Global HIV Incidence Analysis and Implications for Affordability using CAB-LA versus Continuous and Event-Driven Oral PrEP.
HPTN 083/084 trials showed up to 88% increased efficacy of long-acting cabotegravir (CAB-LA) versus continuous oral tenofovir/emtricitabine (TDF/FTC). However, CAB-LA's high price limits the number who can be treated within fixed prevention budgets. Global HIV prevention budgets are highly limited, with TDF/FTC widely available as a low-cost generic. In randomised clinical trials, event-driven TDF/FTC has shown similar preventative efficacy to continuous TDF/FTC. A systematic review of global HIV incidence studies was conducted. Weighted incidence was calculated in each at-risk population. HIV infection rates were evaluated for 5 prevention strategies, with additional HIV testing, education, and service access costs assumed for each ($18pppy). Assumed efficacies were 90% (continuous CAB-LA), 60% (continuous TDF/FTC), and 60% (event-driven TDF/FTC). Using weighted incidence and an assumed 100,000 target population, annual HIV infection rates by population were calculated, for each prevention strategy. 98 studies in 5,230,189 individuals were included. Incidence per 100 person-years (pys) ranged from 0.03 (Blood Donors) to 3.82 (People Who Inject Drugs). Using the Number Needed to Treat to Benefit (NNTB) for each strategy, the mean incidence of 2.6 per 100pys in at-risk populations and a 100,000 target population, current-price continuous CAB-LA cost $949,487 per HIV infection successfully prevented, followed by target-price CAB-LA ($11,453), continuous TDF/FTC ($4,231), then event-driven TDF/FTC ($1,923). High prices of CAB-LA limit numbers treatable within fixed budgets. Low-cost event-driven TDF/FTC consistently prevents the most HIV infections within fixed budgets.


CIP2A regulates proliferation and apoptosis of multiple myeloma cells.
Multiple myeloma (MM) is one of the most common causes of mortality from hematological malignancy in China. Recent studies have demonstrated that cancerous inhibitor of protein phosphatase 2A (CIP2A) may exhibit a role in promoting the growth of cancer; however, the function of CIP2A in MM remains unknown. In the present study, the expression and molecular mechanism underlying the effects of CIP2A in patients with MM and in MM cell lines were elucidated. Firstly, the expression of CIP2A was detected in patients with MM and in MM cell lines by reverse transcription‑quantitative polymerase chain reaction. Furthermore, silencing of CIP2A with short hairpin RNA was performed in MM cells, and the impact on the proliferation and apoptosis of RPMI‑8226 cells was analyzed (as endogenous CIP2A is highly expressed in RPMI‑8226 cell lines compared with other cells). CIP2A was significantly elevated in patients with MM and in MM cell lines, and silencing of CIP2A could inhibit the proliferation ability of RPMI‑8226 cells in vitro. In addition, CIP2A knockdown induced apoptosis and led to substantial reduction of c‑Myc protein levels in MM cell lines. This study suggested that CIP2A inhibition may provide a promising therapeutic strategy for patients with MM.


The impact of right ventricular stroke work on B-type natriuretic peptide levels in patients with mitral stenosis undergoing percutaneous mitral valvuloplasty.
We aimed to explore the relationship between brain natriuretic peptide (BNP) levels and right ventricular (RV) function in patients with mitral stenosis (MS), and to investigate the hemodynamic parameters that predict reduction of BNP levels after percutaneous mitral valvuloplasty (PMV). Few studies have evaluated BNP in the context of MS, specifically the impact of the RV stroke work (RVSW) on serum BNP levels has not been defined. Thirty patients with symptomatic rheumatic MS in sinus rhythm who were referred for a PMV were enrolled. Right and left heart pressures were obtained before and after valvuloplasty. RVSW index (RVSWI) was calculated by cardiac catheterization. Basal BNP levels were elevated in MS patients and correlated with several hemodynamic parameters including pulmonary pressure, pulmonary vascular resistance index, cardiac index (CI), and RVSWI. In multivariate analysis, CI and RVSWI were independent predictors of raised basal BNP levels. PMV resulted in a significant decrease in the RVSWI with a concurrent increase in CI (2.4 ± 0.43 to 2.9 ± 0.8 L/min/m(2), P = 0.010). Overall, plasma BNP levels significantly decreased from 124 (63/234) to 73 (48/148) pg/ml postvalvuloplasty. Multivariate analysis revealed that the reduction of left atrial (LA) pressure post-PMV was an independent predictor of change in BNP levels. Elevated baseline BNP level in MS patients was independently associated with CI and RVSWI. Plasma BNP levels were reduced after successful PMV, which was associated with the reduction of the LA pressure.


Discourse after closed head injury in young children.
This study examined narrative discourse in 23 children, ages 6 to 8 years, who sustained a severe closed head injury (CHI) at least 1 year prior to assessment. Narratives were analyzed at multiple levels using language and information structure measures. Results revealed significant discourse impairments in the CHI group on all measures of information structure, whereas differences in the linguistic domain failed to reach significance. In addition, effects of age at injury and lateralization of lesion on discourse were considered. Although no significant differences were found according to age at injury, a consistent pattern of generally poorer discourse scores was found for the early injured group (< 5 years). With regard to lesion focus, the group findings were unimpressive. However, preliminary examination of individual CHI cases with relatively large lateralized lesions suggested that the late injured children may show the language-brain patterns reported in brain-injured adults, whereas early injured children may not.


Efficacy of neutrophil elastase inhibitor on type A acute aortic dissection.
Surgery for type A acute aortic dissection (AAD) is associated with a high mortality and incidence of postoperative complications, including acute respiratory failure and coagulopathy. Aim of the study was to investigate the effects of sivelestat on pulmonary function and coagulopathy in patients undergoing surgery for AAD. Sixty patients undergoing emergency ascending replacement for AAD were divided into two groups. Group I was administered sivelestat intravenously from the beginning of surgery until extubation. Group II was not treated with sivelestat. The platelet count, antithrombin III (AT III) level, leukocyte count, C-reactive protein (CRP) level, prothrombin time (PT), activated partial thrombin time (APTT), and prothrombin time-international normalized ratio (PT-INR) were measured. The postoperative decrease of AT III and the platelet count on admission to the intensive care unit (ICU) and 3 hours later were significantly less in group I. The leukocyte count and the values of CRP, PT, APTT, and PT-INR did not differ significantly between the groups. The duration of mechanical ventilation after surgery tended to be shorter in group I. Sivelestat significantly reduced the postoperative decreases in AT III and platelet count in patients undergoing emergency surgery for AAD.


New members of the mammalian glycerophosphodiester phosphodiesterase family: GDE4 and GDE7 produce lysophosphatidic acid by lysophospholipase D activity.
The known mammalian glycerophosphodiester phosphodiesterases (GP-PDEs) hydrolyze glycerophosphodiesters. In this study, two novel members of the mammalian GP-PDE family, GDE4 and GDE7, were isolated, and the molecular basis of mammalian GP-PDEs was further explored. The GDE4 and GDE7 sequences are highly homologous and evolutionarily close. GDE4 is expressed in intestinal epithelial cells, spermatids, and macrophages, whereas GDE7 is particularly expressed in gastro-esophageal epithelial cells. Unlike other mammalian GP-PDEs, GDE4 and GDE7 cannot hydrolyze either glycerophosphoinositol or glycerophosphocholine. Unexpectedly, both GDE4 and GDE7 show a lysophospholipase D activity toward lysophosphatidylcholine (lyso-PC). We purified the recombinant GDE4 and GDE7 proteins and show that these enzymes can hydrolyze lyso-PC to produce lysophosphatidic acid (LPA). Further characterization of purified recombinant GDE4 showed that it can also convert lyso-platelet-activating factor (1-O-alkyl-sn-glycero-3-phosphocholine; lyso-PAF) to alkyl-LPA. These data contribute to our current understanding of mammalian GP-PDEs and of their physiological roles via the control of lyso-PC and lyso-PAF metabolism in gastrointestinal epithelial cells and macrophages.


Rapidly dynamic host cell heterogeneity in bacterial adhesion governs susceptibility to infection by Listeria monocytogenes.
Interactions between host cells and individual pathogenic bacteria determine the clinical severity of disease during systemic infection in humans. Vascular endothelial cells, which line the lumen of blood vessels, represent a critical barrier for a bacterium in the bloodstream. These cells adopt a myriad of phenotypes that may modulate their susceptibility to infection; however, the precise determinants of their heterogeneity in susceptibility are not known. Here, we show that heterogeneity in susceptibility to Listeria monocytogenes infection among primary human vascular endothelial cells can be attributed entirely to robust, preexisting host cell heterogeneity in bacterial adhesion, and we find no evidence for significant heterogeneity in later steps of infection. High susceptibility to adhesion decays rapidly, within 30-60 min. Thus, rapidly fluctuating, nongenetic variability in bacterial adhesion diversifies susceptibility to infection, both among host cells and within individual cells over time.


Sleep-stage correlates of hippocampal electroencephalogram in primates.
It has been demonstrated in the rodent hippocampus that rhythmic slow activity (theta) predominantly occurs during rapid eye movement (REM) sleep, while sharp waves and associated ripples occur mainly during non-REM sleep. However, evidence is lacking for correlates of sleep stages with electroencephalogram (EEG) in the hippocampus of monkeys. In the present study, we recorded hippocampal EEG from the dentate gyrus in monkeys overnight under conditions of polysomnographical monitoring. As result, the hippocampal EEG changed in a manner similar to that of the surface EEG: during wakefulness, the hippocampal EEG showed fast, desynchronized waves, which were partly replaced with slower waves of intermediate amplitudes during the shallow stages of non-REM sleep. During the deep stages of non-REM sleep, continuous, slower oscillations (0.5-8 Hz) with high amplitudes were predominant. During REM sleep, the hippocampal EEG again showed fast, desynchronized waves similar to those found during wakefulness. These results indicate that in the monkey, hippocampal rhythmic slow activity rarely occurs during REM sleep, which is in clear contrast to that of rodents. In addition, the increase in the slower oscillations of hippocampal EEG during non-REM sleep, which resembled that of the surface EEG, may at least partly reflect cortical inputs to the dentate gyrus during this behavioral state.


Uptake of inorganic and organic nutrient species during cultivation of a Chlorella isolate in anaerobically digested dairy waste.
A natural assemblage of microalgae from a facultative lagoon system treating municipal wastewater was enriched for growth in the effluents of an anaerobic digester processing dairy waste. A green microalga with close resemblance to Chlorella sp. was found to be dominant after multiple cycles of sub-culturing. Subsequently, the strain (designated as LLAI) was isolated and cultivated in 20× diluted digester effluents under various incident light intensities (255-1,100 µmoles m-2 s-1 ) to systematically assess growth and nutrient utilization. Our results showed that LLAI production increased with increasing incident light and a maximum productivity of 0.34 g L-1 d-1 was attained when the incident irradiance was 1,100 µmoles m-2 s-1 . Lack of growth in the absence of light indicated that the cultures did not grow heterotrophically on the organic compounds present in the medium. However, the cultures were able to uptake organic N and P under phototrophic conditions and our calculations suggest that the carbon associated with these organic nutrients contributed significantly to the production of biomass. Overall, under high light conditions, LLAI cultures utilized half of the soluble organic nitrogen and >90% of the ammonium, orthophosphate, and dissolved organic phosphorus present in the diluted waste. Strain LLAI was also found to accumulate triacylglycerides (TAG) even before the onset of nutrient limitation and a lipid productivity of 37 mg-TAG L-1 d-1 was measured in cultures incubated at an incident irradiance of 1,100 µmoles m-2 s-1 . The results of this study suggest that microalgae isolates from natural environments are well-suited for nutrient remediation and biomass production from wastewater containing diverse inorganic and organic nutrient species. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1336-1342, 2016.


Antibiotics in the treatment of periodontitis.
The emerging worldwide problem of bacterial resistance has resulted from overuse and misuse of systemic antibiotics. It is appropriate therefore to review periodontal treatment strategies to determine whether systemic antibiotics have a role to play in the management of periodontitis. For the great majority of patients presenting with periodontal conditions, systemic antibiotics are not indicated. Instead, treatment should focus on mechanical disruption of plaque biofilms, plaque control and risk factor modification. Systemic antibiotics may be indicated in severe spreading infections, some aggressive forms of periodontitis, and necrotizing periodontal conditions. These conditions present infrequently in general practice, most will require referral to a periodontal specialist and the decision to use systemic antimicrobials as part of periodontal management is more appropriately taken within a specialist centre. Systemic antibiotics are not indicated in the vast majority of periodontal conditions encountered in general dental practice.


The utility of 18F-fluorodeoxyglucose positron emission tomography for early diagnosis of radiation-induced myocardial damage.
We evaluated the clinical significance of focal increased uptake in the basal myocardium on F-fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with esophageal cancer after radiotherapy. Between August 2004 and July 2005, a total of 64 patients who had been irradiated for thoracic esophageal cancer underwent FDG-PET at least three months after the completion of chemoradiotherapy. Some patients showed increased FDG uptake in the basal portion of the myocardium. To clarify the clinical significance of these findings, further examinations of hearts were performed. The dose distribution in the myocardium with high FDG uptake was also analyzed retrospectively. Thirteen (20.3%) of the 64 patients showed high FDG uptake in the basal myocardium corresponding to the irradiated fields compared with FDG uptake in the myocardium outside the irradiated fields. Eight of the 13 patients consented to undergo examinations of the heart. Five of those eight patients showed low 123I-BMIPP uptake and four showed low 201TlCl uptake in the myocardium corresponding with high FDG uptake regions. In two patients, delayed enhancement was found in some parts of the area with high FDG uptake on Gd-DTPA magnetic resonance imaging (MRI), and the delay-enhanced lesion showed hypokinesia on cine-MRI in one patient. FDG-PET often shows focal increased uptake in the basal myocardium after radiotherapy for esophageal cancer. This finding indicates the possibility of radiation-induced cardiac damage, and cardiac function and symptoms of such patients should be followed carefully.


Rapid attentional adaptations due to language (monolingual vs bilingual) context.
Does our general attentional system adapt to the language context we are in? Bilinguals switch between contexts in which only one language is present or both languages are equiprobable. Previous research by Wu and Thierry (2013) suggested that the bilingual language context can modify the workings of inhibitory control mechanisms. Here we investigate whether this can be replicated and whether other attentional mechanisms (alerting and orienting) also adjust depending on whether we are in a bilingual or a monolingual situation. Bilinguals performed the Attentional Network Task (ANT) task, which allows us to measure three types of attentional processes: alerting, orienting and executive control. Crucially, while performing the ANT task, participants also saw words presented in only one language (e.g., Catalan; monolingual context) or in two languages (Catalan and Spanish; bilingual context); this allowed us to assess whether the three attentional processes would be modified by language context. Compared to the monolingual context, in the bilingual context the target-P3 amplitude was enhanced for the alerting and executive control networks but not for the orienting network. This suggests that bilinguals' state of alertness was enhanced when surrounded by words from two languages. Exploratory analyses reveal that within the bilingual context, language switches have an alerting effect, as indexed by a greater target-N1, thus impacting upcoming visual processing of the flanker. Response hand activation is speeded up for congruent trials in a similar way that arbitrary alerting cues speed them up. This speed-up was reflected in a greater LRP in the bilingual context, but it was not reflected in behavioral measures (RTs or ACC). Thus, a bilingual context can enhance attentional capacity towards non-linguistic information. It also reveals how flexible the cognitive system is.


Induction of immunologic memory in infants primed with Haemophilus influenzae type b conjugate vaccines.
The ability of different Haemophilus influenzae type b conjugate vaccines to induce immunologic memory was compared in 381 infants who were vaccinated with one of three conjugate vaccines beginning at 2 months of age. All infants were vaccinated with unconjugated type b capsular polysaccharide, polyribosylribitol phosphate (PRP), at 12 months. In each group, high antibody responses were detected by 6-9 days after vaccination. One month after receiving PRP, infants primed with PRP conjugated to the outer membrane protein of Neisseria meningitidis or PRP oligomers conjugated to the cross-reactive mutant diphtheria protein, CRM197, had twofold higher total anti-PRP antibody concentrations than did infants primed with PRP conjugated to tetanus toxoid (P < .005). After the conjugate and the PRP boost, notable differences were present among vaccine groups with respect to the magnitude of the IgG anti-PRP antibody concentrations and light chain variable region usage as determined by idiotypic analysis. Thus, each of the conjugate vaccines primed infants for the ability to evoke memory antibody responses to PRP, but qualitative and quantitative differences in priming induced by different vaccines may affect their ability to confer protection against disease.


A primary left atrial leiomyosarcoma mimicking myxoma: echocardiographic findings.
Echocardiography is the initial imaging modality to delineate the cardiac mass. Clinically echocardiographic information about morphology, location, motion and hemodynamic consequences of the tumor is very important for decision making in terms of additional imaging studies and treatment. We present a case of left atrial leiomyosarcoma masquerading as myxoma preoperatively and discuss the echocardiographic features for distinguishing leiomyosarcoma from a benign tumor, such as myxoma.


Maxillo-mandibular fixation trends in the United States.
Questionnaires were sent to directors of the 118 oral and maxillofacial surgery training programs in the United States and its territories to survey current trends and recent experience with maxillo-mandibular fixation (MMF). Eighty-eight percent of the respondents indicated that it was customary to keep wire cutters at the bedsides of hospitalized patients who were in MMF, and 49% discharged patients in MMF with wire cutters. The respondents were aware of 17 inpatients and 5 outpatients in their programs who had required emergency release from MMF during the previous 5 years. Emergent MMF release is a rare event. The availability of wire cutters at the hospital bed or issuance of wire cutters to outpatients in MMF should be based on a case-by-case consideration of the procedure performed, postoperative bleeding, vomiting potential, edema, airway integrity, patient dexterity, and patient compliance.


Cortical myoclonus: sensorimotor hyperexcitability.
Cortical or cortical reflex myoclonus is characterized by abnormally enlarged cortical somatosensory evoked potentials (giant SEPs), which most likely reflect pathologically hyperexcitable sensorimotor cortex. To clarify the pathogenesis of myoclonus of cortical origin, we simultaneously recorded SEPs and whole head somatosensory evoked magnetic fields (SEFs) following electric stimulation of the median nerve at the wrist in six patients with cortical myoclonus. N20m and enlarged P30m were observed in all patients and were localized at the posterior bank of the central sulcus (Brodmann area 3b of the primary somatosensory cortex). In addition, P25m and N35m components of SEFs were recognized in five and four patients, respectively. P25m component, that is, the magnetic counterpart of P25 in EEG, was the earliest cortical component showing enhancement in patients. Multidipole analysis combined with magnetic resonance imaging (MRI) coregistration revealed that the generators of P25m were in the precentral gyrus in four patients and in the postcentral gyrus in one patient. The second SEFs around 200 msec after the single stimulus were recorded in three patients at area 3b (repetitive SEFs); two of whom showed negative as well as positive myoclonus. The importance of motor cortex for the generation of cortical reflex myoclonus was thus demonstrated. The pathologic features of SEFs suggest abnormal excitability of primary sensorimotor cortex.


Noise exposure alters long-term neural firing rates and synchrony in primary auditory and rostral belt cortices following bimodal stimulation.
We previously demonstrated that bimodal stimulation (spinal trigeminal nucleus [Sp5] paired with best frequency tone) altered neural tone-evoked and spontaneous firing rates (SFRs) in primary auditory cortex (A1) 15 min after pairing in guinea pigs with and without noise-induced tinnitus. Neural responses were enhanced (+10 ms) or suppressed (0 ms) based on the bimodal pairing interval. Here we investigated whether bimodal stimulation leads to long-term (up to 2 h) changes in tone-evoked and SFRs and neural synchrony (correlate of tinnitus) and if the long-term bimodal effects are altered following noise exposure. To obviate the effects of permanent hearing loss on the results, firing rates and neural synchrony were measured three weeks following unilateral (left ear) noise exposure and a temporary threshold shift. Simultaneous extra-cellular single-unit recordings were made from contralateral (to noise) A1 and dorsal rostral belt (RB); an associative auditory cortical region thought to influence A1, before and after bimodal stimulation (pairing intervals of 0 ms; simultaneous Sp5-tone and +10 ms; Sp5 precedes tone). Sixty and 120 min after 0 ms pairing tone-evoked and SFRs were suppressed in sham A1; an effect only preserved 120 min following pairing in noise. Stimulation at +10 ms only affected SFRs 120 min after pairing in sham and noise-exposed A1. Within sham RB, pairing at 0 and +10 ms persistently suppressed tone-evoked and SFRs, while 0 ms pairing in noise markedly enhanced tone-evoked and SFRs up to 2 h. Together, these findings suggest that bimodal stimulation has long-lasting effects in A1 that also extend to the associative RB that is altered by noise and may have persistent implications for how noise damaged brains process multi-sensory information. Moreover, prior to bimodal stimulation, noise damage increased neural synchrony in A1, RB and between A1 and RB neurons. Bimodal stimulation led to persistent changes in neural synchrony in intact A1 and RB that were also altered by noise-exposure. Given that increases in neural synchrony following noise may be consistent with tinnitus onset, these data implicate that both A1 and RB may be involved in the etiology of phantom sound perception. These data also suggest that noise alters the effects of bimodal stimulation on neural synchrony in A1 and RB; an effect that may also lead to changes in tinnitus perception.


Viral Spread to Enteric Neurons Links Genital HSV-1 Infection to Toxic Megacolon and Lethality.
Herpes simplex virus 1 (HSV-1), a leading cause of genital herpes, infects oral or genital mucosal epithelial cells before infecting the peripheral sensory nervous system. The spread of HSV-1 beyond the sensory nervous system and the resulting broader spectrum of disease are not well understood. Using a mouse model of genital herpes, we found that HSV-1-infection-associated lethality correlated with severe fecal and urinary retention. No inflammation or infection of the brain was evident. Instead, HSV-1 spread via the dorsal root ganglia to the autonomic ganglia of the enteric nervous system (ENS) in the colon. ENS infection led to robust viral gene transcription, pathological inflammatory responses, and neutrophil-mediated destruction of enteric neurons, ultimately resulting in permanent loss of peristalsis and the development of toxic megacolon. Laxative treatment rescued mice from lethality following genital HSV-1 infection. These results reveal an unexpected pathogenesis of HSV associated with ENS infection.


Cyclodextrin-gated mesoporous silica nanoparticles as drug carriers for red light-induced drug release.
Long wavelength light-responsive drug delivery systems based on mesoporous silica nanoparticles (MSNs) have attracted much attention in the last few years. In this paper, a red light (660 nm)-responsive drug delivery system based on low-cost cyclodextrin (CD)-gated MSNs containing a photodynamic therapy (PDT) photosensitizer (Chlorin e6, Ce6) was developed for the first time. The drug release experiment in water demonstrated that with the irradiation of red light, Ce6 can be excited to generate singlet oxygen, which can further cleave the singlet oxygen sensitive linker to trigger the departure of CD and the release of cargo. Further in vitro release experiments confirmed that cargo can be released from MSNs with the irradiation of red light and spread into the entire cell. The relative low power density (0.5 W cm-2) of excitation light together with the short irradiation time (one-three min) result in a low light dose (30-90 J cm-2) for the drug delivery, contributing to their potential clinical applications.


Sirt6 Activation Ameliorates Inflammatory Bone Loss in Ligature-Induced Periodontitis in Mice.
Periodontitis is an inflammatory disease caused by microorganisms that induce the destruction of periodontal tissue. Inflamed and damaged tissue produces various inflammatory cytokines, which activate osteoclasts and induce alveolar bone loss and, eventually, tooth loss. Sirt6 expression suppresses inflammation and bone resorption; however, its role in periodontitis remains unclear. We hypothesized that Sirt6 has a protective role in periodontitis. To understand the role of Sirt6 in periodontitis, we compared periodontitis with ligature placement around the maxillary left second molar in 8-week-old control (C57BL/6J) male mice to Sirt6-overexpressing Tg (Sirt6Tg) mice, and we observed the resulting phenotypes using micro-CT. MDL801, a Sirt6 activator, was used as a therapy for periodontitis through oral gavage. Pro-inflammatory cytokines and increased osteoclast numbers were observed in alveolar bone tissue under periodontitis surgery. In the same condition, interestingly, protein levels from Sirt6 were the most downregulated among sirtuins in alveolar bone tissue. Based on micro-CT and CEJ-ABC distance, Sirt6Tg was observed to resist bone loss against ligature-induced periodontitis. Furthermore, the number of osteoclasts was significantly reduced in Sirt6Tg-ligated mice compared with control-ligated mice, although systemic inflammatory cytokines did not change. Consistent with this observation, we confirmed that bone loss was significantly reduced when MDL801, a Sirt6 activator, was included in the ligation mouse model. Our findings demonstrate that Sirt6 activation prevents bone loss against ligature-induced periodontitis. Thus, a Sirt6 activator may provide a new therapeutic approach for periodontitis.


In vitro model of Bartonella henselae-induced angiogenesis.
Bartonella henselae is a gram-negative pathogen that causes angiogenesis. Here, I establish in vitro models to study Bartonella-induced blood vessel formation. I found that B. henselae induces long-term endothelial survival and tubular differentiation within type I collagen matrix.


Detection of fungi in clinical specimens by phase-contrast microscopy.
During 1973 and 1974, the following fungi were detected in clinical specimens by using phase-contrast microscopy: Blastomyces dermatitidis, 5; Coccidioides immitis, 3; Cryptococcus neoformans, 11; other yeasts 918; dermatophytes, 863; Mucor species, 1; and Aspergillus fumigatus, 16. This technique allows rapid detection and, in many instances, immediate identification of fungi in clinical specimens.


Biopolymeric Anticorrosion Coatings from Cellulose Nanofibrils and Colloidal Lignin Particles.
This study presents a process for preparation of cellulose-lignin barrier coatings for hot-dip galvanized (HDG) steel by aqueous electrophoretic deposition. Initially, a solution of softwood kraft lignin and diethylene glycol monobutyl ether was used to prepare an aqueous dispersion of colloidal lignin particles (CLPs) via solvent exchange. Analysis of the dispersion showed that it comprised submicron particles (D = 146 nm) with spherical morphologies and colloidal stability (ζ-potential = -40 mV). Following successful formation, the CLP dispersion was mixed with a suspension of TEMPO-oxidized cellulose nanofibers (TOCN, 1 and 2 g·L-1) at a fixed volumetric ratio (1:1, TOCN-CLPs), and biopolymers were deposited onto HDG steel surfaces at different potentials (0.5 and 3 V). The effects of these variables on coating formation, dry adhesion, and electrochemical properties (3.5% NaCl) were investigated. The scanning electron microscopy results showed that coalescence of CLPs occurs during the drying of composite coatings, resulting in formation of a barrier layer on HDG steel. The scanning vibrating electrode technique results demonstrated that the TOCN-CLP layers reduced the penetration of the electrolyte (3.5% NaCl) to the metal-coating interface for at least 48 h of immersion, with a more prolonged barrier performance for 3 V-deposited coatings. Additional electrochemical impedance spectroscopy studies showed that all four coatings provided increased levels of charge transfer resistance (Rct)-compared to bare HDG steel-although coatings deposited at a higher potential (3 V) and a higher TOCN concentration provided the maximum charge transfer resistance after 15 days of immersion (13.7 cf. 0.2 kΩ·cm2 for HDG steel). Overall, these results highlight the potential of TOCN-CLP biopolymeric composites as a basis for sustainable corrosion protection coatings.


The composition and properties of the Escherichia coli 5-S RNA-protein complex.
At a high concentration of MgCl2 (30 mM) and a low concentration of proteins from the 50-S subunit (0.2 mg/ml), only three proteins, L15, L18 and L25, bind to 5-S RNA in significant amounts. On the other hand, in a buffer containing only 1 mM Mg Cl2, but otherwise at the same ionic strength (0.2 M), or at a protein concentration about 1.5 mg/ml, a large, stable complex can form between immobilized 5-S RNA and 50-S ribosomal proteins. This complex contains proteins L2, L3, L5, L15, L16, L17, L18, L21, L22, L25, L33 and L34, and it possess properties relevant to the function of the 50-S subunit; it has a binding site for deacylated tRNA, with a dissociation constant of 4.5 x 10(-7) M. The complex formed with 5-S RNA immobilized on an affinity column interacts also with 30-S subunits. The 5-S RNA-protein complex is interpreted as a sub-ribosomal domain which includes a considerable fraction of the peptidyl transferase center of the Escherichia coli ribosome.


Immunological cross-reactivity between simian virus 40 large T antigen and D2 hybrid T antigen.
A specific antiserum was raised in rabbits against D2 hybrid T antigen that had been purified from HeLa cells infected with the adenovirus/simian virus 40 hybrid, Ad2(+)D2. The specificity of this serum was compared with that of a conventional hamster antiserum against simian virus 40-induced tumors by immunoprecipitation and by a new radioimmune assay that can detect nanogram quantities of D2 hybrid T antigen.


Weight Gain and the Risk of Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers.
Weight gain and other anthropometric measures on the risk of ovarian cancer for women with BRCA mutations are not known. We conducted a prospective analysis of weight change since age 18, height, body mass index (BMI) at age 18, and current BMI and the risk of developing ovarian cancer among BRCA1 and BRCA2 mutation carriers. In this prospective cohort study, height, weight, and weight at age 18 were collected at study enrollment. Weight was updated biennially. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for ovarian cancer. This study followed 4,340 women prospectively. There were 121 incident cases of ovarian cancer. Weight gain of more than 20 kg since age 18 was associated with a 2-fold increased risk of ovarian cancer, compared with women who maintained a stable weight (HR, 2.00; 95% CI, 1.13-3.54; P = 0.02). Current BMI of 26.5 kg/m2 or greater was associated with an increased risk of ovarian cancer in BRCA1 mutation carriers, compared with those with a BMI less than 20.8 kg/m2 (Q4 vs. Q1 HR, 2.13; 95% CI, 1.04-4.36; P = 0.04). There were no significant associations between height or BMI at age 18 and risk of ovarian cancer. Adult weight gain is a risk factor for ovarian cancer in women with a BRCA1 or BRCA2 mutation. These findings emphasize the importance of maintaining a healthy body weight throughout adulthood in women at high risk for ovarian cancer.


Relaxed core projector-augmented-wave method.
We extend the full-potential projector-augmented-wave method beyond the frozen core approximation, i.e., include the self-consistent optimization of the core charge density, in such a manner that the valence wave functions remain orthogonal to the core. The method consists of an on-the-fly repseudization of the all-electron problem, solving for the self-consistent core charge density within a spherical approximation. The key ideas in our procedure are to keep the projector functions fixed throughout the electronic minimization and to derive the new pseudopartial waves from these original projector functions, at each step of the electronic minimization procedure. Results of relaxed core calculations for atomic interconfigurational energies, structural energy differences between bulk phases of Fe, atomization energies of a subset of Pople's G2-1 set, and the Rh 3d surface core level shifts for the (log3 x log3)-Rh(111) surface at 1/3 CO coverage are presented.


Formation of a standing-light pulse through collision of gap solitons.
Results of a systematic theoretical study of collisions between moving solitons in a fiber grating are presented. Various outcomes of the collision are identified, the most interesting one being merger of the solitons into a single zero-velocity pulse, which suggests a way to create pulses of "standing light." The merger occurs with the solitons whose energy takes values between 0.15 and 0.35 of the limit value, while their velocity is limited by approximately 0.2 of the limit light velocity in the fiber. If the energy is larger, another noteworthy outcome is acceleration of the solitons as a result of the collision. In the case of mutual passage of the solitons, inelasticity of the collision is quantified by the energy-loss share. Past the soliton's stability limit, the collision results in strong deformation and subsequent destruction of the solitons. Simulations of multiple collisions of two solitons in a fiber-loop configuration are performed too. In this case, the maximum velocity admitting the merger increases to approximately 0.4 of the limit velocity. The influence of an attractive local defect on the collision is also studied, with the conclusion that the defect does not alter the overall picture, although it traps a small-amplitude pulse. Related effects in single-soliton dynamics are considered too, the most important one being the possibility of slowing down the soliton (reducing its velocity to the above-mentioned values that admit fusion of colliding solitons) by passing it through an apodized fiber grating, i.e., one with a gradually increasing Bragg reflectivity. Additionally, transformation of an input sech signal into a gap soliton (which is quantified by the share of lost energy), and the rate of decay of a quiescent gap soliton in a finite fiber grating, due to energy leakage through loose edges, are also studied.


Mislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3.
Severe forms of dilated cardiomyopathy (DCM) are associated with point mutations in the alternative splicing regulator RBM20 that are frequently located in the arginine/serine-rich domain (RS-domain). Such mutations can cause defective splicing and cytoplasmic mislocalization, which leads to the formation of detrimental cytoplasmic granules. Successful development of personalized therapies requires identifying the direct mechanisms of pathogenic RBM20 variants. Here, we decipher the molecular mechanism of RBM20 mislocalization and its specific role in DCM pathogenesis. We demonstrate that mislocalized RBM20 RS-domain variants retain their splice regulatory activity, which reveals that aberrant cellular localization is the main driver of their pathological phenotype. A genome-wide CRISPR knockout screen combined with image-enabled cell sorting identified Transportin-3 (TNPO3) as the main nuclear importer of RBM20. We show that the direct RBM20-TNPO3 interaction involves the RS-domain, and is disrupted by pathogenic variants. Relocalization of pathogenic RBM20 variants to the nucleus restores alternative splicing and dissolves cytoplasmic granules in cell culture and animal models. These findings provide proof-of-principle for developing therapeutic strategies to restore RBM20's nuclear localization in RBM20-DCM patients.


Arsenic and breast cancer: a systematic review of epidemiologic studies.
Arsenic is one of the heavy metals known to be a cause of cancer and many other serious human health problems. The International Agency for Research on Cancer (IARC), has classified arsenic as a Group 1 carcinogen. Studies were performed in different populations to investigate the association between arsenic and breast cancer and the present paper attempts to review these studies. Accessible electronic resources including, PubMed, Web of Knowledge, Science Direct and Scopus and Google Scholar were searched, with relevant phrases up to October 30, 2016. All articles were reviewed by two people separately and among them, original epidemiologic studies that investigated the association between breast cancer and exposure to arsenic were included. Eventually seven articles were selected from 126 retrieved articles. Although three studies (one case-control and two ecological) were not able to show a significant affect, others provide some evidence of a relation between arsenic and breast cancer in specific subgroups. Exposure to arsenic may increase the risk of breast cancer. The strength of this relation can vary due to regional and individual differences.


[Pharmacological interactions in patients treated with oral anticoagulants in a rural health area].
To estimate the prevalence of drugs that interact with oral anticoagulants and establish relationships between variables and haemorrhagic complications. Longitudinal, retrospective study of patient anticoagulant. Colmenar basic health area, Malaga, Spain. Patients on anticoagulants followed up in primary care. Indications, time of follow-up, value of last prothrombin time (INR), complications and therapeutic groups of major use. The 74.2% of the patients had a prothrombin time (INR) in the therapeutic range; 16.14% had minor complications; 60.2% of the patients complied with the criteria of multiple medication and 88.2% complied with the criteria of multiple medication in the last 6 months. The drugs used with a higher capacity to interact are: anti-ulcer (26.9%), locomotor system (10.7%), cardiovascular drugs (2.2%), lipid lowering drugs (8.6%), and antidiabetics (17.2%). The number of drugs used in the last 6 months is associated with the presence of haemorrhagic complications (odds ratio [OR], 1.10). Allopurinol and pantoprazole had a significant relationship with the presence of minor haemorrhages (OR, 19.25 and 7.37, respectively). The variables associated with the presence of a haemorrhage were: allopurinol (OR, 25.84), number of controls with an INR outside the therapeutic range in the last 6 months (OR, 1.31) and time on treatment (OR, 1.07). The percentage of patients within the therapeutic range in the last determination of INR indicates good quality. The number of minor complications exceeded the consensus standard for the control of patients on anticoagulants. The use of drugs with a higher capacity for interacting with oral anticoagulants was very high in the anti-ulcer and antidiabetic groups. Pharmacological control of patients on anticoagulants is necessary and multiple medications should be avoided.


Immunoreactivity for GABA, GAD65, GAD67 and Bestrophin-1 in the meninges and the choroid plexus: implications for non-neuronal sources for GABA in the developing mouse brain.
Neural progenitors in the developing neocortex, neuroepithelial cells and radial glial cells, have a bipolar shape with a basal process contacting the basal membrane of the meninge and an apical plasma membrane facing the lateral ventricle, which the cerebrospinal fluid is filled with. Recent studies revealed that the meninges and the cerebrospinal fluid have certain roles to regulate brain development. γ-aminobutyric acid (GABA) is a neurotransmitter which appears first during development and works as a diffusible factor to regulate the properties of neural progenitors. In this study, we examined whether GABA can be released from the meninges and the choroid plexus in the developing mouse brain. Immunohistochemical analyses showed that glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67), both of which are GABA-synthesizing enzymes, are expressed in the meninges. The epithelial cells in the choroid plexus express GAD65. GABA immunoreactivity could be observed beneath the basal membrane of the meninge and in the epithelial cells of the choroid plexus. Expression analyses on Bestrophin-1, which is known as a GABA-permeable channel in differentiated glial cells, suggested that the cells in the meninges and the epithelial cells in the choroid plexus have the channels able to permeate non-synaptic GABA into the extracellular space. Further studies showed that GAD65/67-expressing meningeal cells appear in a manner with rostral to caudal and lateral to dorsal gradient to cover the entire neocortex by E14.5 during development, while the cells in the choroid plexus in the lateral ventricle start to express GAD65 on E11-E12, the time when the choroid plexus starts to develop in the developing brain. These results totally suggest that the meninges and the choroid plexus can work as non-neuronal sources for ambient GABA which can modulate the properties of neural progenitors during neocortical development.


[First results after implantation of a pyrocarbon-endoprosthesis in patients with degenerative arthritis].
Evaluation of an unconstrained pyrocarbon prosthesis (Ascension) in the treatment of idiopathic degenerative arthritis of the proximal interphalangeal joint of the hand. In this study 10 patients (13 implants), that were treated with this type of prosthesis between February 2002 and January 2005 were clinically and radiologically studied. All but one patient were satisfied with the postoperative situation and would agree to another operation. A significant pain reduction was observed. The average ROM was 58 degrees. Five patients demonstrated a free extension, two patients had a swan neck deformity, which could be actively compensated for, and the remaining six patients had an extension deficit of 30-45 degrees. The average flexion was 76 degrees (+/-12 degrees). X-ray examination was unremarkable in eight patients with a regular position of the endoprosthesis. However, in five patients significant radiolucent lines (>or=1 mm) were observed. So far, a luxation of the prosthesis has not occurred and all implants are still in-situ. However, a dorsal tenoarthrolysis had to be performed in 3 patients. The results of this study show a high rate of patient satisfaction with a significant pain reduction. A missing osteointegration may be an explanation for the radiological results. The prosthesis has to be closely monitored in the future. Long-term results with a higher number of patients are necessary. A central registry for finger implants is recommended.


[The influence of substrate from extracellular matrix proteins on karyotypic variability of the Indian muntjac skin fibroblast two cell lines].
The effect of cell culture conditions on numerical and structural karyotypic variability was investigated in two Indian muntjac skin fibroblast "markerless" cell lines, M and MT. The cells cultivated on the substrate consisting of extracellular matrix proteins (ECM), synthesized by human mesenchymal stem cells (SC5-MSC). The character of cell distribution for chromosome number of cell line M changed after cultivation for 1 and 4 days as compared to control cells, which were cultured on hydrophilic surface without ECM-coating. These changes involve a significant decrease in frequency of cells with modal numbers of chromosomes and an increase in frequency of cells with lower chromosome numbers. Many new types of additional structural variants of the karyotype (SVK) appear. MT cell line, differing from M line in the number of homologous chromosomes, demonstrated similar with M line the character of cell distribution for chromosome number only for 1 day after cultivating on the ECM-substrate, but not after 4 days in the same culture conditions, no difference from the control cells was observed. The observed alterations seem to be due to disturbances in correct chromosome segregation process, which were caused by abrupt shift in the cell culture conditions. The analysis of the structural karyotypic variability revealed significant increase in frequency of chromosomal aberrations in M cell line for 1 and 4 days in culture on the ECM-substrate as compared to the control cells. The frequency of dicentric chromosomes (telomeric associations) was increased and constituted more than 50% of all chromosome aberrations. No increase in frequency of chromosome aberrations was observed for MT cells cultured in the same conditions. The obtained results show that the cell lines of the same origin but of different karyotypic structure react to substrate in a different way. In contrast to M line, in MT line a fast normalization of numerical karyotypic characteristics and no enhancement of structural karyotypic variability takes place. This provides a possibility to cultivate MT cell on the given protein substrate maintaining a balanced karyotypic structure characteristic of MT cell line.


Optimization and mechanisms of methylene blue removal by foxtail millet shell from aqueous water and reuse in biosorption of Pb(II), Cd(II), Cu(II), and Zn(II) for secondary times.
Foxtail millet shell as a raw efficient adsorbent was chosen first to eliminate methylene blue (MB) based on the uneven surface with many micropores, lots of negative charges, various functional groups, and some primary elements. And then the adsorbent-loaded MB was used to remove Pb(II), Cd(II), Cu(II), and Zn(II) from aqueous water for secondary adsorption. The effects of various factors were explored and optimized for removal rates of MB on the surface of the adsorbent using response surface methodology (RSM). After these factors were optimized, the confirmed removal rates of MB by the adsorbents were reached at 92.04, 93.05, and 93.36%, respectively from aqueous water while the solution pH was at 3, 7, and 11, respectively. The behavior of adsorption for MB dye was well-described by Langmuir isotherm (R2 = 0.9951), demonstrating favorable monolayer adsorption of MB on the adsorbent with the maximum capacity of 165.07 mg·L-1 in aqueous water. The data of MB dye removal was better assessed by pseudo-second-order model (R2 ≥ 0.9033), indicating an exchange of electrons has occurred between the adsorbent and MB particles, especially K and Ca ions of the adsorbent. In addition, the adsorbent-loaded MB has still presented better adsorption abilities for Pb(II), Cd(II), Cu(II), and Zn(II), respectively after MB removal in aqueous water. The adsorption mechanisms of adsorption were explored with the characterizations of the adsorbent before and after adsorption for the target pollutants by the methods of TEM, SEM, nitrogen physisorption isotherms, XPS, EDS, IR, and zeta potential classes. In summary, the results presented that the foxtail millet shell could be applied to remove MB dye effectively from aqueous water with the combined effects of electrostatic attraction, ion exchange, functional groups binding, and pore diffusion, but also, the adsorbent loaded with MB can be still applied to eliminate Pb(II), Cd(II), Cu(II), and Zn(II) by effects of electrostatic attraction and functional groups complexation in aqueous water.Novelty Statement In the present work, (a) the raw foxtail millet shell as a new potential adsorbent was used to remove MB dye from aqueous water for the first times, and operational variables of adsorption MB were investigated and optimized using response surface methodology, (b) the foxtail millet shell loaded MB as a disused adsorbent without any chemical reagent added was carried out to remove Pb(II), Cd(II), Cu(II), and Zn(II) ions, respectively in aqueous water for a secondary cycle, (c) adsorption mechanisms of MB removal on the adsorbent and the target heavy metals on the disused adsorbent were explored by the various analytical methods. This work provides evidence for the adsorption of MB on the natural adsorbent and improves the utilization efficiency of the used adsorbent on Pb(II), Cd(II), Cu(II), and Zn(II) removal in aqueous water.


Neurobiology confirms psychopathology. On the antagonism of psychosis and obsessive-compulsive syndromes.
Psychopathological concepts of the 19th and early 20th century postulated an antagonism between psychotic and obsessive-compulsive disorders, assuming obsessions and compulsions to have protective effects on psychotic disintegration. Although both disorders have been subject to intense multimodal research, their pathogeneses are yet to be fully understood. Here, we discuss recent neurobiological findings pointing towards opposite directions which are strongly reminiscent of the historical psychopathological antagonism. Obsessive-compulsive syndromes (OCS) are efficiently treated with serotonergic substances, while on the other hand modern antipsychotic drugs exert antiserotonergic effects. Especially these atypical antipsychotic substances, however, were found to involve the risk of inducing second-onset OCS. Dopamine antagonists are potent antipsychotic substances, whereas the partial dopamine agonist aripiprazole has been associated with an antiobsessive potency. Within the glutamatergic system, reduced NMDA-dependent glutamatergic neurotransmission is discussed to be one major pathomechanism of psychotic disorders, whilst NMDA antagonists have proven to be effective in improving treatment-resistant OCS. While neurogenetic findings seem to separate the populations in heterogeneous samples, detailed neuroimaging studies suggest that both disorders affect similar neurocircuits in different manners. With regard to these findings, future research on schizo-obsessive syndromes will have to be multimodal, integrating psychopathology, neuropsychology, functional imaging, neurogenetics and psychopharmacology. Prospective trials involving these methods might be able to elucidate the dysbalances of neurotransmission and to locate the neuroanatomical and neuropsychological correlates. In particular, this might contribute to defining schizophrenic patients at risk for developing second-onset OCS and to evaluating new treatment strategies in patients suffering from both psychosis and OCS.


[Polymorphism of C4 and factor B in type I diabetes].
The haplotypic frequencies of the fourth component of complement (C4) and factor B (Bf) have been determined in 44 Alsatian type 1 diabetics. An increased frequency of the rare allele Bf F1 (9.1% vs 1.5%) and of the silent alleles of C4 (C4 AQO: 21.6% vers 15.5% -C4 BQO: 29.6% vs 16.0%) was observed in diabetics in comparison to the general population of the same geographic area. A complete HLA haplotype determination has been obtained in 24 type 1 French diabetics. Three haplotypes were associated with the diabetic susceptibility: HLA-A30 CW5 B18 BfF1 C4A3BQO DR3 (18.75% vs 0.86%), HLA-A1 CW7 B8 BfS C4AQOB1 DR3 (15.58% vs 4.17%), HLA-A2 CW3 BW62 BfS C4A3B3 DR4 (6.25% vs 0.45%). The authors suggest that the silent alleles of C4 could modulate the expression of the diabetic susceptibility genes by lowering of the serum C4 hemolytic activity.


HERITABILITIES OF DOMINANCE-RELATED TRAITS IN MALE BANK VOLES (CLETHRIONOMYS GLAREOLUS).
A number of studies have shown that in several animal species females prefer dominant males as mating partners, but fewer attempts have been made to measure possible indirect benefits of this choice. One reason for this may be that, even though dominance is a widely used concept, the definition of dominance still remains controversial Furthermore, defining and measuring the heritability of social behaviors is problematic because they are not individual traits but, by definition, involve interactions between at least two individuals. In this study we estimated heritabilities and coefficients of additive genetic variances (CVA ) for male traits that are closely associated with dominance and female mating preferences in bank voles (Clethrionomys glareolus). The heritability values were estimated using father-offspring regression. All heritability estimates were relatively high ranging from 0.531 (urine marking) to 0.767 (preputial glands). The CVA -values indicated high levels of additive genetic variance especially in the characters most closely related to dominance: the weight of preputial glands and urine marking behavior. All phenotypic correlations among the traits measured were significantly positive and the genetic correlations were of similar magnitude as the corresponding phenotypic counterparts. Even though heritabilities may be lower in the natural environment than under controlled laboratory conditions, our results suggest that characters closely related to dominance may be at least partly genetically determined.


Production of antibodies against antigens released from human pancreatic tumour xenografts.
Antibodies directed against the antigen released from viable tumour cells during growth have been raised by cross-immunization of immunocompetent hairy litter-mates with serum from nude mice bearing pancreatic tumour xenografts. Antisera raised against the components released from a primary pancreatic tumour xenograft (WB) or from a tumour cell-line xenograft (GER) showed a titre greater than 1:625 against cultured pancreatic tumour cells by an I125-binding assay. Five out of 14 of the hairy litter-mates immunized with serum from the same tumour (GER) produced antisera that bound more strongly to pancreatic cancer cells than to 13 other non-pancreatic cell lines (binding ratio greater than 2). Absorption of the antisera with pure CEA reduced the level of binding by 11-25% without affecting the specificity for pancreatic tumour cells. The antibody response could be completely removed by absorption with pancreatic tumour cells, whereas 50% and 18% of the activity remained after absorption with normal pancreas homogenate and a mixed non-pancreatic tumour-cell pool, respectively. Immunofluorescent staining of pancreatic tumour sections indicated that the antibody was localized on the membrane of ductular epithelial cells. Challenge of immunocompetent mice using this procedure has produced a polyspecific antiserum with signs of selectivity for the circulating antigens released from pancreatic cancer cells, and may provide a route to the production of antibody against specific tumour components.


Ghrelin and eating behavior: evidence and insights from genetically-modified mouse models.
Ghrelin is an octanoylated peptide hormone, produced by endocrine cells of the stomach, which acts in the brain to increase food intake and body weight. Our understanding of the mechanisms underlying ghrelin's effects on eating behaviors has been greatly improved by the generation and study of several genetically manipulated mouse models. These models include mice overexpressing ghrelin and also mice with genetic deletion of ghrelin, the ghrelin receptor [the growth hormone secretagogue receptor (GHSR)] or the enzyme that post-translationally modifies ghrelin [ghrelin O-acyltransferase (GOAT)]. In addition, a GHSR-null mouse model in which GHSR transcription is globally blocked but can be cell-specifically reactivated in a Cre recombinase-mediated fashion has been generated. Here, we summarize findings obtained with these genetically manipulated mice, with the aim to highlight the significance of the ghrelin system in the regulation of both homeostatic and hedonic eating, including that occurring in the setting of chronic psychosocial stress.


Rasmussen's encephalitis in a 58-year-old female: still a variant?
We report the case of a 58-year-old female with clinical, radiological, and histopathological evidence of Rasmussen's encephalitis, representing the oldest confirmed case to date. The patient presented with complex partial seizures characterized by numbness of the left face and staring spells. These progressed to a state of epilepsia partialis continua with jerking of the left face, as well as severe cognitive impairment and loss of all communication. The patient responded well to Intravenous Immunoglobulin (IVIG) therapy despite early complications and with ongoing treatment is living independently with minimal cognitive impairment. This represents the oldest confirmed case of Rasmussen's encephalitis and suggests that this diagnosis should be considered in patients of any age with an appropriate clinical picture. We recommend IVIG as a first line therapy for adult cases of Rasmussen's encephalitis.


ZFAS1 Promotes Colorectal Cancer Metastasis Through Modulating miR-34b/SOX4 Targeting.
Colorectal cancer (CRC) belongs to one of gastric cancers that half of cases will develop metastasis, causing higher mortality or chemotherapy resistance. In the present study, the long noncoding RNA zinc finger antisense 1 (ZFAS1) was proved to have high expression level in CRC samples and in advanced stages. Additionally, it also indicated that p53 status is associated with ZFAS1 expression. Silencing ZFAS1 reduced both migration and invasion ability of DLD-1 and HCT-116 cells, which is relevant to the EMT process. In addition, it was confirmed that miR-34b, a tumor suppressor miRNA directly targeted ZFAS1 3' untranslated region (3'UTR) and inhibited ZFAS1 expression. Furthermore, miR-34b partially reversed the effect of ZFAS1 on migration and invasion ability in DLD-1 cells. Meanwhile, p53 status changes by overexpression vectors or siRNA turbulent ZFAS1 expression. Besides, it was found that in most cases, the oncogene SOX4 was directly targeted by miR-34b and positive correlated to ZFAS1 expression. Silencing ZFAS1 induced SOX4 expression in DLD-1 cells. Our data demonstrated the functions and mechanisms of ZFAS1 in CRC metastasis, illustrating miR-34b directly targets ZFAS1 and inhibits metastasis ability of CRC cells. SOX4 is also the direct downstream target of miR-34b, and silencing ZFAS1 can inhibit SOX4 though modulating miR-34b.


Molecular cloning and protein structure of a human blood group Rh polypeptide.
cDNA clones encoding a human blood group Rh polypeptide were isolated from a human bone marrow cDNA library by using a polymerase chain reaction-amplified DNA fragment encoding the known common N-terminal region of the Rh proteins. The entire primary structure of the Rh polypeptide has been deduced from the nucleotide sequence of a 1384-base-pair-long cDNA clone. Translation of the open reading frame indicates that the Rh protein is composed of 417 amino acids, including the initiator methionine, which is removed in the mature protein, lacks a cleavable N-terminal sequence, and has no consensus site for potential N-glycosylation. The predicted molecular mass of the protein is 45,500, while that estimated for the Rh protein analyzed in NaDodSO4/polyacrylamide gels is in the range of 30,000-32,000. These findings suggest either that the hydrophobic Rh protein behaves abnormally on NaDodSO4 gels or that the Rh mRNA may encode a precursor protein, which is further matured by a proteolytic cleavage of the C-terminal region of the polypeptide. Hydropathy analysis and secondary structure predictions suggest the presence of 13 membrane-spanning domains, indicating that the Rh polypeptide is highly hydrophobic and deeply buried within the phospholipid bilayer. In RNA blot-hybridization (Northern) analysis, the Rh cDNA probe detects a major 1.7-kilobase and a minor 3.5-kilobase mRNA species in adult erythroblasts, fetal liver, and erythroid (K562, HEL) and megakaryocytic (MEG01) leukemic cell lines, but not in adult liver and kidney tissues or lymphoid (Jurkat) and promyelocytic (HL60) cell lines. These results suggest that the expression of the Rh gene(s) might be restricted to tissues or cell lines expressing erythroid characters.


Contrasting role morality and professional morality: implications for practice.
The notion of role morality suggests individuals may adopt a different morality depending on the roles they undertake. Investigating role morality is important, since the mentality of role morality may allow agents to believe they can abdicate moral responsibility when acting in a role. This is particularly significant in the literature dealing with professional morality where professionals, because of their special status, may find themselves at odds with their best moral judgments. Here I tell four stories and draw out some distinctions. I conclude that role morality is a genuine and useful distinction. However, I suggest that the purported distinction between role morality and professional morality is over-determined. Therefore, alleged conflicts between the demands of role and profession (such as the different pressures on Pinto designers as employees and as engineers) are not conflicts between different kinds of demands, but rather conflicts arising from divergent roles that most workers will encounter regularly. Another analytical perspective is to look at moral choices at work in terms of power and the ability to bring about change. Finally, I draw the implication that we should stress moral awareness at a fairly abstract level for all employees and reinforce the moral primacy of individual choice.


Is there a difference between levodopa/ dopa-decarboxylase inhibitor and entacapone and levodopa/dopa-decarboxylase inhibitor dose fractionation strategies in Parkinson's disease patients experiencing symptom re-emergence due to wearing-off? The Honeymoon Study.
Two strategies to manage symptom re-emergence due to wearing-off with conventional levodopa/dopa-decarboxylase inhibitor (DDCI) therapy were compared in patients with Parkinson's disease (PD) in this randomized, open-label trial. PD patients receiving 3 daily doses of levodopa/DDCI were randomized to either levodopa/DDCI and entacapone or an increased dose frequency of levodopa/DDCI with or without an increased total daily dose (dose fractionation). After 1 month of treatment, patients were followed up for 1 year. A greater proportion of levodopa/DDCI and entacapone-treated patients had treatment success compared with dose-fractionated patients, according to investigator Clinical Global Impression of Change scores at 1 month (68 vs. 59%, respectively) and 1 year (60 vs. 51%, respectively). Mean 'off' time (time with symptoms) was improved in both groups at 1 month and 1 year, despite a reduction in the mean daily levodopa dose in the levodopa/DDCI and entacapone group at 1 month. The mean daily levodopa dose was increased in the dose fractionation group. At 1 month, there was a 4% reduction in patients experiencing dyskinesia with levodopa/DDCI and entacapone and a 3% increase with dose fractionation. These data suggest that levodopa/DDCI and entacapone reduces time with symptoms, the rate of motor complications and the daily levodopa dose compared with dose fractionation. However, as the observed differences were not statistically significant, further studies are required to confirm these results.


[Influence of needle bevel, age and sex on the appearance of post-puncture headaches].
Two types of intradural needles, 25 gauge (Qincke bevel) and 24 gauge (Sprotte type bevel) in 535 intradural anaesthesias were compared. Sprotte type needle is a modification of the Withacre needle. Postspinal total headache had an incidence of 8.9%, being significantly less (p less than 0.01) with the Sprotte needles (4.9 versus 11.8%). Spinal headache were significantly more frequent in women and in patients with an age less than 40 years, and there was no significance between the two needles when patients were older than forty. We conclude that Sprotte bevel needle decreases significatively the incidence of post-puncture headache if the patients are younger than forty, but it is an important fact that the different factors involved: age, sex and needle type, might be taken into account when we need conclusions to be drawn.


Coarctation of the aorta: stenting in children and adults.
Coarctation of the aorta may present in infants, children, or adults, and it requires treatment to prevent serious morbidity and mortality. Recent advances in equipment and a growing collective experience have made placement of balloon-expandable stents a safe and effective alternative to surgery or angioplasty in a growing range of patients. This review seeks to provide a working aid for stenting of coarctation of the aorta, based on the techniques and technical considerations in practice at our institution. Between 1989 and 2005, the Congenital Cardiovascular Interventional Study Consortium (CCISC), a consortium of 17 centers, of which our institution is the largest contributor, performed 588 stent placements for coarctation of the aorta. Of the 588 procedures, 580 (98.6%) were successful, as defined by reduction of the gradient to less than 20 mm Hg or increase of the ratio of the diameter of the coarctation area (CoA) to the diameter of the descending aorta (DAo) to at least 0.8. There were a total of 84 complications occurring in 69/588 (11.7%) cases. The most common significant complications were femoral access vessel related 15/588 (2.6%), aneurysm formation 13/588 (2.2%), aortic dissection 9/588 (1.5%), and cerebrovascular accident 6/588 (1.0%). There were two procedure-related deaths (0.3%) recorded in the 16-year period. Many of these significant complications occurred in the same patients. Balloon-expandable stents should be considered a safe and very effective treatment modality in a significant subset of patients with coarctation of the aorta.


Optimization of cyclosporine therapy.
Cyclosporine is a potent tool in the immunosuppressive armamentarium. It provides relatively selective inhibition of T-cell responses without dampening nonspecific resistance. However, its use is confounded by a pleiotropic array of side effects, the most important of which is renal dysfunction with the not uncommon sequelae of hypertension, hyperuricemia, and hyperkalemia. The hepatic injury associated with CyA administration, which is characterized by a chronic elevation of serum transaminase values, is potentiated by azathioprine or recrudescent or de novo viral infections. Finally, the proclivity of the drug to produce hyperlipidemia may jeopardize long-term survival; patients not infrequently require gemfibrizol and/or pravastatin therapy to control triglyceride and/or cholesterol levels, respectively. Two strategies appear to be useful. Our concentration-control strategy assesses CyA exposure by analyzing serial pharmacokinetic profiles, titering drug doses to achieve initial steady state concentrations of 400 ng/mL during continuous i.v. infusion, and to achieve average concentrations, namely AUC divided by dosing interval (in hours), of 550 ng/mL initially with trough levels of 200 ng/mL or above. Pretransplant pharmacokinetic profiling permits prediction of the appropriate initial i.v. dose in 73% of patients, and in combination with a posttransplant profile of the oral dose in about 60% of patients. The target oral concentrations are progressively reduced, thereby permitting prospective CyA control and minimizing adverse effects. The second synergistic drug strategy uses the median effect mathematical model to identify new drug combinations. The combination of CyA with RAPA, a macrolide which inhibits lymphokine signal transduction, and with BQR, a difluoro quinoline carboxylic acid analog that inhibits pyrimidine biosynthesis, permits at least a 20-fold reduction of the CyA dose in rat allograft models as well as prevents the activation of some CyA-resistant rejection pathways. Future investigations of pharmacologic strategies are undoubtedly likely to re-enforce the efficacy and safety of CyA administration for a range of immunologic disorders.


Acute regulation of circulating parathyroid hormone (PTH) molecular forms by calcium: utility of PTH fragments/PTH(1-84) ratios derived from three generations of PTH assays.
The quantitative evaluation of circulating PTH peaks revealed by PTH assays after HPLC separation constitutes the best way to study the behavior of PTH molecular forms, but it is also impractical. The objective of the study was to investigate the regulation of circulating PTH molecular forms by calcium through the use of PTH fragments/PTH (1-84) ratios derived from PTH assays with different specificities before and after HPLC separation of circulating PTH. CaCl2 and Na citrate were infused in eight volunteers. PTH was measured in serum and HPLC fractions at different calcium concentrations in PTH assays reacting with regions 1-2 (CA), 12-18 (T), and 65-69 (C) of the PTH structure. From hypo- to hypercalcemia, the C/CA ratio had the highest range (1.92 to 9.75; P < 0.001), and the C/T ratio had a higher range (1.69 to 6.11; P < 0.01) than the T/CA ratio (1.15 to 1.86). Human (h) PTH (1-84) represented 32.7 and 4.3% of circulating PTH in hypo- and hypercalcemic HPLC profiles, respectively. These numbers were 5 and 0.9% for amino-terminal (N)-PTH, an amino-terminal form of PTH distinct from hPTH (1-84), 7.3 and 6.8% for non-(1-84) PTH or large C-PTH fragments with a partially preserved N structure, and 54.9 and 88.1% for C-PTH fragments missing a N structure. The HPLC C-PTH fragments to hPTH (1-84) ratio had the most extensive range (1.67 to 20.58). Despite their quantitative differences, all ratios identified identical behavior of PTH fragments relative to PTH (1-84). PTH assay ratios are an adequate tool to investigate the modulation of PTH molecular forms, even if all PTH assays show some undesirable cross-reactivity with certain circulating forms of PTH.


Motor neurons of grasshopper metathoracic ganglion occur in stereotypic anatomical groups.
Anatomical groups containing identified motor neurons of the main muscles of the legs and the wings are described in a segmental ganglion of the adult grasshopper. The groups occur reproducibly in ganglia of different individuals and are a simplifying and organizing feature of ganglionic morphology. The motor neurons within each group have cell bodies near each other in the cortex of the ganglion and primary neurites that enter the ganglionic core as a discrete bundle. The primary neurite bundles are distinctive in shape and position and have the same composition in every individual, despite variations in the positions of the cell bodies of the contributing motor neurons. The primary neurite bundle of a group is separate from those of other groups and separate from bundles of motor axons that exit or sensory axons that enter the ganglion. Each group of cell bodies in the cortex appears from light microscope examination to be held separately within a glial surround. Areas of glial cell cytoplasm may extend considerably beyond the boundaries of the neuronal cell bodies, to give shape and structural integrity to the cortex. Similarities between the morphology of the adult groups reported here and the descriptions by others of embryonic and larval nervous systems suggest to us that the motor neurons of each group are the progeny of a single neuroblast.


Satisfaction with justice and desire for revenge in survivors of the September 11, 2001, attacks on New York City's World Trade Center.
This study investigated gaps in existing knowledge on justice, desire for revenge, and associated factors in disaster research through data collected nearly three years post disaster on justice and revenge from survivors of the September 11, 2001 (9/11) attacks. A volunteer sample of 379 employees of eight affected businesses completed interviews and self-report questionnaires. Individual ratings on satisfaction with justice and desire for revenge were compared with demographic characteristics, disaster-related experience, posttraumatic stress disorder (PTSD), disaster-related distress, anger, and concerns about danger and safety. High levels of desire for revenge and relatively low levels of satisfaction with accountability for perpetrators of the 9/11 attacks were endorsed. Most of the associations between the justice scores and the revenge score with the disaster response variables were directionally consistent. Dissatisfaction with perpetrator accountability was associated with greater desire for revenge. Both of these variables were associated with greater concerns about danger and endorsement of security regulations at the expense of personal freedoms.


Effects of point mutations at the flexible loop alanine-145 of Escherichia coli dihydrofolate reductase on its stability and function.
To elucidate the role of a flexible loop (residues 142-149) in the stability and function of Escherichia coli dihydrofolate reductase, alanine-145 in this loop was substituted by site-directed mutagenesis with ten amino acids (Glu, Phe, Gly, His, Ile, Leu, Arg, Ser, Thr, and Val). The amount of three mutant proteins (A145E, A145I, and A145L) in cells was too small to allow the measurement of circular dichroism (CD) spectra and urea unfolding. The CD spectra of other seven mutants were identical with those of the wild-type DHFR, indicating that the native conformation of DHFR was not affected by the mutations. The free energy change of unfolding by urea decreased with an increase in the hydrophobicity of amino acid residues introduced, A145T>A145R>A145G>=A145S>=A145H>A145V++ +>wild-type>=A145F. The steady-state kinetic parameters for the enzyme reaction, Km and ksub, were only slightly influenced by the mutations. These results suggest that site 145 in the flexible loop plays an important role in the stability but has little or no effect on the native structure and function of this enzyme. The characteristics of the mutations are discussed in comparison with those of mutations at site 67 [Ohmae et al. (1996) J. Biochem. 119, 703-710] and at site 121 [Gekko et al. (1994) J. Biochem. 116, 34-41] in two other flexible loops.


Autonomous replication of nucleic acids by polymerization/nicking enzyme/DNAzyme cascades for the amplified detection of DNA and the aptamer-cocaine complex.
The progressive development of amplified DNA sensors and aptasensors using replication/nicking enzymes/DNAzyme machineries is described. The sensing platforms are based on the tailoring of a DNA template on which the recognition of the target DNA or the formation of the aptamer-substrate complex trigger on the autonomous isothermal replication/nicking processes and the displacement of a Mg(2+)-dependent DNAzyme that catalyzes the generation of a fluorophore-labeled nucleic acid acting as readout signal for the analyses. Three different DNA sensing configurations are described, where in the ultimate configuration the target sequence is incorporated into a nucleic acid blocker structure associated with the sensing template. The target-triggered isothermal autonomous replication/nicking process on the modified template results in the formation of the Mg(2+)-dependent DNAzyme tethered to a free strand consisting of the target sequence. This activates additional template units for the nucleic acid self-replication process, resulting in the ultrasensitive detection of the target DNA (detection limit 1 aM). Similarly, amplified aptamer-based sensing platforms for cocaine are developed along these concepts. The modification of the cocaine-detection template by the addition of a nucleic acid sequence that enables the autonomous secondary coupled activation of a polymerization/nicking machinery and DNAzyme generation path leads to an improved analysis of cocaine (detection limit 10 nM).


Fate of malathion and chlorpyrifos methyl in rough rice and milling fractions before and after parboiling and cooking.
Long-grain rough rice treated with malathion (14 ppm) or chlorpyrifos methyl (Reldan) (6 ppm or 12 ppm) was sampled after 1,6, and 12 wk. Samples from each treatment were processed raw or were parboiled with fresh steeping water, once-used, and twice-used steeping water. Three replicates of rough rice and of each milling fraction were preserved, and three of milled rice were cooked. Chemical residues were measured on rough rice, hulls, brown rice, bran, milled rice, and cooked rice. Parboiling reduced residues on rough rice and hulls but tended to increase residues in the other fractions. Residues of Reldan in bran were substantially increased by parboiling. Doubling the amount of Reldan applied to rough rice approximately doubled the residues found in the milling fractions. Small amounts of the protectants survived all processing including cooking. Residues of malathion in cooked rice averaged about 0.016 ppm in nonparboiled and 0.013 ppm in parboiled rice. Residue of Reldan in cooked rice was commensurate with the amount applied to rough rice. When applied to rough rice at 6 ppm, residues of Reldan in cooked rice averaged 0.05 ppm in nonparboiled rice and 0l.065 ppm in parboiled rice. When applied to rough rice at 12 ppm, residues in cooked rice averaged .053 ppm in nonparboiled rice and 0.15 ppm in parboiled rice. Legal tolerances were not exceeded in any milling fraction. Reuse of the steeping water had little or no effect on residues.


In vitro cardiotoxicity assessment of environmental chemicals using an organotypic human induced pluripotent stem cell-derived model.
An important target area for addressing data gaps through in vitro screening is the detection of potential cardiotoxicants. Despite the fact that current conservative estimates relate at least 23% of all cardiovascular disease cases to environmental exposures, the identities of the causative agents remain largely uncharacterized. Here, we evaluate the feasibility of a combinatorial in vitro/in silico screening approach for functional and mechanistic cardiotoxicity profiling of environmental hazards using a library of 69 representative environmental chemicals and drugs. Human induced pluripotent stem cell-derived cardiomyocytes were exposed in concentration-response for 30min or 24h and effects on cardiomyocyte beating and cellular and mitochondrial toxicity were assessed by kinetic measurements of intracellular Ca2+ flux and high-content imaging using the nuclear dye Hoechst 33342, the cell viability marker Calcein AM, and the mitochondrial depolarization probe JC-10. More than half of the tested chemicals exhibited effects on cardiomyocyte beating after 30min of exposure. In contrast, after 24h, effects on cell beating without concomitant cytotoxicity were observed in about one third of the compounds. Concentration-response data for in vitro bioactivity phenotypes visualized using the Toxicological Prioritization Index (ToxPi) showed chemical class-specific clustering of environmental chemicals, including pesticides, flame retardants, and polycyclic aromatic hydrocarbons. For environmental chemicals with human exposure predictions, the activity-to-exposure ratios between modeled blood concentrations and in vitro bioactivity were between one and five orders of magnitude. These findings not only demonstrate that some ubiquitous environmental pollutants might have the potential at high exposure levels to alter cardiomyocyte function, but also indicate similarities in the mechanism of these effects both within and among chemicals and classes.


Viability and molecular authentication of Coccidioides spp. isolates from the Instituto de Medicina Tropical de São Paulo culture collection, Brazil.
Coccidioidomycosis is an emerging fungal disease in Brazil; adequate maintenance and authentication of Coccidioides isolates are essential for research into genetic diversity of the environmental organisms, as well as for understanding the human disease. Seventeen Coccidioides isolates maintained under mineral oil since 1975 in the Instituto de Medicina Tropical de São Paulo (IMTSP) culture collection, Brazil, were evaluated with respect to their viability, morphological characteristics and genetic features in order to authenticate these fungal cultures. Only five isolates were viable after almost 30 years, showing typical morphological characteristics, and sequencing analysis using Coi-F and Coi-R primers revealed 99% identity with Coccidioides genera. These five isolates were then preserved in liquid nitrogen and sterile water, and remained viable after two years of storage under these conditions, maintaining the same features.


Controlled growth of silicon nanocrystals in a plasma reactor.
Using a powerful multilevel simulation approach, we "visualize" the complete growth dynamics of hydrogenated silicon nanostructures under realistic experimental conditions of a plasma reactor. For the early stages of the synthesis, we demonstrate for the first time how precise control of atomic hydrogen not only permits one to choose between the production of amorphous and crystalline nanoparticles, but also to "steer" the growth toward the formation of elementary "building blocks" for the synthesis of hexagonal silicon nanowires.


Enhancement of the bioavailability of an antihypertensive drug by transdermal protransfersomal system: formulation and in vivo study.
Timolol Maleate (TiM), a nonselective β-adrenergic blocker, is a potent highly effective agent for management of hypertension. The drug suffers from poor oral bioavailability (50%) due to its first pass effect and a short elimination half-life of 4 h; resulting in its frequent administration. Transdermal formulation may circumvent these problems in the form of protransfersomes. The aim of this study is to develop and optimize transdermal protransfersomal system of Timolol Maleate by film deposition on carrier method where protransfersomes were converted to transfersomes upon skin hydration following transdermal application under occlusive conditions. Two 23 full factorial designs were employed to investigate the influence of three formulation variables which were; phosphatidyl choline: surfactant molar ratio, carrier: mixture and the type of SAA each on particle size, drug entrapment efficiency and release rate. The optimized formulation was evaluated regarding permeation through hairless rat skin and compared with oral administration of aqueous solution on male Wistar rats. Optimized protransfersomal system had excellent permeation rate through shaved rat skin (780.69 μg/cm2/h) and showed six times increase in relative bioavailability with prolonged plasma profile up to 72 h. A potential protransfresomal transdermal system was successfully developed and factorial design was found to be a smart tool in its optimization.


Partial alpha-decay half-lives for alpha-emitting Osmium isotopes: Accurate determinations by a semi-empirical model.
Partial alpha-decay half-life-values for twenty-four cases of alpha-decaying Osmium isotopes (161-174, 184, 186-188Os) have been obtained in the framework of a semi-empirical, one-parameter model based on the quantum mechanical tunneling mechanism through a potential barrier. Here the Coulomb, centrifugal and overlapping contributions to the barrier have been considered within the spherical nucleus approximation. The calculation method enabled to reproduce, within a factor 2, the measured half-lives for ground-state to ground-state (gs-gs) α-transitions of twelve artificially produced Osmium isotopes (162-172, 174Os) and of two naturally occurring isotopes (184, 186Os). In addition, a half-life prediction of T½ = (2.0 ± 0.1) × 1016 a has been found for the gs-gs α-transition of naturally occurring 187Os isotope. Two cases of gamma quanta accompanying α-decay possible of being accessed experimentally have been predicted: 184Os decaying to the first level of 180W, with T½ = (0.73 ± 0.04) × 1015 a, and 186Os decaying to the first level of 182W, with T½ = (3.9 ± 0.2) × 1016 a. New α-decay schemes for 184Os, 186Os, 187Os isotopes have been anticipated, and estimated T½-values for rarer cases of α-transitions of Osmium isotopes have been reported.


The moderating role of meaning in life in the relationship between perceived stress and diurnal cortisol.
Previous studies have suggested that meaning in life may buffer the negative effects of stress. This study is the first to investigate the moderating role of meaning in life in the relationship between the perception of stress and diurnal cortisol in two independent samples of healthy adults. In study 1 (n = 172, men = 82, women = 90, age range = 21-55 years, mean age = 37.58 years), the results of moderated regression analyses revealed that there was a significant positive relationship between overall perceived stress in the past month and both diurnal cortisol levels (area-under-the-curve with respect to the ground; AUCg) and the diurnal cortisol slope (DCS) only in individuals with low levels of meaning in life conceptualized as the degree to which one engages in activities that are personally valued and important. In study 2 (n = 259, men = 125, women = 134, age range = 18-54 years, mean age = 29.06 years), we found a non-significant interaction term between meaning in life conceptualized as having goals and a sense of excitement regarding one's future and perception of stress in a model of both adjusted AUCg and DCS. The results were independent of age, sex, body mass index, education, and race. The results shed light on the importance and the complexity of the construct of meaning in life and offer a possible explanation for why some people who face stressors may be more vulnerable than others to developing stress-related health problems.


Water Oxidation by In Situ Generated [RuII (OH2 )(NCNHC O)(pic)2 ].
A dinuclear ruthenium complex [RuII (NCNHC O)(pic)2 ]22+ (2) was firstly prepared and characterized spectroscopically and electrochemically. Instead of the conventional ligand exchange, complex 2 dissociates in situ to afford two single-site Ru aqua complexes, [RuII (OH2 )(NCNHC O)(pic)2 ]+ , which mediates water oxidation through proton-coupled electron transfer events. In electrokinetic studies, complex 2 demonstrated a TOF of 150.3 s-1 comparable to those state-of-the-art catalysts at neutral conditions. TONs of 2173 and 217 were attained in chemical and photochemical water oxidation when 2 was used as a catalyst, exhibiting good stability. Notably, a TOF of 1.3 s-1 was achieved at CAN-driven water oxidation, which outperformed most of the reported single-site Ru complexes, indicating that complex 2 is one of most active water oxidation catalysts (WOCs) to date. The unique coordination configuration and outstanding catalytic performance of complex 2 might shed light on the design of novel molecular WOCs.


Behavioral Determinants of Objectively Assessed Diet Quality in Obese Pregnancy.
Interventions to promote healthy pregnancy in women with obesity by improving diet quality have been widely unsuccessful. We hypothesized that diet quality is determined by eating behaviors, but evidence in women with obesity is lacking. We evaluated diet quality and eating behavior in 56 women with obesity (mean ± SEM, 36.7 ± 0.7 kg/m2, 46% White, 50% nulliparous) early in pregnancy (14.9 ± 0.1 weeks). Diet quality was objectively assessed with food photography over six days and defined by Healthy Eating Index. Eating behaviors were assessed by validated questionnaires. Women reported consuming diets high in fat (38 ± 1% of energy) and the HEI was considered "poor" on average (46.7 ± 1.3), and for 71% of women. Diet quality was independently associated with education level (p = 0.01), food cravings (p < 0.01), and awareness towards eating (p = 0.01). Cravings for sweets and fast foods were positively correlated with respective intakes of these foods (p < 0.01 and p = 0.04, respectively), whereas cravings for fruits and vegetables did not relate to diet intake. We provide evidence of the determinants of poor diet quality in pregnant women with obesity. Based on this observational study, strategies to improve diet quality and pregnancy outcomes are to satisfy cravings for healthy snacks and foods, and to promote awareness towards eating behaviors.


Sidt2 regulates hepatocellular lipid metabolism through autophagy.
SID1 transmembrane family member 2 (Sidt2) is an integral lysosomal membrane protein. To investigate its explicit function, we generated a global Sidt2 knockout mouse model (Sidt2-/-). Compared with the littermate controls, Sidt2-/- mice exhibited a remarkable accumulation of lipid droplets in liver. First, it was observed that food consumption, hepatocyte fatty acid uptake and de novo lipogenesis, hepatocyte lipolysis, and TG secretion in the form of very low density lipoprotein were comparable between Sidt2-/- and WT mice. However, the hepatic β-oxidation of fatty acids decreased significantly as revealed by a low level of serum β-hydroxybutyrate in the Sidt2-/- mice along with normal mRNA expression of genes involved in fatty acid oxidation. In addition, the classical autophagy pathway marker proteins, p62 and LC3-II, increased in liver, along with compromised autophagic flux in primary hepatocytes, indicating a block of autophagosome maturation due to Sidt2 deficiency, which was also supported by electron microscopy image analysis both in livers and in primary hepatocytes from Sidt2-/- mice. It was concluded that Sidt2 plays an important role in mouse hepatic lipid homeostasis by regulating autophagy at the terminal stage.


Effectiveness of an online group course for depression in adolescents and young adults: a randomized trial.
Depression is a serious mental health problem, whose first onset is usually in adolescence. Online treatment may offer a solution for the current undertreatment of depression in youth. For adults with depressive symptoms, the effectiveness of Internet-based cognitive behavioral therapy has been demonstrated. This study is one of the first randomized controlled trials to investigate the effectiveness online depression treatment for young people with depressive complaints and the first to focus on an online group course. To evaluate and discuss the effectiveness of a guided Web-based group course called Grip op Je Dip (Master Your Mood [MYM]), designed for young people aged 16 to 25 years with depressive symptoms, in comparison with a wait-listed control group. We randomly assigned 244 young people with depressive symptoms to the online MYM course or to a waiting-list control condition. The primary outcome measure was treatment outcome after 3 months on the Center for Epidemiologic Studies Depression Scale. Secondary outcomes were anxiety (measured by the Hospital Anxiety and Depression Scale) and mastery (Mastery Scale). We studied the maintenance of effects in the MYM group 6 months after baseline. Missing data were imputed. The MYM group (n = 121) showed significantly greater improvement in depressive symptoms at 3 months than the control group (n = 123) (t(187 )= 6.62, P < .001), with a large between-group effect size of d = 0.94 (95% confidence interval [CI] 0.64-1.23). The MYM group also showed greater improvement in anxiety (t(187 )= 3.80, P < .001, d = 0.49, 95% CI 0.24-0.75) and mastery (t(187 )= 3.36, P = .001, d = 0.44, 95% CI 0.19-0.70). At 12 weeks, 56% (68/121) of the participants in the MYM group and 20% (24/123) in the control group showed reliable and clinically significant change. This between-group difference was significant (χ(2) (1 )= 35.0, P < .001) and yielded a number needed to treat of 2.7. Improvements in the MYM group were maintained at 6 months. A limitation is the infeasibility of comparing the 6-month outcomes of the MYM and control groups, as the controls had access to MYM after 3 months. The online group course MYM was effective in reducing depressive symptoms and anxiety and in increasing mastery in young people. These effects persisted in the MYM group at 6 months.


Tyrosine kinase inhibitor markedly suppresses the development of coronary lesions induced by long-term treatment with platelet-derived growth factor in pigs in vivo.
Platelet-derived growth factor (PDGF) plays an important role in the development of coronary atherosclerosis. However, it remains to be examined what morphologic and functional changes are induced in vivo by the long-term treatment with PDGF itself or what pharmacologic interventions could suppress those changes in vivo. Our study was designed to address these points. We examined the effects of long-term treatment with PDGF on the porcine coronary artery in vivo. Under aseptic conditions, the proximal segments of the left porcine coronary artery were gently wrapped with cotton mesh absorbing sepharose beads either with or without recombinant human PDGF-AA or -BB. Two weeks after the operation, coronary hyperconstrictions to intracoronary serotonin or histamine were noted at the sites treated with PDGF-AA or -BB. Histologically, neointimal formation and geometric remodeling (reduction of the total vessel area) were noted at the PDGF-treated sites. These functional and histologic changes of the coronary artery induced by PDGF were markedly inhibited by cotreatment with ST 638, a specific inhibitor of tyrosine kinases. A Western blot analysis showed that ST 638 markedly suppressed the PDGF-induced tyrosine phosphorylations in the coronary segment. These results indicate that long-term treatment with PDGF induces neointimal formation, geometric remodeling, and vasospastic responses in vivo, for all of which, activation of tyrosine kinases is substantially involved.


Bombax ceiba Linn. leaf extract rich in phenolic compounds to mitigate non-alcoholic fatty liver-related complications in experimental model.
Obesity, diabetes mellitus, insulin resistance (IR), and hypertriglyceridemia are common features observed in non-alcoholic fatty liver diseases (NAFLD). There is a critical medical necessity to find novel therapeutics that can halt the development of NAFLD. Bombax ceiba Linn. leaf extract was prepared and its phytochemical profile was determined. Standard and high carbohydrate high-fat diets (HCHF) were prepared. Rats were fed HCHF for 18 weeks to induce a non-alcoholic fatty liver (NAFL) model. Forty male rats were divided into control, B. ceiba Linn. leaf extract, NAFL, prophylactic, and treated groups. Serum fasting blood sugar (FBS), insulin, insulin resistance (HOMA-IR), cholesterol, high-density lipoprotein (HDL), triglycerides (TG), low density lipoprotein (LDL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), intelectin-1 (ITLN1), p38 MAP kinase (MAPK), peroxisome proliferator-activated receptor alpha (PPAR-α), and interleukin-6 (IL-6) were evaluated. Data obtained showed that HCHF-induced NAFL resulting in a significant increase in FBS, serum insulin, HOMA-IR, cholesterol, LDL, TG, ALT, AST, and IL-6 and a significant decrease in serum levels of HDL, ITLN1, p38 MAP kinase, and PPAR-α compared to the control group. The analysis of B. ceiba Linn. leaf extract showed high content of phenol compounds which may cause a significant decrease in the levels of FBS, insulin, HOMA-IR values, lipid profile, and levels of IL-6 while a significant increase in serum levels of LDL, ITLN1, p38 MAP kinase, and PPAR-α compared to the NAFL group. B. ceiba Linn. Leaf extract is a highly protective and promising therapeutic agent against inflammation and oxidative stress in the NAFLD model induced by HCHF.