Mapping Conscience: Network Analysis Into the Differences in Maturation of Offending and Non-Offending Adolescents.
Conscience is a diagnostically relevant concept in forensic psychiatry, but often misinterpreted as an all-or-none phenomenon. We conceptualize the conscience as a psychic function in which elements like empathy, self-conscience emotions such as shame, guilt and pride, and moral orientation work together. The differences in conscience functioning can be described in terms of developmental levels of integration. We conducted network analyses on data collected via a questionnaire survey held among 52 offending and 243 non-offending juveniles. We displayed two networks: One representing the non-offenders' normative and one representing the offenders' defiantly maturing conscience. As was hypothesized, in the non-offenders network, almost all elements clustered into one clinically meaningful network, indicating integration of the different elements of the normative maturing conscience. In the offenders network, the correlations between the elements were sporadic, indicating a lack of integration of the defiantly maturing conscience. The difference between the two networks was more prominent for empathy and moral orientation than for self-conscious emotions. This research supports the theory of differences in maturation of conscience instead of being an all-or-none phenomenon and calls for further research, taking a deeper look at the significance of integration of the conscience and its implications for offending behaviour.


Osteochondral transplantation in the elbow leads to good clinical and radiologic long-term results: an 8- to 14-year follow-up examination.
In the long-term follow-up after debridement, microfracture, or drilling of osteochondral lesions in the elbow, subsequent osteoarthritis is a problem. Osteochondral transplantation for these defects has become a more common procedure. However, long-term results are unknown. This study was undertaken to evaluate long-term clinical and radiologic outcomes of advanced osteochondral lesions in the elbow treated with osteochondral transplantation. Case series; Level of evidence, 4. The study included 8 patients with osteochondral lesions in the elbow who were treated by autologous osteochondral transplantation between 1996 and 2002. Patients (average age, 17 years) were evaluated pre- and postoperatively by Broberg-Morrey score to assess elbow function and by American Shoulder and Elbow Surgeons (ASES) score for pain analysis. In addition, radiographs (at the first postoperative day, and at 5-year and 10-year follow-up) and magnetic resonance images (8 to 12 weeks postoperatively, and at 5-year and 10-year follow-up) were made to evaluate the joint status. At last follow-up (range, 8-14 years postoperatively), 7 of 8 patients were seen for clinical examination and radiologic analysis. The Broberg-Morrey score increased from an average of 75.9 ± 13.1 to 96.4 ± 2.4 and ASES score significantly improved as follows: worst pain, 7.9 ± 1.1 to 1.6 ± 1.9; rest pain, 3.14 ± 2.7 to 0.6 ± 1.5; weight-lifting pain, 7.6 ± 0.8 to 3.1 ± 1.6; and repetitive movement pain, 5.3 ± 2.4 to 1.6 ± 1.5. Compared with the contralateral side, there was a mean preoperative flexion lag of 12.5° ± 11.6°. At the final follow-up, flexion was free. The mean extension lag was reduced from average 5.4° ± 5.7° to 0°. Radiographs of 2 patients made at final follow-up showed mild signs of osteoarthritis (Kellgren and Lawrence grade I). Postoperative magnetic resonance images showed graft viability in all and a congruent chondral surface in 6 of 7 patients. Clinical long-term results after osteochondral transplantation in the elbow are good to excellent and comparable with midterm results in the literature. Therefore, this technique is a reliable option for satisfactory long-term results regarding treatment of advanced osteochondral lesions in the elbow.


Blood-based profiles of DNA methylation predict the underlying distribution of cell types: a validation analysis.
The potential influence of underlying differences in relative leukocyte distributions in studies involving blood-based profiling of DNA methylation is well recognized and has prompted development of a set of statistical methods for inferring changes in the distribution of white blood cells using DNA methylation signatures. However, the extent to which this methodology can accurately predict cell-type proportions based on blood-derived DNA methylation data in a large-scale epigenome-wide association study (EWAS) has yet to be examined. We used publicly available data deposited in the Gene Expression Omnibus (GEO) database (accession number GSE37008), which consisted of both blood-derived epigenome-wide DNA methylation data assayed using the Illumina Infinium HumanMethylation27 BeadArray and complete blood cell (CBC) counts among a community cohort of 94 non-diseased individuals. Constrained projection (CP) was used to obtain predictions of the proportions of lymphocytes, monocytes and granulocytes for each of the study samples based on their DNA methylation signatures. Our findings demonstrated high consistency between the average CBC-derived and predicted percentage of monocytes and lymphocytes (17.9% and 17.6% for monocytes and 82.1% and 81.4% for lymphocytes), with root mean squared error (rMSE) of 5% and 6%, for monocytes and lymphocytes, respectively. Similarly, there was moderate-high correlation between the CP-predicted and CBC-derived percentages of monocytes and lymphocytes (0.60 and 0.61, respectively), and these results were robust to the number of leukocyte differentially methylated regions (L-DMRs) used for CP prediction. These results serve as further validation of the CP approach and highlight the promise of this technique for EWAS where DNA methylation is profiled using whole-blood genomic DNA.


The influence of acceptor and donor doping on the protonic surface conduction of TiO2.
The transport of protonic charge carriers along and within the pore surfaces of porous oxide matrices is of significant importance for many catalytic and electrochemical applications, with porous TiO2 being a candidate material both for photocatalytic applications and as an electronically conducting support for polymer-based electrochemical cells. This work investigates the effect of acceptor (Cr and Fe) and donor (Nb) doping on protonic surface conduction in porous TiO2 over a wide range of relative humidity, temperature and oxygen activity. Generally, we find that acceptor dopants on the surface counteract dissociation and reduce the mobility of protons, while donor dopants give rise to enhanced dissociation making protonic surface conduction the highest for donor-doped samples, contrary to conventional bulk proton conductors. Moreover, protonic surface conduction in Cr-doped TiO2 is significantly higher under oxidising conditions compared to reducing conditions, which we relate to the presence of a higher valent species such as Cr6+ on the surface under oxidising conditions, again emphasising that protonic surface conduction increases with higher-valent (donor) and more acidic cations present on the surface.


Bacillus Calmette-Guerin injections for melanoma immunotherapy: potential for a false-positive PET/CT.
An 82-year-old woman presented for routine follow-up PET/CT after undergoing local melanoma resection in the left lower leg, isolated limb infusion chemotherapy, and immunomodulation therapy with Bacillus Calmette-Guérin (BCG) vaccine. Symmetric, bilateral, moderately intense FDG avid axillary and inguinal cutaneous nodules were observed that were new from the prior PET-CT. The patient had developed skin lesions at the BCG injection sites several months before the study. The case raises awareness to PET/CT appearance of local inflammatory response to BCG injection, which could be mistaken by an unaware reader for recurrent melanoma.


[Validation of the Italian version of the "Neuropathic Pain Scale" and its clinical applications].
The Neuropathic Pain Scale is the first specific tool to measure and analyse pain due to a lesion in the nervous system; this kind of pain is usually difficult to describe for the patient because it is characterized by unusual qualities. Aim of this study is to evaluate a possible relation between pain descriptions and underlying pathogenetic mechanisms. The Italian version of the Neuropathic Pain Scale has been administered to 145 patients with neuropathic pain due to chronic radiculopathy, diabetic neuropathy, post-traumatic neuropathy, Complex Regional Pain Syndrome or postherpetic neuralgia. As it has been done in Galer's study, the predictive validity and the items' correlation have been evaluated; moreover, the structure validity of the scale has been studied. Pain values were high in all pain syndromes with the prevalence of certain items in particular pathologies. The correlation of some items with "deep pain" and others with "superficial pain" was also observed. The results have confirmed the statistical validity of the Italian version of the scale; they also pointed out the usefulness of the scale to distinguish between superficial pain, typical of neuropathic pain, and deep pain, typical of somatic pain.


Unruptured Giant Intracerebral Aneurysms: Serious Trouble Requiring Serious Treatment - Case Report and Literature Review.
Giant intracranial aneurysms (ICGA) represent 3 to 5% of all intracranial aneurysms in adults. They are defined as arterial dilatations, with more than 25 mm in diameter. Despite important advances in the research of endovascular techniques of treating giant intracranial aneurysms, the management of these vascular malformations still poses great difficulties for neurologists and interventional radiologists. In particular, these challenges arise from the difficult and modified cerebral anatomy of patients with ICGA. Choosing the best treatment for patients with ICGA involves not only finding the perfect balance between the potential risks and benefits of endovascular treatment, but also taking into consideration the patient's biological condition and associated diseases. The aim of this paper is to describe the decisional algorithm of treating patients with giant intracranial aneurysms and factors which could influence the choice of endovascular technique. We report a clinical case of a 63-year-old female with cardio-vascular risk factors (atrial fibrillation, high blood pressure), diagnosed with a symptomatic giant aneurysm of the right internal carotid artery and multiple cerebral micro-bleeds. Given the very large size of the aneurysm, its characteristics as well as patient's associated comorbidities, it was decided to exclude the ICA aneurysm from circulation by occluding the parent vessel (right internal carotid artery) by using endovascular techniques. Also, a review of the literature on the currently available endovascular methods for treating patients with giant intracranial aneurysms was performed in order to see the indications and possible long-term complications of each method. In selected cases, the risks of serious complications associated with occluding a large cervical-cerebral vessel (as the internal carotid artery) are far exceeded by the risk for rupture of giant aneurysms, which is fatal in many cases. Nevertheless, it is of utmost importance to mention that, although the use of endovascular methods leads to a significant increase in life expectancy, a severe decline in quality of life might be experienced by these patients.


Dermoscopy in tinea manuum.
Tinea manuum is a dermatophytosis which is often mistaken for other keratodermas, especially palmar psoriasis and chronic hand eczema. We report the use of dermoscopy as a diagnostic aid in a case of tinea manuum. The dermoscopic clue turned out to be the presence of whitish scaling located mainly in the furrows. This aspect has never been seen in other keratodermas and therefore can be considered as a useful finding to assist in the recognition of tinea manuum.


Attitudes and practices towards palliative care in chronic heart failure: a survey of cardiovascular nurses and physicians.
Heart failure is a chronic condition with various implications for individuals and families. Although the importance of implementing palliative care is recommended in best practice guidelines, implementation strategies are less clear. This study sought to; (1) determine Australian and New Zealand cardiovascular nurses and physicians' end of life care attitudes and specialist palliative care referral in heart failure and; (2) determine self-reported delivery of supportive care and attitudes towards service names. An electronic survey was emailed to members of four peak bodies and professional networks. Participants were also recruited through social media. Paper-based versions of the survey were completed by attendees of the 66th Cardiac Society of Australia and New Zealand Annual Scientific Meeting, August 2018. There were 113 completed responses included in the analyses. Participants were nurses (n = 75), physicians (n = 32) and allied health professionals (n = 4). Most (67%) reported they were comfortable with providing end of life care; however, fewer respondents agreed they received support for their dying patients and one-third experienced a sense of failure when heart failure progressed. Most (84-100%) participants agreed they would refer a heart failure patient later in the illness trajectory. There was a more favourable attitude towards the service name 'supportive care' than to 'palliative care'. Comfort with end of life discussions is encouraging as it may lead to a greater likelihood of planning future care and identifying palliative care needs. Peer support and supervision may be useful for addressing feelings of failure. The use of needs-based assessment tools, adopting the service name 'supportive care' and further research focusing on primary palliative team-based approach is required to improve palliative care access. Cardiovascular nurses and physicians are comfortable providing end of life care, but referrals to palliative care in the later stages of heart failure persists.


Density-dependent location and interactions of truncated APC and beta-catenin.
Adenomatous polyposis coli (APC) is a multifunctional tumour suppressor protein, central to development and the mature organism. It is mutated in most cases of colorectal cancer, rendering it ineffective in mediating beta-catenin degradation. We show that localization of full-length APC in colon carcinoma and noncancer cell lines is independent of cell density. However, the location of truncated APC is a function of cell density and in high-density cells truncated APC is predominantly not nuclear. Although the distribution of truncated APC and beta-catenin is closely linked in subconfluent SW480 cells, at high cell density they are not colocalized. We postulated that in this cell line this could be due to an increase in beta-catenin bound to E-cadherin with formation of adherens junctions at high cell density. However, while in coimmunoprecipitation assays we observe an increase in binding between beta-catenin and E-cadherin and a corresponding decrease in binding between beta-catenin and APC at high cell density, we did not observe a strict colocalization of beta-catenin and E-cadherin at the membrane of all cells.


Biomarkers of exposure to polycyclic aromatic hydrocarbons (PAHs) and DNA damage: a cross-sectional pilot study among roofers in South Florida.
The main goal of this pilot study was to assess the technical and logistic feasibility of a future study. The research hypothesis is that occupational exposures to polycyclic aromatic hydrocarbons (PAHs) are associated with increased risk of DNA damage among roofers who work with hot asphalt. This is a cross-sectional pilot study. The study included roofers from four different construction sites in Miami-Dade County, Florida. 19 roofers were recruited (six Hispanics and 13 African-Americans, all male), all of whom were eligible (no history of cancer and no history of chronic diseases of kidneys or liver). All participants provided pre-shift samples and 18 provided post-shift samples. Samples of one participant were excluded from the final analyses as they were considered unreliable. Levels of urinary PAH metabolites increased during 6 h of work. Linear regression models of post-shift metabolites included their pre-shift levels, post-shift urinary creatinine levels (for models of 1-OHPyr and 9-OHPhe), and skin burn due to contact with hot asphalt (for models of 1-OHPyr and 1-OHNap). Pre-shift levels of urinary 8-OHdG were not associated with any of the variables considered. For post-shift levels of 8-OHdG, however, post-shift 1-OHPyr (95% CI 0.091 to 0.788) and use of protective gloves (95% CI -1.57 to -0.61) during work explained 86.8% of its variation. Overall, highest levels of urinary PAH metabolites and of 8-OHdG were observed among workers who reported having skin burn and who did not use gloves during work. Urinary 1-OHPyr is a promising predictor of oxidative DNA damage among roofers. Work-related skin burn and use of protective gloves appear to influence PAH exposure and DNA damage levels in this group, suggesting the importance of dermal absorption.


European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine).
These ESCMID guidelines address the targeted antibiotic treatment of third-generation cephalosporin-resistant Enterobacterales (3GCephRE) and carbapenem-resistant Gram-negative bacteria, focusing on the effectiveness of individual antibiotics and on combination versus monotherapy. An expert panel was convened by ESCMID. A systematic review was performed including randomized controlled trials and observational studies, examining different antibiotic treatment regimens for the targeted treatment of infections caused by the 3GCephRE, carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Acinetobacter baumannii. Treatments were classified as head-to-head comparisons between individual antibiotics and between monotherapy and combination therapy regimens, including defined monotherapy and combination regimens only. The primary outcome was all-cause mortality, preferably at 30 days and secondary outcomes included clinical failure, microbiological failure, development of resistance, relapse/recurrence, adverse events and length of hospital stay. The last search of all databases was conducted in December 2019, followed by a focused search for relevant studies up until ECCMID 2021. Data were summarized narratively. The certainty of the evidence for each comparison between antibiotics and between monotherapy and combination therapy regimens was classified by the GRADE recommendations. The strength of the recommendations for or against treatments was classified as strong or conditional (weak). The guideline panel reviewed the evidence per pathogen, preferably per site of infection, critically appraising the existing studies. Many of the comparisons were addressed in small observational studies at high risk of bias only. Notably, there was very little evidence on the effects of the new, recently approved, β-lactam/β-lactamase inhibitors on infections caused by carbapenem-resistant Gram-negative bacteria. Most recommendations are based on very-low- and low-certainty evidence. A high value was placed on antibiotic stewardship considerations in all recommendations, searching for carbapenem-sparing options for 3GCephRE and limiting the recommendations of the new antibiotics for severe infections, as defined by the sepsis-3 criteria. Research needs are addressed.


[The diagnostically related system of groups as the instrument of the estimated cost of inpatient care under the the system of medical insurance].
Analysis of data base for 73,000 patients treated at various hospitals of the Novgorod district demonstrated the efficiency of the system of diagnostically related groups and the "American" cost weight coefficients for assessing the resource requirements of each hospital with due consideration for the inpatient populations; moreover, such an approach is useful in dealing with insurance organizations in connection with each patient treated. The cost weight coefficient was found to be in good correlation with the diagnostic and therapeutic expenditures and less dependent on the duration of hospitalization.


"Holes in my memories": a qualitative study of men affected by father absence.
This qualitative study explored adult men's experiences of father absence. Interviews with 21 men between the ages of 24 and 70 explored narratives of father absence and how the men perceived this influenced their life trajectory. Thematic analysis revealed that these men experienced a range of difficulties and challenges, including episodes of sadness and depression associated with loss and grief for the paternal relationship, self-esteem issues, feelings of anger and rejection, and difficulty forming trusting relationships particularly with other men. This study contributes to understanding mental health issues that can be associated with paternal absence for men.


Effects of microwave heating on the migration of substances from melamine formaldehyde tableware.
Melamine formaldehyde (MF) tableware, after undergoing repeated heating in a microwave oven for 1, 2, 3 or 5 min, was tested for migration into 3% (w/v) acetic acid, a food simulant. Overall migration (OM) consistently increased with an increasing number of heating/washing cycles, while formaldehyde was found at low concentrations or was not detectable. Unexpectedly, the 1-min series caused the most rapid increase in OM; the European Union regulatory limit of 10 mg dm(-2) was exceeded after 25 cycles. The number of cycles required to reach the OM limit rose to 29 and 67 for the 2- and 3-min series, respectively. Only 37 cycles were needed in the case of the 5-min series; however, the cumulative exposure time to microwave irradiation was relatively close to that of the 3-min series. These findings indicate that microwave heating affects the migration of MF in a significantly different manner as compared with conventional heating reported in previous studies. Fourier transform infrared spectroscopy (FTIR) spectra of MF after completing the microwave heating series show that the plastic was not fully cured, as evidenced by the absence of methylene linkages. The majority of migrants obtained from OM tests consisted of low molecular weight methylol melamine derivatives. The results indicate that microwave heating allowed demethylolation, addition and condensation reactions to occur, which was not the case when using conventional heating. This study demonstrates that microwave heating for 1-2 min in a repeated manner is of high concern in terms of consumer health. It was found that the service terms of melamine ware under microwave heating were drastically reduced, by more than 10-fold, as compared with the service terms under conventional heating. Hence, it is strongly recommended that manufacturers of MF articles provide instructions for use, e.g. "Do not use in microwave", which should be clearly visible to consumers and not easily detachable.


Formation of disulfide bond in p53 correlates with inhibition of DNA binding and tetramerization.
The p53 tumor suppressor protein is susceptible to oxidation, which prevents it from binding to its DNA response element. The goal of the current research was to determine the nature of the cysteine residue thiol oxidation that prevents p53 from binding its DNA target and its effect on p53 structure. Recombinant p53, purified in the presence of the reducing agent dithiothreitol (DTT), contains five free thiol groups on the surface of the protein. In the absence of DTT, p53 contains only four thiol groups, indicating that an average of one surface thiol group is readily susceptible to oxidation. Sulfite-mediated disulfide bond cleavage followed by reaction with 2-nitro-5-thiosulfobenzoate showed that oxidized p53 contains a single disulfide bond per monomer. By atomic force microscopy, we determined that reduced p53 binds to a double-stranded DNA containing the p53 promoter element of the MDM2 gene. The DNA-bound reduced p53 has an average cross-sectional diameter of 8.61 nm and a height of 4.12 nm. The amount of oxidized p53 that bound to the promoter element was ninefold lower, and it has an 18% larger average cross-sectional diameter. Electromobility shift assays showed that binding of oxidized p53 to DNA was enhanced upon addition of DTT, indicating that oxidation is reversible. The possibility that oxidized p53 contained significant amounts of sulfenic (-SOH), sulfinic (-SO2H), or sulfonic acid (-SO3H) was ruled out. Gel filtration chromatography indicated that oxidation increases the percentage of p53 monomers and high-molecular-weight oligomers (>1,000 kDa) relative to tetrameric p53. Protein modeling studies suggest that a mixed disulfide glutathione adduct on Cys182 could account for the observed stoichiometry of oxidized thiols and structural changes. The glutathione adduct may prevent proper helix-helix interaction within the DNA binding domain and contribute to tetramer dissociation.


A Blockchain Implementation Prototype for the Electronic Open Source Traceability of Wood along the Whole Supply Chain.
This is the first work to introduce the use of blockchain technology for the electronic traceability of wood from standing tree to final user. Infotracing integrates the information related to the product quality with those related to the traceability [physical and digital documents (Radio Frequency IDentification-RFID-architecture)] within an online information system whose steps (transactions) can be made safe to evidence of alteration through the blockchain. This is a decentralized and distributed ledger that keeps records of digital transactions in such a way that makes them accessible and visible to multiple participants in a network while keeping them secure without the need of a centralized certification organism. This work implements a blockchain architecture within the wood chain electronic traceability. The infotracing system is based on RFID sensors and open source technology. The entire forest wood supply chain was simulated from standing trees to the final product passing through tree cutting and sawmill process. Different kinds of Internet of Things (IoT) open source devices and tags were used, and a specific app aiming the forest operations was engineered to collect and store in a centralized database information (e.g., species, date, position, dendrometric and commercial information).


Primary central nervous system lymphoma in Japan: changes in clinical features, treatment, and prognosis during 1985-2004.
We have conducted nationwide surveys of primary central nervous system lymphoma (PCNSL) treated since 1985. In the present study, we newly collected data between 2000 and 2004 and investigated changes in clinical features and outcome over time. A total of 739 patients with histologically proven PCNSL under going radiotherapy were analyzed. Seventeen institutions were surveyed, and data on 131 patients were collected. These data were compared with updated data that were previously obtained for 466 patients treated during 1985-1994 and 142 patients treated during 1995-1999. Recent trends toward decrease in male/female ratio, increase in aged patients, and increase in patients with multiple lesions were seen. Regarding treatment, decrease in attempts at surgical tumor removal and increases in use of systemic chemotherapy and methotrexate (MTX)-containing regimens were observed. The median survival time was 18, 29, and 24 months for patients seen during 1985-1994, 1995-1999, and 2000-2004, respectively, and the respective 5-year survival rates were 15%, 30%, and 30%. In groups seen during 1995-1999 and during 2000-2004, patients who received systemic or MTX-containing chemotherapy had better prognosis than those who did not. Multivariate analysis of all patients seen during 1985-2004 suggested the usefulness of MTX-containing chemotherapy as well as the importance of age, lactate dehydrogenase level, and tumor multiplicity as prognostic factors. Thus, this study revealed several notable changes in clinical features of PCNSL patients. The prognosis improved during the last 10 years. Advantage of radiation plus chemotherapy, especially MTX-containing chemotherapy, over radiation alone was suggested.


Identification and characterization of the major phosphorylation sites of the B-type natriuretic peptide receptor.
C-type natriuretic peptide (CNP) is a newly discovered factor that stimulates vasorelaxation and inhibits cell proliferation. Natriuretic peptide receptor-B (NPR-B) is the primary signaling molecule for CNP. Recently, the guanylyl cyclase activity of NPR-B was shown to correlate with its phosphorylation state, and it was suggested that receptor dephosphorylation is a mechanism of desensitization. We now report the identification and characterization of the major NPR-B phosphorylation sites. Mutagenesis and comigration studies using synthetic phosphopeptides were employed to identify five residues (Ser-513, Thr-516, Ser-518, Ser-523, and Ser-526) within the kinase homology domain that are phosphorylated when NPR-B is expressed in human 293 cells. Mutation of any of these residues to alanine reduced the receptor's phosphorylation state and CNP-dependent guanylyl cyclase activity. The reductions were not explained by decreases in receptor protein level as indicated by immunoblot analysis and determinations of cyclase activity in the absence of CNP or in the presence of detergent. Elimination of all of the phosphorylation sites resulted in a completely dephosphorylated receptor whose CNP-dependent cyclase activity was decreased by >90%. However, unlike NPR-A, the dephosphorylated receptor was not completely unresponsive to hormone. Finally, two additional residues (Gly-521 and Ser-522) were identified that when mutated to alanine reduced the overall phosphorylation state and hormone responsiveness of the receptor without abolishing the phosphorylation of a specific site. These data indicate that phosphorylation of the kinase homology domain is a critical event in the regulation of NPR-B.


Mice infected with Mycobacterium tuberculosis are resistant to secondary infection with SARS-CoV-2.
Mycobacterium tuberculosis (Mtb) and SARS-CoV-2 (CoV2) are the leading causes of death due to infectious disease. Although Mtb and CoV2 both cause serious and sometimes fatal respiratory infections, the effect of Mtb infection and its associated immune response on secondary infection with CoV2 is unknown. To address this question we applied two mouse models of COVID19, using mice which were chronically infected with Mtb. In both model systems, Mtb-infected mice were resistant to secondary CoV2 infection and its pathological consequences, and CoV2 infection did not affect Mtb burdens. Single cell RNA sequencing of coinfected and monoinfected lungs demonstrated the resistance of Mtb-infected mice is associated with expansion of T and B cell subsets upon viral challenge. Collectively, these data demonstrate that Mtb infection conditions the lung environment in a manner that is not conducive to CoV2 survival. Mycobacterium tuberculosis (Mtb) and SARS-CoV-2 (CoV2) are distinct organisms which both cause lung disease. We report the surprising observation that Mtb-infected mice are resistant to secondary infection with CoV2, with no impact on Mtb burden and resistance associating with lung T and B cell expansion.


Preoperative administration of propranolol reduced the surgical risks of PHACES syndrome in a 14-month-old girl.
PHACES syndrome is an uncommon neurocutaneous disorder first identified in 1996. Patients with PHACES syndrome often require surgical treatment for their anomalies, including intracranial vasculopathy, coarctation/interruption of the aorta, intracardiac defects, glaucoma/cataract and sternal defects. Risk factors associated with the symptoms of intraoperative/perioperative management include ischaemic stroke due to the cerebral vasculopathy, airway obstruction due to the subglottic/tracheal haemangiomas and massive bleeding due to the large haemangiomas. Recently, propranolol is considered as first-line therapy for patients with infantile haemangiomas (IHs). However, until now, there have been no reported cases of PHACES syndrome treated by propranolol to reduce the surgical risks associated with IH. In this report, we describe a case of a 14-month-old Japanese girl with PHACES syndrome treated by propranolol for IH before surgical closure of the ventricular septum defect. Oral administration of propranolol was effective in decreasing the size of IH, leading to the uneventful perioperative course.


Non-Negative Matrix Factorization for Drug Repositioning: Experiments with the repoDB Dataset.
Computational methods for drug repositioning are gaining mainstream attention with the availability of experimental gene expression datasets and manually curated relational information in knowledge bases. When building repurpos-ing tools, a fundamental limitation is the lack of gold standard datasets that contain realistic true negative examples of drug-disease pairs that were shown to be non-indications. To address this gap, the repoDB dataset was created in 2017 as a first of its kind realistic resource to benchmark drug repositioning methods - its positive examples are drawn from FDA approved indications and negatives examples are derivedfrom failed clinical trials. In this paper, we present the first effort for repositioning that directly tests against repoDB instances. By using hand-curated drug-disease indications from the UMLS Metathesaurus and automatically extracted relations from the SemMedDB database, we employ non-negative matrix factorization (NMF) methods to recover repoDB positive indications. Among recoverable approved indications, our NMF methods achieve 96% recall with 80% precision providing further evidence that hand-curated knowledge and matrix completion methods can be exploited for hypothesis generation.


Associations of Coffee Drinking and Cancer Mortality in the Cancer Prevention Study-II.
Background: Associations of coffee consumption with cancer mortality are inconsistent for many types of cancer, and confounding by smoking is an important concern.Methods: Cox proportional hazards regression was used to estimate multivariable-adjusted HRs for coffee consumption associated with death from all cancers combined and from specific cancer types among 922,896 Cancer Prevention Study-II participants ages 28-94 years who completed a four-page questionnaire and were cancer free at baseline in 1982.Results: During follow-up through 2012, there were 118,738 cancer-related deaths. There was a nonlinear association between coffee consumption and all-cancer death among current smokers and former smokers and no association among never smokers. Among nonsmokers, a 2 cup/day increase in coffee consumption was inversely associated with death from colorectal [HR = 0.97; 95% confidence interval (CI) 0.95-0.99], liver [HR = 0.92; 95% CI, 0.88-0.96], and female breast (HR = 0.97; 95% CI, 0.94-0.99) cancers, and positively associated with esophageal cancer-related death (HR = 1.07; 95% CI, 1.02-1.12). For head and neck cancer, a nonlinear inverse association was observed starting at 2-3 cups per day (HR = 0.72; 95% CI, 0.55-0.95), with similar associations observed at higher levels of consumption.Conclusions: These findings are consistent with many other studies that suggest coffee drinking is associated with a lower risk of colorectal, liver, female breast, and head and neck cancer. The association of coffee consumption with higher risk of esophageal cancer among nonsmokers in our study should be confirmed.Impact: These results underscore the importance of assessing associations between coffee consumption and cancer mortality by smoking status. Cancer Epidemiol Biomarkers Prev; 26(10); 1477-86. ©2017 AACR.


Are IVC filters required in combat support hospitals?
Haemorrhagic shock from traumatic injuries is now often treated using a damage control resuscitation strategy that transfuses packed red blood cells, plasma and platelets in a 1:1:1 ratio, early use of activated recombinant factor VII and transfusion of fresh whole blood. These therapies are aimed at promoting thrombosis in injured vessels. Such patients are at high risk for thrombotic complications and thromboprophylaxis is necessary, but frequently impossible to use in the early phase of care. We describe the case of an Afghan civilian worker who suffered a vertical shear pelvic fracture with massive bleeding in a pedestrian/truck collision that was treated with a damage control resuscitation strategy, and who later suffered a severe pulmonary embolus. The potential use of a temporary inferior vena cava [IVC] filters is discussed. Care providers and policy makers must recognize that the increased use of prothrombotic strategies of resuscitation will likely increase the incidence of thrombotic complications in the high risk population of severely injured patients in combat support hospitals. Monitoring the incidence of these complications and development of strategies for prevention and treatment are required to avoid undermining the positive outcomes of damage control resuscitation. These strategies could include supplying combat support hospitals with the equipment and training necessary for placement of temporary IVC filters under fluoroscopic guidance.


Synchytrium endobioticum, the potato wart disease pathogen.
Potato wart disease is considered one of the most important quarantine pests for cultivated potato and is caused by the obligate biotrophic chytrid fungus Synchytrium endobioticum. This review integrates observations from early potato wart research and recent molecular, genetic, and genomic studies of the pathogen and its host potato. Taxonomy, epidemiology, pathology, and formation of new pathotypes are discussed, and a model for molecular S. endobioticum-potato interaction is proposed. Currently classified as kingdom: Fungi, phylum: Chytridiomycota, class: Chytridiomycetes, order: Chytridiales, family: Synchytriaceae, genus: Synchytrium, species: Synchytrium endobioticum, there is strong molecular support for Synchytriaceae to be transferred to the order Synchytriales. Solanum tuberosum is the main host for S. endobioticum but other solanaceous species have been reported as alternative hosts. It is not known if these alternative hosts play a role in the survival of the pathogen in (borders of) infested fields. Disease symptoms on potato tubers are characterized by the warty cauliflower-like malformations that are the result of cell enlargement and cell multiplication induced by the pathogen. Meristematic tissue on tubers, stolons, eyes, sprouts, and inflorescences can be infected while the potato root system seems to be immune. For S. endobioticum over 40 pathotypes, which are defined as groups of isolates with a similar response to a set of differential potato varieties, are described. Pathotypes 1(D1), 2(G1), 6(O1), and 18(T1) are currently regarded to be most widespread. However, with the current differential set other pathogen diversity largely remains undetected. A single effector has been described for S. endobioticum (AvrSen1), which is recognized by the potato Sen1 resistance gene product. This is also the first effector that has been described in Chytridiomycota, showing that in this fungal division resistance also fits the gene-for-gene concept. Although significant progress was made in the last decade in mapping wart disease resistance loci, not all resistances present in potato breeding germplasm could be identified. The use of resistant varieties plays an essential role in disease management.


Mouse hematopoietic cell-targeted STAT3 deletion: stem/progenitor cell defects, mitochondrial dysfunction, ROS overproduction, and a rapid aging-like phenotype.
Nuclear transcription factor Stat3 is important for proper regulation of hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) proliferation, survival, and cytokine signaling responses. A new, noncanonical role for Stat3 in mitochondrial function has been discovered recently. However, there is little information on the role(s) of mitochondrial Stat3 in HSC/HPC function, especially potential effects of Stat3/mitochondrial dysregulation in human diseases. We investigated hematopoietic cell-targeted deletion of the STAT3 gene in HSCs/HPCs with a focus on mitochondrial function. We found that STAT3(-/-) mice, which have a very shortened lifespan, dysfunctional/dysregulated mitochondrial function and excessive reactive oxygen species production in HSCs/HPCs that coincides with pronounced defects in function. These animals have a blood phenotype with similarities to premature aging and to human diseases of myelodysplastic syndrome and myeloproliferative neoplasms such as erythroid dysplasia, anemia, excessive myeloproliferation, and lymphomyeloid ratio shifts. We show herein that the lifespan of STAT3(-/-) animals is lengthened by treatment with a reactive oxygen species scavenger, which lessened the severity of the blood phenotype. These data suggest a need for more detailed studies of role(s) of Stat3 in HSC/HPC mitochondrial function in human diseases and raise the idea that mitochondrial Stat3 could be used as a potential therapeutic target.


Vortex and air assisted liquid-liquid microextraction as a sample preparation method for high-performed liquid chromatography determinations.
A novel, simple and sensitive method based on vortex and air assisted liquid-liquid microextraction (VAALLME) technique coupled with high-performance liquid chromatography (HPLC) has been developed for quantitative analysis of β-naphthol, naphthalene and anthracene as model analytes. Unlike the dispersive liquid-liquid microextraction (DLLME), dispersive solvent and centrifuging step were eliminated in proposed technique. In this technique, extraction solvent was dispersed into the aqueous sample solution by using vortex. Phase separation was achieved via motion of air bubbles from the bottom to top of the extraction tube, which promoted the analytes transfer into the supernatant organic phase. Influential parameters on the extraction efficiency such as type and volume of extraction solvent, salt type and its concentration, vortex and aeration times, and sample pH were evaluated and optimized. The calibration curves showed good linearity (r(2)>0.9947) and precision (RSD<5.0%) in the working concentration ranges. The limit of detection (LOD) for β-naphthol, naphthalene and anthracene were 10, 5.0 and 0.5 ng mL(-1), respectively. The recoveries were in the range of 97.0-102.0% with RSD values ranging from 2.2 to 5.2%.


[Probable epitopes of adenovirus capsid proteins].
The hydrophilicity and flexibility patterns of two capsid proteins of type 2 human adenovirus (hexon and fiber) were obtained. Several sites with maximal hydrophilicity and flexibility were revealed; their correlation was partly established. The role of these sites in the formation of adenoviral capsid protein epitopes is discussed.


In-situ temperature-controllable shear flow device for neutron scattering measurement--an example of aligned bicellar mixtures.
We have designed and constructed a temperature-controllable shear flow cell for in-situ study on flow alignable systems. The device has been tested in the neutron diffraction and has the potential to be applied in the small angle neutron scattering configuration to characterize the nanostructures of the materials under flow. The required sample amount is as small as 1 ml. The shear rate on the sample is controlled by the flow rate produced by an external pump and can potentially vary from 0.11 to 3.8 × 10(5) s(-1). Both unidirectional and oscillational flows are achievable by the setting of the pump. The instrument is validated by using a lipid bicellar mixture, which yields non-alignable nanodisc-like bicelles at low T and shear-alignable membranes at high T. Using the shear cell, the bicellar membranes can be aligned at 31 °C under the flow with a shear rate of 11.11 s(-1). Multiple high-order Bragg peaks are observed and the full width at half maximum of the "rocking curve" around the Bragg's condition is found to be 3.5°-4.1°. It is noteworthy that a portion of the membranes remains aligned even after the flow stops. Detailed and comprehensive intensity correction for the rocking curve has been derived based on the finite rectangular sample geometry and the absorption of the neutrons as a function of sample angle [See supplementary material at http://dx.doi.org/10.1063/1.4908165 for the detailed derivation of the absorption correction]. The device offers a new capability to study the conformational or orientational anisotropy of the solvated macromolecules or aggregates induced by the hydrodynamic interaction in a flow field.


Biochemical and genetic analysis of hydrogen metabolism in Escherichia coli: the hydB gene.
Production of active hydrogenase by Escherichia coli requires several gene products. One of the essential genes, hydB, is encoded by a DNA fragment of approximately 1.0 kilobase. The hydB gene produced a protein with an apparent molecular weight of 32,000. The hydB gene was transcribed only under anaerobic conditions. Oxygen and nitrate repressed transcription of this gene. hydB gene transcription also required sigma 60, the product of the rpoN gene.


Prevalence and factors associated with the coexistence of overweight/obesity and anaemia among women of reproductive age in Guinea.
To determine the prevalence and associated factors of the coexistence of overweight or obesity (OWOB) and anaemia among non-pregnant Guinean women aged 15-49 years. The analysis was performed using data from the 2018 Guinean Demographic and Health Survey. Multivariate logistic regression was used to identify factors associated with the coexistence of OWOB and anaemia (OWOB + anaemia) among non-pregnant Guinean women. Guinea. A total of 4783 non-pregnant women aged 15-49 years with valid data on the nutritional status (BMI and Hb level) were included in the analysis. The prevalence of coexistence of OWOB and anaemia among non-pregnant women was 11·16 % (95% CI: 10·05, 12·37). The following variables were associated with OWOB + anaemia in multivariate models (adjusted OR (AOR) 95% CI): higher wealth index (AOR = 4·69; 95% CI: 2·62, 8·39), middle wealth index (AOR = 1·96; 95% CI: 1·31, 2·93), four or more antenatal visits (AOR = 1·62; CI: 1·16, 2·28), having four or more children (AOR = 2·47; 95% CI: 1·37, 4·43) and the rural areas (AOR = 0·59; 95% CI: 0·37, 0·95). The current study's findings reveal that OWOB + anaemia concerned one-tenth of non-pregnant women. Associated factors were household wealth index, multiparity, antenatal visits and rural areas. Thus, there is a need to design specific interventions to prevent the double burden of malnutrition among women of reproductive age. Interventions should include promoting physical exercise, family planning, healthy eating and raising awareness of behavioural change.


[Role of essential fatty acids in trophometabolic interactions in the freshwater ecosystems (a review)].
Polyunsaturated fatty acids (PUFA) of omega3 family are of crucial physiological importance for the most animals and they are an essential and deficient component of human nutrition. These compounds are most effectively synthesized by some groups of algae, hence, aquatic ecosystems are considered to be the main source of these PUFA for human nutrition. Factors controlling the content and distribution of omega3 PUFA in freshwater organisms of basic trophic levels and determined PUFA final production in freshwater ecosystems are considered in the review. PUFA biosynthesis is known to be tightly related to basic fatty acid metabolic pathways. Hence, fatty composition and the PUFA content of major freshwater hydrobiont groups, including bacteria, algae, invertebrates and vertebrates, and environmental and population age effects are described. The peculiarities of PUFA transfer between organisms of various trophic levels are discussed. The essential omega3 PUFA is one of the important parameter of food quality of aquatic consumers and they can determine the rate of energy and matter transfer between producers and primary consumers and, as a result, in a whole freshwater food chain. Analysis of PUFA content and its regulation in biomass of various fish populations indicates that freshwater ecosystems are of the same value in respect of PUFA sources as marine ecosystems. Despite the great practical importance, the studies focused on production and whole pools of omega3 PUFA in different freshwater ecosystems are still scarce and need to be continued.


Changes in kinematic chain dynamics between calcaneal pronation/supination and shank rotation during load bearing associated with ankle position during plantar and dorsiflexion.
[Purpose] This study aimed to elucidate the dynamics of the kinematic chain of shank rotation accompanying calcaneal pronation/supination during weight-bearing changes associated with ankle positions during plantar/dorsiflexion and whether this biomechanical phenomenon is affected by age. [Participants and Methods] The study included 54 participants (108 legs, 25 young and 29 old participants). A 3-dimensional motion analysis system measured the calcaneal pronation/supination and the shank rotation angles during pronation/supination of the foot when upright. The kinematic chain ratio was defined as the linear regression coefficient (shank rotation angle/calcaneal pronation/supination angle). The kinematic chain ratio was measured during plantar flexion, in an intermediate position, and dorsiflexion. [Results] Significant differences in the kinematic chain ratio were related to ankle position but not age. The mean kinematic chain ratio in all participants was 0.9 ± 0.3 for plantar flexion, 1.0 ± 0.2 for an intermediate position, and 1.3 ± 0.4 for dorsiflexion, showing significant differences between the 3 ankle positions. [Conclusion] During dorsiflexion, the long axis of the shank and that of the subtalar joint are nearly parallel; thus, shank rotation increases (larger kinematic chain ratio). During plantar flexion, a larger angle is created; thus, shank rotation decreases (smaller kinematic chain ratio). When analyzing the kinematic chain between calcaneal pronation/supination and shank rotation, it is essential to consider the ankle position during plantar/dorsiflexion.


Elevated B-type natriuretic peptide is associated with increased in-hospital mortality or cardiac arrest in patients undergoing implantable cardioverter-defibrillator implantation.
The implantable cardioverter-defibrillator (ICD) is the most effective treatment for preventing arrhythmic deaths in patients with heart failure, but periprocedural complications, including in-hospital mortality or cardiac arrest, may occur, and little is known about risk factors. We asked whether elevated B-type natriuretic peptide (BNP) level is associated with increased risk of in-hospital mortality or cardiac arrest in patients undergoing ICD implantation. From the National Cardiovascular Data Registry ICD Registry, we identified 53 198 patients who received ICD implants and underwent preoperative BNP measurement from 2006 to 2008. The patients were categorized into 4 groups by BNP levels (<100, 100 to <300, 300 to <1000, and ≥1000 pg/mL). Complication rates were compared among groups, and odds ratios for in-hospital mortality or cardiac arrest were estimated by multiple hierarchical logistic regressions. There were 2952 complications reported, including 510 in-hospital deaths and 365 cardiac arrests. The rate of in-hospital mortality or cardiac arrest significantly increased with elevated BNP level (P<0.001). The adjusted odds ratios of in-hospital mortality or cardiac arrest were statistically significant in all 3 higher BNP groups [odds ratio (95% CI), 1.99 (1.17 to 3.39), 2.49 (1.50 to 4.13), and 4.25 (2.57 to 7.06) in the second, third, and fourth groups using <100 as reference]. Among subgroups, the association was more significant in men, patients with renal dysfunction, and patients undergoing biventricular ICD implantation. Elevated BNP level was significantly associated with increased risk of in-hospital mortality or cardiac arrest in patients undergoing ICD implant. Strategies aimed at reducing preprocedural BNP or creating systems to manage procedural risk merit further investigation.


P2X2/3 and P2X3 receptors contribute to the metaboreceptor component of the exercise pressor reflex.
The exercise pressor reflex is due to activation of thin fiber afferents within contracting muscle. These afferents are in part stimulated by ATP activation of purinergic 2X (P2X) receptors during contraction. Which of the P2X receptors contribute to the reflex is unknown; however, P2X2/3 and P2X3 receptor subtypes are good candidates because they are located on thin fiber afferents and are involved in sensory neurotransmission. To determine if P2X2/3 and P2X3 receptors evoke the metabolic component of the exercise pressor reflex, we examined the effect of two P2X2/3 and P2X3 antagonists, A-317491 (10 mg/kg) and RO-3 (10 mg/kg), on the pressor response to injections of α,β-methylene ATP (α,β-MeATP; 50 μg/kg), freely perfused static contraction, contraction of the triceps surae muscles while the circulation was occluded, and postcontraction circulatory occlusion in decerebrate cats. We found that the antagonists reduced the pressor response to α,β-MeATP injection (before Δ 20 ± 3 mmHg; drug Δ 11 ± 3 mmHg; P < 0.05), suggesting the antagonists were effective in blocking P2X2/3 and P2X3 receptors. P2X2/3 and P2X3 receptor blockade reduced the pressor response to freely perfused contraction (before Δ 33 ± 5 mmHg; drug Δ 15 ± 5 mmHg; P < 0.05), contraction with the circulation occluded (before Δ 52 ± 7 mmHg; drug Δ 20 ± 4 mmHg; P < 0.05), and during postcontraction circulatory occlusion (before Δ 15 ± 1 mmHg; drug Δ 5 ± 1 mmHg; P < 0.05). Our findings suggest that P2X2/3 and P2X3 receptors contribute to the metabolic component of the exercise pressor reflex in decerebrate cats.


1,3-Substituted β-Carboline Derivatives as Potent Chemotherapy for the Treatment of Cystic Echinococcosis.
Echinococcosis is a global public health issue that generally occurs in areas with developed animal husbandry. In search of safe and effective therapeutic agents against echinococcosis, we designed and synthesized new 1,3-substituted β-carboline derivatives based on harmine. Among them, compounds 1a, 1c, and 1e displayed potent inhibitory activity against Echinococcus granulosus in vitro, significantly better than albendazole and harmine. The morphological detection revealed that 1a, 1c, and 1e significantly changed the ultrastructure of Echinococcus granulosus protoscolices (PSCs). Furthermore, pharmacokinetic studies suggested that 1a possessed a better metabolic property. Encouragingly, 1a exhibited a highest cyst inhibition rate as 76.8% in vivo and did not display neurotoxicity in mice. Further mechanistic research illustrated that 1a has the potential to induce autophagy in PSCs, which may be responsible for the therapeutic effect of the drugs. Together, 1a could be a promising therapeutic agent against echinococcosis, warranting further study.


Efficacy of Recombinant Human Soluble Thrombomodulin in Treating Disseminated Intravascular Coagulation Complicating Allogeneic Hematopoietic Stem Cell Transplantation.
The prognosis for patients who experience hemostatic complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is poor. However, no report has investigated disseminated intravascular coagulation (DIC) caused by the complications of allo-HSCT without infection. Recombinant human soluble thrombomodulin (rhTM) was used to treat 12 episodes of DIC (n = 10; group 1) caused by allo-HSCT complications such as acute graft-versus-host disease (aGVHD) or thrombotic microangiopathy (TMA), and the clinical outcomes were compared with those of historical controls (n = 9; group 2) treated for DIC without rhTM. In group 1, the mean DIC score was significantly improved after using rhTM. Fibrinogen degeneration product (FDP), C-reactive protein (CRP), and the inflammatory cytokine high-mobility group box 1 (HMGB1) were also significantly decreased. Serial changes from the baseline values of platelet counts and levels of FDP were significantly better in group 1 than in group 2. The recovery rate from DIC was significantly higher in group 1 than in group 2. These findings suggest that rhTM is effective against both DIC and systemic inflammatory complications after allo-HSCT.


[Clinical application of directional catheter-mediated atherectomy in patients with ischaemic-form diabetic foot syndrome].
The authors share their experience gained with the device designed for directional catheter-mediated atherectomy SilverHawk (eV3, U.S.A.) used as an alternative to the conventional procedure of balloon angioplasty and stenting in patients presenting with an ischaemic form of the diabetic foot syndrome. A conclusion was drawn on feasibility of directional catheter-mediated atherectomy in management of diabetic patients presenting with occlusive and stenotic lesions of lower-limb arteries.


Identification of reactive toxicants: structure-activity relationships for amides.
A diverse series of amides were evaluated for aquatic toxicity (IGC(50)) assessed in the Tetrahymena pyriformis population growth impairment assay and for reactivity (EC(50)) with the model soft nucleophile thiol in the form of the cysteine residue of the tripeptide glutathione. All alkylamides along with some halo-substituted amides are well predicted by the simple hydrophobicity (log K (ow))-electrophilicity (E (lumo)) response-surface model [log(IGC(-1) (50)) = 0.45(log K (ow)) - 0.342(E (lumo)) - 1.11]. However, 2-halo amides with the halogen at the end of the molecule and alpha,beta-unsaturated primary amides are among those derivatives identified as being more toxic than predicted by the model. Amides, which exhibit excess toxicity, were capable of forming covalent bonds through an S(N)2 displacement or a Michael addition. Moreover, only those amides exhibiting excess toxicity were reactive with thiol, suggesting that the reactivity with model nucleophiles such as the thiol group may provide a means of accurately defining reactive toxicants.


Phenylalanine Tolerance over Time in Phenylketonuria: A Systematic Review and Meta-Analysis.
In phenylketonuria (PKU), natural protein tolerance is defined as the maximum natural protein intake maintaining a blood phenylalanine (Phe) concentration within a target therapeutic range. Tolerance is affected by several factors, and it may differ throughout a person's lifespan. Data on lifelong Phe/natural protein tolerance are limited and mostly reported in studies with low subject numbers. This systematic review aimed to investigate how Phe/natural protein tolerance changes from birth to adulthood in well-controlled patients with PKU on a Phe-restricted diet. Five electronic databases were searched for articles published until July 2020. From a total of 1334 results, 37 articles met the eligibility criteria (n = 2464 patients), and 18 were included in the meta-analysis. The mean Phe (mg/day) and natural protein (g/day) intake gradually increased from birth until 6 y (at the age of 6 months, the mean Phe intake was 267 mg/day, and natural protein intake was 5.4 g/day; at the age of 5 y, the mean Phe intake was 377 mg/day, and the natural protein intake was 8.9 g/day). However, an increase in Phe/natural protein tolerance was more apparent at the beginning of late childhood and was >1.5-fold that of the Phe tolerance in early childhood. During the pubertal growth spurt, the mean natural protein/Phe tolerance was approximately three times higher than in the first year of life, reaching a mean Phe intake of 709 mg/day and a mean natural protein intake of 18 g/day. Post adolescence, a pooled analysis could only be performed for natural protein intake. The mean natural protein tolerance reached its highest (32.4 g/day) point at the age of 17 y and remained consistent (31.6 g/day) in adulthood, but limited data were available. The results of the meta-analysis showed that Phe/natural protein tolerance (expressed as mg or g per day) increases with age, particularly at the beginning of puberty, and reaches its highest level at the end of adolescence. This needs to be interpreted with caution as limited data were available in adult patients. There was also a high degree of heterogeneity between studies due to differences in sample size, the severity of PKU, and target therapeutic levels for blood Phe control.


Ear-canal reflectance, umbo velocity, and tympanometry in normal-hearing adults.
This study compares measurements of ear-canal reflectance (ECR) to other objective measurements of middle ear function including audiometry, umbo velocity (VU), and tympanometry in a population of strictly defined normal-hearing ears. Data were prospectively gathered from 58 ears of 29 normal-hearing subjects, 16 females and 13 males, aged 22 to 64 yr. Subjects met all of the following criteria to be considered as having normal hearing: (1) no history of significant middle ear disease; (2) no history of otologic surgery; (3) normal tympanic membrane on otoscopy; (4) pure-tone audiometric thresholds of 20 dB HL or better for 0.25 to 8 kHz; (5) air-bone gaps no greater than 15 dB at 0.25 kHz and 10 dB for 0.5 to 4 kHz; (6) normal, type-A peaked tympanograms; and (7) all subjects had two "normal" ears (as defined by these criteria). Measurements included pure-tone audiometry for 0.25 to 8 kHz, standard 226 Hz tympanometry, ECR for 0.2 to 6 kHz at 60 dB SPL using the Mimosa Acoustics HearID system, and umbo velocity (VU) for 0.3 to 6 kHz at 70 to 90 dB SPL using the HLV-1000 laser Doppler vibrometer (Polytec Inc). Mean power reflectance (|ECR|) was near 1.0 at 0.2 to 0.3 kHz, decreased to a broad minimum of 0.3 to 0.4 between 1 and 4 kHz, and then sharply increased to almost 0.8 by 6 kHz. The mean pressure reflectance phase angle (∠ECR) plotted on a linear frequency scale showed a group delay of approximately 0.1 msec for 0.2 to 6 kHz. Small significant differences were observed in |ECR| at the lowest frequencies between right and left ears and between males and females at 4 kHz. |ECR| decreased with age but reached significance only at 1 kHz. Our ECR measurements were generally similar to previous published reports. Highly significant negative correlations were found between |ECR| and VU for frequencies below 1 kHz. Significant correlations were also found between the tympanometrically determined peak total compliance and |ECR| and VU at frequencies below 1 kHz. The results suggest that middle ear compliance contributes significantly to the measured power reflectance and umbo velocity at frequencies below 1 kHz but not at higher frequencies. This study has established a database of objective measurements of middle ear function (ECR, umbo velocity, tympanometry) in a population of strictly defined normal-hearing ears. These data will promote our understanding of normal middle ear function and will serve as a control for comparison to similar measurements made in pathological ears.


Evaluation of complications and prognostic factors associated with administration of total parenteral nutrition in cats: 75 cases (1994-2001).
To determine frequency and types of complications, prognostic factors, and primary diseases affecting clinical outcome associated with administration of total parenteral nutrition (TPN) in cats. Retrospective study. 75 cats that received TPN for > or = 12 hours. Medical records were reviewed, and information was obtained on signalment, history, problems at initial evaluation, physical examination findings, weight and changes in weight while receiving TPN, duration in the hospital before initiation of TPN, the type of TPN catheter used, duration of TPN administration, and final diagnosis. Laboratory results obtained immediately prior to TPN and at 24 and 96 hours following initiation of TPN administration were compared. Reports of weight loss at initial evaluation, hyperglycemia at 24 hours, or diagnosis of chronic renal failure were significantly associated with increased mortality rate. Greater serum albumin concentrations prior to and at 96 hours following TPN administration were significantly associated with decreased mortality rate. Mechanical and septic complications were infrequent and not associated with increased mortality rate. Most cats had multiple diseases. The overall mortality rate was 52%; among 75 cats, 36 recovered, 23 were euthanatized, and 16 died as a result of their primary illness or complications associated with their illness. Results indicated high mortality rate in cats maintained onTPN that had multiple concurrent diseases associated with a poor prognosis. Indicators of poor prognosis included a history of weight loss, hyperglycemia at 24 hours following TPN administration, hypoalbuminemia, and chronic renal failure.


[Relation between diet protein and calciuria in children and adolescents with nephrolitiasis].
The objective was to evaluate the quality of diet and the relationship between protein diet and calciuria in children and adolescents with nephrolithiasis. Forty-nine children and adolescents (28 male and 21 female; 10.1 +/- 3.16 years old) with nephrolithiasis were included in study. Diet evaluation was performed over a 3 day period in order to determine nutrient consumption. The analysis of diets were carried out by DietWin Clínico 3.0 software. One 24-hour urine sample was collected for the measurement of calcium. Nutritional status was also assessed by Body Mass Index (BMI). The diet of patients containe insufficient energy and calcium. High levels of protein (69.64 +/- 16.42 gm), mainly animal source (65.81 +/- 11.45%) and low levels of calcium (500.95 +/- 284.64 mg) was observed (95%). Analysis of 24 hour urine samples revealed that 25.0% of the patients presented hypercalciuria. A positive correlation (r = 0.26680) between animal protein intake and calciuria was found, in opposite of vegetable protein and calciuria correlation (r = -0.2675). Animal protein of the diet has a significant effect in urinary excretion of calcium in patients with nephrolithiasis.


Pentoxifylline and Vitamin E Can Restrict Radiation Necrosis via Vascular Pathways, Experimental Study in an Animal Model.
Radiation necrosis (RN) is a long-term side effect of Gamma Knife stereotactic radiosurgery that may require surgical intervention. Pentoxifylline and vitamin E have previously been shown to be effective in the treatment of RN in the published literature, but there are no data on the prophylactic use of these molecules or, more importantly, whether prophylaxis is required. The iatrogenic RN model included 50 Sprague-Dawley rats of both sexes. There were 7 treatment subgroups established. Gamma-Plan 8.32 was used to plan after magnetic resonance scans were performed in a specially designed frame. The injection doses used in the treatment groups were vitamin E (30 mg/kg/day in a single dose) and pentoxifylline (50 mg/kg/day in 2 doses). Control magnetic resonance scans were performed at the end of a 16-week treatment, and the subjects were decapitated for pathological evaluations. The intensity of hypoxia - inducible factor 1α immunoreactivity is statistically significantly lower in the therapeutic vitamin E, prophylactic pentoxifylline and vitamin E, and therapeutic pentoxifylline and vitamin E groups than in the other groups. Similarly, the intensity of vascular endothelial growth factor immunoreactivity was reduced in the therapeutic vitamin E and prophylactic pentoxifylline and vitamin E treatment modality groups. When compared with other groups, the therapeutic pentoxifylline group had significantly fewer vascular endothelial growth factor-immunoreactive cells in the perinecrotic area, with an accompanying decreased contrast enhancement pattern. Both vitamin E and pentoxifylline are effective for the treatment and/or restriction of RN, either alone or in combination. The use of these molecules as a preventive measure did not outperform the therapeutic treatment.


Evidence that DNA-A of a geminivirus associated with severe cassava mosaic disease in Uganda has arisen by interspecific recombination.
Geminivirus isolates associated with the epidemic of severe cassava mosaic disease in Uganda were studied and compared with virus isolates from the part of Uganda outside the epidemic area, and with African cassava mosaic virus (ACMV) and East African cassava mosaic virus (EACMV). Isolates of a novel type [the Uganda variant (UgV)] were detected in severely affected plants from the epidemic area, whereas those from plants outside the epidemic area were typical of ACMV. The complete nucleotide sequences of DNA-A of UgV (2799 nt) and of a Tanzanian isolate of EACMV (2801 nt) were determined and are extremely similar, except for the coat protein (CP) gene. The CP gene of UgV has three distinct regions: the 5' 219 nt are 99% identical to EACMV (only 79% to ACMV); the following 459 nt are 99% identical to ACMV (75% to EACMV); and the 3' 93 nt are 98% identical to EACMV (76% to ACMV). UgV DNA-A therefore is considered to have arisen by interspecific recombination of EACMV and ACMV. Despite the hybrid nature of their CP, UgV isolates were indistinguishable from ACMV in tests with 20 monoclonal antibodies (MAbs), including seven which reacted with ACMV but not EACMV. The discontinuous epitopes detected by these seven MAbs must involve amino acids which lie in the central part of the CP (residues 74-226) and which differ in ACMV and EACMV. UgV isolates were detected in severely mosaic-affected plants from all 11 widely separated locations sampled. The probable role of recombination in geminivirus evolution in the short to medium term is discussed.


Cancer incidence and mortality in Portugal.
In this paper, we present estimates of national cancer incidence in Portugal in 1996-1998, predictions for the year 2000, and interpret the recent cancer mortality trends in light of observations from epidemiological research and risk factor patterns. In Portugal, national mortality data from vital statistics are available from 1960, while cancer registration has been mandatory since 1988, when three regional cancer registries covering the mainland of the Portuguese Republic were set up. Up until now, however, none of these registries has been able to produce data with an acceptable completeness of registration--hence this study. Mortality data from Portugal for 1996-1998 and incidence data for 1990-1995 from Vila Nova de Gaia (RVNG) (the most complete of the Portuguese cancer registries), 14 Italian registries and nine Spanish registries were assembled to produce the best possible estimates of numbers of incident cases for each age group and gender. A total of 19,880 new cancer cases are estimated to have been diagnosed among men in the year 2000, and nearly 17,000 new cancer cases in women. The most common cancer among Portuguese men in 2000 is cancer of the colorectum (3173 new cases), followed by cancers of the prostate (2973), lung (2611), stomach (2206) and urinary bladder (1360). In women, breast cancer is the most common cancer (4358) followed by cancers of the colorectum (2541), stomach (1494) and corpus uteri (1083). The overall age-standardised cancer mortality rate for men in Portugal increased steeply (1.4% annually) during the period 1988-1998, with prostate cancer (3.6% annually), colon and rectum (3.3%) and lung (2.4%) mostly contributing. Among women, the overall cancer mortality rate was stable (a non-significant decrease of approximately 0.2% per year). These remarkable results, particularly in males, demonstrate the need for a comprehensive national programme against cancer. Since the increasing epidemic of lung cancer (in men), as well as other tobacco-related cancers, is observed in Portugal, the important component of such a programme should be a nationwide tobacco control programme. Improving accessibility to highly effective diagnostic and treatment procedures for cancer in general and colorectal and prostatic cancers in particular should be a priority in the fight against cancer.


Neuroradiologic manifestations of COVID-19: what the emergency radiologist needs to know.
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a global pandemic with a wide spectrum of clinical signs and symptoms. Neurologic manifestations are relatively common, with severe cases often demonstrating striking findings on neuroimaging. Because the neuroradiologic findings may be the first evidence of COVID-19, the emergency radiologist has a critical role to play in not only the detection and management of the disease but also in the safety of other patients and hospital staff. Therefore, radiologists, especially those who specialize in emergency radiology, need to be aware of the neuroradiologic manifestations of COVID-19.


Uptake of galactose, ouabain and taurocholate into centrilobular and periportal enriched hepatocyte subpopulations.
Rat hepatocytes were isolated by a collagenase perfusion technique with subsequent subfractionation on Metrizamide gradients into subpopulations which have been designated band I and band II and are likely to be enriched with centrilobular and periportal cells, respectively. Band I was found to have a higher concentration of 5'-nucleotidase and band II a higher concentration of alcohol dehydrogenase. Furthermore, pretreatment of rats with phenobarbital led to higher cytochrome P-450 in the band I (centrilobular enriched) as compared to the band II (periportal enriched) subpopulations of hepatocytes. These data support their ascribed lobular origins. The uptake of a single concentration of galactose, ouabain and taurocholate into each of the two subpopulations was investigated until the concentration within the hepatocytes no longer increased. No difference was found in the uptake of [14C]galactose (25 mM) between the two hepatocyte subpopulations. However, the uptake of [3H]ouabain (125 microM) was greater in the centrilobular as compared to periportal enriched fraction of the hepatocytes. An even greater difference was found for the uptake of [3H]taurocholate (25 microM). The kinetics of taurocholate uptake were subsequently investigated. The Km for each subpopulation was 21 microM, while the Vmax of the centrilobular enriched fraction was 2.03 and that of the periportal enriched fraction was 1.57 nmol/min/mg of protein. These results show that there is a difference in uptake into hepatocytes of centrilobular and periportal origin for ouabain and taurocholate, but not for galactose.


The detection of hydromorphone in urine specimens with high morphine concentrations.
A previous study suggested that small amounts of morphine are metabolically converted to hydromorphone. In the present study, morphine positive urine specimens obtained from a postmortem laboratory and a random urinalysis program were tested for morphine, codeine, hydromorphone, hydrocodone, oxymorphone, and oxycodone to assess the possibility that small amounts of hydromorphone are produced from the metabolism of morphine. The opioids were analyzed by gas chromatography-mass spectrometry as their respective trimethylsilyl derivatives following solid phase extraction. The limit of detection for hydromorphone was 5 ng/mL. A total of 73 morphine positive urine specimens were analyzed, with morphine concentrations ranging from 131 to 297,000 ng/mL. Hydromorphone was present at a concentration > or =5 ng/mL in 36 of these specimens at concentrations ranging from 0.02% to 12% of the morphine concentration. Hydrocodone was not detected in these specimens at the assay detection limit of 25 ng/mL. These results support earlier work suggesting that the detection of hydromorphone in urine specimens does not necessarily mean that exogenous hydromorphone or hydrocodone was used.


[Pain and painkillers: 2. Biochemical components].
Besides the neurophysiological component of pain, subject of a previous article, biochemical components exist. Humorals, released in case of tissue damage and inflammation, cause among others vasodilatation, increased permeability of the blood vessels, itching and pain. Other endogenous biochemical products, among which endorphin beta, lessen the pain. It is also possible to further diminish the noxious (painful) action of the biochemical products with anti-biochemical medication.


Patients undergoing total laryngectomy: an at-risk population for 30-day unplanned readmission.
Patients undergoing total laryngectomy are at high risk for hospital readmission. Hospital readmissions are increasingly scrutinized because they are used as a metric of quality care and are subject to financial penalties. To determine the rate of, reasons for, and risk factors that predict 30-day unplanned readmission for patients undergoing total laryngectomy. Retrospective cohort study at a single academic tertiary referral medical center. The study population comprised 155 patients who underwent total laryngectomy with or without flap closure between January 2007 and December 2012 as either a primary treatment or salvage treatment for prior nonsurgical management. Total laryngectomy. Rate of 30-day unplanned readmission, readmission diagnoses, and risk factors for unplanned readmission. Univariable and multivariable logistic regression were performed to identify risk factors for unplanned readmission within 30 days of discharge. The 30-day unplanned readmission rate for patients following discharge after total laryngectomy was 26.5% (41 of 155). The most common readmission diagnoses were pharyngocutaneous fistula (27% of readmissions; n = 11) and stomal cellulitis (16% of readmissions; n = 7). The median time to unplanned readmission was 7 days. Thirty-four percent of readmissions (14 of 41) occurred within 3 days of discharge. Significant predictors of 30-day unplanned readmission on multivariable analysis were postoperative complication after discharge (odds ratio [OR], 11.50; 95% CI, 4.10-32.28), visit to the emergency department within 30 days after discharge (OR, 5.25; 95% CI, 1.84-14.99), salvage total laryngectomy (OR, 3.52; 95% CI, 1.56-13.12), and chyle fistula during the index hospitalization (OR, 5.25; 95% CI, 0.86-29.92). The discriminative ability of the model to predict unplanned readmission, as measured by the C statistic, was 0.88. Patients undergoing total laryngectomy are an at-risk patient population with a high rate of unplanned readmission within 30 days of discharge. By identifying the risk factors that predict 30-day unplanned readmission, these data can be used to design and implement quality-improvement interventions to decrease readmissions.


Learning to predict expression efficacy of vectors in recombinant protein production.
Recombinant protein production is a useful biotechnology to produce a large quantity of highly soluble proteins. Currently, the most widely used production system is to fuse a target protein into different vectors in Escherichia coli (E. coli). However, the production efficacy of different vectors varies for different target proteins. Trial-and-error is still the common practice to find out the efficacy of a vector for a given target protein. Previous studies are limited in that they assumed that proteins would be over-expressed and focused only on the solubility of expressed proteins. In fact, many pairings of vectors and proteins result in no expression. In this study, we applied machine learning to train prediction models to predict whether a pairing of vector-protein will express or not express in E. coli. For expressed cases, the models further predict whether the expressed proteins would be soluble. We collected a set of real cases from the clients of our recombinant protein production core facility, where six different vectors were designed and studied. This set of cases is used in both training and evaluation of our models. We evaluate three different models based on the support vector machines (SVM) and their ensembles. Unlike many previous works, these models consider the sequence of the target protein as well as the sequence of the whole fusion vector as the features. We show that a model that classifies a case into one of the three classes (no expression, inclusion body and soluble) outperforms a model that considers the nested structure of the three classes, while a model that can take advantage of the hierarchical structure of the three classes performs slight worse but comparably to the best model. Meanwhile, compared to previous works, we show that the prediction accuracy of our best method still performs the best. Lastly, we briefly present two methods to use the trained model in the design of the recombinant protein production systems to improve the chance of high soluble protein production. In this paper, we show that a machine learning approach to the prediction of the efficacy of a vector for a target protein in a recombinant protein production system is promising and may compliment traditional knowledge-driven study of the efficacy. We will release our program to share with other labs in the public domain when this paper is published.


Surface assembly and nanofabrication of 1,1,1-tris(mercaptomethyl)heptadecane on Au(111) studied with time-lapse atomic force microscopy.
The solution self-assembly of multidentate organothiols onto Au(111) was studied in situ using scanning probe nanolithography and time-lapse atomic force microscopy (AFM). Self-assembled monolayers (SAMs) prepared from dilute solutions of multidentate thiols were found to assemble slowly, requiring more than six hours to generate films. A clean gold substrate was first imaged in ethanolic media using liquid AFM. Next, a 0.01 mM solution of multidentate thiol was injected into the liquid cell. As time progressed, molecular-level details of the surface changes at different time intervals were captured by successive AFM images. Scanning probe based nanofabrication was accomplished using protocols of nanografting and nanoshaving with n-alkanethiols and a tridentate molecule, 1,1,1-tris(mercaptomethyl)heptadecane (TMMH). Nanografted patterns of TMMH could be inscribed within n-alkanethiol SAMs; however, the molecular packing of the nanopatterns was less homogeneous compared to nanopatterns produced with monothiolates. The multidentate molecules have a more complex assembly pathway than monothiol counterparts, mediated by sequential steps of forming S-Au bonds to the substrate.


Cytotoxic T lymphocyte responsiveness after resolution of chronic hepatitis B virus infection.
Clearance of the hepatitis B virus (HBV) during acute hepatitis is associated with a strong, polyclonal, multispecific cytotoxic T lymphocyte (CTL) response to the viral envelope, nucleocapsid and polymerase proteins that persists for decades after clinical recovery. In contrast, chronically infected patients usually fail to mount a strong CTL response to this virus. In this study we demonstrate that chronically infected patients who experience a spontaneous or interferon-induced remission develop a CTL response to HBV that is similar in strength and specificity to patients who have recovered from acute hepatitis. The results suggest that specific immunotherapeutic enhancement of the CTL response to HBV should be possible in chronically infected patients, and that it could lead to viral clearance in these individuals with resolution of chronic liver disease.


Next Generation Cancer Data Discovery, Access, and Integration Using Prizms and Nanopublications.
To encourage data sharing in the life sciences, supporting tools need to minimize effort and maximize incentives. We have created infrastructure that makes it easy to create portals that supports dataset sharing and simplified publishing of the datasets as high quality linked data. We report here on our infrastructure and its use in the creation of a melanoma dataset portal. This portal is based on the Comprehensive Knowledge Archive Network (CKAN) and Prizms, an infrastructure to acquire, integrate, and publish data using Linked Data principles. In addition, we introduce an extension to CKAN that makes it easy for others to cite datasets from within both publications and subsequently-derived datasets using the emerging nanopublication and World Wide Web Consortium provenance standards.


Lack of association between hepatitis C infection and development of AIDS-related lymphoma.
Hepatitis C virus (HCV) has been associated with various lymphoproliferative disorders, and a high prevalence (9%-32%) of chronic HCV infection has been demonstrated among patients with lymphoma. Dual coinfection by HIV and HCV has been demonstrated in approximately 40% of certain populations of HIV-infected individuals. Because of this high prevalence of coinfection by HIV and HCV, the known relations between HCV and lymphoproliferative disorders, and the association of HIV and B cell lymphoma, the potential association between chronic HCV and the development of AIDS-related lymphoma was examined. The prevalence of HCV infection in HIV-infected patients with lymphoma was compared with that in patients with AIDS, diagnosed on the basis of an illness other than lymphoma. Risk factors for HCV infection, overall, were also evaluated. Evidence of HCV infection was ascertained by assessing anti-HCV antibodies, and HCV RNA in serum. The study consisted of 99 homosexual/bisexual men with AIDS-related lymphoma, and 43 other AIDS patients. HCV infection was detected in 11 of 99 (11.1 %) men with lymphoma, and in 5 of 43 (11.6%) other AIDS patients. Further, in patients with AIDS-related lymphoma, no relation was found between HCV infection and lymphoma histology or site. History of use of injected illicit drugs was associated with a significantly elevated risk of HCV infection in the combined group of lymphoma and other AIDS patients. The current study demonstrates no relation between dual infection by HIV and HCV and subsequent increased risk of lymphoma.


Acknowledging the primacy of continuity of care experiences in midwifery education.
Continuity of midwifery care is the best maternity care model for women at any risk level, and there is a global imperative to improve access to midwifery-led care. However, diverse perspectives about how best to prepare graduates for working in midwifery continuity of care models persist. The continuity of care experience standard in Australia was anticipated to address this. To challenge the dearth of published information about the structures and processes in midwifery education programs by identifying: the educational value and pedagogical intent of the continuity of care experience; issues with the implementation, completion and assessment of learning associated with continuity of care experience; and discuss curriculum models that facilitate optimal learning outcomes associated with this experience. We discuss the primacy of continuity of care experience in midwifery education programs in Australia. The inclusion of continuity of care experience in midwifery programs in Australia became mandatory in 2010 requiring 20, however this number was reduced to 10 in 2014. Research has shown the beneficial outcomes of continuity of care experience to both students and women. Continuity of care experience builds mutual support and nurturing between women and students, fosters clinical confidence, resilience, and influences career goals. We require curriculum coherence with both structural and conceptual elements focusing on continuity of care experience. Education standards that preference continuity of care experience as the optimal clinical education model with measurable learning outcomes, and alignment to a whole of program philosophy and program learning outcomes is required.


Isolation and characterization of an Arabidopsis thaliana C-8,7 sterol isomerase: functional and structural similarities to mammalian C-8,7 sterol isomerase/emopamil-binding protein.
The yeast C-8,7 sterol isomerase contains a polyvalent high-affinity drug binding site similar to mammalian sigma receptors. Exogenously supplied sigma ligands inhibit sterol biosynthesis in yeast, demonstrating a pharmacological relationship between sigma ligand-binding and C-8,7 sterol isomerase activity. We report the isolation of an Arabidopsis thaliana C-8,7 sterol isomerase by functional complementation of the corresponding sterol mutant in yeast and its characterization by exposure to sigma ligands. The yeast erg2 mutant, which lacks the C-8,7 sterol isomerase gene and activity, was transformed with an Arabidopsis cDNA yeast expression library. Transformed colonies were selected for restoration of C-8,7 sterol isomerase activity (i.e. wild-type ergosterol production) by enhanced resistance to the antibiotic cycloheximide. Sterols produced in complemented lines were characterized by gas chromatography-mass spectroscopy (GC-MS). The full-length A. thaliana cDNA (pA.t.SI1) that complemented the erg2 mutation contains an open reading frame encoding a 21 kDa protein that shares 68% similarity and 35% amino acid identity to the recently isolated mouse C-8,7 sterol isomerase. The sigma ligands, haloperidol, ifenprodil and verapamil inhibited the production of ergosterol in wild-type Saccharomyces cerevisiae and in the erg2 mutant complemented with pA.t.SI1. Structural and biochemical similarities between the A. thaliana C-8,7 sterol isomerase and the mammalian emopamil-binding protein (EBP) are discussed.


Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis.
The epidemiology of bacterial meningitis has changed as a result of the widespread use of conjugate vaccines and preventive antimicrobial treatment of pregnant women. Given the significant morbidity and mortality associated with bacterial meningitis, accurate information is necessary regarding the important etiological agents and populations at risk to ascertain public health measures and ensure appropriate management. In this review, we describe the changing epidemiology of bacterial meningitis in the United States and throughout the world by reviewing the global changes in etiological agents followed by specific microorganism data on the impact of the development and widespread use of conjugate vaccines. We provide recommendations for empirical antimicrobial and adjunctive treatments for clinical subgroups and review available laboratory methods in making the etiological diagnosis of bacterial meningitis. Finally, we summarize risk factors, clinical features, and microbiological diagnostics for the specific bacteria causing this disease.


Electrocardiographic manifestations in acute methanol poisoning cannot predict mortality.
The aim of this retrospective observational case series was to determine electrocardiographic (ECG) manifestations in patients poisoned with methanol and see whether they could predict mortality. We also wanted to see whether there was an association between ECG changes and time elapsed between ingestion and treatment, age, sex, seizure, coma (Glasgow Coma Scale ≤8), arterial blood gas (ABG) parameters, and serum potassium levels on hospital admission. The study included 42 patients aged 31.14±12.5 years. Twenty-five survived and 17 died. Almost all patients had one or more abnormal ECG findings, including heart rate, rhythm, and conduction abnormalities. However, we found no significant difference between survivors and non-survivors. QTc interval did not correlate with time elapsed between ingestion and treatment, age, sex, seizure and coma, HCO3(-), or serum potassium level. Similarly, T waves showed no correlation with serum potassium. ECG abnormalities did not correlate with coma or seizure. Even though cardiotoxicity in methanol poisoning is high, none of the ECG abnormalities found in our study predicted mortality. This however does not rule out the need to routinely run ECG for cardiotoxicity in every single patient poisoned by methanol.


Improved cognitive outcomes with endovascular coiling of ruptured intracranial aneurysms: neuropsychological outcomes from the International Subarachnoid Aneurysm Trial (ISAT).
The International Subarachnoid Aneurysm Trial (ISAT) reported lower rates of death and disability with endovascular versus neurosurgical treatment of ruptured intracranial aneurysms. However, assessment of functional outcome was limited to the modified Rankin Scale, which is known to be insensitive to cognitive function. A neuropsychological substudy (N-ISAT) was therefore done in all recruits from 8 ISAT centers in the United Kingdom. Detailed neuropsychological assessment was performed at a 12-month follow-up visit. Impairment was defined as performance below the 5th percentile of the study population on at least 2 tests in >or=2 major cognitive domains. Analysis was restricted to patients who were not known to be otherwise disabled according to the modified Rankin Scale (ie, modified Rankin Scale 0 to 2). Of 836 patients randomized in ISAT in the 8 UK centers (411 allocated endovascular treatment versus 425 neurosurgery), 224 were dead or disabled before 12-month follow-up (78 allocated endovascular treatment versus 135 neurosurgery). Of the remaining 612 patients eligible for neuropsychological assessment, 137 (65 allocated endovascular treatment versus 72 neurosurgery) did not attend. Of the 474 nondisabled patients who were assessed, 152 (32.1%) had cognitive impairment. Patients with cognitive impairment had reduced self-reported health-related quality of life (P<0.001) in both treatment groups, but cognitive impairment was less common in those allocated endovascular treatment (70 of 262 versus 82 of 212 allocated neurosurgery, OR=0.58, 95% CI 0.38 to 0.87, P=0.0055). The incidence of epilepsy was also lower in the N-ISAT endovascular group (7 versus 18, OR=0.30, 0.11 to 0.77, P=0.005) but was independent of the effect on cognitive function. Cognitive impairment occurred in approximately one third of patients who were not otherwise disabled according to the modified Rankin Scale in N-ISAT and was more frequent in the neurosurgery group. These results have implications for management of ruptured intracranial aneurysms and more generally for interpretation of the outcomes of clinical trials that use the modified Rankin Scale.


Combined vitamin C and E supplementation during pregnancy for preeclampsia prevention: a systematic review.
The effect of combined vitamin C and E supplementation during pregnancy on the prevention of preeclampsia and major adverse infant outcomes has been reviewed. We searched MEDLINE and the Central Library of Controlled Trials of the Cochrane Library through August 2006 for relevant clinical trials. Interstudy heterogeneity was evaluated using the chi(2) statistic (Q statistic) test. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated with a fixed or random-effects model as appropriate. Four trials that collectively randomized 4680 pregnant women to either the combination of vitamin C and vitamin E or placebo were included in the analysis. There were no significant differences between the vitamin and placebo groups in the risk of preeclampsia, 11% versus 11.4%, RR 0.97 (95% CI 0.82-1.13), fetal or neonatal loss, 2.6% versus 2.3%, RR 1.10 (95% CI 0.78-1.57), or small for gestational age (SGA) infant, 20.6% versus 20%, RR 0.94 (95% CI 0.74-1.19). Although there was a higher risk for preterm birth in the vitamin group, 19.5% versus 18%, RR 1.07 (95% CI 0.96-1.20), this finding was not significant. Combined vitamin C and E supplementation during pregnancy does not reduce the risk of preeclampsia, fetal or neonatal loss, small for gestational age infant, or preterm birth. Such supplementation should be discouraged unless solid supporting data from randomized trials become available. Obstetricians & Gynecologists, Family Physicians After completion of this article, the reader should be able to recall that many methods have been used to prevent preeclampsia, state that increased oxidative stress has been postulated and many trials have used antioxidants to prevent the disease, and explain that MEDLINE analysis of the literature questions the use of vitamin C and E supplements.


[L-2-hydroxyglutaric aciduria, an error of metabolism].
The neurometabolic disorder L-2-hydroxyglutaric aciduria was recently shown to be due to a defect in L-2-hydroxyglutarate dehydrogenase. This FAD-linked enzyme catalyses the irreversible conversion of L-2-hydroxyglutarate to alpha-ketoglutarate. The formation of L-2-hydroxyglutarate results from a side-activity of mitochondrial L-malate dehydrogenase, the enzyme which normally catalyses the interconversion of oxaloacetate and L-malate, but which also catalyses the NADH-dependent conversion of alpha-ketoglutarate to L-2-hydroxyglutarate. Though very slow, this activity accounts for the in vivo formation of L-2-hydroxyglutarate. As the latter compound is most likely toxic, L-2-hydroxyglutarate dehydrogenase catalyses a metabolite repair reaction.


Pyrocatechol as a stabilizing agent for o-tolidine and o-dianisidine: a sensitive new method for HRP neurohistochemistry.
A new procedure for detecting HRP in nerve tissue is described which is based on the use of pyrocatechol to stabilize the oxidation products of o-tolidine and o-dianisidine in citric acid/ammonium acetate buffer of pH 4.85. In both cases the precipitate obtained is insoluble, stable and more visible than when any variant of the diaminobenzidine method is employed, and the morphological image of neurons and nerve fibres labelled with HRP is superior to that produced by the tetramethylbenzidine/sodium nitroprusside method. There is no non-specific precipitation, and no retraction of nerve tissue has been observed. The performance of the method is improved further using either o-tolidine/pyrocatechol or o-dianisidine/pyrocatechol in conjunction with glucose oxidase, which may be useful if it is desired to obtain Golgi-like images of HRP-bearing cells or to display weakly HRP-labelled nerve fibres.