aging (AAA). Color measurements were obtained using a spectrophotometer at baseline (T0) and at 3.5 (T1) and 7 (T2) days after immersion. For AAA, measurements were obtained at baseline (T0) and after exposure to controlled irradiance of 150 kJ/m² (T1) and 300 kJ/m² (T2). Mean and standard deviations were calculated on CIEDE2000 color differences (ΔE₀₀), translucency parameter (TP₀₀) and treatment-dependent changes in the translucency parameter (ΔTP₀ ₀). Differences between materials and test conditions were tested by one-way ANOVA (α= 0.05). Results were additionally interpreted using visual color difference thresholds in dentistry ΔE₀₀= 0.8 for the 50:50 perceptibility threshold (PT) and ΔE₀₀= 1.8 for the 50:50 acceptability threshold (AT). ΔTP₀₀ values were interpreted using 5058;50 TPT₀₀= 0.6 and 50:0% TAT₀₀= 2.6. Statistically significant differences were found among the materials when exposed to the different test conditions. At the T0-T1 time interval, the highest color difference was found with wine (0.1-2.2) on all materials except CT, which showed the highest ΔE₀₀ with AAA (2.5). The second highest color differences were obtained upon exposure to AAA (0.2-2.5) and tea (0.5-1.1). The TP₀₀ at baseline ranged from 5.1 to 9.8. Significant differences in ΔTP₀₀ were found among the tested materials and staining/aging conditions, but no significant differences were found among the staining/aging intervals (T0-T1, T0-T2 and T1-T2). Staining- and artificial aging-dependent changes of 3D-printed and milled resin modified ceramics used for definitive restorations could represent a challenge in terms of restoration acceptability or dissatisfaction. Staining and aging conditions produced significant color changes, while translucency changes were not significant.


"Great powers and great responsibilities": A brief comment on "A brief mobile app reduces nonsuicidal and suicidal self-injury: Evidence from three randomized controlled trials" (Franklin et al., 2016).
Online and mobile mental health applications (apps) herald exciting new opportunities for the treatment and prevention of self-injurious thoughts and behaviors (SITBs). With such rapid technological advances, it is paramount that health care innovation not be achieved to the detriment of intervention quality. Franklin et al.'s (2016) therapeutic evaluative conditioning (TEC) app is a novel and timely addition to the mobile health landscape; uncommonly for such apps, it is evidence based. There are, however, several crucial challenges to be surmounted for TEC to be successful; arguably, interventions ought to build lasting skills that can be subsequently and consciously recruited to manage distress beyond the intervention period. Furthermore, SITBs are a coping mechanism (albeit maladaptive); thus, extinguishing SITBs via TEC must be bolstered by the development of alternative coping strategies, particularly if the psychological distress that underlies SITBs is not addressed therapeutically. Stigma exacerbates the psychological distress of those engaging in SITBs; therefore, we question whether the types of stimuli employed in TEC may further add to this stigma, potentially affecting future help seeking. One solution may be to explore a positive-only TEC; enhancing positive self-worth may provide a more sustainable and meaningful treatment target, particularly when used as an adjunct to therapy or as a waiting list intervention. Mobile interventions for SITBs bring unique ethical challenges, including individuals' right to be fully informed about potentially distressing stimuli. This commentary aims to highlight the methodological and ethical challenges faced by TEC and encourage further discussion around this topic. (PsycINFO Database Record


Adults' Online and Offline Psychological Intimate Partner Violence Experiences.
Digital media offer ample possibilities for individuals to control and monitor their dating or romantic partner and to make hurtful comments. Although online psychological intimate partner violence has received increased research attention over the past few years, much remains unknown about its nature and its association with offline psychological intimate partner violence, especially among the adult population. Previous research remains inconclusive regarding the gendered nature of online intimate partner violence, and differences among various age groups have yet to be examined. The present study is intended to address these gaps in the literature by assessing the co-occurrence of psychological intimate partner violence victimization and perpetration, and the overlap between offline and online forms thereof. We conducted a large-scale survey study among a representative sample of 1,587 adults between the ages of 18 and 94 (M = 48.1, SD = 18.6), of which 1,144 (Mage = 47.7 years, 51.3% female) were in relationships at the time of data collection (2019). Our study findings indicate that experiences of online and offline psychological intimate partner violence tend to co-occur, as do victimization and perpetration experiences. Furthermore, we found that men were more often victims of both online and offline psychological partner violence than women, and women were more often perpetrators of both forms of psychological intimate partner violence than men. Younger age groups reported more victimization and perpetration of online and offline psychological intimate partner violence than older respondents. The results of our study underscore the need for age-appropriate intimate partner violence prevention.


Evaluation of the Lactate Pro blood lactate analyser.
An evaluation of the hand-held portable Lactate Pro Analyser (KDK) was undertaken to assess its accuracy, reliability and versatility. Capillary blood samples were drawn from elite athletes in both laboratory and field settings and analysed in parallel. Accuracy was determined in relation to three other lactate analysers: (1) the ABL 700 Series Acid-Base analyser (n = 172 cases), (2) the Accusport Lactate Meter (n = 118 cases), and (3) the YSI 2300 Stat lactate analyser (n = 22 cases). The level of agreement was determined over the range of 1-18 mM. The repeatability of results between two different Lactate Pro analysers was also determined over the same range. Versatility was assessed in the field, where the Lactate Pro was used with elite athletes under a range of outdoor and indoor testing conditions. The correlations between the Lactate Pro and the ABL 700 Series Acid-Base analyser, YSI 2300 and Accusport were r = 0.98, r = 0.99, r = 0.97. The correlation between the two Lactate Pro analysers on the same sample (n = 96 cases) was r = 0.99. The level of agreement between the Lactate Pro and other analysers was generally less than +/- 2.0 mM over the physiological range of 1.0-18.0 mM (range of mean difference: -0.06 mM to 0.52 mM). The Lactate Pro was easy to operate and successfully completed the sample analysis in 100% of the tests performed. In summary, the Lactate Pro is accurate, reliable and exhibits a high degree of agreement with other lactate analysers.


Oligomeric IgA: the major component of the in vitro primary response of mouse spleen fragments.
The primary antibody response elicited from mouse spleen explants by conjugates of the 3-nitro-5-iodo-4-hydroxyphenylacetic acid (NIP) hapten consisted mostly of the IgA class. Poly-L-lysine, pneumococcal polysaccharide Type SIII, keyhole limpet hemocyanin, and sheep erythrocytes were effective carriers in this system, whereas chicken globulin was not. The anti-NIP response against all of the immunogenic conjugates was detectable in culture media 4 days after explantation and immunization, and reached peak titers by 8-10 days. IgA was identified by sucrose gradient velocity centrifugation in conjunction with the use of a class-specific antiserum. The media collected at 4 days contained low titers of IgM antibody, whereas the peak response at 8 days consisted almost entirely of IgA. The primary response IgA secreted by the spleen fragments was characterized as polymeric by its sedimentation rate through a sucrose gradient, and as polyvalent by its drastically greater avidity for NIP(14)BSA than for free NIP-aminocaproic acid. Its haptenated phage-inactivating activity was abolished by treatment with 0.1 M 2-mercaptoethanol. These experiments indicate that precursor cells existing in the spleen before primary immunization can give rise to production of polymeric IgA.


The hospital mortality of patients admitted to the ICU on weekends.
Previous studies have suggested that patients are more likely to die in the hospital if they are admitted on a weekend than on a weekday. This study was conducted to determine whether weekend admission to the ICU increases the risk of dying in the hospital. Retrospective cohort study. ICU of a single tertiary care medical center. A total of 29,084 patients admitted to medical, surgical, and multispecialty ICUs from October 1994 through September 2002. None. The weekend ICU admissions comprised 27.9% of all ICU admissions (8,108 ICU admissions). The overall hospital mortality rate was 8.2% (2,385 deaths). Weekend ICU admission was associated with a higher unadjusted hospital mortality rate than that for weekday ICU admission (11.3% vs 7.0%, respectively; odds ratio [OR], 1.70; 95% confidence interval [CI], 1.55 to 1.85). In multivariable analyses controlling for the factors associated with mortality such as APACHE (acute physiology and chronic health evaluation) III predicted mortality rate, ICU admission source, and intensity of treatment, no statistically significant difference in hospital mortality was found between weekend and weekday admissions in the overall study population (OR, 1.06; 95% CI, 0.95 to 1.17). For weekend ICU admissions, the observed hospital mortality rates of the medical, multispecialty, and surgical ICUs were 15.2%, 17.2%, and 6.4%, respectively, and for weekday ICU admissions the rates were 16.3%, 10.1%, and 3.5%, respectively. Subgroup analyses showed that weekend ICU admission was associated with higher adjusted hospital mortality rates than was weekday ICU admission in the surgical ICU (OR, 1.23; 95% CI, 1.03 to 1.48), but not in the medical or multispecialty ICUs. The overall adjusted hospital mortality rate of patients admitted to the ICU on a weekend was not higher than that of patients admitted on a weekday. However, weekend ICU admission to the surgical ICU was associated with an increased hospital mortality rate.


Supplementation of IVF medium with melatonin: effect on sperm functionality and in vitro produced bovine embryos.
Gamete co-incubation generates high free radical levels surrounding growing zygotes which may impair subsequent embryo viability. Melatonin eliminates a wide variety of free radicals; hence, we tried to improve in vitro embryo production by adding melatonin to in vitro fertilisation (IVF) media in high (Exp. 1) and low concentrations (Exp. 2), and we evaluated its effect on bull sperm function during IVF co-incubation time (Exp. 3). In Experiment 1, we supplemented IVF media culture with 0.01, 0.1 and 1 mmol of melatonin, along with a no melatonin control group. In Experiment 2, melatonin levels were reduced to 10, 100 and 1000 nmol, with a no melatonin control group. In Experiment 3, spermatozoa were incubated in IVF media with melatonin (as Exp. 2) and functional parameters were analysed at 0, 4 and 18 h. In Experiment 1, only 1 mmol melatonin showed lesser blastocyst rates than control (C: 23.2 ± 6.7% versus 1 mmol: 2.0 ± 1.7%). In Experiment 2, no statistical differences were found in cleavage percentage, blastocyst percentage and total cell count for any melatonin treatment. In Experiment 3, sperm samples with 1000 nmol melatonin had a significantly higher wobbler (WOB) coefficient, a lower percentage of intact acrosomes, a lower percentage of viable spermatozoa with ROS, greater DNA fragmentation and higher DNA oxidation than controls. Total fluorescence intensity for ROS at 10 nmol melatonin was significantly greater than controls (P < 0.05). IVF media with 1 mmol melatonin is deleterious for embryo development, and in lower concentrations, it modulated sperm functionality, but had no effects on embryo production.


Male nurses and chemical dependency: masterminding the nursing environment.
Florida men in nursing who are chemically dependent represent a greater percentage of the total number of male nurses than female nurses who are chemically dependent. This study identifies characteristics of 9 men who completed the Florida Intervention Project for Nurses. All participants were interviewed independently and data were analyzed to determine common themes in their behaviors and relationships and how they successfully manipulated professional nursing systems to remain professionally active for prolonged period of time while impaired. A model of caring for nurses with professional impairment graphically depicted the interaction of 2 overarching themes of person and profession. The person theme had 3 subthemes of predetermined risk, altered values, and sensation-seeking behaviors. The profession theme had 6 subthemes of masterminding, professional heteronomy, getting caught, rehabilitation, spirituality, and the nurse becoming the nursed. Findings imply that chemical dependency among male nurses starts in childhood in an abusive family environment and continues throughout the educational process and into the work environment. Findings supporting diversion success include a lack of awareness of the signs and symptoms of impairment by supervisors, poor compliance to drug control procedures, and a common acceptance by peers that impaired men are clinically competent and clinical leaders. When these 3 situations are present, there is greater success in masterminding daily events to maintain undetected drug access.


Two transpallidal pathways originating in the rat nucleus accumbens.
The striatopallidal projection originating in the nucleus accumbens was investigated by using anterograde transport of PHA-L in combination with peptide immunohistochemistry in order to localize the injection sites and transported lectin with respect to neurochemically defined subterritories in the nucleus accumbens and subcommissural ventral pallidum. The results reported here supplement our previous observations, which indicated that the subcommissural ventral pallidum of the rat comprises two immunohistochemically defined subterritories (Zahm and Heimer, '88: J. Comp. Neurol., 272:516-535) which give rise to dichotomous downstream projection systems (Zahm, '89: Neuroscience, 30:33-50). The present data indicate that the neurotensin immunoreactivity-rich ventromedial district of ventral pallidum receives its accumbal input almost exclusively from the shell district of the nucleus accumbens. The accumbal core, alternatively, projects to the dorsolateral ventral pallidal subterritory that lacks appreciable neurotensin immunoreactivity and in many other respects more resembles the adjoining striatopallidal components of the caudate-putamen. In addition to direct topographic relationships in the frontal plane among the accumbal injection sites and ventral pallidal terminations, it was observed that more caudally placed core injections resulted in patches of striatopallidal terminations that were more caudally located in ventral pallidum. Shell injections, in contrast, produced columns of terminations that extended continuously from the rostralmost level that they appeared to the caudal end of ventromedial ventral pallidum. The accumbal shell, its exclusive projection to the ventromedial subterritory in the subcommissural ventral pallidum, and the previously reported, almost exclusive projection of that pallidal subdistrict to the mesencephalic ventral tegmental area are discussed in terms of a number of other neurochemical and hodological features that serve to distinguish them sufficiently to suggest that they represent a uniquely specialized part of the basal ganglia.


Noise, sampling, and the number of projections in cone-beam CT with a flat-panel detector.
To investigate the effect of the number of projection views on image noise in cone-beam CT (CBCT) with a flat-panel detector. This fairly fundamental consideration in CBCT system design and operation was addressed experimentally (using a phantom presenting a uniform medium as well as statistically motivated "clutter") and theoretically (using a cascaded systems model describing CBCT noise) to elucidate the contributing factors of quantum noise (σ(Q)), electronic noise (σ(E)), and view aliasing (σ(view)). Analysis included investigation of the noise, noise-power spectrum, and modulation transfer function as a function of the number of projections (N(proj)), dose (D(tot)), and voxel size (b(vox)). The results reveal a nonmonotonic relationship between image noise and N(proj) at fixed total dose: for the CBCT system considered, noise decreased with increasing N(proj) due to reduction of view sampling effects in the regime N(proj) <~200, above which noise increased with N(proj) due to increased electronic noise. View sampling effects were shown to depend on the heterogeneity of the object in a direct analytical relationship to power-law anatomical clutter of the form κ/f(β)--and a general model of individual noise components (σ(Q), σ(E), and σ(view)) demonstrated agreement with measurements over a broad range in N(proj), D(tot), and b(vox). The work elucidates fairly basic elements of CBCT noise in a manner that demonstrates the role of distinct noise components (viz., quantum, electronic, and view sampling noise). For configurations fairly typical of CBCT with a flat-panel detector (FPD), the analysis reveals a "sweet spot" (i.e., minimum noise) in the range N(proj) ~ 250-350, nearly an order of magnitude lower in N(proj) than typical of multidetector CT, owing to the relatively high electronic noise in FPDs. The analysis explicitly relates view aliasing and quantum noise in a manner that includes aspects of the object ("clutter") and imaging chain (including nonidealities of detector blur and electronic noise) to provide a more rigorous basis for commonly held intuition and heurism in CBCT system design and operation.


Match injuries in professional soccer: inter-seasonal variation and effects of competition type, match congestion and positional role.
In this prospective observational study, injuries sustained in official match-play in players belonging to a professional soccer club were investigated. Incidence and patterns of injury were compared across four-seasons (2005-2006: S1, 2006-2007: S2, 2007-2008: S3 and 2008-2009: S4) and 3 match formats (domestic League/Cup games and European club competition). In addition, the effects of both fixture congestion and the positional role of players were investigated. Injury incidence (per 1 000 match-hours) did not vary between seasons (range 31.2-59.2 observed in S2 and S4, respectively, p=0.12) or fixture formats (range 32.6-40.8 observed in European and League matches, respectively, p=0.49). In contrast, rates varied in players (n=7) who participated in all four seasons as more injuries were sustained in S1 compared to S2 and S3, respectively (88.4 vs. 49.0 vs. 49.2, both p<0.05). The incidence of muscle strains was higher in S4 versus S3 (24.7 vs. 9.9, p<0.05) as were injuries sustained to the ankle region in S4 versus S2 (15.1 vs. 4.5, p<0.05). The incidence of joint sprains differed between fixture formats with a higher rate observed in League versus both Cup and European competition, respectively (10.1 vs. 3.0 vs. 3.0, both p<0.05). Injury incidence was not associated to the time delay (number of days) separating games (r=0.04, p=0.58). A very short interval (< or = 3 days) between fixtures did not result in a greater injury rate (p=0.40) or number of days lost to injury (p=0.73) compared to a longer interval (> or = 4 days). Finally, the incidence of injury and muscle strains (both p<0.001) varied across positional roles with the highest rates observed in centre-forwards. These findings provide further knowledge on the risk of injury in contemporary professional soccer match-play and may aid in the care and management of playing resources.


Retreatment after excimer laser photorefractive keratectomy. The Melbourne Excimer Laser Group.
To determine the risk factors for undercorrection of myopia after photorefractive keratectomy and to evaluate the efficacy and safety of retreatment. A VISX Twenty/Twenty excimer laser was used to treat myopia and myopic astigmatism of up to -15.00 diopters (spherical equivalent) at the corneal plane. Retreatments were performed primarily for undercorrection with or without coexistent corneal haze or abnormalities on videokeratoscopy. Not every patient who was undercorrected requested retreatment. Of 645 eyes (440 patients) followed up for more than 12 months, 58 eyes (9%) required retreatment. The retreatment rate increased with increasing myopia: 17 (5%) eyes with myopia of less than -5.00 diopters, 30 (13%) eyes with myopia of -5.01 to -10.00 diopters, and 11 (19%) eyes with myopia of greater than -10.00 diopters required a second procedure. A higher retreatment rate was observed after astigmatic corrections than after spherical corrections. Corneal haze after retreatment was no greater than that observed after initial procedures. Twelve months after primary procedures, 378 (75%) of 504 eyes were within 1.00 diopter of emmetropia, whereas 27 (69%) of 39 eyes attained this result after retreatment. A total of 383 (76%) of 504 eyes attained uncorrected visual acuity of 20/40 or better after primary procedures, compared with 25 (64%) of 39 eyes after retreatment. The risk of undercorrection requiring retreatment after photorefractive keratectomy increases with the magnitude of the primary treatment. Although less successful than initial procedures, retreatment appears to enhance the results of photorefractive keratectomy.


Treatment beyond progression and locoregional approaches in selected patients with BRAF-mutated metastatic melanoma.
The clinical management of BRAF-mutated metastatic melanoma had an important turning point after the introduction of the targeted therapy. Despite the efficacy and good tolerability of this treatment, the development of resistance mechanisms causes disease progression. The aim of this review is to investigate the role of treatment beyond progression and locoregional approaches in BRAF-mutated metastatic melanoma and provide oncologists dealing with this malignancy a useful road map on when and why to choose this strategy. The article is structured in the form of a narrative review reporting the most significant studies on the subject. Most of the available articles are represented by retrospective studies and case reports, leading to limitations in the final interpretations. Nevertheless, a correct analysis of the selected studies allows the drawing of some conclusions. In well-selected cases, treatment beyond progression could play an important role in the treatment sequence of patients with BRAF-mutated advanced melanoma and would seem to produce good disease control rates and positive survival outcomes. A careful evaluation of the radiological examinations and laboratory tests, based on the clinical conditions, allows the identification of which patients can benefit from this strategy. Such patients are those who, at the time of progression, have favourable features such as a lower performance status according to Eastern Cooperative Oncology Group (ECOG-PS), normal lactate dehydrogenase levels and lower disease burden. The clinical benefit is also consolidated by the addition of locoregional approaches. Locoregional approaches can include electrochemotherapy, radiotherapy or surgery, and their use provides local disease control and a better quality of life for patients.


The SOAR stroke score predicts hospital length of stay in acute stroke: an external validation study.
The objective of this study is to externally validate the SOAR stroke score (Stroke subtype, Oxfordshire Community Stroke Project Classification, Age and prestroke modified Rankin score) in predicting hospital length of stay (LOS) following an admission for acute stroke. We conducted a multi-centre observational study in eight National Health Service hospital trusts in the Anglia Stroke & Heart Clinical Network between September 2008 and April 2011. The usefulness of the SOAR stroke score in predicting hospital LOS in the acute settings was examined for all stroke and then stratified by discharge status (discharged alive or died during the admission). A total of 3596 patients (mean age 77 years) with first-ever or recurrent stroke (92% ischaemic) were included. Increasing LOS was observed with increasing SOAR stroke score (p < 0.001 for both mean and median) and the SOAR stroke score of 0 had the shortest mean LOS (12 ± 20 days) while the SOAR stroke score of 6 had the longest mean LOS (26 ± 28 days). Among patients who were discharged alive, increasing SOAR stroke score had a significantly higher mean and median LOS (p < 0.001 for both mean and median) and the LOS peaked among patients with score value of 6 [mean (SD) 35 ± 31 days, median (IQR) 23 (14-48) days]. For patients who died as in-patient, there was no significant difference in mean or median LOS with increasing SOAR stroke score (p = 0.68 and p = 0.79, respectively). This external validation study confirms the usefulness of the SOAR stroke score in predicting LOS in patients with acute stroke especially in those who are likely to survive to discharge. This provides a simple prognostic score useful for clinicians, patients and service providers.


[Pulmonary embolism associated with paradoxical arterial embolism in a patient with patent foramen ovale].
Paradoxical embolism and patent foramen ovale have represented an issue of great interest during the last years, because of the strong correlation with cryptogenic stroke in young patients. The coexistence of pulmonary and paradoxical embolism is even more rare. We present the case of a patient with evidence of concomitant pulmonary embolism and paradoxical systemic arterial embolism, which suggests the presence of patent foramen ovale. The available literature about this infrequent clinical event is also reviewed.


Characterizing the Human Immunodeficiency Virus Care Continuum Among Transgender Women and Cisgender Women and Men in Clinical Care: A Retrospective Time-series Analysis.
Prior studies suggest that transgender women (TW) with human immunodeficiency virus (HIV) are less likely to be virally suppressed than cisgender women (CW) and cisgender men (CM). However, prior data are limited by small sample sizes and cross-sectional designs. We sought to characterize the HIV care continuum comparing TW to CW and CM in the United States and Canada. We analyzed annual HIV care continuum outcomes by gender status from January 2001 through December 2015 among adults (aged ≥18 years) in 15 clinical cohorts. Outcomes were retention in care and viral suppression. The study population included TW (n = 396), CW (n = 14 094), and CM (n = 101 667). TW had lower proportions retained in care than CW and CM (P < .01). Estimates of retention in care were consistently lower in TW, with little change over time within each group. TW and CW had similar proportions virally suppressed over time (TW, 36% in 2001 and 80% in 2015; CW, 35% in 2001 and 83% in 2015) and were lower than CM (41% in 2001 and 87% in 2015). These differences did not reach statistical significance after adjusting for age, race, HIV risk group, and cohort. TW experience challenges with retention in HIV care. However, TW who are engaged in care achieve viral suppression that is comparable to that of CW and CM of similar age, race, and HIV risk group. Further research is needed to understand care engagement disparities.


Microarray-based analysis: identification of hypoxia-regulated microRNAs in retinoblastoma cells.
Hypoxia is an essential feature of retinoblastoma and contributes to poor prognosis and resistance to conventional therapy. MicroRNAs (miRNAs) are small non-coding RNAs involved in a wide variety of biological processes, including cell differentiation, proliferation, death and metabolism. However, the relationship between hypoxia and the expression of miRNAs in retinoblastoma is not well understood. In this study, we aimed to analyze the pattern of miRNA expression in a retinoblastoma cell line under hypoxic conditions and to identify the miRNAs regulated by hypoxia, as well as their possible functions. miRNA expression profiling in retinoblastoma cells (HXO-RB44) under normal and hypoxic conditions was assessed by microarray techniques. The differentially expressed miRNAs were subjected to bioinformatic analyses to predict and categorise the key miRNAs and their target genes. A quantitative real-time RT-PCR approach was used to validate their expression. A Cell Counting kit was used to evaluate the functional significance of miR-181b in RB cell proliferation. There were 46 miRNAs that changed expression more than 2-fold in response to hypoxia (34 up-regulated and 12 down-regulated). We identified a cluster of miRNAs that includes miR-181b, miR-125a-3p, miR-30c-2, miR-497 and miR-491-3p as hypoxia-regulated miRNAs (HRMs) in retinoblastoma cells, of which miR-181b was the most typically differentially expressed miRNA under hypoxic conditions. Functionally, these HRMs are involved in apoptosis, cell adhesion, cell proliferation and mRNA processing, all processes that associate closely with the hypoxia response of cancer cells. Additionally, we found that administration of miR-181b inhibitor can suppress proliferation of retinoblastoma cells. These findings provide the first evidence that miRNAs play an important role in the hypoxia response of retinoblastoma cells. MiR-181b, the most typically up-regulated miRNA may aid in future clinical intervention of retinoblastoma.


REM sleep muscle activity in idiopathic REM sleep behavior disorder predicts phenoconversion.
To determine whether REM sleep without atonia (RSWA) during polysomnography (PSG) predicts phenoconversion in patients with idiopathic REM sleep behavior disorder (iRBD), a prodromal feature of a neurodegenerative disease. We analyzed RSWA in 60 patients with iRBD, including manual phasic, tonic, and any muscle activity in the submentalis and anterior tibialis muscles and the automated REM atonia index in the submentals. We identified patients who developed parkinsonism or mild cognitive impairment (MCI) during at least 3 years of follow-up after PSG. Kaplan-Meier analysis was performed and receiver operator curves were calculated to determine RSWA cutoffs predicting faster phenoconversion. Twenty-six (43%) patients developed parkinsonism (n = 17) or MCI (n = 9). Phenoconverters were older at iRBD diagnosis (p = 0.02). Median time to phenoconversion was 3.9 ± 2.5 years. iRBD phenoconverters had significantly more RSWA at diagnosis. Phenoconversion risk from iRBD diagnosis was 20% and 35% at 3 and 5 years, respectively, with greater risk in patients with iRBD with >46.4% any combined RSWA, which increased further to 30% and 55% at 3 and 5 years for patients >65 years of age at diagnosis. Patients with iRBD with higher amounts of polysomnographic RSWA had a greater risk of developing Parkinson disease or MCI. Patients with older age and higher RSWA amounts had more rapid phenoconversion than younger patients with RBD. Our study suggests that RSWA is a potential biomarker for risk stratification of iRBD phenoconversion that could facilitate prognostication for patients with iRBD. This study provides Class II evidence that for patients with iRBD, increased RSWA correlates with increased risk for developing parkinsonism or MCI.


The silencing suppressor P25 of Potato virus X interacts with Argonaute1 and mediates its degradation through the proteasome pathway.
Previous evidence has indicated that the P25 protein encoded by Potato virus X (PVX) inhibits either the assembly or function of the effector complexes in the RNA silencing-based antiviral defence system (Bayne et al., Cell-to-cell movement of Potato Potexvirus X is dependent on suppression of RNA silencing. Plant J.44, 471-482). This finding prompted us to investigate the possibility that P25 targets the Argonaute (AGO) effector nuclease of RNA silencing. Co-immunoprecipitation and Western blot analysis indicated that there is a strong interaction between P25 and AGO1 of Arabidopsis when these proteins are transiently co-expressed in Nicotiana benthamiana. P25 also interacts with AGO1, AGO2, AGO3 and AGO4, but not with AGO5 and AGO9. As an effective suppressor, the amount of AGO1 accumulated in the presence of P25 was dramatically lower than that infiltrated with HcPro, but was restored when treated with a proteasome inhibitor MG132. These findings are consistent with the idea that RNA silencing is an antiviral defence mechanism and that the counter-defence role of P25 is through the degradation of AGO proteins via the proteasome pathway. Further support for this idea is provided by the observation that plants treated with MG132 are less susceptible to PVX and its relative Bamboo mosaic virus.


Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner.
The tyrosine kinase inhibitor imatinib (imatinib, STI571, Glivec, and Gleevec) is increasingly used in patients undergoing allogeneic transplantation for leukemia. However, little is known regarding its potential immunoregulatory effects. Here, we investigate the effect of imatinib on T-cell receptor (TCR)-mediated activation of human T cells. Following stimulation with the anti-CD3 antibody 12F6, proliferation of activated T cells was almost completely inhibited by 10 microM imatinib. Furthermore, antigen-triggered expansion of CD8+ T cells in response to immunodominant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) peptides was significantly reduced. Up-regulation of the activation markers CD25 and CD69 in response to TCR cross-linking was suppressed by imatinib at a mean inhibitory concentration 50% (IC50) of 5.4 microM and 7.3 microM, respectively; interleukin 2 (IL-2) production was also impaired. Analysis of the TCR-induced signaling cascade showed that imatinib substantially reduced tyrosine phosphorylation of ZAP70 and LAT in response to activation through the TCR. Sequence comparisons of all 90 tyrosine kinase genes in the human genome for homology in the adenosine triphosphate (ATP) binding pocket identified LCK, which is required for ZAP70 activation, as a likely target for imatinib. The IC50 for LCK inhibition by imatinib was 0.6 microM to 0.8 microM in an in vitro tyrosine kinase assay. In summary, imatinib can interfere with T-cell activation in vitro, and its impact on the frequency of opportunistic infections and graft-versus-host or graft-versus-leukemia reactions after transplantation should be investigated in clinical trials.


Dual number-based variational data assimilation: Constructing exact tangent linear and adjoint code from nonlinear model evaluations.
Dual numbers allow for automatic, exact evaluation of the numerical derivative of high-dimensional functions at an arbitrary point with minimal coding effort. We use dual numbers to construct tangent linear and adjoint model code for a biogeochemical ocean model and apply it to a variational (4D-Var) data assimilation system when coupled to a realistic physical ocean circulation model with existing data assimilation capabilities. The resulting data assimilation system takes modestly longer to run than its hand-coded equivalent but is considerably easier to implement and updates automatically when modifications are made to the biogeochemical model, thus making its maintenance with code changes trivial.


Postpartum hemorrhage and reevaluation of uterine packing.
Postpartum hemorrhage, occurring in 153 patients, is categorized according to etiology, predisposing conditions, and severity. Ruptured uterus is considered as a cause of postpartum hemorrhage, with an incidence of 7.1% overall and 11.9% in patients with severe hemorrhage. The effectiveness and complications of the uterine pack, used in 33 patients, are evaluated.


Auditory localization: role of auditory pathways in brain stem of the cat.
Cats were trained to localize sound in space. The animals' localization accuracy was determined before and after one of the following operations: 1) transection of the trapezoid body, 2) unilateral and 3) bilateral transection of the lateral lemniscus, 4) unilateral and 5) bilateral transection of the brachium of the inferior colliculus. The results after bilateral transections of the lateral lemniscus and the one deep bilateral transection of the brachium of the inferior colliculus indicate that some portion of the ascending auditory system must be intact above the medulla for an animal to be able to localize sound. A small loss in accuracy of localization was found after unilateral transection of the lateral lemniscus or brachium of the inferior colliculus. This loss, when compared with the much larger loss that monaural animals show, is an indication that binaural analysis, important for sound localization, occurs at the level of the medulla. Some transections of the trapezoid body resulted in a deficit in localization ability that appeared to be complete and permanent. The position of the lesions in the trapezoid body indicated that important encoding of the binaural cues to localization most likely occurs at the superior olivary complex, probably at the medial superior olive. But the trapezoid body or other commissures of the brain stem auditory system are probably also involved in transmission of information necessary for localization to higher centers.


Does measuring the medial gap before bone resection in total knee arthroplasty provide optimum gap adjustment and prevent bone recutting?
This study aimed to demonstrate that measuring the medial gap before bone resection during total knee arthroplasty (TKA) provides an optimum gap adjustment in varus knees. In this study, patients were separated into two groups. Group 1 included patients whose medial joint gap was measured before bone resection and Group 2 included patients who underwent conventional technique without measuring. The medial joint gap was measured with a custom-made gap measuring device up to the point that the knee was corrected and aligned along its mechanical axis. Medial joint gap distances, distal medial femoral bone cut thicknesses, amounts of tibial resection calculated; gap internal distances measured after cutting and the thicknesses of the trial inserts were recorded. A comparison was made between the groups concerning the number of patients requiring an additional tibial bone cut and the distribution of insert thicknesses. Extra tibial bone resections were performed in two (5.7%) patients in Group 1 and 10 (28.6%) patients in Group 2. In Group 1, where the medial joint gap was measured, the need for an additional bone resection was statistically less (p=0.018). In comparing the distribution of insert size by group, the number of patients on whom an 8 mm insert had been used was significantly greater in Group 1 (p=0.024). The findings obtained in this study suggest that measuring the medial joint gap before bone resection in total knee arthroplasty may prevent repeated bone recutting and additional bone resections.


Significance of extracellular enveloped virus in the in vitro and in vivo dissemination of vaccinia.
The significance of extracellular enveloped vaccinia (EEV) for the in vitro and in vivo dissemination of vaccinia virus was investigated. The quantity of in vitro released extracellular virus correlated very closely with the ability of 13 vaccinia strains to cause long-range spread of infection (comet formation) in cell cultures infected at low m.o.i. but was not correlated with plaque size. The kinetics of virus spread after low m.o.i. was related to the amount of virus released from primary infected cells but not to their content of intracellular naked vaccinia (INV). Most extracellular vaccinia virus from IHD-J-infected RK-13 cells banded in CsCl density gradients as EEV (88%) while very little banded as INV (2%). Antisera to the enveloped prevented comet formation while antisera to INV did not. CsCl centrifugation of blood-borne extracellular virus from rabbits infected intravenously with vaccinia virus after cyclophosphamide treatment revealed that 64% of the virus banded as EEV but only 11% as INV. High in vitro EEV-yielding vaccinia strains were able to spread from the respiratory tract to the brains of mice and cause death. Low in vitro EEV-yielding vaccinia strains were generally not able to disseminate in vivo or cause mouse mortality. The notable exception to this trend was strain WR, which, although releasing small amounts of virus in vitro, could nevertheless very effectively disseminate in vivo, causing a high rate of mouse mortality. Treatment with anti-envelope serum protected mice from a lethal vaccinia infection whereas antiserum to inactivated INV did not. These results indicate that the in vitro dissemination of vaccinia infection is mediated by EEV and implicate EEV as having a role in the in vivo dissemination.


Behavioral interventions for obesity in children and adults: Evidence base, novel approaches, and translation into practice.
Obesity in adults has nearly doubled in the past 30 years and has risen similarly in children and adolescents. Obesity affects all systems of the body, and the serious health consequences of obesity include an increased risk for cardiovascular disease, such as Type 2 diabetes or high blood pressure, which are occurring at ever younger ages. The present article introduces traditional behavioral weight loss strategies designed to change energy-balance behaviors (i.e., dietary and physical activity behaviors) and the contexts within which these interventions have typically been delivered. The applicability of findings from behavioral economics, cognitive processing, and clinical research that may lead to more potent weight loss and weight loss maintenance interventions are also considered. Given the pervasiveness of obesity, this article concludes with a discussion of efforts toward wider scale dissemination and implementation of behavioral treatments designed to address obesity and to reduce the risk of cardiovascular disease. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


[Sweet's syndrome associated with acute myeloid leukemia. Report of one case].
Sweet's syndrome, also known as acute febrile neutrophilic dermatosis, is characterized by fever, neutrophilia, erythematous and tender skin lesions that typically show a diffuse infiltrate of neutrophils in the upper dermis. This disorder has been associated with myeloproliferative syndromes. We report the case of a 53-year-old woman with an acute myeloid leukemia, presenting a Sweet's syndrome. A worsening of cutaneous lesions injuries was observed when granulocyte colony stimulating factor was added to treatment.


The impact of lockdown during the COVID-19 pandemic on mental and social health of children and adolescents.
During the COVID-19 pandemic in the Netherlands, governmental regulations resulted in a lockdown for adults as well as children/adolescents. Schools were closed and contact with other people was limited. In this cross-sectional, population-based study, we aimed to investigate the mental/social health of children/adolescents during COVID-19 lockdown. Two representative samples of Dutch children/adolescents (8-18 years) before COVID-19 (2018, N = 2401) and during lockdown (April 2020, N = 844) were compared on the Patient-Reported Outcomes Measurement Information System (PROMIS) domains: global health, peer relationships, anxiety, depressive symptoms, anger, sleep-related impairment by linear mixed models and calculating relative risks (RR (95% CI)) for the proportion of severe scores. Variables associated with worse mental/social health during COVID-19 were explored through multivariable regression models. The impact of COVID-19 regulations on the daily life of children was qualitatively analyzed. Participants reported worse PROMIS T-scores on all domains during COVID-19 lockdown compared to before (absolute mean difference range 2.1-7.1 (95% CI 1.3-7.9). During lockdown, more children reported severe Anxiety (RR = 1.95 (1.55-2.46) and Sleep-Related Impairment (RR = 1.89 (1.29-2.78) and fewer children reported poor Global Health (RR = 0.36 (0.20-0.65)). Associated factors with worse mental/social health were single-parent family, ≥ three children in the family, negative change in work situation of parents due to COVID-19 regulations, and a relative/friend infected with COVID-19. A large majority (> 90%) reported a negative impact of the COVID-19 regulations on daily life. This study showed that governmental regulations regarding lockdown pose a serious mental/social health threat on children/adolescents that should be brought to the forefront of political decision-making and mental healthcare policy, intervention, and prevention.


ORAI1 channel gating and selectivity is differentially altered by natural mutations in the first or third transmembrane domain.
Gain-of-function mutations in the highly selective Ca2+ channel ORAI1 cause tubular aggregate myopathy (TAM) characterized by muscular pain, weakness and cramping. TAM-associated mutations in ORAI1 first and third transmembrane domain facilitate channel opening by STIM1, causing constitutive Ca2+ influx and increasing the currents evoked by Ca2+ store depletion. Mutation V107M additionally decreases the channel selectivity for Ca2+ ions and its inhibition by acidic pH, while mutation T184M does not alter the channel sensitivity to pH or to reactive oxygen species. The ORAI blocker GSK-7975A prevents the constitutive activity of TAM-associated channels and might be used in therapy for patients suffering from TAM. Skeletal muscle differentiation relies on store-operated Ca2+ entry (SOCE) mediated by STIM proteins linking the depletion of endoplasmic/sarcoplasmic reticulum Ca2+ stores to the activation of membrane Ca2+ -permeable ORAI channels. Gain-of-function mutations in STIM1 or ORAI1 isoforms cause tubular aggregate myopathy (TAM), a skeletal muscle disorder with muscular pain, weakness and cramping. Here, we characterize two overactive ORAI1 mutants from patients with TAM: V107M and T184M, located in the first and third transmembrane domain of the channel. When ectopically expressed in HEK-293T cells or human primary myoblasts, the mutated channels increased basal and store-operated Ca2+ entry. The constitutive activity of V107M, L138F, T184M and P245L mutants was prevented by low concentrations of GSK-7975A while the G98S mutant was resistant to inhibition. Electrophysiological recordings confirmed ORAI1-V107M constitutive activity and revealed larger STIM1-gated V107M- and T184M-mediated currents with conserved fast and slow Ca2+ -dependent inactivation. Mutation V107M altered the channel selectivity for Ca2+ ions and conferred resistance to acidic inhibition. Ca2+ imaging and molecular dynamics simulations showed a preserved sensitivity of T184M to the negative regulation by reactive oxygen species. Both mutants were able to mediate SOCE in Stim1-/- /Stim2-/- mouse embryonic fibroblasts expressing the binding-deficient STIM1-F394H mutant, indicating a higher sensitivity for STIM1-mediated gating, with ORAI1-T184M gain-of-function being strictly dependent on STIM1. These findings provide new insights into the permeation and regulatory properties of ORAI1 mutants that might translate into therapies against diseases with gain-of-function mutations in ORAI1.


Cutting edge: central nervous system plasmacytoid dendritic cells regulate the severity of relapsing experimental autoimmune encephalomyelitis.
Plasmacytoid dendritic cells (pDCs) have both stimulatory and regulatory effects on T cells. pDCs are a major CNS-infiltrating dendritic cell population during experimental autoimmune encephalomyelitis but, unlike myeloid dendritic cells, have a minor role in T cell activation and epitope spreading. We show that depletion of pDCs during either the acute or relapse phases of experimental autoimmune encephalomyelitis resulted in exacerbation of disease severity. pDC depletion significantly enhanced CNS but not peripheral CD4(+) T cell activation, as well as IL-17 and IFN-gamma production. Moreover, CNS pDCs suppressed CNS myeloid dendritic cell-driven production of IL-17, IFN-gamma, and IL-10 in an IDO-independent manner. The data demonstrate that pDCs play a critical regulatory role in negatively regulating pathogenic CNS CD4(+) T cell responses, highlighting a new role for pDCs in inflammatory autoimmune disease.


Probing the Cytotoxic Signaling Induced by Eupenifeldin in Ovarian Cancer Models.
High-grade serous ovarian cancer (HGSOC) is the most common and lethal ovarian cancer histotype. Lack of early detection methods, limited therapeutic agents, and low 5-year survival rate reflect the urgent need to develop new therapies. Eupenifeldin, a bistropolone, originally isolated from Eupenicillium brefeldianum, is a cytotoxic fungal metabolite. In three HSGOC cell lines (OVCAR3, OVCAR5, OVCAR8), eupenifeldin was found to have an IC50 value less than 10 nM, while 10 times higher concentrations were required for cytotoxicity in nontumorigenic fallopian tube secretory epithelial cell lines (FTSEC). An in vivo hollow fiber assay showed significant cytotoxicity in OVCAR3. Eupenifeldin significantly increased Annexin V staining in OVCAR3 and -8, but not OVCAR5. Eupenifeldin activated caspases 3/7 in OVCAR3, OVCAR5, and OVCAR8; however, cleaved PARP was only detected in OVCAR3. Quantitative proteomics performed on OVCAR3 implicated ferroptosis as the most enriched cell death pathway. However, validation experiments did not support ferroptosis as part of the cytotoxic mechanism of eupenifeldin. Autophagic flux and LC3B puncta assays found that eupenifeldin displayed weak autophagic induction in OVCAR3. Inhibition of autophagy by cotreatment with bafilomycin reduced the toxicity of eupenifeldin, supporting the idea that induction of autophagy contributes to the cytotoxic mechanism of eupenifeldin.