Neuroprotective effects of progesterone on damage elicited by acute global cerebral ischemia in neurons of the caudate nucleus.
In addition to the hippocampus, the dorsolateral caudate nucleus (CN) and the pars reticularis of the substantia nigra (SNr) are among the most vulnerable brain areas to ischemia. A possible association of the neuronal injury in these two subcortical nuclei has been proposed, the primary damage affecting the CN GABAergic neurons innervating the SNr, and secondarily the SNr neurons as a result of an imbalance of GABAergic and glutamatergic input to the SNr. Progesterone (P(4)) exerts a GABAergic action on the central nervous system (CNS) and is known to protect neurons in the cat hippocampus from the damaging effect of acute global cerebral ischemia (AGCI). The effects of AGCI on the neuronal populations of the CN and SNr, in addition to the possible neuroprotective effects of P(4), were assessed in cats in the present study. Ovariectomized adult cats were treated subcutaneously (s.c.) with either P(4) (10 mg/kg/day) or corn oil during the 7 days before and 7 days after being subjected to a period of AGCI by 15 min of cardiorespiratory arrest followed by 4 min of reanimation. After 14 days of survival, animals were sacrificed and their brains perfused in situ with phosphate-buffered 10% formaldehyde for histologic examination. ACGI resulted in an intense glial reaction in the CN and a significant loss (43%) of medium-sized neurons of the CN, but no difference was found in the densities of SNr neurons between controls and ischemic oil- and P(4)-treated cats. Progesterone treatment completely prevented CN neuronal loss. The overall results point to the higher vulnerability of CN neurons to ischemia as compared to neurons in the SNr and show the protective effects of P(4) upon CN neuronal damage after ischemia.


Evaluation of heavy metals in water and sediments, pollution, and risk indices of Naltar Lakes, Pakistan.
This study examined the physicochemical parameters of water and sediments in the Naltar Lakes, northern Pakistan. Water and sediments were sampled and analyzed for physicochemical parameters. Heavy metals such as iron (Fe, 11% and 12%), nickel (Ni, 100% and 88%), chromium (Cr, 22% and 12%), and arsenic (As, 0% and 12%) of sampling sites had surpassed the threshold of drinking water set by world health organization (WHO) in the Naltar Lake I (Naltar I) and Naltar Lake II (Naltar II), respectively. Water quality parameters were evaluated for the drinking and irrigation water quality indices (WQI). Drinking WQI values were found within the excellent category for Naltar I and Naltar II, except for the 6% of sampling sites observed in the good category. Toxic parameter concentrations were used for the risk indices, which revealed the highest average daily dose (ADD) values of 138 µg/kg-day and hazard quotient (HQ) 1.8 for children through nitrate (NO3) and As consumption in drinking water from the Naltar I and Naltar II, respectively. Water of the Naltar Lakes were characterized by rock weathering dominance. Heavy metal concentrations of sediments showed a moderate level of contamination that poses a low risk to the Naltar Lake ecosystem.


Collaborative PrEP Implementation Strategies for Latino Men Who have Sex with Men: A Health Center-Community Consensus Process.
Community-based organizations (CBOs) deliver services in culturally-responsive ways, and could effectively partner with health centers to deliver HIV pre-exposure prophylaxis (PrEP) to Latino men who have sex with men (LMSM). However, few such models exist. We conducted a planning study in collaboration with three CBOs serving LMSM to identify optimal PrEP delivery strategies for health centers and CBOs to implement jointly. We established a Community Expert Panel (CEP) of eight client-facing CBO and health center staff. Over 6 months, the panel met monthly to identify collaborative strategies for PrEP delivery, using a modified Delphi method consisting of the following steps: (1) brainstorming strategies; (2) rating strategies on acceptability, appropriateness and feasibility; (3) review of data from qualitative focus group discussions with CBO clients; and (4) final strategy selection. The panel initially identified 25 potential strategies spread across three categories: improving communication between health centers and CBOs; using low-barrier PrEP options (e.g. telemedicine), and developing locally-relevant, culturally-sensitive outreach materials. Focus groups with CBO clients highlighted a desire for flexible options for PrEP-related care and emphasized trust in CBOs. The final package of strategies consisted of: (1) a web-based referral tool; (2) telemedicine appointments; (3) geographically-convenient options for lab specimen collection; (4) tailored print and social media; and (5) regular coaching sessions with CBO staff. Through a community-engaged process, we identified a package of PrEP delivery strategies that CBOs and health centers can implement in partnership, which have the potential to overcome barriers to PrEP for LMSM.


[Our ultrasound-guided paravertebral block experiences in thoracic surgery].
Ultrasound-guided thoracic paravertebral block (TPVB) may be employed for postoperative analgesia in thoracic surgery. In application of TPVB, single injections, multiple injections or catheter techniques may be used. In this paper we present our experiences with ultrasound-guided TPVB in thoracic surgery patients for postoperative analgesia. Patients undergoing thoracic surgery and on whom ultrasound-guided TPVB was performed for postoperative analgesia from January 2012 to March 2013 in our clinic were analyzed retrospectively. Demographic data, block technique, complications and 1st, 6th, 12th and 24th hour VAS scores were recorded. A total of 18 patients had TPVB. Single injection was administered to 9 patients, multiple injections to 5, and catheters to 4. While statistically insignificant, 1st hour VAS scores were found to be greater than 3 in the single injection and catheter groups. Similarly to multiple injection and continuous TPVB administration, ultrasound-guided single injection TPVB provides effective 24-hour postoperative analgesia.


Management Trends and Outcomes for Stage I to II Mantle Cell Lymphoma Using the National Cancer Data Base: Ascertaining the Ideal Treatment Paradigm.
Mantle cell lymphoma (MCL) is a rare, albeit aggressive subset of non-Hodgkin lymphoma, resulting in varied treatment approaches. Given the paucity of data defining the optimal management for early-stage MCL, we conducted an analysis using the National Cancer Data Base (NCDB) to identify practice patterns and outcomes. The NCDB was queried for patients with stage I to II MCL diagnosed from 1998 to 2012 receiving chemotherapy (CT) or radiation therapy (RT), or both (CT+RT). Univariate and multivariable analyses for factors associated with treatment selection were completed using logistic regression. Propensity scores with inverse probability treatment weighting (IPTW) were calculated based on the conditional probability of receiving CT+RT. The log-rank test and Cox proportional hazards modeling with IPTW adjustment were conducted for the survival analyses. In total, 2539 patients were identified. The key characteristics were as follows: 69% were male, 71% were aged ≥60 years, 28% had extranodal involvement, and 51% had stage I disease. Of the 2539 patients, 70% underwent CT, 11% underwent RT, and 19% underwent CT+RT. The use of CT+RT decreased from 23.1% to 14.1% in 1998 to 2002 and 2010 to 2012 (P<.001). CT+RT usage was lower for patients with the following characteristics: age ≥60 years, female sex, stage II disease, and the presence of B symptoms. With a median follow-up period of 42.8 months, the unadjusted 3-year overall survival estimates for patients receiving CT, RT, or CT+RT were 67.8%, 72.4%, and 79.8%, respectively (P<.001). After correcting for indication bias through IPTW-adjusted modeling, CT+RT reduced the risk of overall mortality compared with monotherapy (hazard ratio 0.65, P=.029). Although uncommon, patients with stage I-II MCL can have favorable outcomes. Despite a continued decline in the usage of consolidative RT, combined modality therapy improves survival in this cohort compared with monotherapy.


Microsatellite instability and gastric non-invasive neoplasia in a high risk population in Cesena, Italy.
In the natural history of gastric cancer, non-invasive neoplasia (NiN) precedes invasive carcinoma. A histological classification of gastric NiN has recently been proposed by a World Health Organisation international panel of experts. Genetic instability is known to be among the molecular pathways involved in gastric oncogenesis. In this retrospective cross sectional study, microsatellite instability (MSI) was analysed in a consecutive series of NiN and NiN related histological alterations from a northern Italian region at high risk for gastric cancer. Fifty five consecutive cases (indefinite for NiN, 29 cases; low grade NiN, 17 cases; high grade NiN, nine cases) were analysed by radioactive polymerase chain reaction and electrophoresis for microsatellite alterations at six loci (BAT25, BAT26, D2S123, D5S346, D17S250, and D3S1317). MSI was defined according to the Bethesda criteria distinguishing: (1) no instability in the analysed loci; (2) low frequency MSI (MSI-L); and (3) high frequency MSI (MSI-H). Immunohistochemical expression of MLH1 and MSH2 proteins was also analysed in all cases. Overall, MSI was found in 11 of 55 cases (indefinite for NiN, five of 29 (MSI-L, four; MSI-H, one); low grade NiN, three of 17 (MSI-L, one; MSI-H, two); high grade NiN, three of nine (MSI-L, one; MSI-H, two). In an Italian high risk area for gastric cancer, MSI is part of the spectrum of genetic alterations in gastric non-invasive neoplasia. In European populations at high risk of gastric cancer, DNA repair system alterations are thought to be among the early molecular events in gastric carcinogenesis.


Did the 1997 balanced budget act reduce use of physical and occupational therapy services?
To investigate whether use of physical therapy (PT) and occupational therapy (OT) services decreased after the passage of the 1997 Balanced Budget Act (BBA). Data from the nationally representative Medicare Current Beneficiary Survey (MCBS) were merged with Medicare claims data. We conducted cross-sectional analyses of data from 1995 (n=7978), 1999 (n=7863), and 2001 (n=7973). All analyses used MCBS sampling weights to provide estimates that can be generalized to the Medicare population with 5 common conditions. Skilled nursing facilities (SNFs), home health agencies, inpatient rehabilitation facilities (IRFs), and outpatient rehabilitation settings. Medicare beneficiaries who participated in the MCBS survey in each of the study years and had 1 or more of the following conditions: acute stroke, acute myocardial infarction, chronic obstructive pulmonary disease, arthritis or degenerative joint disease, or mobility problems. Not applicable. Percentage of persons meeting our inclusion criteria who received PT or OT in each setting, and total units of PT and OT received in each setting. Multivariable logistic regression revealed no statistically significant differences in the proportion of people who met our inclusion criteria who used PT or OT from home health agencies across the 3 time points. For SNFs, an increase in the odds of receiving PT was statistically significant from 1995 to 1999 (odds ratio [OR]=1.42; 95% confidence interval [CI], 1.19-1.69) and 1995 to 2001 (OR=1.69; 95% CI, 1.39-2.05). For IRF and outpatient settings, a significant increase was observed between 1995 and 2001 (OR=1.71, OR=1.27, respectively). For OT, a statistically significant increase was observed for IRF and outpatient rehabilitation settings from 1995 to 2001. For SNF, the increase was statistically significant from 1995 to 1999 and 1995 to 2001. Mean total PT and OT units received also increased across all settings from 1995 to 2001 except for IRFs. Despite BBA mandates restricting postacute care expenditures, this nationally representative study showed no decreases in the percentage of Medicare beneficiaries with 5 common diagnoses receiving PT and/or OT across all settings and no decreases in units of PT and/or OT services received between 1995 and 2001 except for those in IRFs. This study suggests that the delivery of PT and OT services did not decline among persons with conditions for which rehabilitation services are often clinically indicated.


Characteristics of Integrated Thoracic Surgery Residency Matriculants: A Survey of Program Directors.
The 6-year Integrated Thoracic Surgery (I-6) residency programs have evolved over the past decade. Despite the rising number of programs, there are minimal data published about the criteria utilized by program directors to select candidates. We analyze the characteristics and qualities of successful matriculants using the American Association of Medical College's (AAMC) data reports and survey responses from program directors. Using a survey administered through the RedCap service, program directors were asked to rate the importance of a variety of factors in their evaluations of candidates. The AAMC data reports from 2018 to 2020 provided information on the mean matriculant research productivity, United States Medical Licensing Examination (USMLE) step 1 scores, and step 2 clinical knowledge (CK) scores. Responses were received from 19 of 33 I-6 programs (58%). Program directors consistently rated interview performance as a very important factor in their evaluation of applicants. Matching into the specialty is becoming more competitive, with mean USMLE step 1, step 2 CK, and research productivity increasing over the past few years; matriculants had mean step 1 and step 2 CK scores of 247.3 and 254.2, respectively, in the 2020 match. Thoracic surgery program directors place high value on applicant interview performance, letters of recommendation, and professionalism. Program directors agree that a forthcoming pass/fail USMLE step 1 score report will lead to closer scrutiny of other factors during the decision-making process and may cause future evaluation of applicants to be heavily reliant on letters of recommendation and medical school pedigree.


Obesity and socioeconomic position measured at three stages of the life course in the elderly.
To investigate the association between socioeconomic position, measured at three stages of the life course, and obesity in the elderly. Cross-sectional study carried out in 2000-2001. In total, 4009 subjects aged 60 y and older, representative of the Spanish noninstitutionalised population. We estimated body mass index (BMI) and waist circumference (WC) by social class in childhood, by educational level and by adult social class, as well as the association between these two obesity measures and each socioeconomic characteristic after adjusting for the other two. In men, no relation was found between the two measures of obesity studied and socioeconomic circumstances throughout the life course. Nor was any relation found in women between social class in childhood and the two measures of obesity after adjusting for the other two socioeconomic variables. In contrast, BMI and WC in women showed a statistically significant inverse gradient with educational level and with adult social class after adjusting for age and the rest of the socioeconomic variables. In general, these results support the small amount of existing evidence on the association between obesity and abdominal obesity and socioeconomic position by educational level and adult social class. The results for social class in childhood do not support the existing evidence, and suggest that this association may depend on specific historic and cultural circumstances.


Antagonism of Bacillus spp. isolated from marine biofilms against terrestrial phytopathogenic fungi.
We aimed at determining the antagonistic behavior of bacteria derived from marine biofilms against terrestrial phytopathogenic fungi. Some bacteria closely related to Bacillus mojavensis (three isolates) and Bacillus firmus (one isolate) displayed antagonistic activity against Colletotrichum gloeosporioides ATCC 42374, selected as first screen organism. The four isolates were further quantitatively tested against C. gloeosporioides, Colletotrichum fragariae, and Fusarium oxysporum on two culture media, potato dextrose agar (PDA) and a marine medium-based agar [yeast extract agar (YEA)] at different times of growth of the antagonists (early, co-inoculation with the pathogen and late). Overall antagonistic assays showed differential susceptibility among the pathogens as a function of the type of culture media and time of colonization (P < 0.05). In general, higher suppressive activities were recorded for assays performed on YEA than on PDA; and also when the antagonists were allowed to grow 24 h earlier than the pathogen. F. oxysporum was the most resistant fungus while the most sensitive was C. gloeosporioides ATCC 42374. Significant differences in antagonistic activity (P < 0.05) were found between the different isolates. In general, Bacillus sp. MC3B-22 displayed a greater antagonistic effect than the commercial biocontrol strain Bacillus subtilis G03 (Kodiak). Further incubation studies and scanning electronic microscopy revealed that Bacillus sp. MC3B-22 was able to colonize, multiply, and inhibit C. gloeosporioides ATCC 42374 when tested in a mango leaf assay, showing its potential for fungal biocontrol. Additional studies are required to definitively identify the active isolates and to determine their mode of antifungal action, safety, and biocompatibility.


Complex formation of class I transplantation antigens and a viral glycoprotein.
Indirect immunoprecipitations of labeled glycoproteins from the adenovirus-transformed rat cell line A2T2C4 and from adenovirus-infected HeLa cells revealed that the class I major histocompatibility antigens co-precipitated with the viral E19 protein. The degree of co-precipitation was highly dependent on the antiserum used. The identity of the co-precipitated components was verified by peptide mapping and radiochemical amino acid sequencing. Cell-free translation of mRNA for the E19 protein and the class I antigen heavy chains demonstrated that the E19 protein-class I antigen interaction is an inherent property of the participating components. In intact cells the virus protein and the transplantation antigens form large complexes, held together by weak, noncovalent interactions.


Structure of the rat liver ribosome 40 S subunit: freeze-drying and high-resolution shadow casting.
Small ribosomal subunits from rat liver have been studied by electron microscopy using freeze-drying and high-resolution shadow casting. The absolute hand of the asymmetric subunit has been determined and its three-dimensional model with a 'right' location of the side protuberance has been constructed. The results evidence that pro- and eukaryotic ribosomes have a unique and principally similar structural organization.


Self-reported Lupus flare: Association with everyday home and personal product exposure.
The number of chemicals in household products has driven concern about potential adverse health through their use. Most research concentrates on product chemicals with reproductive and carcinogenic consequences, however some evidence exists that immune effects can lead to exacerbation of autoimmune illnesses such as lupus (SLE). This paper examines household and personal product exposure patterns in a pilot case/control study of female Australians. We also examined associations between common product exposure and SLE symptom exacerbation over a year period. We enrolled 41 control and 80 SLE participants aged 18-80 years. Qualitative techniques of structured interview and thematic analysis retrospectively explored patterns of product use, and flare history data of SLE participants. Negative binomial regression models explored associations between self-reported flare (SRF) days and exposure to 34 common home product groups. Mean product counts did not differ between participant groups (mean 33.1: SD 11.8), or flare groups (flare mean 32.6:SD 12, no-flare 31.8:SD 6.6). Products used for personal hygiene and general house cleaning were most frequently used.Significant association with increased SRF day relative risk (IRR) was seen for bath oil use (IRR 1.008, CI 1.00-1.02). Paradoxical "protective" effects, (reduced SRF days) were found for cleansing beauty (IRR 0.999, CI 0.998-0.999), make-up (IRR 0.998, CI 0.997-0.999); adhesives (IRR 0.994, CI 0.991-0.997) and paint (IRR 0.99, CI 0.986-0.995). Everyday product exposures can impact on symptom exacerbation in SLE. Some offering protection and others increased health risk. Identifying environmental associations offer the possibility of life-style interventions to reduce illness impact.


The patency of sequential and individual vein coronary bypass grafts: a systematic review.
Saphenous vein grafts continue to be the backbone of daily coronary revascularization practice, but controversy still exists about whether to use them as an individual or sequential graft. We undertook a systematic review and meta-analysis of cohort studies to compare the midterm or long-term patency of sequential vein coronary bypass grafts with those of vein grafts. A comprehensive search strategy was run in PubMed, Embase, the Cochrane Library, and the Chinese Biomedical Literature Database. Inclusion criteria were the following: (1) two cohorts of patients received sequential and single saphenous vein coronary bypass grafting, respectively; (2) prospective or retrospective cohort design; and (3) graft patency examined by angiography or ultrafast computed tomography. Two researchers independently performed the literature search, data extraction, and quality assessment. We identified 1,385 titles, reviewed 38 articles for inclusion criteria, and included 12 studies in the meta-analysis. The risk of occlusion in sequential grafts was lower (risk ratio [RR] = 0.67, 95% confidence interval [CI] 0.60 to 0.74) than that in single grafts. The risk of occlusion in side-to-side anastomoses was lower (RR = 0.52; 95% CI, 0.34 to 0.80) than that of end-to-side anastomoses for sequential vein grafts. There was no difference in occlusion between the distal end-to-side anastomoses of sequential vein grafts and those of single vein grafts (RR = 0.85; 95% CI, 0.68 to 1.06). The midterm and long-term patency of sequential vein grafts appears to be better than that of single vein grafts and the patency of side-to-side anastomoses appears to be better than that of end-to-side anastomoses for sequential vein grafts.


Breaking the flow of thought: Increase of empty pauses in the connected speech of people with mild and moderate Alzheimer's disease.
The profile of spontaneous speech in Alzheimer's disease (AD) includes increased pausing as a window into cognitive decline. We here aimed to further characterize the pausing profile of AD by linking pauses to the syntactic positions in which they appear and disease progression. Speech was obtained through a picture description task, thus minimizing demands on episodic memory (EM), from a group of mild (N = 21) and moderate AD (N = 19), and healthy elderly controls (N = 40). Pauses were sub-indexed according to whether they occurred within-clauses, clause-initially, or utterance-initially, and whether they preceded nouns, verbs, or adjectives/adverbs, when occurring within-clauses. Additionally, relations to verbal fluency (VF) measures at the single-word level were explored. Pause rate but not duration distinguished controls from both AD groups, while fillers did not distinguish any groups. The analysis by syntactic position revealed a highly differentiated picture, with largest effect sizes of significant group differences seen in the utterance-initial pause rate. The two AD groups patterned differently when compared to controls, while none of the measures differentiated the AD groups. Specifically, moderate but not mild AD differed from controls in clause-initial pauses, while mild but not moderate AD differed from controls in within-clause positions. At the within-clause level, the effect dividing controls from mild-AD was specifically driven by pauses ahead of nouns. A significant negative correlation emerged between pausing rate in spontaneous speech and VF measures in the mild-AD group only. Increased empty (non-filled) pauses in AD are not confined to pauses in within-clause positions, which are most directly related to problems in the retrieval of words. Even in early disease stages, where these within-clause pause effects are seen, they are confined to nouns, revealing a grammatically specific problem possibly related to the referencing of objects. At all disease stages, pauses increase in utterance-sized units of structure, indicating progressive problems in the creative configuration of complete thoughts.


[COVID-19 and micronutrients to regulate the immune response].
Our social environment shapes our eating habits, notably our consumption of fruit and vegetables rich in micronutrients (vitamins and trace elements), essential for regulating the immune system. Ensuring a balanced intake of micronutrients could prove to be particularly beneficial for patients with severe forms of COVID-19 suffering from critical immune dysregulation.


An alternate sucrose binding mode in the E203Q Arabidopsis invertase mutant: an X-ray crystallography and docking study.
In the present study, we report on the X-ray crystallographic structure of a GH32 invertase mutant, (i.e., the Arabidopsis thaliana cell-wall invertase 1-E203Q, AtcwINV1-mutant) in complex with sucrose. This structure was solved to reveal the features of sugar binding in the catalytic pocket. However, as demonstrated by the X-ray structure the sugar binding and the catalytic pocket arrangement is significantly altered as compared with what was expected based on previous X-ray structures on GH-J clan enzymes. We performed a series of docking and molecular dynamics simulations on various derivatives of AtcwINV1 to reveal the reasons behind this modified sugar binding. Our results demonstrate that the E203Q mutation introduced into the catalytic pocket triggers conformational changes that alter the wild type substrate binding. In addition, this study also reveals the putative productive sucrose binding modus in the wild type enzyme.


Splanchnic vascular endothelial dysfunction in rat endotoxemia: role of superoxide radicals.
Intravenous lipopolysaccharide, 30 mg/kg, results in rapid systemic hypotension in anesthetized rats. Interaction of lipopolysaccharide with the vascular endothelium and blood borne cells results in the elaboration of cytokines and oxygen-derived free radicals, all of which can be injurious to normal endothelial function. To evaluate endothelial function, superior mesenteric artery rings were isolated from endotoxemic rats just prior to death. Endotoxemia significantly blunted superior mesenteric artery ring vasorelaxations to acetylcholine and to A23187 but not to NaNO2. Contraction of superior mesenteric artery rings from endotoxemic rats induced by U46619 was not altered. Treatment with human superoxide dismutase or U74006F, an aminosteroid, significantly preserved vasorelaxation to acetylcholine and A23187. However, the hydroxyl radical scavenger N-(2-mercaptopropionyl)-glycine did not protect the endothelium. Thus, intravenous lipopolysaccharide can induce endothelial dysfunction in superior mesenteric artery rings. Furthermore, because superoxide dismutase but not N-(2-mercaptopropionyl)-glycine preserves endothelial function, it is likely that superoxide radicals mediate the endothelial dysfunction observed in endotoxemic rats.


Detecting direct oral anticoagulants in trauma patients using liquid chromatography-mass spectrometry: A novel approach to medication reconciliation.
Accurate medication reconciliation in trauma patients is essential but difficult. Currently, there is no established clinical method of detecting direct oral anticoagulants (DOACs) in trauma patients. We hypothesized that a liquid chromatography-mass spectrometry (LCMS)-based assay can be used to accurately detect DOACs in trauma patients upon hospital arrival. Plasma samples were collected from 356 patients who provided informed consent including 10 healthy controls, 19 known positive or negative controls, and 327 trauma patients older than 65 years who were evaluated at our large, urban level 1 trauma center. The assay methodology was developed in healthy and known controls to detect apixaban, rivaroxaban, and dabigatran using LCMS and then applied to 327 samples from trauma patients. Standard medication reconciliation processes in the electronic medical record documenting DOAC usage were compared with LCMS results to determine overall accuracy, sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of the assay. Of 356 patients, 39 (10.96%) were on DOACs: 21 were on apixaban, 14 on rivaroxaban, and 4 on dabigatran. The overall accuracy of the assay for detecting any DOAC was 98.60%, with a sensitivity of 94.87% and specificity of 99.05% (PPV, 92.50%; NPV, 99.37%). The assay detected apixaban with a sensitivity of 90.48% and specificity of 99.10% (PPV, 86.36%; NPV 99.40%). There were three false-positive results and two false-negative LCMS results for apixaban. Dabigatran and rivaroxaban were detected with 100% sensitivity and specificity. This LCMS-based assay was highly accurate in detecting DOACs in trauma patients. Further studies need to confirm the clinical efficacy of this LCMS assay and its value for medication reconciliation in trauma patients. Diagnostic Test, level III.


Evaluation of trans-tetrachloro-1,2-diaminocyclohexane platinum (IV) in murine leukemia L1210 resistant and sensitive to cis-diamminedichloroplatinum (II).
trans-Tetrachloro-1,2-diaminocyclohexane platinum (IV) (tetraplatin) was therapeutically effective in mice bearing leukemia L1210 resistant (L1210/DDPt) or sensitive (L1210/0) to cis-diamminedichloroplatinum (II) (cisplatin). Furthermore, the sensitivity of cultured L1210/DDPt and L1210/0 cell populations to tetraplatin, cisplatin, and dichloro-trans-dihydroxyisopropylamine platinum (IV) (CHIP) was a function of the concentrations used for each compound. The relative degree of sensitivity between cultured L1210/DDPt and L1210/0 cells for each compound on the basis of the LC99 (the concentration of each compound required to reduce the number of viable cells by 99% in each cell line) was 3-fold for cisplatin, 2-fold for tetraplatin, and 3-fold for CHIP; thus the cultured L1210/0 cells exhibited a greater degree of sensitivity than the L1210/DDPt cells to the platinum compounds. The data indicate that if reduction of platinum IV compounds to platinum II compounds or metabolites is required for antitumor activity, then the cultured L1210 cells are capable of this bioreduction independently of any host factors.


Therapeutic potential of targeting regulatory mechanisms of hepatic stellate cell activation in liver fibrosis.
Hepatic fibrosis is a manifestation of different etiologies of liver disease with the involvement of multiple mediators in complex network interactions. Activated hepatic stellate cells (aHSCs) are the central driver of hepatic fibrosis, given their potential to induce connective tissue formation and extracellular matrix (ECM) protein accumulation. Therefore, identifying the cellular and molecular pathways involved in the activation of HSCs is crucial in gaining mechanistic and therapeutic perspectives to more effectively target the disease. In addition to a comprehensive summary of our current understanding of the role of HSCs in liver fibrosis, we also discuss here the proposed therapeutic strategies based on targeting HSCs.


Addressing neurodegeneration in lysosomal storage disorders: Advances in Niemann Pick diseases.
Most lysosomal storage disorders (LSDs) cause progressive neurodegeneration leading to early death. While the genetic defects that cause these disorders impact all cells of the body, neurons are particularly affected. This vulnerability may be explained by neuronal cells' critical dependence on the lysosomal degradative capacity, as they cannot use division to eliminate their waste. However, mounting evidence supports the extension of storage beyond lysosomes to other cellular compartments (mitochondria, plasma membrane and synapses) as a key event in pathogenesis. Impaired energy supply, oxidative stress, calcium imbalance, synaptic failure and glial alterations may all contribute to neuronal death and thus could be suitable therapeutic targets for these disorders. Here we review the pathological mechanisms underlying neurodegeneration in Niemann Pick diseases and therapeutic strategies developed in animal models and patients suffering from these devastating disorders. This article is part of the special issue entitled 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.


Tourniquet Use Improves Intraoperative Parameters, Leading to Similar Postoperative Outcomes Compared With No Tourniquet Use in Anterior Cruciate Ligament Reconstruction: A Prospective, Double-Blind, Randomized Clinical Trial.
To examine the effect of tourniquet use in arthroscopic anterior cruciate ligament reconstruction in terms of: (1) intraoperative visualization with operative time and consumption of sterile saline, and (2) intra- and postoperative blood loss, postoperative pain, opioid consumption, swelling, serum creatine phosphokinase (CPK) and hemoglobin (Hb) concentrations, clinical outcomes, and graft healing. In this prospective randomized clinical trial, patients were assigned to tourniquet inflation (tourniquet-up) or tourniquet deflation (tourniquet-down) groups. Primary outcomes were intraoperative visualization with operative time and sterile saline consumption. Secondary outcomes were intra- and postoperative blood loss, postoperative pain, opioid consumption, swelling, serum CPK, Hb concentration, subjective and objective functional scores, and graft healing. Intraoperative visualization was satisfactory in 100 of 100 cases in the tourniquet-up group and 64 of 100 cases in the tourniquet-down group (P < .05). The mean operative time was 58.4 ± 5.7 minutes in the tourniquet-up group and 72.5 ± 8.6 minutes in the tourniquet-down group (P < .05). The mean sterile saline consumption was 6.4 ± 2.5 L in the tourniquet-up group and 8.7 ± 4.6 L in the tourniquet-down group (P < .05). The respective amounts of estimated intraoperative and postoperative blood loss were 95.3 ± 25.1 mL and 240.3 ± 44.5 mL in the tourniquet-up group and 230.2 ± 22.3 mL and 75.6 ± 15.3 mL in the tourniquet-down group (P < .05). Our results showed no significant difference in postoperative pain, opioid consumption, percentage of patients using opioids, swelling, mean serum CPK and Hb levels, subjective and objective functional scores, or graft healing (P > .05) between the 2 groups. Tourniquet use during anterior cruciate ligament reconstruction significantly improves intraoperative visualization, shortens operative time, and decreases intraoperative sterile saline consumption and blood loss without serious adverse events or greater complication rates based on early postoperative outcomes. Level I, randomized controlled trial.


Gallbladder contraction, gastric emptying and antral motility: single visit assessment of upper GI function in untreated celiac disease using echo-planar MRI.
To assess gallbladder contraction, gastric emptying, and antral motility in untreated celiac patients and healthy controls using a single MRI examination. Gallbladder emptying, gastric emptying, and antral motility were measured in 15 celiac patients and 15 age/sex-matched healthy controls following a 323-kcal test meal using EPI techniques. Postprandial dyspepsia scores were recorded on a questionnaire. Fasting gallbladder volume (P=0.01) and the volume of bile ejected postprandially (P=0.014) were increased in celiacs. Gastric emptying tended to be slower in celiacs (P=0.142). Three celiac patients with severe postprandial dyspepsia and total villous atrophy had pathologically delayed gastric emptying and increased fasting gallbladder volume. Antral contractions were absent in five out of 14 patients (36%) five minutes after the meal, but in none of 10 volunteers in whom the antrum could be visualized (P=0.128). This study shows that using MRI, multiple parameters related to upper gastrointestinal function in celiac disease can be measured in a single noninvasive study, whereas previously three separate visits would have been required. Celiacs have increased fasting gallbladder volumes and tend to have slower gastric emptying.


Differential renal function using technetium-99m dimercaptosuccinic acid (DMSA): in vitro correlation.
The relationship between differential renal uptake of Tc-99m 2-3 dimercaptosuccinic acid (DMSA) and differential renal function was examined in normal and abnormal dogs by correlating Tc-99m DMSA localization with relative renal blood flow and creatining clearance. There was close correlation of fractional Tc-99m DMSA localization with relative renal function.


Physical Activity and Screen Time among Hungarian High School Students during the COVID-19 Pandemic Caused Distance Education Period.
High school education took place in the form of distance learning during SARS-CoV-2 pandemic worldwide, including Hungary. Decreased physical activity and an increase in inactive behaviours may lead to an increased risk of obesity, diabetes, and cardiovascular disease. Our study targeted changes in physical activity (aerobic exercise, muscle strengthening) and screen time in adolescents and young adults during the pandemic. High school students were interviewed in 66 public schools in 37 Hungarian cities (N = 2508). Survey items on physical activity and screen time were derived from the WHO Health Behaviour of School-aged Children Survey and the Centers for Disease Control Youth Risk Behavior Survey. A 2 × 2 factorial ANCOVA was used to test the effects of gender (male vs. female) and/or age (adolescents vs. young adults) on the reported changes in physical activity and screen time before and during lockdown (covariate: BMI Z-score). The majority of the cohort indicated less physical activity. Aerobic and muscle-strengthening type of exercises significantly decreased, and screen time increased during distance education. Male individuals showed a higher decrease in the level of aerobic exercise, and young adults reported a higher increase in the time spent in front of the screen.


[Effects of total triterpenes of Centella asiatica on the corticosterone levels in serum and contents of monoamine in depression rat brain].
To investigate the possible effect of antidepressant effect of total triterpentes of Centella asiatica. The corticosterone levels in serum were measured by fluorescence spectroscopy. The contents of monoamine neurotransmitters and their metabolites in rats cortex, hippocamopus and thalamus were evaluated by using HPLC with electrochemical detector. Significant reduction of the corticosterone level in serum and increase of the contents of 5-HT, NE, DA and their metabolites 5-HIAA, MHPG in rat brain were observed. The antidepressant effect of total triterpenes of Centella asiatica may be involved in ameliorating the function of HPA axis and increasing the contents of monoamine neurotransmitters.


Depression and osteoarthritis.
Depression is significant among patients with arthritis and musculoskeletal illnesses. However, the impact of depression on osteoarthritis has not been extensively studied. This article highlights the close links between these 2 prevalent chronic conditions, and the associated individual and societal burden. Results from a large clinical trial of depressed older patients with arthritis showed that a focused, collaborative depression care intervention not only decreased depression but also improved arthritis-associated outcomes, such as pain severity and arthritis-related limitations in daily activities. Relative to patients given usual care, patients receiving intervention also reported better health status and higher quality of life. Analyses of the depression interventions uncovered a reciprocal interrelation between depression and pain. Higher severity of either depression or pain decreased the benefits of systematic depression treatment and was associated with worse pain and depression outcomes. Current approaches to management of depression and arthritis do not reflect readily-available evidence-based treatment. A pilot study using a combined approach to address both depression and pain problems among elderly patients with depression and osteoarthritis suggested that benefits for depression, pain, and functional outcomes are strengthened by providing both pain and depression care management. An integrated depression and pain program using evidenced-based pharmacologic and nonpharmacologic treatments is needed to achieve optimal depression and pain outcomes. Currently, a randomized trial is under way to evaluate effectiveness of a combined pain and depression intervention using pharmacologic and nonpharmacologic therapies. Key intervention components in these 2 innovative and integrated depression and pain programs can guide clinicians to treat both depression and pain with more focus and intensity.


Oral manifestations of herpes simplex virus infections.
Most individuals are infected with Herpes Simplex in childhood usually suffering a mild febrile illness of no consequence. Later some individuals suffer recurrent infections which appear as cold sores on the lip while others intermittently shed virus in the oro-pharygeal secretions. Adults uninfected in childhood may be exposed to viruses for example by kissing and develop an acute primary herpes with fever and gingivo-stomatitis occasionally requiring hospital admission. Awareness of this condition is required for diagnosis after which the majority of patients seen in otolaryngological practice need only supportive therapy, explanation and reassurance. Recurrent cold sores are no more that a nuisance in most patients, but occasionally they are severe and in others the cold sore may precipitate oral erythema multiforme. Unfortunately the treatments available for recurrent cold sores are rather unsatisfactory.


Overexpression of 3-phosphoinositide-dependent protein kinase-1 is associated with prognosis of gastric carcinoma.
This study investigated the correlation between the expression of 3-phosphoinositide-dependent protein kinase-1 (PDK1) and the prognosis of gastric carcinoma patients. A total of 156 paired tumor and matched normal samples were collected from patients of gastric carcinoma who underwent surgical resection. The expression of PDK1 was analyzed by real-time quantitative PCR and immunohistochemistry method. Potential correlation between PDK1 protein expression and the clinicopathological characteristics was determined by chi-square test and Spearman correlation analysis. The influence of PDK1 expression on 5-year survival rate and survival length was determined by Kaplan-Meier analysis. The expression of PDK1 mRNA and protein were significantly higher in tumor samples comparing to those in adjacent normal samples (paired t test, P = 0.007). Immunohistochemical staining results indicated that PDK1 protein level was positively correlated with infiltration (P = 0.006). However, no associations with age, sex, clinical stage, lymph node metastasis, and distant metastasis were observed (P > 0.05). The 5-year survival rate was 20.1 and 63.4 % of the patients with high and low expression level of PDK1, respectively (P < 0.05). The median survival length was 32.5 months (95 % CI 22.8-37.6) for patients with high level of PDK1 and 63.1 months (95 % CI 52.3-64.7) for patients with low level of PDK1 (×2 = 20.153, P < 0.05). Kaplan-Meier survival curves demonstrated that elevated expression of PDK1 was an independent negative prognostic factor of gastric carcinoma (P<0.05). Our study indicated that PDK1 might serve as a candidate pro-oncogene and a potential prognostic biomarker for gastric carcinoma.


Enhancement of survival in acute experimental fowl typhoid in chicks by the administration of iron dextran.
Chicks aged 15 days were infected orally with 10(6-4) living Salmonella gallinarum. Iron from iron dextran or ferric ammonium citrate (DFe and CFe respectively), in doses of 2-0 or 0-4 mg/kg given intramuscularly at the time of infection, had no effect on subsequent mortality compared with infected controls. Increasing the amount of CFe to the maximum (20 mg/kg) that was non-toxic intramuscularly was also ineffective but when the dose of DFe was increased to 20 or 50 mg/kg the survival rate rose sharply. If given at other times in relation to the time of infection, or more frequently, 50 mg/kg or more of DFe was less active. The increased survival rate among infected chicks given 50 mg/kg of DFe at the time of infection was accompanied by decreases in the severity of the morbid changes in the disease, and by reductions of between c 10- to 100-fold in the numbers of viable S gallinarum in the liver, spleen or blood at the height of the acute infection. DFe (50 mg/kg) given at the time of infection also eliminated the difference in the survival rate noted previously between infected chicks fed respectively with diets containing fish or meat meal as the sole source of supplementary protein.


Professional isolation and pandemic teleworkers' satisfaction and commitment: The role of perceived organizational and supervisor support.
The COVID-19 pandemic has abruptly and profoundly changed the way people interact with their organization, their colleagues and their supervisor. This study assesses the effects of telework-induced professional isolation due to the pandemic. Drawing on organizational support theory, this study examines the relationship between professional isolation and satisfaction with the telework experience and affective organizational commitment during mandatory teleworking caused by the COVID-19 crisis. It does so by focusing on the moderating role of perceived organizational and supervisor support in these relations. Data was collected via self-reported survey questionnaires from 728 pandemic teleworkers from various industry sectors in Quebec during the COVID-19 crisis. The study's hypotheses were tested using structural equation modeling (SEM), and moderation effects were probed with the Johnson-Neyman technique. The results reveal that professional isolation negatively affects satisfaction with the telework experience, but does not affect affective organizational commitment. The relationship between satisfaction with telework and professional isolation was moderated by perceived organizational support, and the relationship between affective organizational commitment and professional isolation was moderated by perceived supervisor support. This study expands the organizational support theory by examining perceived organizational and supervisor support during a crisis as a counterbalance to a challenging social and organizational climate that has led to professional isolation. The implications of the findings as well as future directions for research on professional isolation and telework are discussed.


TP-2Rho Is a Sensitive Solvatochromic Red-Shifted Probe for Monitoring the Interactions between CDK4 and Cyclin D.
Understanding the intricate steps of protein kinase regulation requires characterization of protein-protein interactions between the catalytic subunit, its regulatory partners and the substrate. Fluorescent probes are useful tools with which to study such interactions and to gain insight into their affinities and specificities. Solvatochromic probes, which display changes in their fluorescence emission in response to changes in the polarity of the medium, are particularly attractive. Here we describe conjugation of a switchable fluorescent dye, TP-2Rho, to peptide and protein derivatives of cyclin-dependent kinase 4 (CDK4) and its application to characterization of the interactions between the catalytic subunit of this kinase, its regulatory partner cyclin D1 and a peptide substrate. We demonstrate the sensitivity of TP-2Rho in relation to of those other dyes used for monitoring peptide-protein and protein-protein interactions. Moreover, we show that TP-Rho-labelled peptides can be introduced into living cells to probe endogenous CDK4/cyclin D.


The Ross procedure in adults: intermediate-term results.
The durability of the Ross procedure may be optimized by appropriate geometric matching of the aortic and pulmonary artery roots. We employed a surgical strategy to standardize the operation in order to avoid more readily a geometric mismatch. The Ross procedure was performed as a root replacement. Without regard for patient body surface area, the aortic annulus was plicated to 23 mm and externally buttressed with felt. Geometric mismatch of the distal autograft anastomosis was avoided by liberal use of a synthetic interposition graft, and the anastomosis was also externally buttressed with felt. An over-sized pulmonary homograft (27 to 28 mm) was routinely used to reconstruct the right ventricular outflow tract. Forty-four consecutive patients (27 men and 17 women; mean age, 49 +/- 9 years) were operated on between January 1997 and March 2002. Mean follow-up was 38 +/- 5 months. Twenty-nine patients had aortic stenosis and 15 had aortic regurgitation. Aortic annular plication was done in 41 (93%) and an aortic interposition was used in 14 (32%). There were three hospital deaths, with no subsequent deaths. Only 1 patient required reoperation 2.5 years postoperatively from recurrent endocarditis. No patient has more that "trivial" autograft insufficiency, and the mean autograft gradient was 7 +/- 3 mm Hg. No patient has significant pulmonary homograft stenosis. Geometric matching of the aortic and pulmonary roots may be readily accomplished using a standardized approach to the Ross procedure. In turn, this may optimize the durability of the operation.


Metabolic studies on eel (Anguilla anguilla L.) hepatocytes in primary culture: effect of 17 beta-estradiol and growth hormone.
Previous studies demonstrated that native and recombinant growth hormone from mammalian and fish species potentiate the estrogenic induction of vitellogenin synthesis by cultured eel hepatocytes. In the present study, the metabolic competence (respiratory activity and estradiol catabolism) of cultured hepatocytes and their functional capacity to synthesize a specific protein, vitellogenin, in the presence of estradiol and/or bovine growth hormone was investigated. In addition, we examined the possible role of insulin-like growth factors as mediators of growth hormone. Hepatocytes retain a high level of metabolic activity under the primary culture conditions applied. Estradiol has a half life of several hours in the hepatocyte culture, and is metabolized into conjugated forms. Estradiol and/or growth hormone had no effects on respiratory activity of the cultured hepatocytes. Moreover, the estradiol catabolic parameters were not affected by growth hormone. Finally, human and trout recombinant insulin-like growth factors do not potentiate vitellogenin synthesis induced by estradiol.


Clear and present danger: Mechanical heart valves in pregnancy.
Specialists in Obstetric Haematology continue to be challenged by pregnant women with mechanical heart valves, who are at high risk of death or severe morbidity. Effective anticoagulation to reduce valve thrombosis inevitably increases risk of obstetric haemorrhage and fetal loss or harm, and difficult decisions need to be made. Lester and mulitdisciplinary colleagues on behalf of the British Society for Haematology review available evidence and provide comprehensive recommendations to guide management in this difficult area. Commentary on: Lester et al. British Society for Haematology guideline for anticoagulant management of pregnant individuals with mechanical heart valves. Br J Haematol 2023;202:465-478.


An open-label, phase 1 study evaluating safety, tolerability, and pharmacokinetics of linifanib (ABT-869) in Japanese patients with solid tumors.
This phase 1 study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of linifanib in Japanese patients with advanced solid tumors. Patients were assigned to one of four sequential cohorts (0.05, 0.10, 0.20, or 0.25 mg/kg) of oral, once-daily linifanib on a 21-day cycle. Adverse events (AEs) were assessed per common terminology criteria for adverse events v3.0; tumor responses were assessed by response evaluation criteria in solid tumors. Eighteen patients were enrolled. Eleven (61%) received ≥3 prior therapies. Dose-limiting toxicities were Grade 3 ALT increase (0.10 mg/kg linifanib) and Grade 1 T-wave inversion (0.25 mg/kg linifanib) requiring dose interruption for >7 days and discontinuation on day 29. The most common linifanib-related AE was hypertension. Other significant treatment-related AEs included proteinuria, fatigue, and palmar-plantar erythrodysaesthesia. Linifanib pharmacokinetics were dose-proportional across 0.10-0.25 mg/kg. Two patients (11.1%) had confirmed partial responses, 12 had a best response of stable disease (11 had stable disease for ≥12 weeks), and four patients were not evaluable due to incomplete data. Four patients (lung cancer, breast cancer, thymic cancer, sarcoma) have continued linifanib for ≥48 weeks (range, 48-96+ weeks). Linifanib was well tolerated with promising preliminary clinical activity in Japanese patients. Later-phase global studies examining linifanib efficacy will include Japanese patients.


Model-Informed Support of Dose Selection for Prophylactic Treatment with Dalcinonacog Alfa in Adult and Paediatric Hemophilia B Patients.
Dalcinonacog alfa (DalcA), a novel subcutaneously administered recombinant human factor IX (FIX) variant is being developed for adult and paediatric patients with hemophilia B (HB). DalcA has been shown to raise FIX to clinically meaningful levels in adults with HB. This work aimed to support dosing regimen selection in adults and perform first-in-paediatric dose extrapolations using a model-based pharmacokinetic (PK) approach. A population PK model was built using adult data from two clinical trials (NCT03186677, NCT03995784). With allometry in the model, clinical trial simulations were performed to study alternative dosing regimens in adults and children. Steady-state trough levels and the time-to-reach target were derived to inform dose selection. Almost 90% of the adults were predicted to achieve desirable FIX levels, i.e. 10% FIX activity, following daily 100 IU/kg dosing, with 90% of the subjects reaching target within 1.6-7.1 days. No every-other-day regimen met the target. A dose of 125 IU/kg resulted in adequate FIX levels down to 6 years, whereas a 150 IU/kg dose was needed below 6 down to 2 years of age. For subjects down to 6 years that did not reach target with 125 IU/kg, a dose escalation to 150 IU/kg was appropriate. The children below 6 to 2 years were shown to need a dose escalation to 200 IU/kg if 150 IU/kg given daily was insufficient. This study supported the adult dose selection for DalcA in the presence of sparse data and enabled first-in-paediatric dose selection to achieve FIX levels that reduce risk of spontaneous bleeds.


Optical determination of Shockley-Read-Hall and interface recombination currents in hybrid perovskites.
Metal-halide perovskite solar cells rival the best inorganic solar cells in power conversion efficiency, providing the outlook for efficient, cheap devices. In order for the technology to mature and approach the ideal Shockley-Queissier efficiency, experimental tools are needed to diagnose what processes limit performances, beyond simply measuring electrical characteristics often affected by parasitic effects and difficult to interpret. Here we study the microscopic origin of recombination currents causing photoconversion losses with an all-optical technique, measuring the electron-hole free energy as a function of the exciting light intensity. Our method allows assessing the ideality factor and breaks down the electron-hole recombination current into bulk defect and interface contributions, providing an estimate of the limit photoconversion efficiency, without any real charge current flowing through the device. We identify Shockley-Read-Hall recombination as the main decay process in insulated perovskite layers and quantify the additional performance degradation due to interface recombination in heterojunctions.


RNA metabolism and poly(A) distribution in mouse liver following administration of dimethylnitrosamine.
Dimethylnitrosamine (DMNA) strongly inhibited RNA synthesis in mouse liver under conditions when the nucleotide pattern, rate of nucleotide synthesis and phosphorylation ratio were unaffected. (An unidentified, probably non-nucleotide, component in the acid-soluble liver fraction was selectively reduced.) The inhibition of RNA synthesis was associated with a decrease in the RNA polymerase activity of isolated liver nuclei, well established already 45 min after DMNA administration. The reduced activity included both Mg2+- and Mn2+/(NH4)2SO4-stimulated polymerase functions. The inhibition in vivo involved the whole complement of RNA, including poly (A)-containing RNA and isolated poly(A) sequences. The transfer of labelled RNA from the nucleus to the cytoplasm was not impaired. There was no detachment of poly(A)-containing RNA from the microsomes, and the proportion of tightly membrane-bound microsomal RNA and poly(A) sequences was not reduced as determined by use of a flotation technique. No breakage or shortening of the poly(A) chains was indicated by sedimentation analysis.


Equations for vapour pressure versus temperature: derivation and use of the Antoine equation on a hand-held programmable calculator.
The Antoine equation is a semi-empirical equation which expresses vapour pressure as a function of temperature. A new, rapid and highly accurate method for obtaining its three constants from experimental data is presented and applied to ethanol, water and 14 anaesthetic substances. Alternative vapour pressure equations are discussed and references for original temperature--vapour pressure data are summarized. A series of equations utilizing vapour pressure is detailed: these formulas are of use in both the practice and teaching of anaesthesia.


Redo aortic root surgery for failure of an aortic homograft is a major technical challenge.
Aortic homografts offer many advantages over prosthetic valves. However, homograft dysfunction due to degeneration or infection may lead to reoperation. Aortic valve replacement in patients who have undergone previous aortic root replacement with an aortic homograft remains a technical challenge. To assess reoperation events a retrospective review was conducted. From January 2000 to October 2006, 20 consecutive patients (38.8+/-14.9 years old) underwent repeat surgery for aortic homograft failure. Reoperation was performed 7.2+/-3.5 years after implantation of the aortic homograft as a root. Indication was homograft degeneration (n=18 [90%]) and endocarditis (n=2 [10%]). In patients with major homograft wall calcifications or endocarditis, nine aortic root reconstructions were performed (Bentall procedure n=7; homograft implantation n=2). Each homograft was dissected with electrical cauterization and removed 'en-bloc' sparing the coronary buttons. In case of flexible homograft wall, stented prostheses (mechanical n=10, bioprosthesis n=1) were implanted along the homograft annulus. Additional procedures consisted of mitral valve replacements (n=8), tricuspid repairs (n=4), Konno procedure (n=1) and coronary bypass (n=5). Perioperative complications occurred in seven (35%) patients: sternal re-entry accident (n=2); reoperations for mediastinitis (n=1) or bleeding (n=2); renal insufficiency (n=1); total heart block (n=1). No association was found between operative procedures and postoperative complications (Fisher's exact test). Two patients (10%) died from multiorgan failure in the early postoperative period. In total, 94.4% of the survivors remained free from reoperation at 74 months. Reoperation on patients with an aortic homograft as a root presents a relatively high perioperative morbidity. The surgical strategy depends on the degree of homograft wall calcification.


Sub-ohm vaping increases the levels of carbonyls, is cytotoxic, and alters gene expression in human bronchial epithelial cells exposed at the air-liquid interface.
Exposure to electronic-cigarette (e-cig) aerosols induces potentially fatal e-cig or vaping-associated lung injury (EVALI). The cellular and molecular mechanisms underlying these effects, however, are unknown. We used an air-liquid interface (ALI) in vitro model to determine the influence of two design characteristics of third-generation tank-style e-cig devices-resistance and voltage-on (1) e-cig aerosol composition and (2) cellular toxicity. Human bronchial epithelial cells (H292) were exposed to either butter-flavored or cinnamon-flavored e-cig aerosols at the ALI in a Vitrocell exposure system connected to a third-generation e-cig device. Exposures were conducted following a standard vaping topography profile for 2 h per day, for 1 or 3 consecutive days. 24 h after ALI exposures cellular and molecular outcomes were assessed. We found that butter-flavored e-cig aerosol produced under 'sub-ohm' conditions (< 0.5 Ω) contains high levels of carbonyls (7-15 μg/puff), including formaldehyde, acetaldehyde and acrolein. E-cig aerosol produced under regular vaping conditions (resistance > 1 Ω and voltage > 4.5 V), contains lower carbonyl levels (< 2 μg/puff). We also found that the levels of carbonyls produced in the cinnamon-flavored e-cig aerosols were much lower than that of the butter-flavored aerosols. H292 cells exposed to butter-flavored or cinnamon-flavored e-cig aerosol at the ALI under 'sub-ohm' conditions for 1 or 3 days displayed significant cytotoxicity, decreased tight junction integrity, increased reactive oxygen species production, and dysregulated gene expression related to biotransformation, inflammation and oxidative stress (OS). Additionally, the cinnamon-flavored e-cig aerosol induced pro-oxidant effects as evidenced by increases in 8-hydroxy-2-deoxyguanosine protein levels. Moreover, we confirmed the involvement of OS as a toxicity process for cinnamon-flavored e-cig aerosol by pre-treating the cells with N-acetyl cysteine (NAC), an antioxidant that prevented the cells from the OS-mediated damage induced by the e-cig aerosol. The production of high levels of carbonyls may be flavor specific. Overall, inhaling e-cig aerosols produced under 'sub-ohm' conditions is detrimental to lung epithelial cells, potentially via mechanisms associated with OS. This information could help policymakers take the necessary steps to prevent the manufacturing of sub-ohm atomizers for e-cig devices.


Network modeling of anxiety and psychological characteristics on suicidal behavior: Cross-sectional study.
Suicide is influenced by complex interactions among various psychopathological features. We aimed to examine the relationship between suicide risk and psychological risk factors such as defense mechanisms, personality, and anxiety. We established a psychiatric database by utilizing the Observational Medical Outcomes Partnership Common Data Model. We conducted a 1:1 propensity score matching with age, sex, and depression severity, and identified a sample (n = 258) with two groups: those with suicidal behavior and those with non-suicidal behavior. Using principal component analysis, we extracted nine psychological scales and applied network analysis to compare relationships among psychological factors between the two groups. Patients with non-suicidal behaviors showed associations between trait anxiety and defense mechanisms, while those with suicidal behaviors did not. For patients with suicidal ideation there was an association between somatization and trait anxiety. Patients with suicide attempts showed associations between paranoia and dissociation connected to trait anxiety. Longitudinal research is required to fully observe transitions from suicidal ideation to attempts and recurrent suicidal events. In addition, these networks may not generalize suicidal behaviors because the group participants are not homogeneous. Lastly, data from self-report questionnaires limits the reliability of responses. We presented important new insights on suicidal behavior by estimating psychological networks. Patients with non-suicidal behavior may exhibit discrete relationships between defense mechanisms and anxiety, compared to those with suicidal behavior. Patients with suicidal ideation and suicide attempts may show distinct associations between anxiety and psychopathological features.


The effect of parental condition on egg-size and reproductive success in short-tailed shearwaters Puffinus tenuirostris.
Eggs were exchanged between 50 pairs of shorttailed shearwaters Puffinus tenuirostris on Great Dog Island, Bass Strait, Australia, in an attempt to distinguish the intrinsic effects of egg-size from any effects stemming from differential quality of parental care. At 64 "experimental" nests, large and small eggs were exchanged whereas at 36 "control" nests, eggs of equivalent, medium, size were exchanged. Egg-size appeared independent of maternal effects. In both groups, hatching and fledging success were independent both of eggsize and of the body condition of the attending parents. This suggests that breeding success in these birds may be more closely related to the behavioural traits of parents than to physiological factors.


Associations of anti-GAD antibodies with islet cell antibodies and insulin autoantibodies in first-degree relatives of type I diabetic patients.
Sera from 114 first-degree relatives of insulin-dependent diabetes mellitus (type I diabetes) patients and 81 healthy individuals living in Germany were analyzed for antibodies to rat brain glutamic acid decarboxylase (GAD-ab) using an immunoprecipitation assay. The determination of GAD-ab in the 81 islet cell antibody (ICA) and insulin autoantibody (IAA) negative healthy individuals established a normal range (mean +/- 2 SD); 2 healthy individuals (2.5%) possessed GAD-ab levels above this range, but became negative on follow-up. None of 86 ICA-/IAA- first-degree relatives had GAD-ab; whereas, 42.9% of 28 ICA+ and/or IAA+ relatives were positive for GAD-ab. Presence of GAD-ab was negatively correlated with IAA (P = 0.02) and positively with ICA (P = 0.0006). Follow-up samples were obtained from 25 of 28 ICA+ and/or IAA+ relatives with a mean (+/- SD) follow-up period of 20.6 +/- 12.1 months. In these 25 relatives, GAD-ab were positive in 70% ICA+/IAA-, 0% ICA-/IAA+, and 57.1% ICA+/IAA+ relatives in the first sample and in 57.1% ICA+/IAA-, 0% ICA-/IAA+, and 70% ICA+/IAA+ relatives in the last sample. GAD-ab, once detected, persisted in 9 of 11 GAD-ab+ relatives. Of the relatives, 2 converted to GAD-positivity, concomitant with the appearance of ICA, and 2 others lost GAD-ab during follow-up. Of the 28 ICA+ and/or IAA+ relatives, 6 progressed to overt type I diabetes on follow-up, and GAD-ab were detectable in 4 of these relatives.(ABSTRACT TRUNCATED AT 250 WORDS)


An evaluation of the use of spelling error analysis in the diagnosis of reading disabilities.
This study examined whether significant differences could be observed in types of errors made by normal versus retarded readers (fifth graders) on the WRAT spelling test. Although researchers have reported high numbers of certain types of errors, such as reversals, this study revealed that the proportion of errors attributed to any particular error type is virtually identical for both normal and retarded readers. Retarded readers were thus shown to be unlike normal readers in the number of errors committed but like normal readers in the types of errors committed.


Initiation of carbamazepine therapy in partial epilepsy: a regional cerebral blood flow study.
The effect of the initiation of carbamazepine (CBZ) treatment on regional cerebral blood flow (rCBF) was studied using the intravenous Xenon technique in a group of epileptic patients suffering from complex partial seizures. A slight increase in mean rCBF (10.8 +/- 8.8%, P less than 0.01) was observed in 12 patients after the first month of CBZ treatment, while no rCBF change was found after 6 months of CBZ treatment. Regional analysis showed that the rCBF increase following 1 month of CBZ treatment involved all cortical regions with the exception of the right occipital region, irrespective of the initial value. Repeated rCBF measurements performed in normal volunteers (N = 6) and in epileptic patients (N = 10), chronically treated and not subjected to therapeutic modification, showed no significant change. The initial effect of CBZ on CBF found at the onset of the treatment but not after 4-6 months may be related to the improvement in epilepsy and in cerebral function (as suggested by cognitive findings).


MR visualization of CSF flow through a ventriculo-cisternostomy.
The MRI findings in a 6-year-old boy with an astrocytoma of the mesancephalon are reported. A ventriculocisternostomy had been performed in order to reduce the hydrocephalus. At the site of the ventriculocisternostomy, the T2-weighted images showed a low signal in the anterior part of the third ventricle, the interpeduncular and the pontine cistern. This was attributed to CSF flow void. We conclude that MRI can provide information about the precise location and normal functioning of a ventriculocisternostomy.


On the molecular structure of some prostaglandin receptors.
Hypotheses are presented of the detailed molecular structure of two prostaglandin receptors both concerned in tumor-promotion processes. These structures have been derived by the comparison of the molecular structure of agents active at the site with (i) a simple theoretical protein structure and (ii) the known x-ray structure of phospholipase A2. The first model receptor is stimulatory to the tumor-promotion process and may be located on the control system for ornithine decarboxylase. The binding of PG here is cooperative with the binding of Ca++. Naturally-occurring agonists at this receptor may include members of the cathartic class of drugs such as colocynth, chrysarobin, etc. Naturally-occurring antagonists at this site may include a number of anti-tumor compounds such as datiscoside. The second model receptor (PGE1) is inhibitory to the tumor-promotion process and is located at a specific allosteric site on the x-ray-determined structure of phospholipase A2. This site overlaps for one for lysolecithin (excitatory), for which tumor-promoting phorbol esters such as TPA are agonists and some anti-tumor drugs such as maytansine may be antagonists.


Early B cells repopulation in multiple sclerosis patients treated with rituximab is not predictive of a risk of relapse or clinical progression.
It is currently unknown whether early B cell reconstitution (EBR) in MS patients under rituximab is associated with a risk of relapse or progression. Analyzing EBR in rituximab-treated patients and its putative association with clinical findings. Prospective lymphocytes immunophenotyping was performed in a monocentric cohort of MS patients treated by rituximab for 2 years. EBR was defined when B cells concentration was > 5 cells/mm3. B cell subsets were retrospectively associated with clinical data. Clinical and radiological monitoring included relapses, EDSS (Expanded Disability Status Scale), SDMT (Symbol Digit Modalities Test), and MRI. 182 patients were analyzed (61 remitting-relapsing and 121 progressive-active). 38.5% experienced EBR at least once, but very few (7/182) showed systematic reconstitution. Most patients remained stable upon treatment, regardless of the occurrence of EBR. Dynamics of B cell reconstitution featured increased naïve/transitional B cells, and decreased memory subsets. Homeostasis of the B cell compartment differed at baseline between patients experiencing or not EBR upon treatment. In patients with EBR, reciprocal dynamics of transitional and pro-inflammatory double-negative B cell subsets was associated with better response to rituximab treatment. EBR is common in rituximab-treated MS patients and is not associated with clinical disease activity. EBR in the peripheral blood may reflect regulatory immunological phenomena in subgroup of patients.


Vasodilator therapy of hypertensive acute left ventricular failure: comparison of captopril-prazosin with hydralazine-isosorbide dinitrate.
A prospective study to evaluate and compare the cardiorespiratory effects and clinical efficacy of the Neurohormonal inhibitors (Captopril 50 mg+prazosin 1 mg only) and direct arteriolar and venular dilators (Intravenous hydralazine 30 mg+oral isosorbide dinitrate 30 mg) used as vasodilator therapy, was undertaken in a randomized, single blind study in 17 Nigerian patients with hypertensive acute left ventricular failure. Both vasodilator regimes separately and significantly reduced the systolic and diastolic blood pressures (P<0.001 ANOVA), heart rate (P<0.001 ANOVA), and the respiratory rate (P<0.05 ANOVA), the double product, but increased the peak expiratory flow rate (P<0.05 ANOVA). However, the neurohormonal antagonists, captopril and prazosin (n=9) caused a statistically significantly greater reduction in heart rate (P<0.05 ANOVA) respiratory rate (P<0.05 ANOVA) and induced a significantly greater increase in the self-paced exercise capacity, 24 h after initiation of treatment, (P<0.02) compared to the hydralazine and isosorbide dinitrate combination (n=8). Five of the nine patients on the neurohormonal antagonist therapy were ambulant at 24 h, compared to none of the eight patients receiving conventional venular and arteriolar dilators hydralazine and isosorbide dinitrate (chi2=5.84 dfi P<0.05). There was a significant inverse correlation between the systolic blood pressure heart rate product, and the distance covered during symptom limited self paced exercise capacity (r=-0.58, P=0.0146 ANOVA). One of eight patients in the hydralazine+isosorbide nitrate combination died, but there was no mortality in the captopril+prazosin group. These findings collectively suggest that captopril+prazosin combination may be a superior vasodilator therapy compared to hydralazine-isosorbide dinitrate, in hypertensive acute pulmonary oedema.


Selective Hydrogen Atom Abstraction from Dihydroflavonol by a Nonheme Iron Center Is the Key Step in the Enzymatic Flavonol Synthesis and Avoids Byproducts.
The plant non-heme iron dioxygenase flavonol synthase performs a regioselective desaturation reaction as part of the biosynthesis of the signaling molecule flavonol that triggers the growing of leaves and flowers. These compounds also have health benefits for humans. Desaturation of aliphatic compounds generally proceeds through two consecutive hydrogen atom abstraction steps from two adjacent carbon atoms and in nature often is performed by a high-valent iron(IV)-oxo species. We show that the order of the hydrogen atom abstraction steps, however, is opposite of those expected from the C-H bond strengths in the substrate and determines the product distributions. As such, flavonol synthase follows a negative catalysis mechanism. Using density functional theory methods on large active-site model complexes, we investigated pathways for desaturation and hydroxylation by an iron(IV)-oxo active-site model. Contrary to thermochemical predictions, we find that the oxidant abstracts the hydrogen atom from the strong C2-H bond rather than the weaker C3-H bond of the substrate first. We analyze the origin of this unexpected selective hydrogen atom abstraction pathway and find that the alternative C3-H hydrogen atom abstraction would be followed by a low-energy and competitive substrate hydroxylation mechanism hence, should give considerable amount of byproducts. Our computational modeling studies show that substrate positioning in flavonol synthase is essential, as it guides the reactivity to a chemo- and regioselective substrate desaturation from the C2-H group, leading to desaturation products efficiently.


Heterogeneity of Igh-linked allotypic determinants expressed on functional T cell subsets as detected by monoclonal antibodies.
Hybridomas producing monoclonal antibodies (mAb) specific for immunoglobulin heavy chain (Igh) allotype-linked gene products expressed only on functional T cells but not on B cells and macrophages were established by fusion of allotype congenic SJL (Igh-1b) and SJA /9 (Igh-1a) B cells immunized reciprocally with partner spleen cells with a myeloma P3-X63-Ag8-653 of BALB/c origin. Nine mAb have been selected on the criteria that they can specifically block various antigen-dependent functions of known T cell subsets in in vitro immune responses of mouse strains having the corresponding Igh allotype, but not the other one. These included (a) four mAb that augment the in vitro secondary antibody response of either Igh-1a or Igh-1b strains and thus are considered to react with the Igh-linked allotypic determinant expressed on suppressor T cells, (b) one mAb that inhibits the helper T cell activity of Igh-1b but not of Igh-1a strains, (c) two mAb that inhibit the antigen-induced proliferative response of Igh-1a but not Igh-1b strains, and (d) two mAb that block the cytotoxicity of alloreactive cytotoxic T cells of Igh-1a strains. The linkage to Igh-1 allotype of the T cell products was established by testing with Igh-1-congenic strains with different backgrounds including the H-2 complex. Some of the mAb were able to react with cloned hybridomas and a continuous cell line of the given allotype and functions. Each mAb was able to block one of the known functions of T cell subsets, but not others, indicating the existence of the heterogeneity and multiplicity of the Igh allotype-linked products on T cells.


Suspension feeding in Bithynia tentaculata (Prosobranchia, Bithyniidae), as affected by body size, food and temperature.
The suspension feeding of Bithynia tentaculata was tested in laboratory experiments. The animals were fed in 1-1 aerated glass beakers, and filtration rates were calculated from changes in cell concentrations during the 6-h experiment. Temperature influenced the filtering rate, with minimum values of 5ml · ind-1 · h-1 at 5° C and maxima of 17.2 ml · ind-1 · h-1 at 18° C. Three food species of different size, motility and cell surface characteristics (Chlamydomonas reinhardii, Chlorella vulgaris and Chlorogonium elongatum) did not affect filtration rates. Suspension feeding increased with increasing food concentrations up to 12 nl · ml-1, above which feeding rate was kept constant by lowering the filtering rates. Even the smallest animals tested (<4 mm body length) were found to be feeding on suspended food at a rate of 2.7 ml · ind-1 · h-1, and increasing rates up to 8.4 ml were found in the 6-7 mm size class. All size classes of Bithynia showed a circannual fluctuation of their filtration rates. The ecological consequences of Bithynia's ability to switch between two feeding modes, grazing and suspension feeding, are discussed.


The process of metastasisation for breast cancer.
To investigate the process of metastasis, primary clinical data and disease events such as metastases, local recurrence and survival (median follow-up 9.4 years) from the Munich Cancer Registry from 1978 to 1996 were analysed. Since metastases, even from small tumours, may be initiated before the diagnosis of the primary tumour, the growth of the primary tumour and metastasisation may be two autonomous processes. In our data, survival following metastases was almost unrelated to primary tumour size. However, the number of M1 cases and the time to metastasisation depended on the tumour diameter at diagnosis. The time from initiation of metastases to its diagnosis was estimated as 5.8 years. The growth of metastases was almost homogeneous. However, the growth time following metastasisation-depending on the metastases-free time, receptor status and histological grade-only varied by approximately a factor of 2. Local recurrence, above all, was an indicator of metastases. Furthermore, local recurrence may also have the potential to metastasise. Excess mortality due to local recurrence was estimated up to 9.3 years after diagnosis. Our hypothesised metastases model illustrates the importance of early detection, the concept of breast-conserving therapy and additional metastases from local recurrence. It highlights the benefits of optimal local therapy of the primary tumour and the limitations of systemic therapy. It also questions the use of axilla dissection and lymph node irradiation. Its generalisation to solid tumours may help to clarify many of the current controversial debates.


Full length parathyroid hormone, PTH(1-84), for the treatment of severe osteoporosis in postmenopausal women.
To review and analyse the evidence supporting the use of full length parathyroid hormone, PTH(1-84), in the treatment of osteoporosis based on a search of several literature sources; articles selected for review were published between 1990 and 2008. PTH(1-84) is approved for the treatment of osteoporosis in postmenopausal women at high risk of fracture in Europe. It was well tolerated in clinical trials and demonstrated bone building properties and fracture prevention particularly for the lumbar spine in the treatment of postmenopausal women. The TOP clinical trial showed that PTH(1-84) treatment for 18 months resulted in a 61% reduction (p = 0.001) in new vertebral fracture incidence when compared with placebo and reduced the risk of a first vertebral fracture by 68% (p = 0.006) in women without a prevalent fracture at baseline. PTH(1-84) increased bone mineral density (BMD) at vertebral and non-vertebral sites the lumbar spine BMD increasing regardless of T-score, age, prior osteoporosis therapy or number of years post-menopause. The PaTH study showed that treatment with PTH(1-84) for 12 months increased BMD at the trabecular spine and hip. Lumbar spine BMD gains were largest with sequential administration of PTH(1-84) followed by alendronate but were smaller with concurrent administration involving anabolic and antiresorptive agents. Lumbar spine BMD increases were also seen in trials involving PTH with raloxifene and PTH in combination with hormone replacement therapy. PTH(1-84) has demonstrated effective bone building qualities and extends the therapeutic options available to osteoporotic women. The use of PTH(1-84) followed by sequential administration of an antiresorptive has proved effective at increasing trabecular BMD and points towards new treatment regimens offering improvements in BMD and fracture prevention.


Studies on the biosynthesis of avermectins.
To elucidate the pathway of avermectin biosynthesis, the biosynthetic relationships of avermectins A1a, A2a, B1a, B2a, and their respective monosaccharides and aglycones were studied. 14C-labeled avermectin compounds prepared from [1-14C]acetate were fed to Streptomyces avermitilis strain MA5502 and their metabolites were determined. Two furan ring-free aglycones, 6,8a-seco-6,8a-deoxy-5-keto avermectin B1a and B2a, have been isolated from the fermentation broth of a blocked mutant of S. avermitilis. Addition of the compounds and a semisynthetic compound, 5-keto avermectin B2a aglycone, to the fermentation medium of a second blocked mutant established that the two compounds are intermediates in the avermectin biosynthetic pathway immediately preceding avermectin aglycones.


Long-term Prognostic Impact of Physical Activity in Patients With Stable Coronary Heart Disease.
Stable coronary heart disease (CHD) patients are advised to practice regular physical activity (PA). However, data on very long-term prognosis impact of regular exercise remain scarce. We aimed to evaluate the impact of physical activity level on mortality at long term in stable CHD patients. We analyzed 822 patients with stable CHD. They answered questionnaires on medical history, underwent a standardized clinical examination, and provided a fasting blood sample. PA was evaluated by the MOSPA questionnaire. Three tertiles of patients were individualized according to PA level: 0.0-9 Metabolic Equivalent of Task (METs) hour per week (n = 267); 10-39.9 METs hour per week (n = 279); and ≥40 METs hour per week (n = 276). After a median follow-up of 14.6 years, 324 patients had died. In a multivariate analysis adjusted for age, dyslipidemia, smoking status, diabetes, high blood pressure, waist circumference, left ventricular ejection fraction, Gensini score, heart rate, ankle-brachial index and duration of disease, physical activity was significantly and independently associated with all-cause mortality. Compared to the lowest PA tertile, both the median and the highest PA tertiles, were associated to a reduction of all-cause mortality risk with hazard ratios at 0.79 (95%confidence interval [0.61:1.03], P = 0.08) and 0.71 ([0.53:0.96], P = 0.025) respectively; P for trend = 0.02. Adjusted hazard ratios for an increase of 10 METs hour per week was 0.95 [0.92 to 0.98], (P <0.002). In conclusion, our study demonstrates an independent association between PA and long term vital prognosis with a 5% total mortality decrease for an increase of 10 METs hour per week.


Philadelphia chromosome-negative acute hematopoietic malignancy: ultrastructural, cytochemical and immunocytochemical evidence of mast cell and basophil differentiation.
We describe a patient with fever and multiple osteolytic bone lesions accompanied by hypercalcemia, a duodenal ulcer, anemia, and thrombocytopenia. Bone marrow showed a dense infiltration by abnormal cells characterized by small basophil granula, erythrophagocytosis and nuclear atypia. These cells were positive for toluidine blue and partly for myeloperoxidase and chloroacetate esterase, expressed myeloid differentiation markers, and exhibited multiple numerical and structural chromosome aberrations. Molecular genetic analysis showed no breakpoint cluster region rearrangement. Electron microscopy demonstrated granula both of basophil and mast cell type. Concluding, in this patient an acute hematopoietic malignancy with many features of malignant mastocytosis but also with signs of a basophil differentiation. This is further support for a hematopoietic stem cell origin of human mast cells.


P2Y(1) receptor activation enhances the rate of rat pinealocyte-induced extracellular acidification via a calcium-dependent mechanism.
Pineal gland G-protein coupled P2Y(1) receptors potentiate noradrenaline-induced N'-acetylserotonin production, a long term response which occurs after 5 h incubation. In the current study we show that a short-term effect of stimulation of P2Y(1) receptors is the increase in extracellular acidification rate (ECAR), which is mediated by an increase in intracellular calcium concentration ([Ca(2+)](i)). The pD(2) values for ATP (3.06 +/- 0.12)-induced ECAR increase was significantly smaller (p < 0.01) than that for ADP (3.64 +/- 0.18), 2MeSATP (3.56 +/- 0.02) and 2MeSADP (3.65 +/- 0.13). The selective P2Y(1) receptor antagonists A3'P-5'P and A3'P-5'PS inhibited the increase in ECAR-induced by ADP. Clamping [Ca(2+)](i) with BAPTA (30 and 50 micromol/l) led to inhibition of ADP-induced increase in ECAR. Agonist and antagonist data indicate P2Y(1) activation leads to a [Ca(2+)](i)-dependent acidification of the extracellular medium.


Bioremediation of emerging micropollutants in irrigation water. The alternative of microalgae-based treatments.
The present study evaluated the efficiency of a semi-closed horizontal tubular photobioreactor (PBR) at demonstrative scale to remove a total of 35 target compounds, including benzotriazoles, benzophenones, antibiotics and different pharmaceuticals present in irrigation water in a peri-urban rural area. This water run through an open channel and was a mixture of reclaimed wastewater from a nearby wastewater treatment plant (WWTP) and run-off from the different agricultural fields in the area. Most of the compounds studied are usually not fully eliminated during conventional wastewater treatment, which justifies the need to investigate alternative treatment strategies. A total of 21 of these compounds were detected in the irrigation water. Benzotriazoles were only partially removed after the microalgae treatment, with elimination rates similar to those of conventional WWTPs. The UV filter benzophenone-3 (BP3) showed variable removals, ranging from no elimination to 51%, whereas 4-methylbenzilidenecamphor (4MBC) was completely eliminated. Regarding pharmaceuticals, average removals were higher, in the range of 60-100%, with the exception of the antibiotics sulfamethoxazole (46%) and sulfapyridine, which was not removed. Despite the low biomass productivity of the PBR, parameters such as the size of the reactors, the specific mixed cultures developed and the high temperatures and pH in the closed system may account for the overall good results, The efficiency and sustainability of these systems make them a solid, feasible treatment choice.


Vibrational spectra of room-temperature rhodopsin: concentration dependence in picosecond resonance coherent anti-Stokes Raman scattering.
The vibrational degrees of freedom of room-temperature rhodopsin (RhRT), the central trans-membrane protein in vision, are measured at room temperature by picosecond resonance coherent anti-Stokes Raman scattering (PR/CARS). High signal-to-noise PR/CARS data for the ethylenic stretching, Schiff base, and hydrogen-out-of-plane modes of the retinal chromophore are quantitatively analyzed via third-order susceptibility relationships. The accurate determination of spectral features permit the PR/CARS bandshapes to be analyzed as a function of RhRT concentration, an essential factor in using picosecond time-resolved CARS techniques to measure the vibrational spectroscopy of picosecond intermediates in the RhRT photosequence. Of particular importance is the recognition that PR/CARS bandshapes are sensitive functions of both the chromophore concentration and the excitation wavelength, as measured relative to the absorption spectra of specific chromophores (static and transient).


Decreased Transition Rate From Situational Insomnia to Chronic Insomnia by One-Week Internet Cognitive Behavioral Treatments for Insomnia During the COVID-19 Pandemic.
The purpose of the study was to determine the long-term effects of one-week self-guided internet cognitive behavioral treatments for insomnia (CBTI) on situational insomnia during the COVID-19 pandemic. The participants with situational insomnia (n = 194) were recruited from March 2020 to April 2020 in Guangzhou, China. The insomnia severity index (ISI), pre-sleep arousal scale (PSAS), and hospital anxiety and depression scale (HADS) were evaluated at baseline and a one-week internet CBTI program was delivered to all individuals. The participants were divided into the complete treatment group (the participants completed all seven modules of the CBTI course, n = 75), and the incomplete treatment group (the participants completed 0-6 modules of the CBTI course, n = 119). A total of 135 participants completed the post-intervention assessments. At 3 months follow-up, a total of 117 participants (complete treatment group: n = 51; incomplete treatment group: n = 66) completed the assessments of the ISI, PSAS and HADS. The transition rate from situational insomnia to chronic insomnia (duration of insomnia ≥ 3 months and ISI ≥ 8) was calculated in the two groups. Linear mixed effect model was used to investigate the effect of group (between the two groups), time (baseline vs. follow-up), and interaction (group x time) on various questionnaire score. The transition rate from situational insomnia to chronic insomnia was significantly lower in the complete treatment group compared to the incomplete treatment group (27.5%, 14/51 vs. 48.5%, 32/66, p = 0.023). There were significant differences in group effect (p = 0.032), time effect (p = 0.000) and group × time effect (p = 0.048) between the two groups in the ISI total score. The ISI total scores decreased in both groups during follow-up compared to their baseline values, with a greater magnitude of decrease in the complete treatment group. There were no significant group x time effects between the two groups in the PSAS-total score, PSAS-somatic, PSAS-cognitive score, HADS total score, HADS anxiety score or HADS depression score. Our results suggested that one-week self-guided internet CBTI prevented the development of chronic insomnia from situational insomnia during the COVID-19 pandemic.


Development of resting membrane potentials in differentiating murine neuroblastoma cells (N1E-115) evaluated by flow cytometry.
With the aid of a voltage-sensitive oxonol dye, flow cytometry was used to measure relative changes in resting membrane potential (V(m)) and forward angle light scatter (FALS) profiles of a differentiating/differentiated murine neuroblastoma cell line (N1E-115). Electrophysiological differentiation was characterized by V(m) establishment. The (V(m))-time profile was found to be seed cell concentration-dependent for cell densities of less than 2 × 10(4) cells/cm(2). At higher initial cell densities, under differentiating culture conditions, V(m) development commenced on day 2 and reached a steady-state on day 12. The relative distribution of differentiated cells between low and high FALS has been proposed as a potential culture electrophysiological differentiation state index. These experiments offer a general methodology to characterize cultured excitable cells of nervous system origin, with respect to electrophysiological differentiation. This information is valuable in studies employing neuroblastoma cells as in vitro screening models for safety/hazard evaluation and/or risk assessment of therapeutical and industrial chemicals under development.


Initial experience with minimally invasive endoscopic evacuation of intracerebral hemorrhage in the setting of radiographic herniation.
Spontaneous intracerebral hemorrhage (ICH) can rapidly result in cerebral herniation, leading to poor neurologic outcomes or mortality. To date, neither decompressive hemicraniectomy (DH) nor hematoma evacuation have been conclusively shown to improve outcomes for comatose ICH patients presenting with cerebral herniation, with these patients largely excluded from clinical trials. Here we present the outcomes of a series of patients presenting with ICH and radiographic herniation who underwent emergent minimally invasive (MIS) ICH evacuation. We reviewed our prospectively collected registry of patients undergoing MIS ICH evacuation at a single institution from 01/01/2017 to 10/01/2021. We selected all consecutive patients with Glasgow coma scale (GCS) ≤ 8 and radiographic herniation for this case series. Clinical and radiographic variables were collected, including admission GCS score, preoperative and postoperative hematoma volumes, National Institute of Health stroke scale (NIHSS) scores, and modified Rankin scale (mRS) scores at last follow-up. Of 176 patients with spontaneous supratentorial ICH who underwent minimally invasive endoscopic evacuation during the study time period, a total of 9 patients presented with GCS ≤ 8 and evidence of radiographic herniation. Among these patients, the mean age was 62 ± 12 years, the median GCS at presentation was 5 [IQR 4-6], the mean preoperative hematoma volume was 94 ± 44 mL, the mean time from ictus to evacuation was 12 ± 5 h, and the mean postoperative hematoma volume was 11 ± 16 mL, for a median evacuation percentage of 97% [83-99]. Three patients (33%) died, four (44%) survived with mRS 5 and two (22%) with mRS 4. Patients had a median NIHSS improvement of 5 compared to their initial NIHSS. Age was very strongly correlate to improvements in NIHSS (r2 = 0.90). Data from this initial experience suggest emergent MIS hematoma evacuation in the setting of ICH with radiographic herniation is feasible and technically effective. Further randomized studies are required to determine if such an intervention offers overall benefits to patients and their families.


All retinas are not created equal: Fovea-to-macula thickness ratio and foveal microvasculature in healthy young children.
Markers for the relationships between structural and microvasculature measures given by optical coherence tomography angiography are necessary to increase the diagnostic and prognostic value of this technique. The aim of this study was to investigate relationships between structural and microvasculature measures around the fovea in healthy eyes of healthy children. Observational cross-sectional study involving children aged 8-17 years, born at full-term, with no eye disease. The better of two 3 × 3 mm macular scans obtained with a Cirrus 5000HD-OCT was analysed. Images were corrected for lateral magnification errors. Vessel density and perfusion were measured with ImageJ/Fiji software for the superficial capillary plexus. Structural measures including foveal and macular thicknesses were performed manually. The sample included 86 participants, 51 (59%) females. Mean age was 12.4 years (SD = 2.5); mean best-corrected acuity was -0.10 logMAR (SD = 0.09); mean refractive error was +0.59 D (SD = 1.3) and mean axial length was 23.1 mm (SD = 0.86). Mean area of the foveal avascular zone (AFAZ) was 0.20 mm2 (SD = 0.88); median fovea-to-macula thickness ratio (FMTR) was 0.63 (IQR = 0.08); mean central vessel density was 12.42 mm-1 (SD = 2.78) and mean central perfusion was 38.66% (SD = 3.83). AFAZ was correlated with central vessel density (p < 0.001), perfusion (p < 0.001), foveal thickness (p < 0.001) and FMTR (p < 0.001). Central vessel density was correlated with foveal thickness (p < 0.001) and FMTR, (p = 0.01). Central perfusion was correlated with foveal thickness (p < 0.001) and FMTR, (p = 0.003). In this study, foveal thickness, FMTR and foveal microvasculature measurements were correlated. Clinicians need to be aware that shallow foveal pits and persistent foveal microvasculature are likely to occur in optical coherence tomography angiography images. In healthy eyes from healthy children, an atypical high FMTR and a small AFAZ may be associated with incomplete foveal development. The mechanism and functional implications of this remain unknown.