Does bicuculline antagonize NMDA receptors? Further evidence in the rat striatum.
In two areas of the rat striatum, the in vitro N-methyl-D-aspartate (NMDA, 50 microM)-evoked release of [3H]dopamine was studied in the presence of bicuculline (5 and 50 microM), an antagonist of GABAA receptors. The responses observed with the higher concentration (50 microM) is compatible with an antagonistic activity of bicuculline on NMDA receptor, as recently reported by Wright and Nowak.


Valproate reverses mania-like behaviors in mice via preferential targeting of HDAC2.
Valproate (VPA) has been used in the treatment of bipolar disorder since the 1990s. However, the therapeutic targets of VPA have remained elusive. Here we employ a preclinical model to identify the therapeutic targets of VPA. We find compounds that inhibit histone deacetylase proteins (HDACs) are effective in normalizing manic-like behavior, and that class I HDACs (e.g., HDAC1 and HDAC2) are most important in this response. Using an RNAi approach, we find that HDAC2, but not HDAC1, inhibition in the ventral tegmental area (VTA) is sufficient to normalize behavior. Furthermore, HDAC2 overexpression in the VTA prevents the actions of VPA. We used RNA sequencing in both mice and human induced pluripotent stem cells (iPSCs) derived from bipolar patients to further identify important molecular targets. Together, these studies identify HDAC2 and downstream targets for the development of novel therapeutics for bipolar mania.


Higher Urinary Levels of 8-Hydroxy-2'-deoxyguanosine Are Associated with a Worse RANKL/OPG Ratio in Postmenopausal Women with Osteopenia.
Postmenopausal osteoporosis (PO) is a major public health issue which affects a large fraction of elderly women. Emerging in vitro evidence suggests a central role of oxidative stress (OxS) in postmenopausal osteoporosis (PO) development. Contrariwise, the human studies on this topic are still scarce and inconclusive. In the attempt to address this issue, we sought to determine if OxS, as assessed by 8-hydroxy-2-deoxyguanosine (8-OHdG), may influence the level of receptor activator of nuclear factor-κb ligand (RANKL)/osteoprotegerin (OPG) ratio (a central regulator of bone metabolism) in a sample (n = 124), including postmenopausal women with osteoporosis, osteopenia and normal bone mass density (BMD). The most striking result that emerged in our study was the independent and positive (beta = 0.449, p = 0.004, and R(2) = 0.185) association between the OxS marker and RANKL/OPG ratio which was found in osteopenic but not in the other 2 sample groups. If confirmed by longitudinal studies, our findings would suggest that OxS is implicated in the derangement of bone homeostasis which precedes PO development. In line with these considerations, antioxidant treatment of postmenopausal women with moderately low BMD might contribute to preventing PO and related complications.


Are the environmental niches of Vibrio cholerae O139 different from those of Vibrio cholerae O1 El Tor?
Vibrio cholerae are known to be normal inhabitants of surface water. However, the environmental niches of the different strains of cholera are not well known, and therefore, populations at risk for cholera outbreaks cannot be clearly identified. This study identifies environmental risk factors for cholera caused by V. cholerae O1 El Tor and O139 and environmental niches of the two strains present in Matlab, a cholera endemic area of Bangladesh. The study year was 1993, the year that the O139 strain first appeared in the study area. Patients who had either strain of cholera identified in a laboratory were included in the study. A geographic information system was used to map the household locations of the patients, to describe the human sanitary environment and population density, and to address potential anthropogenic and environmental risk factors of the disease. Spatial point pattern and exploratory spatial data analysis techniques were used to define the environmental niches of the two cholera strains. The study suggests the niches of O1 El Tor and O139 strains of V. cholerae appear to be similar, based on common environmental risk factors. The results of this study support a theory that O1 El Tor could possibly be replaced by the newer O139 strain in the future.


Preharvest application of hydrogen nanobubble water enhances strawberry flavor and consumer preferences.
The improvement of fruit flavor is a challenge for producers and breeders. This study investigated the effects and mechanisms of preharvest hydrogen nanobubble water (HNW) application on the flavor of cultivated strawberry (Fragaria × ananassa 'Benihoppe'). Compared with surface water, HNW enhanced the volatile profiles, sugar-acid ratio, and sensory attributes (e.g., aroma, flavor, and overall liking) with/without fertilizer application. Meanwhile, flavor components such as esters (e.g., ethyl hexanoate), acids (e.g., hexanoic acid), and soluble sugars (including glucose, fructose, and sucrose) significantly contributed to increased strawberry flavor achieved with HNW. Importantly, HNW may alleviate the negative effects of fertilizers on strawberry fruit aroma. Further study elucidated that the aroma-related genes (including FaLOX, FaADH, FaAAT, FaQR, FaOMT, and FaNES1) were involved in the accumulation of specific volatiles after HNW treatment. This study provided evidence that the practical application of H2 can improve horticultural product quality at a lower carbon cost.


Probabilistic modeling of the evolution of gene synteny within reconciled phylogenies.
Most models of genome evolution concern either genetic sequences, gene content or gene order. They sometimes integrate two of the three levels, but rarely the three of them. Probabilistic models of gene order evolution usually have to assume constant gene content or adopt a presence/absence coding of gene neighborhoods which is blind to complex events modifying gene content. We propose a probabilistic evolutionary model for gene neighborhoods, allowing genes to be inserted, duplicated or lost. It uses reconciled phylogenies, which integrate sequence and gene content evolution. We are then able to optimize parameters such as phylogeny branch lengths, or probabilistic laws depicting the diversity of susceptibility of syntenic regions to rearrangements. We reconstruct a structure for ancestral genomes by optimizing a likelihood, keeping track of all evolutionary events at the level of gene content and gene synteny. Ancestral syntenies are associated with a probability of presence.


Sphingosine-1-phosphate: characterization of its inhibition of platelet aggregation.
In this study, the ability of sphingosine-1-phosphate (S1P) to modulate platelet aggregation induced by other agents in platelet-rich plasma (PRP) was investigated. S1P alone did not stimulate platelet aggregation in PRP. S1P inhibited the platelet aggregation induced by the TRAP peptide (6.75 microM), noradrenaline (NA; 12.5 microM) and the Ca2+ ionophore (5.0-9.5 microM). S1P also increased the response time of platelets to arachidonic acid (AA), but decreased the response time to PMA. S1P displayed a dual effect on sodium fluoride (NaF)-induced platelet aggregation and had no effect on the aggregation induced by ADP or lysophosphatidic acid (LPA). Furthermore, S1P blocked the synergistic interaction of oleyol-lysophosphatidic acid (O-LPA) with the TRAP peptide or noradrenaline, while the synergistic interaction of O-LPA with ADP remained largely unaffected.


Solvent-based paclitaxel or nab-paclitaxel for heavily treated relapsed/refractory small cell lung cancer: Retrospective single-institution observational study.
Treatment options for patients with relapsed/refractory small cell lung cancer (R/R SCLC) are limited, and the efficacy of salvage therapies for heavily treated patients should be assessed. Here, we evaluated the efficacy of paclitaxel (PTX) in R/R SCLC patients.A single-institute retrospective chart review was conducted. The primary endpoint was overall survival (OS), whereas the secondary endpoints were progression-free survival (PFS), overall response rate, disease control rate (DCR), and safety.Thirty-one patients (median age, 69 [range, 56-80] years) were analyzed. The median follow-up period was 122 (range, 28-1121) days. The median OS and PFS were 4.4 and 2.2 months, respectively. Adverse events of grade 3 or higher, other than hematological toxicity, were febrile neutropenia and neuropathy. Multivariate analyses identified the following independent predictors of poor OS: performance status and lactate dehydrogenase at the upper limit of normal.PTX monotherapy showed moderate efficacy with acceptable toxicity in heavily treated patients with R/R SCLC patients.


Comprehensive geriatric assessment in older patients with cancer: an external validation of the multidimensional prognostic index in a French prospective cohort study.
Older patients with cancer require specific and individualized management. The 3-group Multidimensional Prognostic Index (MPI) based on the Comprehensive Geriatric Assessment (CGA) has shown a predictive interest in terms of mortality. The objective of our study was to assess the prognostic value of MPI for 1-year mortality in an external prospective French cohort of elderly patients with cancer. From March 2015 to March 2017 a prospective single-center cohort study enrolled all patients with cancer, aged 75 years and older referred to the geriatric oncology clinic. We used a proportional hazard model for 1-year mortality adjusted for age, sex, tumor sites and metastatic status. C-statistics were used to assess the incremental predictive value of MPI index to these risk factors. overall, 433 patients underwent CGA with MPI (women 42%; mean age 82.8 ± 4.8 years). The most common tumor sites were prostate (23%), skin (17%), colorectum (15%) and breast (12%); 29% of patients had a metastatic disease; 231 patients (53%) belonged to the "MPI-1" group, 172 (40%) to the "MPI-2" group and 30 patients were classified in the "MPI-3" group. One-year mortality rate was 32% (23% in MPI-1, 41% in MPI-2 and 53% in MPI-3, p = 0.024). All domains of MPI except cognition and living status were significantly associated with mortality at one-year, as well as tumor sites and metastatic status. Higher MPI was associated with a higher mortality risk (adjusted HR 1.56 [95%CI 1.70-2.09] and 1.72 [1.33-2.22] for MPI groups 2 and 3 compared to 1; p < 0.0001). In addition to established risk factors, MPI improves risk prediction of 1-year mortality. This practical prognostic tool may help to optimize management of these vulnerable patients.


Human papillomavirus in tonsillectomy specimen from China and Pakistan - Prevalence and genotype distribution.
The expected corresponding increase in tonsillar human papillomavirus (HPV) infection associated with increasing incidence of oropharyngeal squamous cell carcinoma (OPSCC) substantiate the evaluation of normal tonsillar tissue in different population. The epidemiology of HPV in tonsillar tissue varies geographically. This study evaluated samples from two countries to determine the prevalence in respective samples. To characterize HPV infection in non-malignant tonsillar tissue from Shaanxi, China (herein after referred to as China) and Punjab, Pakistan (herein after referred to as Pakistan). The DNA extracted from formalin-fixed, paraffin-embedded tumor free tonsillar tissue was evaluated using polymerase chain reaction (PCR). A total of 367 cases from China and 139 cases from Pakistan were screened for HPV DNA using GP5+/GP6+ consensus primer. Genotype of the positive cases was determined for common HPV types (6, 11, 16, 18, 52, 58) simultaneously by type-specific PCR. The mean age of cohorts in China was 13.42 (Median age 7, Range 2-72 years) while in Pakistan it was 10.77 (Median age 8, Range 3-42 years) the gender distribution was 61.6% male in China and in Pakistan they were 56.8%, rest were females. The overall prevalence of HPV in China was 2.45% and 2.16% in Pakistan. High risk human papillomavirus was 1.63% in China with 5 cases positive for HPV 16 and HPV 58 in 1 case. In Pakistan, 2 cases (1.43%) of HPV 16 were detected. Low-risk types include HPV 11 present in 2 cases from China, while HPV 6 was detected in 1 case each from both the countries. A low prevalence of HPV was found in China and Pakistan; high-risk and low-risk HPV were detectable in tonsillar tissue from both countries. Age stratification (< 5 years, 5-14 years, 15-25 years, > 25 years) suggest that sexual and non-sexual transmission of the virus can occur. The difference in the genotype distribution geographically within China and with Pakistan was observed in the case of HPV 58. The most common type in both the countries was HPV 16.


Effect of nephrotoxic treatment with gentamicin on rats chronically exposed to uranium.
Uranium is a radioactive heavy metal with a predominantly chemical toxicity, affecting especially the kidneys and more particularly the proximal tubular structure. Until now, few experimental studies have examined the effect of chronic low-dose exposure to uranium on kidney integrity: these mainly analyse standard markers such as creatinine and urea, and none has studied the effect of additional co-exposure to a nephrotoxic agent on rats chronically exposed to uranium. The aim of the present study is to examine the potential cumulative effect of treating uranium-exposed rats with a nephrotoxic drug. Neither physiological indicators (diuresis and creatinine clearance) nor standard plasma and urine markers (creatinine, urea and total protein) levels were deteriorated when uranium exposure was combined with gentamicin-induced nephrotoxicity. A histological study confirmed the preferential impact of gentamicin on the tubular structure and showed that uranium did not aggravate the histopathological renal lesions. Finally, the use of novel markers of kidney toxicity, such as KIM-1, osteopontin and kallikrein, provides new knowledge about the nephrotoxicity threshold of gentamicin, and allows us to conclude that under our experimental conditions, low dose uranium exposure did not induce signs of nephrotoxicity or enhance renal sensitivity to another nephrotoxicant.


Brain neuronal RNA metabolism during acute soman toxication: effects of antidotal pretreatments.
Effects of various antidotal treatments on neuronal RNA contents and on soman induced RNA and acetylcholinesterase (AChE) depletion were monitored using quantitative cytochemical techniques. In rats only with antidotes, atropine depressed whereas pralidoxime (2-PAM) elevated RNA contents of both caudate and cerebrocortical (Layer V) neurons. Soman produced a virtually complete inhibition of AChE activity and a moderate decline in neuronal RNA contents. Atropine pretreatment partially restored neuronal RNA levels. Atropine + 2-PAM prophylaxis eventuated in a complete restoration of RNA levels but no reactivation of AChE. Addition of physostigmine to the atropine + 2-PAM treatment regimen resulted in appreciable AChE reactivation but reduced RNA levels. The overall data indicate that: (1) soman-induced neuronal RNA depletion can be completely reversed by antidotal pretreatments; (2) no precise relationship exists between the extents of antidote-induced restoration of RNA and AChE levels; and (3) 2-PAM exerts marked effects on the brain neuronal network which are unrelated to AChE reactivation. It is postulated that effects of soman and antidotes on neuronal RNA metabolism may signify alterations in acetylcholine (ACh) sensitivity and that pharmacologic manipulation of ACh responsiveness during organophosphate cholinesterase poisoning may be a mechanism for additional therapeutic intervention.


Myeloid cell leukaemia 1 has a vital role in retinoic acid-mediated protection of Toll-like receptor 9-stimulated B cells from spontaneous and DNA damage-induced apoptosis.
Vitamin A is an essential anti-infective agent with pleiotropic effects on cells of the immune system. The goal of the present study was to unravel the impact of the vitamin A metabolite retinoic acid (RA) on B-cell survival related both to normal B-cell homeostasis and to the detrimental effects imposed by DNA-damaging agents. By combining RA with Toll-like receptor 9 (TLR9) ligands, we show that RA prevents spontaneous, irradiation- and doxorubicin-induced apoptosis of human B cells in an RA receptor-dependent manner. RA-mediated survival involved up-regulation of the anti-apoptotic protein myeloid cell leukemia 1 (MCL1) at the transcriptional level, and knock down of MCL1 by small interfering RNA partially reversed the effects of RA. To ensure that the combination of TLR9-ligands and RA would not promote the survival of malignant B cells, the combined effects of stimulation with RA and TLR9 ligands was assessed on cells from patients with B-cell malignancies. In contrast to the effects on normal B cells, the combination of TLR9 stimulation and RA neither enhanced the MCL1 levels nor inhibited the death of malignant B cells challenged by DNA-damaging agents. Taken together, the present results reveal a vital role of MCL1 in RA-mediated survival of normal B cells. Moreover, the findings suggest that RA in combination with TLR9 ligands might be useful adjuvants in the treatment of B-cell malignancies by selectively protecting normal and not malignant B cells from DNA-damage-induced cell death.


Which Clinical Features of Children on Initial Presentation to the Emergency Department With Head Injury Are Associated With Clinically Important Traumatic Brain Injury, Classification as Abuse, and Poor Prognosis?
Pediatric traumatic brain injury (TBI) and abusive head trauma (AHT) are leading causes of morbidity and mortality. Clinicians may not be aware of AHT at presentation to the emergency department (ED). The objective of this study was to determine which clinical features associated with head injury in children on initial presentation to the ED trauma bay predict 3 outcomes including clinically important TBI (CiTBI), classification as confirmed abuse by Child Protection Team (CPT), and poor neurologic status on hospital discharge. Inclusion for this study were children 3 years or younger, presenting to the ED with significant TBI. In addition, presentations where the mechanism of injury was not verifiable such as with falls, being struck by object, or no mechanism of injury reported by caregiver were included. Researchers used 3 sources of information for this analysis: a regional trauma registry, hospital records, and the CPT database. Clinical features included demographics, mechanisms of injury, physical, radiological findings, and CPT classification. On pairwise analysis, seizures, apnea, and no mechanism of injury reported by caregiver were the only clinical features related to all 3 outcomes (P < 0.001). Rib fractures (relative risk [RR], 3.3; P < 0.001), long bone fractures (RR, 3.1; P < 0.001), retinal hemorrhages (RR, 3.0; P < 0.001), seizures (RR, 3.6; P < 0.001), apnea (RR, 4.4; P < 0.001), and younger than 6 months (RR, 1.8; P < 0.001) were related to AHT. On multivariable logistic regression, no mechanism of injury reported by caregiver and seizures remained significantly related to CiTBI; seizures and retinal hemorrhage remained significantly related to classification as abuse by CPT, and no mechanism of injury by the caregiver, apnea, and seizures were significantly related to poor outcome on hospital discharge. No mechanism of injury reported by the caregiver, seizures, and apnea at the time of presentation to the ED are important features associated with CiTBI, classification as AHT, and poor prognosis. In addition, younger age, retinal hemorrhage, rib, and long bone fractures were found to be important clinical features associated with AHT.


MicroRNA expression profiles during cotton (Gossypium hirsutum L) fiber early development.
The role of microRNAs (miRNAs) during cotton fiber development remains unclear. Here, a total of 54 miRNAs belonging to 39 families were selected to characterize miRNA regulatory mechanism in eight different fiber development stages in upland cotton cv BM-1. Among 54 miRNAs, 18 miRNAs were involved in cotton fiber initiation and eight miRNAs were related to fiber elongation and secondary wall biosynthesis. Additionally, 3,576 protein-coding genes were candidate target genes of these miRNAs, which are potentially involved in cotton fiber development. We also investigated the regulatory network of miRNAs and corresponding targets in fiber initiation and elongation, and secondary wall formation. Our Gene Ontology-based term classification and KEGG-based pathway enrichment analyses showed that the miRNA targets covered 220 biological processes, 67 molecular functions, 45 cellular components, and 10 KEGG pathways. Three of ten KEGG pathways were involved in lignan synthesis, cell elongation, and fatty acid biosynthesis, all of which have important roles in fiber development. Overall, our study shows the potential regulatory roles of miRNAs in cotton fiber development and the importance of miRNAs in regulating different cell types. This is helpful to design miRNA-based biotechnology for improving fiber quality and yield.


Bioequivalence studies of film-coated tablet and chewable tablet generic formulations of montelukast in healthy volunteers.
Two studies were conducted in order to assess the bioequivalence of montelukast (CAS 151767-02-1) 10 mg film-coated tablet (FCT) and 5 mg chewable tablet (CT) test formulations in comparison with the original brands. Under fasting conditions, healthy male and female volunteers received one 10 mg FCT or 5 mg CT orally as a single dose of a test or reference formulation. Both studies were designed as open-label, randomized, two-period, two-sequence, crossover studies with a 7-day washout interval. Plasma samples were collected up to 24 h after drug administration and montelukast levels were determined by a validated LC/ MS/MS method. Pharmacokinetic parameters were calculated using non-compartmental analysis and were statistically compared by analysis of variance for test and reference formulation. Bioequivalence between products was determined by calculating 90% confidence interval of the ratio test/reference of least-square means of logarithmically transformed Cmax and AUC0-t parameters. AUC0-infinity was also analysed to obtain additional information. The calculated 90% confidence intervals for the ratios of Cmax and AUC0-t parameters were 89.33-110.52 and 92.06-109.46, respectively, in the FCT study, and 91.58-101.86 and 92.15-98.83, respectively, in the CT study, which are all within the bioequivalence acceptance range of 80-125%. Based on the results, it can be concluded that the evaluated test FCT and CT formulations are bioequivalent to their respective reference formulation in terms of rate and extent of absorption.


[State of respiratory system under prolonged exposure to aerosols and vapors of heavy metals salts].
Study covering 480 male workers of chemical enterprise revealed that chronic exposure to allowable ambient air concentrations of metal salts doubles occurrence of respiratory tract diseases. 75% of the healthy workers constantly exposed to heavy metal salts demonstrate lower level of oxidative processes, and 15% of the examinees were diagnosed as having primary histotoxic hypometabolism.


Advances in cryopreservation: we are not frozen in time.
Life is like riding a bicycle, to keep your balance you must keep moving. -Albert Einstein.


Donor transfer of pulmonary coccidioidomycosis in lung transplantation.
Transplant recipients living in endemic areas are at high risk of aerosol-transmitted fungal infections because of environmental exposure while on immunosuppressive drugs, as well as reactivation of latent infection from either the patient's or the donor's organs. The latter may account for early development of coccidioidomycosis after transplantation. We describe a case of pulmonary coccidioidomycosis in a lung transplant recipient who acquired the infection from the donor lung and presented with fulminant pneumonia in the immediate postoperative period.


The changing pattern of severe neonatal staphylococcal infection: a 10-year study.
Forty-two cases of severe staphylococcal infection occurring over a 10-year period in the neonatal unit at Queen Mary Hospital are described. There was a 4.5-fold increase in incidence in the latter half of the study period, when methicillin-resistant Staphylococcus aureus (MRSA) emerged. The isolated MRSA were also resistant to gentamicin, but sensitive to vancomycin, fusidic acid, co-trimoxazole and amikacin. Comparison between MRSA and methicillin-sensitive cases showed that the former was associated with a longer hospital stay after diagnosis. Overall mortality was 9.5%. Two cases with meningitis died. MRSA is at least as virulent as its methicillin-sensitive counterparts. The treatment implications of severe neonatal staphylococcal infection are discussed.


Alpha 2 HS-glycoprotein phenotype and allele distribution in continental Italy and Sardinia.
The genetic polymorphism of alpha 2 HS-glycoprotein (A2HS) was studied in continental Italy (Rome and L'Aquila) and in Sardinia (Cagliari). The two continental populations did not differ significantly in the A2HS gene distribution, whereas the Sardinian population showed an A2HS*1 frequency significantly higher than in continental Italy.


Sudden unexpected death in epilepsy (SUDEP): A bibliometric analysis.
The literature on sudden unexpected death in epilepsy (SUDEP) has been evolving at a staggering rate. We conducted a bibliometric analysis of the SUDEP literature with the aim of presenting its structure, performance, and trends. The Scopus database was searched in April 2023 for documents explicitly detailing SUDEP in their title, abstract, or keywords. After the removal of duplicate documents, bibliometric analysis was performed using the R package bibliometrix and the program VOSviewer. Performance metrics were computed to describe the literature's annual productivity, most relevant authors and countries, and most important publications. Science mapping was performed to visualize the relationships between research constituents by constructing a country collaboration network, co-authorship network, keyword co-occurrence network, and document co-citation network. A total of 2140 documents were analyzed. These documents were published from 1989 onward, with an average number of citations per document of 25.78. Annual productivity had been on the rise since 2006. Out of 6502 authors, five authors were in both the list of the ten most productive and the list of the ten most cited authors: Devinsky O, Sander JW, Tomson T, Ryvlin P, and Lhatoo SD. The USA and the United Kingdom were the most productive and cited countries. Collaborations between American authors and European authors were particularly rich. Prominent themes in the literature included those related to pathophysiology (e.g., cardiac arrhythmia, apnea, autonomic dysfunction), epilepsy characteristics (e.g., epilepsy type, refractoriness, antiseizure medications), and epidemiology (e.g., incidence, age, sex). Emerging themes included sleep, genetics, epilepsy refractoriness, and non-human studies. The body of literature on SUDEP is rich, fast-growing, and benefiting from frequent international collaborations. Some research themes such as sleep, genetics, and animal studies have become more prevalent over recent years.


POR overexpression induces tamoxifen-resistance in breast cancer through the STAT1/c-Myc pathway.
Breast cancer is the most common cancer in women worldwide. Although tamoxifen (TAM), a selective estrogen receptor (ER) modulator, is widely used to treat ER-positive breast cancers, resistance to TAM remains a major clinical problem. NADPH-dependent cytochrome P450 reductase (POR) is known to participate in drug metabolism and steroid metabolism. Recent studies showed that high POR expression was correlated with poor outcomes in triple-negative breast cancer (TNBC), and POR might be a prognostic biomarker in TNBC. However, the role of POR in TAM resistance is still elusive. In this study, we found that high POR expression was associated with poor prognosis of ER-positive and TAM-treated breast cancer patients. In addition, COX analysis showed that POR expression was an independent prognostic biomarker for ER-positive as well as TAM-treated breast cancer patients. Furthermore, our results suggested that POR overexpression promoted TAM resistance by activating the STAT1/c-Myc pathway in ER-positive breast cancer cells. Immunohistochemical analysis showed that high POR/STAT1 expression was correlated with poor prognosis in TAM-treated breast cancer patients. Notably, combined treatment with TAM and a specific STAT1 inhibitor Fludarabine was more effective for inhibiting TAM-resistant breast cancer cells. Altogether, our findings suggested that POR overexpression induced TAM resistance through STAT1/c-Myc pathway and might serve as an independent prognostic biomarker in TAM-treated breast cancer patients. Combining TAM and STAT1 inhibitors might be an effective strategy for treating POR-induced TAM-resistant breast cancer.


Acute rupture of the pericardium with delayed dislocation of the heart: a case report.
A case is presented in which the right side of the pericardium was ruptured as a result of a fall. The heart dislocated through the rent on the fourth day and was irreducible, having to be replaced surgically. The possible mechanism of the delayed dislocation is discussed.


Trimethylsilylethynyl ketones as surrogates for ethynyl ketones in the double Michael reaction.
Trimethylsilylethynyl ketones can be desilylated in the presence of a tethered carbon diacid and induced to undergo a double Michael reaction in situ. The trimethylsilylethynyl ketones can serve as surrogates of ethynyl ketones that are difficult to prepare or isolate.


Mean glandular dose in digital mamography in women with breast implants.
Mean Glandular Dose (MGD) is the quantity related to the risk of radiation-induced breast cancer. This study aimed to evaluate the MGD in screening mammography for women with breast implants. This retrospective study used data of 2680 mammographies of 335 asymptomatic women with mammary implants examined in a digital direct x-ray unit. Each woman had a total of eight images: four in standard views and four with posterior displacement of the implant (ID). Data on kV, mAs, target/filter combination, compressed breast thickness and MGD were obtained from the DICOM header of the stored images. Quantitative variables were presented through descriptive statistics for median (5th-95th percentiles); and the qualitative variables were presented by numbers and percentages. Mean glandular doses of standard views and ID views were compared and statistical analysis was used to assess the influence of implant position, breast glandularity and thickness on mean glandular doses. Median MGD for standard views were 3.30 (2.60-4.00) mGy for CC and 3.31 (2.70-4.20) mGy for MLO. For ID views, median were 1.20 (0.90-2.20) mGy and 1.40 (0.97-3.74) mGy for CC and MLO views, respectively. Median MGD for the whole examination of women with breast implants was 9.60 (7.92-12.07) mGy, ranging from 6.25 to 21.50 mGy. When comparing MGD median for standard and ID views it was found a statistically significant difference (p < 0.05), with higher doses for the standard views due to the greater compressed breast thickness in these views. It was observed that, in the standard views, MGD decreases with increasing breast thickness due to the manual radiographic techniques used to expose the women. It was also observed that implant position does not affect MGD in breast augmentation mammography. Mammography of women with mammary implants gives higher radiation doses when compared with those without implants. For more accurate dose assessment in augmented breast mammography, it is necessary that specific conversion factors for the calculation of MGD based on air kerma at entrance of breasts with implants are made available.


The yin and yang faces of the mitochondrial deacetylase sirtuin 3 in age-related disorders.
Aging, the most important risk factor for many of the chronic diseases affecting Western society, is associated with a decline in mitochondrial function and dynamics. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase that has emerged as a key regulator of fundamental processes which are frequently dysregulated in aging and related disorders. This review highlights recent advances and controversies regarding the yin and yang functions of SIRT3 in metabolic, cardiovascular and neurodegenerative diseases, as well as the use of SIRT3 modulators as a therapeutic strategy against those disorders. Although most studies point to a protective role upon SIRT3 activation, there are conflicting findings that need a better elucidation. The discovery of novel SIRT3 modulators with higher selectivity together with the assessment of the relative importance of different SIRT3 enzymatic activities and the relevance of crosstalk between distinct sirtuin isoforms will be pivotal to validate SIRT3 as a useful drug target for the prevention and treatment of age-related diseases.


Perioperative and long-term functional outcomes of robot-assisted versus open partial nephrectomy: A single-center retrospective study of a Japanese cohort.
This study aimed to compare the perioperative and long-term functional outcomes between robot-assisted partial nephrectomy (RAPN) and open partial nephrectomy (OPN) in Japanese patients. We retrospectively analyzed 242 patients who underwent either RAPN or OPN between 2007 and 2017 at our hospital. Propensity score matching was carried out between the two groups at a ratio of 1:1. Perioperative outcomes and postoperative estimated glomerular filtration rates (eGFR) were compared at one and three years of follow-up. After propensity score matching, we evaluated 39 patients from each group. The ischemia duration of the RAPN group was significantly shorter than that of the OPN group (18 vs. 24, p < 0.001). Moreover, the estimated blood loss (EBL) was significantly lower in the RAPN group than in the OPN group (50 vs. 174, p < 0.001). However, there were no significant differences in the postoperative eGFR between the two groups at one or three years of follow-up (OPN 54.8 vs. RAPN 61.2, p = 0.109, and OPN 54.8 vs. RAPN 55.5, p = 0.262, respectively). RAPN resulted in shorter ischemia durations and lower rates of EBL than did OPN; however, no differences in long-term renal function were observed between RAPN and OPN in our propensity-score matched Japanese cohort.


Ocular manifestations of leukemia. A review.
Ophthalmologists are familiar with the commonly observed leukemic retinopathy and orbital infiltration in patients with both acute and chronic leukemia. With the advent of more successful and aggressive chemotherapeutic regimens and more sophisticated radiation therapy, the eye is not uncommonly involved in patients who are in either meningeal or hematological relapse. In rare instances, ophthalmologic involvement may be the only manifestation of recurrence of the leukemic process. In addition, retinal microaneurysms, capillary closure, and neovascularization have been documented in individuals with chronic leukemia. This paper will review leukemic retinopathy and leukemic infiltration of the orbit. In addition, a discussion of the frequency and pathogenesis of the retinal vascular abnormalities will be presented. The clinical picture and treatment of optic nerve, choroid and iris infiltration will be discussed. Unusual ocular manifestations as the presenting sign of leukemia will also be detailed.


Opportunity costs associated with caring for older Mexican-Americans.
Long-term care use among older Mexican-Americans is poorly understood, despite the adverse effects on health and economic disadvantage in this vulnerable population. This study examines gender-based risk of long-term care use in 628 women and 391 men, age 70 and over in the 2000-2001 and 2004-2005 waves of the Hispanic Established Populations for Epidemiologic Studies of the Elderly. Logistic regression models are employed to assess the impact of the opportunity cost implications of family support (kin availability and co-residence) relative to health care needs (quality-adjusted life years (QALY) weighted scores and functional limitations) on women's risk of entry into a nursing home. A small percentage (~5%) of men and women had entered a long-term care facility. Women had lower weights for QALY weights and greater disability than men, but on average were more likely to live with or in closer proximity to an adult child. Higher disability rates (p < 0.01) increased the risk of institutionalization regardless of gender because disability increases time burdens. Families with fewer adult children faced higher time burdens per child in caring for elderly parents; particularly for elderly mothers. Demographic trends suggest that the number of adult children available to share the caregiving load may decrease long-term care use.


Urgent therapeutic plasma exchange.
Therapeutic plasma exchange (TPE) is a well-established therapeutic procedure commonly used in many disorders of autoimmune etiology. The beneficial effects of TPE occur through the removal of pathognomonic inflammatory mediators; including autoantibodies, complement components, and cytokines. The use of TPE in the emergency setting is limited to a few indications. In this chapter, we focus on four conditions that we are most frequently faced with in the urgency setting: neuromyelitis optica-spectrum disorders, solid organ transplantation, and two metabolic conditions such as major hypertriglyceridemia and hyperthyroidism. We discuss the clinical setting defining the urgent character of TPE, the timing of treatment onset, the therapeutic pattern of TPE and the level of evidence currently available for each condition.


Children at risk in traffic: improvement potentials in the Swedish context.
To investigate the social risk distribution and improvement potentials for road traffic injuries among Swedish children by considering three categories of road users. A population-based cohort study of children aged 1-14 y was carried out. Subjects were taken from the Swedish Population and Housing Census of 1990 (n = 1406405), and followed-up in the National Hospital Discharge Register for the years 1991-1999 focusing on injuries incurred as pedestrians, bicyclists or car passengers (n = 16084). Household socio-economic position was measured using social class, education and disposable income. Relative risks were calculated using Poisson regression for each measure of socio-economic position and by combining them, adjusting for sex, age of child and age of mother at delivery. Population-attributable risks were compiled for each category of road user and each measure of socio-economic position. Children of farmers and the self-employed are at greater risk for injuries as car passengers (RR 2.40, CI 1.79-3.20 and RR 1.44, CI 1.16-1.79, respectively), but not for pedestrian- and bicycle-related injuries. Children of unskilled workers are at greater risk for pedestrian injuries (RR 1.39, CI 1.15-1.67). Controlling for education and disposable income did not affect the relative risks to the same extent according to the social class and category of road user. The highest population-attributable risks were related to family disposable income and were indicated for pedestrians and car passengers (19-20%). By taking children's limited ability to deal with different types of traffic situations into consideration, considerable improvements in children's risk levels have been observed. Now there is a need to add equity in the road traffic safety equation.


Identification of plant metabolite classes from Waltheria Indica L. extracts regulating inflammatory immune responses via COX-2 inhibition.
Waltheria Indica L. is traditionally used in Africa, South America and Hawaii to treat pain, anemia, diarrhea, epilepsy and inflammatory related diseases. This study aimed to identify extraction parameters to maximize tiliroside yield and to quantitative secondary metabolite composition of Waltheria Indica under various extraction conditions. The extracts were tested for COX-2 inhibition and their activity correlated with the type and quantity of the secondary metabolites. Insight was gained about how extraction parameters influence the extract composition and thus the COX-2 enzymatic inhibitory activity. Powdered leaves of Waltheria Indica were extracted using water, methanol, ethyl acetate and ethanol at different temperatures. Tiliroside was identified by HPLC-HRMS n and quantified using a tiliroside standard. The compound groups of the secondary metabolites were quantified by spectrometric methods. Inhibitory potential of different Waltheria extracts against the COX-2 enzyme was determined using a fluorometric COX-2 inhibition assay. The molecule, tiliroside, exhibited a COX-2 inhibition of 10.4% starting at a concentration of 15 μM and increased in a dose dependent manner up to 51.2% at 150 μM. The ethanolic extract at 30 °C and the ethyl acetate extract at 90 °C inhibited COX-2 with 37.7% and 38.9%, while the methanolic and aqueous extract showed a lower inhibition of 21.9% and 9.2% respectively. The results concerning phenol, alkaloid and tiliroside concentration in the extracts showed no dependence on COX-2 inhibition. The extracts demonstrated a direct correlation of COX-2 inhibitory activity with their triterpenoid-/steroidal-saponin concentration. COX-2 inhibition increased linearly with the concentration of the saponins. The data suggest that Waltheria Indica extracts inhibit the key inflammatory enzyme, COX-2, as a function of triterpenoid- and steroidal-saponin concentration and support the known efficacy of extracted Waltheria Indica leaves as a traditional treatment against inflammation related diseases.


Influence of amphotericin B on leucine uptake in 3T3 cells.
By studying the effect of leucine competitors we found that activation of the specific leucine-transport system underlies the enhancement of leucine uptake in mouse 3T3 fibroblast cells induced by sublethal doses of Amphotericin B (synergic effect). The relation of the antibiotic activity and the alteration of the membrane cholesterol interaction with lipids is discussed.


Lysosomal membrane permeabilization in cell death.
Mitochondrial outer membrane permeabilization (MOMP) constitutes one of the major checkpoint(s) of apoptotic and necrotic cell death. Recently, the permeabilization of yet another organelle, the lysosome, has been shown to initiate a cell death pathway, in specific circumstances. Lysosomal membrane permeabilization (LMP) causes the release of cathepsins and other hydrolases from the lysosomal lumen to the cytosol. LMP is induced by a plethora of distinct stimuli including reactive oxygen species, lysosomotropic compounds with detergent activity, as well as some endogenous cell death effectors such as Bax. LMP is a potentially lethal event because the ectopic presence of lysosomal proteases in the cytosol causes digestion of vital proteins and the activation of additional hydrolases including caspases. This latter process is usually mediated indirectly, through a cascade in which LMP causes the proteolytic activation of Bid (which is cleaved by the two lysosomal cathepsins B and D), which then induces MOMP, resulting in cytochrome c release and apoptosome-dependent caspase activation. However, massive LMP often results in cell death without caspase activation; this cell death may adopt a subapoptotic or necrotic appearance. The regulation of LMP is perturbed in cancer cells, suggesting that specific strategies for LMP induction might lead to novel therapeutic avenues.


The effect of copper on erythrocyte deformability: a possible mechanism of hemolysis in acute copper intoxication.
Although the development of hemolytic anemia as a complication of acute copper intoxication is well documented, the precise mechanism by which copper produces accelerated erythrocyte destruction is unknown. Normal erythrocyte survival depends in part on the ability of the cell to deform and pass through narrow areas of microcirculation in the liver and especially in the spleen. In the present study, it is demonstrated that toxic concentrations of copper rapidly and markedly reduce erythrocyte deformability. This reduction in cell deformability is associated with a marked increase in membrane permeability and osmotic fragility of copper-treated cells. Further, the decrease in deformability occurs despite normal levels of cell ATP and the apparent absence of oxidative damage to the cell. These observations indicate that copper-mediated changes in the erythrocyte membrane may be responsible for reducing the flexibility of the cell. The loss of deformability could act to reduce erythrocyte survival and thus explain the hemolysis associated with copper intoxication in vivo.


Concave versus planar geometries for the hierarchical organization of mesoscopic 3D helical fibers.
Chromophore-peptide systems: a study on a series of pentapeptides covalently connected to planar π systems (1 a and 1 b) or to a curved π system (1 c) showed the influence of the concave shape on the efficient chiral transmission at nano- and mesoscales. Control over the hierarchical growth by H bonding, π-π, and solvophobic interactions made possible the efficient generation of electroactive 3D helical fibers.


Receptive-field construction in cortical inhibitory interneurons.
In the somatosensory 'barrel' cortex (where each barrel represents an individual whisker) the receptive fields of cortical spiny neurons show considerable specificity for the direction of whisker displacement, as do the receptive fields of thalamocortical (TC) neurons that provide input to the barrels. In contrast, putative fast-spike inhibitory interneurons in layer 4 of the barrel cortex lack directional preference, but are exquisitely sensitive to low stimulus intensities. Here we show, in adult rabbits, that these sensitive and broadly tuned inhibitory receptive fields are generated by an unselective pooling of convergent functional inputs from topographically aligned TC neurons with very diverse response properties.


The cytosolic phorboid receptor correlates with hormone dependency in six mammary carcinoma cell lines.
Potent, structurally different tumor promoters inhibited growth of 6 human mammary carcinoma cell lines (ROOS et al, PNAS in press). This growth inhibition was investigated by measuring the phorboid receptor binding using [3H] PDBu (4 beta-phorbol 12, 13 dibutyrate). Specific, high affinity receptors were found in all six cell lines. [3H] PDBu binding affinities were higher in the cytosolic fractions than in the corresponding intact cells (K alpha = app. 1nM vs K alpha = app. 15nM). The hormone-independent cell lines (BT-20, HBL-100 and MDA-MB-231) exhibited significantly higher levels of cytosolic [3H] PDBu receptors than the hormone-dependent cells (MCF-7, T-47-D and ZR-75-1). The subcellular distribution of the [3H] PDBu binding correlated well with the distribution of the protein kinase C activity (r = 0.95).


A retrospective review of patients with atypical femoral fractures while on long-term bisphosphonates: including pertinent biochemical and imaging studies.
To elucidate the effects of prolonged bisphosphonate (BP) exposure on the development of atypical fragility fractures, and to define the associated risk factors. Approval was obtained from the institutional review board, and a retrospective chart analysis was performed on 51 patients who had been on BPs for at least 3 years and had complete subtrochanteric or diaphyseal femoral fracture(s) between January 2005 and April 2011. All relevant data were available for 25 patients (mean age, 67.52 years). All fractures included in the study were low- or no-energy. Relevant clinical and demographic data were collected regarding age, gender, ethnicity, height, weight, and comorbid medical conditions. Imaging and laboratory data collected on all patients included: calcium, alkaline phosphatase, 25-hydroxyvitamin D (25-OHD), intact parathyroid hormone, serum c-telopeptide, and urine n-telopeptide levels, bone mineral density, radiography, and magnetic resonance imaging. Most of the patients in this study were Caucasian, were on alendronate, had bilateral findings, and almost half had prodromal symptoms. The 25-OHD level was suboptimal (<30 ng/mL) in 45.8% of the patients. Mean BP duration was 9.84 years, and mean bone density was in the osteopenic, not osteoporotic, range. Characteristics of patients with atypical BP-related fracture include relatively young age, long duration of BP use, suboptimal 25-OHD level, and bone density in the nonosteoporotic range. All of these may be significant risk factors for insufficiency fracture development.


The variability of arsenic in blood and urine of humans.
Humans are exposed to inorganic and organic arsenic. The total arsenic (As) concentration in urine is a commonly used biomarker of exposure. However, little is known about variability of As in biological fluids and the diurnal variation of As excretion. Main objectives were to assess the variability of As in urine, plasma (P-As), whole blood (B-As), and the blood cell fraction (C-As), and to assess diurnal variation of As excretion. Six urine samples were collected at fixed times during 24 h on two different days around one week apart among 29 men and 31 women. Blood samples were collected when the morning urine samples were delivered. The intra-class correlation coefficient (ICC) was calculated as the ratio of the between-individuals variance to the total observed variance. Geometric mean (GM) 24 h urinary excretions of As (U-As24 h) were 41 and 39 µg/24 h on the two days of sampling. Concentrations of B-As, P-As and C-As were highly correlated with U-As24 h and As in first void morning urine. No statistically significant differences were observed for the urinary As excretion rate between the different sampling times. A high ICC was observed for As in the cellular blood fraction (0.803), while ICC for first morning urine corrected for creatine was low (0.316). The study suggests that C-As is the most reliable biomarker for use in exposure assessment of individual exposure. Morning urine samples have low reliability for such use. No apparent diurnal variation was observed in the urinary As excretion rate.


Intravenous Oncolytic Vaccinia Virus Therapy Results in a Differential Immune Response between Cancer Patients.
Pexa-Vec is an engineered Wyeth-strain vaccinia oncolytic virus (OV), which has been tested extensively in clinical trials, demonstrating enhanced cytotoxic T cell infiltration into tumours following treatment. Favourable immune consequences to Pexa-Vec include the induction of an interferon (IFN) response, followed by inflammatory cytokine/chemokine secretion. This promotes tumour immune infiltration, innate and adaptive immune cell activation and T cell priming, culminating in targeted tumour cell killing, i.e., an immunologically 'cold' tumour microenvironment is transformed into a 'hot' tumour. However, as with all immunotherapies, not all patients respond in a uniformly favourable manner. Our study herein, shows a differential immune response by patients to intravenous Pexa-Vec therapy, whereby some patients responded to the virus in a typical and expected manner, demonstrating a significant IFN induction and subsequent peripheral immune activation. However, other patients experienced a markedly subdued immune response and appeared to exhibit an exhausted phenotype at baseline, characterised by higher baseline immune checkpoint expression and regulatory T cell (Treg) levels. This differential baseline immunological profile accurately predicted the subsequent response to Pexa-Vec and may, therefore, enable the development of predictive biomarkers for Pexa-Vec and OV therapies more widely. If confirmed in larger clinical trials, these immunological biomarkers may enable a personalised approach, whereby patients with an exhausted baseline immune profile are treated with immune checkpoint blockade, with the aim of reversing immune exhaustion, prior to or alongside OV therapy.


Exploiting Novel Unfused-Ring Acceptor for Efficient Organic Solar Cells with Record Open-Circuit Voltage and Fill Factor.
Unfused-ring acceptors (UFAs) show bright application prospects in organic solar cells (OSCs) thanks to their easy synthesis, low cost, and good device performance. The selection of central-core building block and suitable side chain are the key factors to achieve high-performance UFAs. Current tremendous endeavors for the development of UFAs mainly concentrate on obtaining higher short-circuit current density (Jsc ), albeit accompanied by low open-circuit voltage (Voc ) and modest fill factor (FF). Herein, two novel A-D-A'-D-A type UFAs (BTCD-IC and BTCD-2FIC), which have the same new electron-withdrawing central-core dithieno[3',2':3,4;2'',3'':5,6]-benzo[1,2-c][1,2,5]thiadia-zole (DTBT) and cyclopentadithiophene unit (CPDT, substituted by 2-butyl-1-octyl alkyl chain) coupling with different terminals, were designed and synthesized. Two UFAs showed strong and broad light absorption in the wavelength range of 300-850 nm owing to the strong intramolecular charge transfer effect favorable by DTBT core. Compared with BTCD-IC, BTCD-2FIC with F-containing terminal group exhibited higher molar extinction coefficient, lower energy level, higher charge mobility, stronger crystallinity, more ordered molecular stacking, and better film morphology. As a result, when blended with donor polymer PBDB-T (poly[(2,6-(4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)benzo[1,2-b:4,5-b']dithiophene)-co-(1,3-di(5-thiophene-2-yl)-5,7-bis(2-ethylhexyl)benzo[1,2-c:4,5-c']-dithiophene-4,8-dione)]), the BTCD-2FIC-based OSC achieved a superior power conversion efficiency (PCE) of 11.32 %, with a high Voc of 0.85 V, a Jsc of 18.24 mA cm-2 , and a FF of 73 %, than BTCD-IC-based OSC (PCE=8.96 %). Impressively, the simultaneously enhanced Voc and FF values of the PBDB-T:BTCD-2FIC device were the highest values of the A-D-A'-D-A-type UFAs. The results demonstrate the application of electron-withdrawing DTBT central-core unit in efficient UFAs provides meaningful molecular design guidance for high-performance OSCs.


Complete Genome Sequence of a Rare Pigment-Producing Strain of Acinetobacter johnsonii, Isolated from the Bile of a Patient in Hangzhou, China.
Here, we report the complete genome sequence of a rare pigment-producing strain of Acinetobacter johnsonii. The genome consists of a 3,360,823-bp circular chromosome (G+C content, 41.56%) and an 8,887-bp plasmid (G+C content, 33.71%). It possesses 3,038 coding gene sequences, 19 rRNA genes, 87 tRNA genes, and 4 noncoding RNA (ncRNA) genes.


An Audio/Video Reporting Workflow to Supplement Standardized Radiology Reports.
Radiology studies are inherently visual and the information contained within is best conveyed by visual methodology. Advanced reporting software allows the incorporation of annotated key images into text reports, but such features may be less effective compared with in-person consultations. The use of web technology and screen capture software to create retrievable on-demand audio/visual reports has not yet been investigated. This approach may preempt potential curbside consultations while providing referring clinicians with a more engaged imaging service. In this work, we develop and evaluate a video reporting tool that utilizes modern screen capture software and web technology. We hypothesize that referring clinicians would find that recorded on-demand video reports add value to clinical practice, education, and that such technology would be welcome in future practice. A total of 45 case videos were prepared by radiologists for 14 attending and 15 trainee physicians from emergency and internal medicine specialties. Positive survey feedback from referring clinicians about the video reporting system was statistically significant in all areas measured, including video quality, clinical helpfulness, and willingness to use such technology in the future. Trainees unanimously found educational value in video reporting. These results suggest the potential for video technology to re-establish the radiologist's role as a pivotal member of patient care and integral clinical educator. Future work is needed to streamline these methods in order to minimize work redundancy with traditional text reporting. Additionally, integration with an existing PACS and dictation system will be essential to ensuring ease of use and widespread adoption.


A dose-comparative endocrine-clinical study of leuprorelin in premenopausal breast cancer patients.
Twelve premenopausal patients with advanced breast cancer were randomised to receive 3.75 or 7.5 mg of a slow release formulation of the luteinising hormone releasing hormone agonist leuprorelin once every 4 weeks. All patients were oestrogen receptor positive or unknown. Serum levels of gonadotrophins and oestrogens were suppressed markedly by both doses. All oestrogen values during treatment were within the postmenopausal range except for a single oestradiol level (274 pmol l-1) in one patient on the lower dose. There was no other indication that this lower dose was less effective as an oestrogen suppressant. There were two objective responders to the 3.75 mg dose and three to the 7.5 mg dose. Toxicity was confined almost entirely to hot flushes which occurred in 11/12 patients. We conclude that the slow release formulation of leuprorelin is effective in breast cancer treatment and that there is no major detriment to the use of the 3.75 rather than 7.5 mg dose.


Molecular composition of the terminal membrane and fluid-phase C5b-9 complexes of rabbit complement. Absence of disulphide-bonded C9 dimers in the membrane complex.
The terminal membrane C5b-9(m) and fluid-phase SC5b-9 complexes of rabbit complement were isolated from target sheep erythrocyte membranes and from inulin-activated rabbit serum respectively. In the electron microscope, rabbit C5b-9(m) was observed as a hollow protein cylinder, a structure identical with that of human C5b-9(m). Monodispersed rabbit C5b-9(m) exhibited an apparent sedimentation coefficient of 29 S in deoxycholate-containing sucrose density gradients, corresponding to a composite protein-detergent molecular-weight of approx. 1.4 X 10(6). Protein subunits corresponding to human C5b-C9 were found on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. By densitometry, there were consistently six molecules of monomeric C9 present for each monomeric C5b-8 complex. Fluid-phase rabbit SC5b-9 was a hydrophilic 23 S ma macromolecule that differed in subunit composition from its membrane counterpart in that it contained S-protein and only two to three molecules of C9 per monomer complex. The data are in accord with the previous report on human C5b-9 that C5b-9(m) contains more C9 molecules than SC5b-9 [Ware & Kolb (1981) Proc. Natl. Acad. Sci. U.S.A. 78, 6426-6430]. They corroborate the previous molecular-weight estimate of approx. 10(6) for C5b-9(m) and thus support the concept that the fully assembled, unit lesion of complement is a C5b-9 monomer [Bhakdi & Tranum-Jensen (1981) Proc. Natl. Acad. Sci. U.S.A. 78, 1818-1822]. They also show that C9 dimer formation is not required for assembly of the rabbit C5b-9(m) protein cylinder, or for expression of its membrane-damaging function.


Peroxynitrite-Induced Tyrosine Nitration Contributes to Matrix Metalloprotease-3 Activation: Relevance to Hyperglycemic Ischemic Brain Injury and Tissue Plasminogen Activator.
Matrix metalloprotease-3 (MMP3) activation mediates the tissue plasminogen activator (tPA)-induced hemorrhagic transformation after stroke. Hyperglycemia (HG) further exacerbates this outcome. We have recently shown that HG increases MMP3 activity in the brain after stroke. However, the combined HG-tPA effect on MMP3 activation, and the mechanisms through which MMP3 is activated were not previously reported. Accordingly, this study tested the hypothesis that tPA and HG increases MMP3 activity in the brain after stroke through peroxynitrite induced tyrosine nitration. Normoglycemic and mildly hyperglycemic male Wistar rats were subjected to middle cerebral artery suture occlusion for 90 min or thromboembolic occlusion, and up to 24 h reperfusion, with and without tPA. MMP3 activity and tyrosine nitration were evaluated in brain homogenates at 24 h. Brain microvascular endothelial cells (BMVEC) were subjected to either 3 h hypoxia or 6 h OGD under either normal or high glucose conditions with or without tPA, with or without peroxynitrite scavenger, FeTPPs. MMP3 activity and MMP3 tyrosine nitration were assessed at 24 h. HG and tPA significantly increased activity and tyrosine nitration of MMP3 in the brain. In BMVECs, tPA but not HG increased MMP3 activity. Treating BMVEC with FeTPPs significantly reduced the tPA-induced increase in MMP3 activity and nitration. Augmented oxidative and nitrative stress may be potential mechanisms contributing to MMP3 activation in hyperglycemic stroke, especially with tPA administration. Peroxynitrite may be playing a critical role in mediating MMP3 activation through tyrosine nitration in hyperglycemic stroke.


Clinical outcomes and neural correlates of 20 sessions of repetitive transcranial magnetic stimulation in severe and enduring anorexia nervosa (the TIARA study): study protocol for a randomised controlled feasibility trial.
Anorexia nervosa (AN) is a serious mental disorder with multiple comorbidities and complications. In those with a severe and enduring form of the illness (SEED-AN), treatment responsivity is poor and the evidence base limited. Thus, there is a need for novel treatment strategies. This paper describes the theoretical background and protocol of a feasibility randomised controlled trial (RCT) of real versus sham (placebo) therapeutic repetitive transcranial magnetic stimulation (rTMS) in SEED-AN. The aim of this trial is to obtain information that will guide decision making and protocol development in relation to a future large-scale RCT of rTMS in this group of patients, and also to assess the preliminary efficacy and neural correlates of rTMS treatment. Forty-four adults from the community with a DSM-5 diagnosis of AN, an illness duration>3 years and a previous course of unsuccessful treatment will be randomly allocated to receive 20 sessions of either real or sham rTMS, in a parallel group design. As this is a feasibility study, no primary outcome has been defined and a broad range of outcome variables will be examined. These include weight/body mass index (BMI), eating disorder psychopathology, other psychopathology (for example, depression, anxiety), quality of life, neuropsychological processes (such as self-regulation, attentional bias and food choice behaviour), neuroimaging measures (that is, changes in brain structure or function), tolerability and acceptability of rTMS, and additional service utilisation. The feasibility of conducting a large-scale RCT of rTMS and the appropriateness of rTMS as a treatment for SEED-AN will be evaluated through: assessment of recruitment and retention rates, acceptability of random allocation, blinding success (allocation concealment), completion of treatment sessions and research assessments (baseline, post-treatment and follow-up assessments). The acceptability and tolerability of the treatment will be assessed via semi-structured interviews. The effect sizes generated and other findings from this trial will inform a future large-scale RCT with respect to decisions on primary outcome measures and other aspects of protocol development. Additionally, results from this study will provide a preliminary indication of the efficacy of rTMS treatment for AN, the neural correlates of the illness, and potential biomarkers of clinical response. ISRCTN14329415 . Date of registration: 23 July 2015.


Inositol lipids in cell signalling.
In the past year, major advances have been made in our understanding of the regulation of phosphoinositidase C, and of the action of the inositol trisphosphate receptor and how it may generate 'quantal' Ca2+ release. The functions of inositol tetrakisphosphate and of the 3-phosphorylated inositol lipids continue to generate controversy, but both may be well on the way towards some clarification. Finally, we may have to extend our concept of the inositide cycle to include an intranuclear signalling function.


Iron and zinc homeostases in female rats with physically active and sedentary lifestyles.
To determine the effects of repeated physical activity on iron and zinc homeostases in a living system, we quantified blood and tissue levels of these two metals in sedentary and physically active Long-Evans rats. At post-natal day (PND) 22, female rats were assigned to either a sedentary or an active treatment group (n = 10/group). The physically active rats increased their use of a commercially-constructed stainless steel wire wheel so that, by the end of the study (PND 101), they were running an average of 512.8 ± 31.9 (mean ± standard error) min/night. After euthanization, plasma and aliquots of liver, lung, heart, and gastrocnemius muscle were obtained. Following digestion, non-heme iron and zinc concentrations in plasma and tissues were measured using inductively coupled plasma optical emission spectroscopy. Concentrations of both non-heme iron and zinc in plasma and liver were significantly decreased among the physically active rats relative to the sedentary animals. In the lung, both metals were increased in concentration among the physically active animals but the change in zinc did not reach significance. Similarly, tissue non-heme iron and zinc levels were both increased in heart and muscle from the physically active group. It is concluded that repeated physical activity in an animal model can be associated with a translocation of both iron and zinc from sites of storage (e.g. liver) to tissues with increased metabolism (e.g. the lung, heart, and skeletal muscle).


Supercritical water oxidation for the destruction of spent media wastes generated from PFAS treatment.
Granular activated carbon (GAC) and anion exchange resin (AIX) have been successfully demonstrated to remove per- and polyfluoroalkyl substances (PFAS) from contaminated water and wastewater. These treatment technologies, when applied for PFAS removal, generate spent media loaded with a high mass of PFAS requiring further treatment and disposal. This project is the first study on the use of supercritical water oxidation (SCWO) to destroy both the spent media and the PFAS adsorbed onto it. One sample of spent GAC and one sample of spent AIX were collected from full-scale groundwater remediation systems treating PFAS. A second spent AIX sample was collected from a mobile PFAS treatment unit. The total PFAS concentrations reported in the GAC, AIX and second AIX feedstock slurries were 0.21 mg/kg, 1.3 mg/kg and 0.9 mg/kg, respectively. Each feedstock was processed separately in a one (1) wet metric ton per day tubular reactor SCWO system. The study demonstrated that SCWO is a very effective PFAS destruction technology for spent GAC and AIX, derived from water remediation systems treating PFAS. The spent media were completely mineralized to water, carbon dioxide (CO2) and a negligible amount of residual minerals. Total target PFAS compound concentrations in the SCWO system effluents after treating spent GAC, AIX and second AIX feedstocks were 548, 77 and 796 ng/L, respectively. The results indicated that the percentage elimination of perfluorocarboxylic acids (PFCAs) was better than that of perfluosulfonic acids (PFSAs) and long-chain PFAS elimination was better than short-chain PFAS.


Effects of praziquantel and oxamniquine on a Saudi Arabian strain of Schistosoma mansoni in mice.
The prophylactic and curative effects of praziquantel and oxamniquine on a Saudi Arabian strain of Schistosoma mansoni in MF-1 mice were assessed. The drugs were administered orally. At 240 mg/kg praziquantel, there was a reduction of 89.1% in adult worm recovery and a marked reduction in tissue deposited eggs. The reduction in adult worm recovery after dosing with 50 mg/kg oxamniquine was 89.2%. At low doses (40 mg/kg praziquantel and 30 mg/kg oxamniquine) administered at 11 days, 5 days and 3 h before and 5, 21 and 49 days after infection, the reduction in adult worm recovery was 0.0%, 65.1%, 58.8%, 33.6%, 0.0% and 76.0% for praziquantel and 0.0%, 66.0%, 60.0%, 41.3%, 10.8% and 79.0% for oxamniquine. Numbers of lung schistosomula and the size of hepatic granulomata were also reduced.


Laryngotracheal separation in an infant with severe dysgenesis of the larynx.
We describe management of an infant with chronic aspiration as a result of severe and rarely described laryngeal dysgenesis. A neonate with severe maldevelopment of the laryngeal structures required tracheostomy for respiratory distress on day-of-life 1, but the patient continued to have aspiration pneumonias. After failing to improve with conservative measures, the infant underwent laryngotracheal separation (LTS), which was successful in preventing aspiration. The patient has had no further pneumonias. The presented case illustrates that LTS may be considered a safe and effective initial treatment option for chronic aspiration in select infants with severe dysgenesis of the larynx.


Sputum interleukin-6, tumor necrosis factor-α and Salivary cortisol as new biomarkers of depression in lung cancer patients.
Depression is common among lung cancer patients. Increasing evidence has suggested that hypothalamic-pituitary-adrenal (HPA) axis and pro-inflammatory cytokines may play a key role in the pathophysiology of depression as well as cancer. This pilot study investigated the efficacy of sputum interleukin (IL)-6, tumor necrosis factor (TNF)-α and salivary cortisol as new markers to support the diagnosis of depression in lung cancer patients. The diurnal rhythms of sputum IL-6, sputum TNF-α and salivary cortisol were measured in lung cancer patients with and without depression as well as depressed controls and healthy controls. The area under the diurnal variation curves (AUC) over the 24h time course and relative diurnal variation (VAR) were calculated. Receiver operating characteristic (ROC) analysis was performed. Patients with co-morbid depression and lung cancer showed highest level of sputum IL-6 AUC, sputum TNF-α AUC and lowest level of cortisol VAR (P<0.001). As a biomarker for depression, salivary cortisol VAR demonstrated an optimal cutoff point at 77.8% (AUC=0.94; 95% CI, 0.85-0.98), which is associated with a sensitivity of 82.1% and a specificity of 96.0%. Sputum IL-6 AUC demonstrated a sensitivity of 74.4% and a specificity of 92.0% (AUC=0.81; 95% CI, 0.69-0.90). These findings suggested that higher 24h overall levels of sputum IL-6, TNF-α and flattened diurnal salivary cortisol slopes were associated with depression in lung cancer patients. Sputum IL-6 AUC and salivary cortisol VAR performed best as biomarkers in the diagnosis of depression in lung cancer patients.


N-[4-(1,1'-biphenyl)methyl]-4-(4-thiomorpholinylmethyl) benzenamines as non-oxazolidinone analogues of antimycobacterial U-100480.
Thiomorpholine analogues of U-100480 with the biphenylmethyl group replacing the acetamidomethyloxazolidinone moiety have been synthesized and tested as antimycobacterial agents together with various related derivatives. Some biphenyl derivatives were endowed with high activity against Mycobacterium tuberculosis and other non-tuberculous mycobacteria.


Preparation and efficacy of an inactivated subunit vaccine (NFUIBHK) against type 2 Herpes simplex virus infection.
A vaccine against Herpes simplex virus infection was prepared by Nonidet NP 40 and formalin treatment of a type 1, infected-cell extract; virus particles were removed by ultracentrifugation over sucrose. These procedures were not detrimental to the antigenic quality of the vaccine preparation. The vaccine afforded significant protection to experimental type 2 genital herpes virus infection in mice, as adjudged by clinical observations, cytopathological change, and virus yields.


A cooperative model for protonmotive heme-copper oxidases. The role of heme a in the proton pump of cytochrome c oxidase.
Oxido-reductions of metal centers in cytochrome c oxidase are linked to pK shifts of acidic groups in the enzyme (redox Bohr effects). The linkage at heme a results in proton uptake from the inner space upon reduction and proton release in the external space upon oxidation of the metal. The relationship of this process to the features of the proton pump in cytochrome c oxidase and its atomic structure revealed by X-ray crystallography to 2.8-2.3 A resolution is examined. A mechanism for the proton pump of cytochrome c oxidase, based on cooperative coupling at heme a, is proposed.


Preventive Administration of the Heat Shock Protein Hsp70 Relieves Endotoxemia-Induced Febrile Reaction in Pigeons ( Columba livia ) and Rats.
The stress-inducible 70 kDa heat shock protein (Hsp70) can exert a protective effect on endotoxemia and sepsis due to its ability to interact with immune cells and modulate the immune response. However, it remains unknown whether Hsp70 is able to relieve endotoxemia-induced fever. We carried out a comparative study of the effects of preventive administration of the human recombinant Hsp70 (HSPA1A) on lipopolysaccharide (LPS)-induced endotoxemia in pigeons and rats with preimplanted electrodes and thermistors for recording the thermoregulation parameters (brain temperature, peripheral vasomotor reaction, muscular contractile activity). Additionally, we analyzed the dynamics of the white blood cell (WBC) count in rats under the same conditions. It was found that preventive administration of Hsp70 relieves the LPS-induced febrile reaction in pigeons and rats and accelerates the restoration of the WBC count in rats. The data obtained suggest that these warm-blooded animals share a common physiological mechanism that underlies the protective effect of Hsp70.


ATR-mediated regulation of nuclear and cellular plasticity.
ATR (Ataxia Telangiectasia and Rad3-related) is a member of the Phosphatidylinositol 3-kinase-related kinases (PIKKs) family, amongst six other vertebrate proteins known so far. ATR is indispensable for cell survival and its essential role is in sensing DNA damage and initiating appropriate repair responses. In this review we highlight emerging and recent observations connecting ATR to alternative roles in controlling the nuclear envelope, nucleolus, centrosome and other organelles in response to both internal and external stress conditions. We propose that ATR functions control cell plasticity by sensing structural deformations of different cellular components, including DNA and initiating appropriate repair responses, most of which are yet to be understood completely.


Involvement of small heat shock proteins, trehalose, and lipids in the thermal stress management in Schizosaccharomyces pombe.
Changes in the levels of three structurally and functionally different important thermoprotectant molecules, namely small heat shock proteins (sHsps), trehalose, and lipids, have been investigated upon heat shock in Schizosaccharomyces pombe. Both α-crystallin-type sHsps (Hsp15.8 and Hsp16) were induced after prolonged high-temperature treatment but with different kinetic profiles. The shsp null mutants display a weak, but significant, heat sensitivity indicating their importance in the thermal stress management. The heat induction of sHsps is different in wild type and in highly heat-sensitive trehalose-deficient (tps1Δ) cells; however, trehalose level did not show significant alteration in shsp mutants. The altered timing of trehalose accumulation and induction of sHsps suggest that the disaccharide might provide protection at the early stage of the heat stress while elevated amount of sHsps are required at the later phase. The cellular lipid compositions of two different temperature-adapted wild-type S. pombe cells are also altered according to the rule of homeoviscous adaptation, indicating their crucial role in adapting to the environmental temperature changes. Both Hsp15.8 and Hsp16 are able to bind to different lipids isolated from S. pombe, whose interaction might provide a powerful protection against heat-induced damages of the membranes. Our data suggest that all the three investigated thermoprotectant macromolecules play a pivotal role during the thermal stress management in the fission yeast.


Where Does the Time Go? Displacement of Device-Measured Sedentary Time in Effective Sedentary Behaviour Interventions: Systematic Review and Meta-Analysis.
Research has shown the effectiveness of sedentary behaviour interventions on reducing sedentary time. However, no systematic review has studied where the reduced sedentary time after such interventions is displaced to. Our objective was to synthesize the evidence from interventions that have reduced sedentary behaviour and test the displacement of sedentary time into physical activity (light physical activity [LPA], moderate-to-vigorous physical activity [MVPA], standing, and stepping). Two independent researchers performed a systematic search of the EBSCOhost, PubMed, Scopus, and Web of Science electronic databases. Meta-analyses were performed to examine the time reallocated from sedentary behaviour to physical activity during working time and the whole day in intervention trials (randomized/non-randomized controlled/non-controlled). A total of 36 studies met all the eligibility criteria and were included in the systematic review, with 26 studies included in the meta-analysis. Interventions showed a significant overall increase in worksite LPA (effect size [ES] 0.24; 95% confidence interval [CI] 0.05 to 0.43; P < 0.013) and daily LPA (ES 0.62; 95% CI 0.34 to 0.91; P = 0.001). A statistically significant increase in daily MVPA was observed (ES 0.47; 95% CI 0.26 to 0.67; P < 0.001). There was a significant overall increase in worksite standing time (ES 0.76; 95% CI 0.56 to 0.95; P < 0.001), daily standing time (ES 0.52; 95% CI 0.38 to 0.65; P < 0.001), and worksite stepping time (ES 0.12; 95% CI 0.04 to 0.20; P = 0.002). Effective interventions aimed at reducing sedentary behaviour result in a consistent displacement of sedentary time to LPA and standing time, both at worksites and across the whole day, whereas changes in stepping time or MVPA are dependent on the intervention setting. Strategies to reduce sedentary behaviour should not be limited to worksite settings, and further efforts may be required to promote daily MVPA. PROSPERO registration number CRD42020153958.


Optimized Mass Spectrometry Analysis Workflow with Polarimetric Guidance for ex vivo and in situ Sampling of Biological Tissues.
Spatially Targeted Mass Spectrometry (MS) analysis using survey scans with an imaging modality often requires consecutive tissue slices, because of the tissue damage during survey scan or due to incompatible sample preparation requirements between the survey modality and MS. We report two spatially targeted MS analysis workflows based on polarized light imaging guidance that use the same tissue sample for survey and targeted analysis. The first workflow is applicable for thin-slice analysis, and uses transmission-polarimetry-guided Desorption ElectroSpray Ionization Mass Spectrometry (DESI-MS), and confirmatory H&E histopathology analysis on the same slice; this is validated using quantitative digital pathology methods. The second workflow explores a polarimetry-guided MS platform for thick tissue assessment by developing reflection-mode polarimetric imaging coupled with a hand-held Picosecond InfraRed Laser (PIRL) MS ablation probe that requires minimal tissue removal to produce detectable signal. Tissue differentiation within 5-10 s of sampling with the hand-held probe is shown using multivariate statistical methods of the MS profiles. Both workflows were tasked with differentiating necrotic cancer sites from viable cancers using a breast tumour model, and their performance was evaluated. The use of the same tissue surface addresses mismatches in guidance due to intrinsic changes in tissue morphology over consecutive sections.


Coronavirus Disease 2019 Infection in a Patient Population with Lung Cancer: Incidence, Presentation, and Alternative Diagnostic Considerations.
Lung cancer is associated with severe coronavirus disease 2019 (COVID-19) infections. Symptom overlap between COVID-19 and lung cancer may complicate diagnostic evaluation. We aimed to investigate the incidence, symptoms, differential diagnosis, and outcomes of COVID-19 in patients with lung cancer. To determine an at-risk population for COVID-19, we retrospectively identified patients with lung cancer receiving longitudinal care within a single institution in the 12 months (April 1, 2019 to March 31, 2020) immediately preceding the COVID-19 pandemic, including an "active therapy population" treated within the last 60 days of this period. Among patients subsequently referred for COVID-19 testing, we compared symptoms, laboratory values, radiographic findings, and outcomes of positive versus negative patients. Between April 1, 2019 and March 31, 2020, a total of 696 patients received longitudinal care, including 406 (58%) in the active therapy population. Among 55 patients referred for COVID-19 testing, 24 (44%) were positive for COVID-19, representing a cumulative incidence of 3.4% (longitudinal population) and 1.5% (active therapy population). Compared with patients who were COVID-19 negative, those who were COVID-19 positive were more likely to have a supplemental oxygen requirement (11% versus 54%, p = 0.005) and to have typical COVID-19 pneumonia imaging findings (5 versus 56%, p = 0.001). Otherwise, there were no marked differences in presenting symptoms. Among patients who were COVID-19 negative, alternative etiologies included treatment-related toxicity (26%), atypical pneumonia (22%), and disease progression (22%). A total of 16 patients positive for COVID-19 (67%) required hospitalization, and seven (29%) died from COVID-related complications. COVID-19 was infrequent in this lung cancer population, but these patients experienced high rates of morbidity and mortality. Oncologists should maintain a low threshold for COVID-19 testing in patients with lung cancer presenting with acute symptoms.


Insulin-stimulated microtubule associated protein kinase is detectable by analytical gel chromatography as a 35-kDa protein in myocytes, adipocytes, and hepatocytes.
Insulin stimulates a novel Ser/Thr kinase, which phosphorylates microtubule associated protein-2 (MAP-2) in vitro. MAP kinase was studied in cell models of the principal insulin responsive tissues using analytical fast-protein liquid chromatography for partial purification of the enzyme. Stimulation of MAP kinase (1.3- to 2-fold) by insulin was readily detected in BC3H1 smooth and 23A2 skeletal muscle cells; 3T3-L1 adipocytes; and isolated rat hepatocytes and adipocytes. No phosphatase activity was detectable under the assay conditions used, proving that stimulation of a kinase, not inhibition of a phosphatase, is responsible for the increased incorporation of 32PO4 catalyzed by supernatants from insulin-treated 3T3-L1 cells. In H4 hepatoma cells, stimulation of MAP kinase was much less evident after gel filtration in comparison to the other cell types. The activated enzyme present in supernatants from insulin-treated cells migrated as a single peak of approximately 35 kDa apparent molecular mass (except in the case of isolated hepatocytes in which a shoulder was present). These results suggest that the insulin-stimulatable MAP kinase may be ubiquitous in insulin responsive cells.


Putting data to work for precision medicine.
We discuss the One Stop Shop for Clinical Research (OSCAR) project that links clinical data, patient-reported outcomes, genomic data, and health registry data, employing a rigorous data privacy protection technology, to provide insights into treatment efficacy and safety and serve as a comparator for single-arm trials. This could inspire further initiatives to advance precision medicine.


Changes in the energy metabolism of cultured lens epithelial cells in comparison with the fresh lens.
Energy metabolism of bovine cultured lens epithelial cells (CLEC) was compared to that of fresh bovine lens. CLEC contained high levels of ATP (44 nmol mg protein-1) and creatine phosphate (13 nmol mg protein-1). An ATP/ADP ratio of ten and a creatine phosphate/creatine ratio of two indicated the cells were in a well-energized state. ATP concentration in fresh epithelium was comparable to that of CLEC; however in the anterior cortex it was tenfold lower. In contrast to fresh lenses, CLEC were able to oxidize glucose, lactate and palmitic acid. Lactate was oxidized at the highest rate. In CLEC, 42% of the ATP generated by catabolizing glucose resulted from oxidative phosphorylation. Glucose (5 mM) was degraded to lactate and CO2 at a 2:1 ratio. The hexose monophosphate pathway accounted for two thirds of the CO2 produced. In the fresh whole bovine lens palmitate was not oxidized and lactate was oxidized to a lesser degree than in CLEC. Only one-tenth of the ATP generated by glucose catabolism in the fresh whole lens was derived from oxidative phosphorylation. This was also the case for a preparation of fresh epithelium, maintained in air and 100% oxygen, demonstrating that the preferential glycolytic catabolism of glucose in lens is not caused by limited oxygen diffusion. In the fresh bovine lens the epithelium accounted for one third of the glucose catabolism of the whole lens, even though it had only about 0.1% of its protein mass. In fresh human lenses, conversion of glucose into lactate was even more pronounced--the lactate/CO2 ratio was 73:1.(ABSTRACT TRUNCATED AT 250 WORDS)


What the hec is up with mouse oocyte meiosis?
In this issue of Developmental Cell, Gui and Homer (2013) report that the proper execution of meiosis I in mouse oocytes requires the stabilization of cyclin B2 by the kinetochore protein Hec1, revealing unanticipated functions for both proteins.


Transosseous transposition of a pedicled rectus abdominis flap to cover hip wounds.
Bone-marrow transplantation may be complicated by aseptic necrosis of the femoral head. Prolonged immunosuppression places the patient at increased risk of infection and is of particular concern if replacement arthroplasty is contemplated. Infection of a prosthesis usually requires thorough debridement and removal of the device. However, attention must also be paid to the resultant cavity and soft-tissue cover. Several flaps have been reported for this problem, though limitations of flap size may make it difficult to achieve both objectives. This report describes the use a pedicled rectus abdominis flap that was tunnelled through the acetabulum in order to gain direct access to the hip and allow adequate length both to fill the dead-space and to provide cover.


Efficient synthesis of tyrosine-derived marine sponge metabolites via acylation of amines with a coumarin.
Condensation of N-acetylglycine with aldehyde 15 in acetic anhydride gave acetamido coumarin 16. Hydrolysis to the enol coumarin 17 and reaction with hydroxylamine gave the oximino coumarin 18. Reaction of the oximino coumarin 18 with a range of nucleophiles gave the phenolic oximes in excellent yield. The rates of acylation of histamine with the oximino coumarin 18 and methyl ester 9 were compared. Oxidative spirocyclization of three representative phenolic oximes with polymer-supported (diacetoxyiodo) benzene gave the spiroisoxazolines.


3-(2-Meth-oxy-phen-yl)-2,3-di-hydro-1H-benzo[f]chromen-1-one.
In the title compound, C20H16O3, the 2-meth-oxy-phenyl ring is tilted by 50.67 (3)° with respect to the naphthyl ring system. The central pyran ring has an envelope conformation with the C atom bearing the pendant ring system as the flap. The meth-oxy group attached to the benzene ring is slightly twisted [C-C-O-C = -15.2 (1)°] from the ring. In the crystal, weak C-H⋯O inter-actions link the mol-ecules into C(7) chains propagating along [101].


Bioaccumulation and risk assessment of radiocesium in the Northwest Pacific Ocean from Fukushima Dai-ichi Nuclear Power Plant accident.
To understand which biota are more exposed to radionuclides, the bioaccumulation and risk assessment of radiocesium (137Cs and 134Cs) release from FDNPP in the Northwest Pacific Ocean were analyzed using ERICA tools. The activity level was determined by the Japanese Nuclear Regulatory Authority (RNA) in 2013. The data were used as input to the ERICA Tool modeling software to evaluate the accumulation and dose of marine organisms. The highest and lowest accumulate concentration rate were observed in birds (4.78E+02 Bq kg-1/Bq L-1) and the Vascular plant (1.04E+01 Bq kg-1/Bq L-1), respectively. The total dose rate range for the 137Cs and 134Cs ranged between 7.39E-04 and 2.65E+00 μGy h-1 and 4.24E-05 and 2.91E-01 μGy h-1, respectively. There is no considerable risk to the marine biota in the research region since the cumulative dose rates of radiocesium to the chosen species were all less than 10 μGy h-1.


Parenteral medium-chain triglyceride-induced neutrophil activation is not mediated by a Pertussis Toxin sensitive receptor.
Lipid-induced immune modulation might contribute to the increased infection rate that is observed in patients using parenteral nutrition. We previously showed that emulsions containing medium-chain triglycerides (LCT/MCTs or pure MCTs), but not pure long-chain triglycerides (LCTs), impair neutrophil functions, modulate cell-signaling and induce neutrophil activation in vitro. It has recently been shown that medium-chain fatty acids are ligands for GPR84, a pertussis toxin (PT)-sensitive G-protein-coupled receptor (GPCR). This finding urged us to investigate whether MCT-induced neutrophil activation is mediated by PT-sensitive GPCRs. Neutrophils isolated from blood of healthy volunteers were pre-incubated with PT (0.5-1 microg/mL, 1.5 h) and analyzed for the effect of this pre-incubation on LCT/MCT (2.5 mmol/L)-dependent modulation of serum-treated zymosan (STZ)-induced intracellular Ca(2+) mobilization and on LCT/MCT (5 mmol/L)-induced expression of cell surface adhesion (CD11b) and degranulation (CD66b) markers and oxygen radical (ROS) production. PT did not inhibit the effects of LCT/MCT on the STZ-induced increase in cytosolic free Ca(2+) concentration. LCT/MCT increased ROS production to 146% of unstimulated cells. However, pre-incubation with PT did not inhibit the LCT/MCT-induced ROS production. Furthermore, the LCT/MCT-induced increase in CD11b and CD66b expression (196% and 235% of unstimulated cells, respectively) was not inhibited by pre-incubation with PT. LCT/MCT-induced neutrophil activation does not involve the action of a PT-sensitive G-protein-coupled receptor.


Potential chances for natural fertility influence results of intrauterine inseminations.
Intra-uterine insemination (IUI) is widely used for different indications. The aim of the present study was to evaluate the efficiency of intra-uterine insemination as a function of indication and origin of the inseminated spermatozoa. The retrospective study involved 827 first attempts of IUI in 827 couples between January 2011 and July 2017 in the Toulouse university hospital. Of these, 642 used fresh sperm from the husband, 40 frozen sperm from the husband and 145 frozen sperm from donors. The measured outcome parameter was live birth rate per attempt. When comparing couples lacking functional gametes (due to male or female causes), to couples who could potentially conceive spontaneously, i.e. subfertile, the latter were found to have a significantly lower live birth rate (18% vs 26%; P < 0.05). Even when adjusted for demographic parameters, which differed significantly between the 2 groups (female age, percentage of women suffering from primary infertility, BMI, number of inseminated motile spermatozoa and stimulation duration), this difference remained statistically significant (OR = 0.639 [0.425-0.961]; P = 0.0316). When compared to couples lacking functional gametes, subfertile couples have poor IUI outcomes, suggesting a hidden cause of infertility, despite no apparent differences in ovarian reserve, tubal potency, results of ovarian stimulation and normal conventional sperm parameters. Further studies are required to better characterise and identify this subgroup of women with poor IUI outcomes.


The hypothalamo-hypophysial system in the ground squirrel, Citellus erythrogenys Brandt. II. Seasonal changes in the classical neurosecretory system of a hibernator.
Monthly observations of the "Gomori-positive" hypothalamo-hypophysial neurosecretory system (HHNS) of the ground squirrel, Citellus erythrogenys Brandt, were carried out light microscopically using several quantitative methods. From the beginning of hibernation, formation of neurosecretory material (NSM) in the neurosecretory cells (NSC) progressively decreases and release of neurohormones from the HHNS is almost fully inhibited. A maximal accumulation of NSM in the perikarya of the NSC and in the posterior pituitary (PP) is found in December. By this time the volume of the cell nuclei and nucleoli is at a minimum. Signs of activation of the HHNS appear and become more conspicuous as the time of arousal from torpor approaches. The amount of NSM in the NSC and the PP decreases simultaneously with the increase in volume of the NSC. Hyperemia and activation of glial elements is visible throughout the HHNS. The morphological signs of activation reach their peak in March. After reproduction is completed (April to beginning of May), the NSC and the PP are almost devoid of NSM. Beginning with June and during the summer and autumn months a progressive accumulation of NSM in the NSC and the PP parallels gradual diminution in the volume of the NSC structures and the glial cells. Mechanisms and effector pathways by which the HHNS influences seasonal adaptation of the organism and reproduction are discussed.


Acetate inhibition of chick bone cell proliferation and bone growth in vitro.
A hypothesis has been advanced that parenteral solutions as commonly formulated for use in clinical practice have a toxic effect on cell metabolism. A specific component of these solutions, sodium acetate, has been suggested to disrupt normal bone turnover and therefore to contribute to the osteopenia observed in patients receiving hemodialysis and parenteral nutrition (PN). We developed an in vitro model to test the hypothesis that sodium acetate at concentrations that are infused in PN solutions has a deleterious effect on bone metabolism. Osteoblasts and preosteoblasts from 16- to 17-day-old embryonic chick calvaria, and tibiae and femora from 10-day-old embryonic chicks were grown in BGJb medium (control) or in BGJb medium plus sodium acetate (5, 10, or 20 mM). Calvarial cell proliferation was quantified by direct cell counts as well as by incorporation of [3H]TdR into DNA as an index of cell proliferation. Calvarial cell alkaline phosphatase activity was quantified by the ability of extracts of the cultured cells to hydrolyze p-nitrophenyl phosphate to p-nitrophenol, and bone growth was determined by measuring final dry weight. Calvarial cell counts as well as DNA synthesis showed a dose-dependent decrease in the presence of sodium acetate (5-20 mM) compared with controls. [3H]TdR incorporation was decreased a mean 19% with 5 mM, 38% with 10 mM, and 63% with 20 mM acetate. Alkaline phosphatase activity per cell increased 48% with 5 mM, 140% with 10 mM, and 355% with 20 mM acetate. Cell viability as assessed by trypan blue exclusion was identical for test and control media (greater than 95%).(ABSTRACT TRUNCATED AT 250 WORDS)


Nursing Leadership and Care Coordination: Creating Excellence in Coordinating Care Across the Continuum.
Continuum Care is different today from in the past. It requires care coordination with an emphasis on relationships and new roles. Nurses and nurse leaders must be located at the epicenter of developing strategies to align resources with patients and family along all points of the continuum.


Antisense prevention of neuronal damages following head injury in mice.
Closed head injury (CHI) is an important cause of death among young adults and a prominent risk factor for nonfamilial Alzheimer's disease. Emergency intervention following CHI should therefore strive to improve survival, promote recovery, and prevent delayed neuropathologies. We employed high-resolution nonradioactive in situ hybridization to determine whether a single intracerebro-ventricular injection of 500 ng 2'-O-methyl RNA-capped antisense oligonucleotide (AS-ODN) against acetylcholinesterase (AChE) mRNA blocks overexpression of the stress-related readthrough AChE (AChE-R) mRNA splicing variant in head-injured mice. Silver-based Golgi staining revealed pronounced dendrite outgrowth in somatosensory cortex of traumatized mice 14 days postinjury that was associated with sites of AChE-R mRNA overexpression and suppressed by anti-AChE AS-ODNs. Furthermore, antisense treatment reduced the number of dead CA3 hippocampal neurons in injured mice, and facilitated neurological recovery as determined by performance in tests of neuromotor coordination. In trauma-sensitive transgenic mice overproducing AChE, antisense treatment reduced mortality from 50% to 20%, similar to that displayed by head-injured control mice. These findings demonstrate the potential of antisense therapeutics in treating acute injury, and suggest antisense prevention of AChE-R overproduction to mitigate the detrimental consequences of various traumatic brain insults.


A gene expression study denies the ability of 25 candidate biomarkers to predict the interferon-beta treatment response in multiple sclerosis patients.
We studied the baseline expression level of 25 interferon-regulated genes (MxA, GPR3, IL17RC, ISG15, TRAIL, OASL, IFIT1, IFIT2, RSAD2, OAS3, IFI44L, TRIM22, IL10, CXCL10, STAT1, OAS1, OAS2, IFNAR1, IFNAR2, IFNβ, ISG20, IFI6, PKR, IRF7, USP18), recurrently proposed in the literature as predictive biomarkers of interferon-beta treatment response, in whole blood of 10 "responders" and 10 "non-responders" multiple sclerosis relapsing-remitting patients, retrospectively selected on the basis of stringent clinical criteria after a five years follow-up. However, we cannot confirm the predictive value of these candidate biomarkers.