The diagnostic value of 11q13 amplification and protein expression in the detection of nodal metastasis from oral squamous cell carcinoma: a systematic review and meta-analysis.
Despite improvements in both diagnostic and therapeutic strategies, the prognosis of oral squamous cell carcinoma (OSCC) has not changed significantly over the last decades. Prognosis of OSCC particularly depends on the presence of nodal metastasis in the neck. Therefore, proper determination of the nodal status is pivotal for appropriate treatment. Unfortunately, current available imaging techniques (magnetic resonance imaging or ultrasound even with fine needle aspiration of suspected lymph nodes (LNs)) fail to detect occult nodal disease accurately. Clinicians in head and neck oncology urgently need new diagnostic tools to reliably determine the presence of nodal metastasis of the neck. Gain of the chromosomal region 11q13 is one of the most prominent genetic alterations in head and neck cancer and is associated with poor prognosis and metastasis. The aim of this systematic review and meta-analysis was to determine the diagnostic value of either 11q13 amplification or amplification/protein overexpression of individual genes located on 11q13 to detect nodal metastasis in OSCC. A search was conducted in Pubmed, EMBASE, and Cochrane, and 947 unique citations were retrieved. Two researchers independently screened all articles and only 18 were found to meet our inclusion criteria and were considered of sufficient quality for meta-analysis. Pooled results of those show that both amplification of CCND1 and protein overexpression of cyclin D1 significantly correlate with lymph node metastasis (LNM) in OSCC. In addition, amplification of CCND1 shows a negative predictive value of 80 % in the detection of LNM in early stage OSCCs which are clinically lymph node negative although this evidence is sparse and should be validated in a larger homogeneous cohort of T1-2 OSCC.


Current guidelines for dyspepsia management.
Dyspepsia is a global problem and the management of the condition remains a considerable burden on health care resources. Many countries have adopted evidence-based guidelines for the management of the condition, in an attempt to reduce health care expenditure. This article compares and contrasts dyspepsia management guidelines from several geographical regions. We obtained current guidelines from five regions and examined composition of guideline development groups, methodology involved, definition of dyspepsia utilized, and recommendations in terms of first-line approach, age cutoff for prompt upper gastrointestinal (GI) endoscopy, and subsequent role of endoscopy. All guidelines carried out extensive reviews of the literature to inform their recommendations. The majority used a definition of dyspepsia in line with the Rome criteria. All agreed that alarm symptoms at any age warranted prompt endoscopy, and most recommended an age cutoff of between 50 and 55 years for endoscopy as an initial management strategy. In young patients without alarm symptoms, either 'test and treat' or empirical acid suppression were the initial management strategies of choice in all cases, with only one guideline recommending mandatory endoscopy in those whose symptoms failed to settle after this approach. Despite varying composition of guideline development groups and the different geographical regions, the recommendation of all the guidelines were remarkably similar, reflecting the quality of research conducted by the GI community as a whole.


Photoacoustic ophthalmoscopy for in vivo retinal imaging.
We have developed a non-invasive photoacoustic ophthalmoscopy (PAOM) for in vivo retinal imaging. PAOM detects the photoacoustic signal induced by pulsed laser light shined onto the retina. By using a stationary ultrasonic transducer in contact with the eyelids and scanning only the laser light across the retina, PAOM provides volumetric imaging of the retinal micro-vasculature and retinal pigment epithelium at a high speed. For B-scan frames containing 256 A-lines, the current PAOM has a frame rate of 93 Hz, which is comparable with state-of-the-art commercial spectral-domain optical coherence tomography (SD-OCT). By integrating PAOM with SD-OCT, we further achieved OCT-guided PAOM, which can provide multi-modal retinal imaging simultaneously. The capabilities of this novel technology were demonstrated by imaging both the microanatomy and microvasculature of the rat retina in vivo.


Torovirus non-discontinuous transcription: mutational analysis of a subgenomic mRNA promoter.
Toroviruses (order Nidovirales) are enveloped positive-strand RNA viruses of mammals. The prototype torovirus, equine torovirus strain Berne (Berne virus [BEV]), uses two different transcription strategies to produce a 3'-coterminal nested set of subgenomic (sg) mRNAs. Its mRNA 2 carries a leader sequence derived from the 5' end of the genome and is produced via discontinuous transcription. The remaining three sg mRNAs, 3 to 5, are colinear with the 3' end of the genome and are made via non-discontinuous RNA synthesis. Their synthesis is supposedly regulated by short conserved sequence motifs, 5'-ACN3-4CUUUAGA-3', within the noncoding intergenic regions that precede the M, HE, and N genes (A. L. van Vliet, S. L. Smits, P. J. Rottier, and R. J. de Groot, EMBO J. 21:6571-6580, 2002). We have now studied the--for nidoviruses unusual--non-discontinuous transcription mechanism in further detail by probing the role of the postulated transcription-regulating sequences (TRSs). To this end, we constructed a synthetic defective interfering (DI) RNA, carrying a 24-nucleotide segment of the intergenic region between the HE and N genes. We demonstrate that this DI RNA, when introduced into BEV-infected cells, directs the synthesis of a sg DI RNA species; in fact, a 16-nucleotide cassette containing the TRS already proved sufficient. Synthesis of this sg DI RNA, like that of mRNAs 3 to 5 of the standard virus, initiated at the 5'-most adenylate of the TRS. An extensive mutational analysis of the TRS is presented. Our results provide first and formal experimental evidence that the conserved motifs within the BEV intergenic sequences indeed drive sg RNA synthesis.


Modeling SARS-CoV-2 and influenza infections and antiviral treatments in human lung epithelial tissue equivalents.
There is a critical need for physiologically relevant, robust, and ready-to-use in vitro cellular assay platforms to rapidly model the infectivity of emerging viruses and develop new antiviral treatments. Here we describe the cellular complexity of human alveolar and tracheobronchial air liquid interface (ALI) tissue models during SARS-CoV-2 and influenza A virus (IAV) infections. Our results showed that both SARS-CoV-2 and IAV effectively infect these ALI tissues, with SARS-CoV-2 exhibiting a slower replication peaking at later time-points compared to IAV. We detected tissue-specific chemokine and cytokine storms in response to viral infection, including well-defined biomarkers in severe SARS-CoV-2 and IAV infections such as CXCL10, IL-6, and IL-10. Our single-cell RNA sequencing analysis showed similar findings to that found in vivo for SARS-CoV-2 infection, including dampened IFN response, increased chemokine induction, and inhibition of MHC Class I presentation not observed for IAV infected tissues. Finally, we demonstrate the pharmacological validity of these ALI tissue models as antiviral drug screening assay platforms, with the potential to be easily adapted to include other cell types and increase the throughput to test relevant pathogens.


Ribosomal internal transcribed spacer 2 (ITS2) exhibits a common core of secondary structure in vertebrates and yeast.
Molecular mechanisms of ITS2 processing, a eukaryotic insertion between the 5.8S and LSU rRNA, remain largely elusive even in yeast. To delineate ITS2 structural and functional features which could be common to eukaryotes, we first produced phylo-genetically supported folding models in the vertebrate lineage, then tested them in deeper branchings and, more particularly, among yeasts. ITS2 comparisons between four Teleostei, a Chondrichthyes specimen and two jawless organisms have revealed a common folding architecture in four to five domains of secondary structure emerging from a preserved structural core. This folding, largely reminiscent of ITS2 architecture in mammals, is also preserved in amphibia and in chicken, despite dramatic sequence variations. Preferential conservation is located around a central loop and at the apex of a long stem in the ITS2 3'-half. Interestingly, these two independent structural features contain, respectively, the 3'-ends of the two transient rRNA precursors 8S and 12S RNA identified in mammals, suggesting a preservation of these intermediates of processing over the entire vertebrate group. Surprising similarities between the vertebrate ITS2 folding shape and that of invertebrates as well as protista have made intriguing the significant differences from the yeast model. A detailed comparative analysis including four relatively close species and Schizosaccharomyces pombe, a deep yeast branching, has revealed an alternative phylogenetically supported four-domain folding presenting strong similarities to the vertebrate model. Remarkably, the two best conserved regions of vertebrates have unambiguously preserved counterparts which are also sites for internal processing in yeast. Therefore, molecular mechanisms involved in ITS2 excision in vertebrates and yeast might be more closely related than currently believed and might require a very similar trans -acting machinery.


Inhibition of Chronic Pancreatitis and Murine Pancreatic Intraepithelial Neoplasia by a Dual Inhibitor of c-RAF and Soluble Epoxide Hydrolase in LSL-KrasG¹²D/Pdx-1-Cre Mice.
Mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS) and chronic pancreatitis are the most common pathogenic events involved in human pancreatic carcinogenesis. In the process of long-standing chronic inflammation, aberrant metabolites of arachidonic acid play a crucial role in promoting carcinogenesis, in which the soluble epoxide hydrolase (sEH), as a pro-inflammatory enzyme, generally inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs). Herein, we determined the effect of our newly-synthesized novel compound trans-4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-cyclohexyloxy}-pyridine-2-carboxylic acid methylamide (t-CUPM), a dual inhibitor of sEH and RAF1 proto-oncogene serine/threonine kinase (c-RAF), on inhibiting the development of pancreatitis and pancreatic intraepithelial neoplasia (mPanIN) in LSL-Kras(G12D)/Pdx1-Cre mice. The results showed that t-CUPM significantly reduced the severity of chronic pancreatitis, as measured by the extent of acini loss, inflammatory cell infiltration and stromal fibrosis. The progression of low-grade mPanIN I to high-grade mPanIN II/III was significantly suppressed. Inhibition of mutant Kras-transmitted phosphorylation of mitogen-activated protein kinase's kinase/extracellular signal-regulated kinases was demonstrated in pancreatic tissues by western blots. Quantitative real-time polymerase chain reaction analysis revealed that t-CUPM treatment significantly reduced the levels of inflammatory cytokines including tumor necrosis facor-α, monocyte chemoattractant protein-1, as well as vascular adhesion molecule-1, and the levels of Sonic hedgehog and Gli transcription factor (Hedgehog pathway). Analysis of the eicosanoid profile revealed a significant increase of the EETs/dihydroxyeicosatrienoic acids ratio, which further confirmed sEH inhibition by t-CUPM. These results indicate that simultaneous inhibition of sEH and c-RAF by t-CUPM is important in preventing chronic pancreatitis and carcinogenesis.


Repairing Effect of New Dexamethasone Nanoparticles in the Treatment of Acute Lung Injury and Cluster Nursing.
The repairing effect of new dexamethasone nanoparticles in the treatment of acute lung injury was investigated in this study, as well as cluster nursing. In this study, new dexamethasone model drugs were prepared by the aqueous solvent diffusion method, such as anti-ICAM-I monoclonal antibody-modified anionic dexamethasone NLCs and anti-ICAM-I monoclonal antibody-modified cationic dexamethasone NLCs. Besides, the physical and chemical properties and repairing effects of cationic dexamethasone on acute lung injury were compared. A mouse model of acute lung injury was established, and the anti-inflammatory effect of dexamethasone was evaluated by intravenous injection of dexamethasone nanoparticles in the intervention group and normal healthy mice in the control group. A total of 100 patients with acute lung injury in Hai'an People's Hospital Affiliated with Nantong University were selected, of which 50 cases were given cluster nursing intervention and the other 50 cases were taken as the control group. A human vascular endothelial cell line was applied to establish the model cells, and a model of inflammatory endothelial cells in acute lung injury was constructed using lipopolysaccharide stimulation, to verify the cytotoxicity of dexamethasone NLCs. It was found that the anion particle size was 250.12 ± 20.15 nm, the cationic particle size was 245.7 ± 2.1 nm; their Zeta potentials were -31 ± 0.5 mV and 38 ± 0.6 mV in turn; their encapsulation rates were 91% and 83%, respectively; the drug loading was 3.7% and 3.4% in sequence; the release lowest rate was 60%. The 50% lethal dose of anionic cells was higher than 600 g/mL, while that of cationic cells was lower. The respiratory function of the cluster nursing intervention group was better markedly than that of the control group, and the lung infection rate was 2.5% in the intervention group and 15% in the control group. In conclusion, dexamethasone nanoparticles had good anti-inflammatory effects. Anionic ICAM NLCs were less toxic than cationic cells and could better bind to lung vascular endothelial cells, which might reduce adverse drug reactions. Therefore, the building of bundled nursing could effectively alleviate respiratory dysfunction and reduce the infection rate of patients.


In vivo MR imaging of intravascularly injected magnetically labeled mesenchymal stem cells in rat kidney and liver.
To evaluate in vivo magnetic resonance (MR) imaging with a conventional 1.5-T system for depiction and tracking of intravascularly injected superparamagnetic iron oxide (SPIO)-labeled mesenchymal stem cells (MSCs). This study was conducted in accordance with French law governing animal research and met guidelines for animal care and use. Rat MSCs were labeled with SPIO and transfection agent. Relaxation rates at 1.5 T, cell viability, proliferation, differentiation capacity, and labeling stability were assessed in vitro as a function of SPIO concentration. MSCs were injected into renal arteries of healthy rats (labeled cells in four, unlabeled cells in two) and portal veins of rats treated with carbon tetrachloride to induce centrolobular liver necrosis (labeled cells and unlabeled cells in two each). Follow-up serial T2*-weighted gradient-echo MR imaging and R2* mapping were performed. MR imaging findings were compared histologically. SPIO labeling caused a strong R2* effect that increased linearly with iron dose; R2* increase for cells labeled for 48 hours with 50 microg of iron per milliliter was 50 sec(-1) per million cells per milliliter. R2* was proportional to iron load of cells. SPIO labeling did not affect cell viability (P > .27). Labeled cells were able to differentiate into adipocytes and osteocytes. Proliferation was substantially limited for MSCs labeled with 100 microg Fe/mL or greater. Label half-life was longer than 11 days. In normal kidneys, labeled MSCs caused signal intensity loss in renal cortex. After labeled MSC injection, diseased liver had diffuse granular appearance. Cells were detected for up to 7 days in kidney and 12 days in liver. Signal intensity loss and fading over time were confirmed with serial R2* mapping. At histologic analysis, signal intensity loss correlated with iron-loaded cells, primarily in renal glomeruli and hepatic sinusoids; immunohistochemical analysis results confirmed these cells were MSCs. MR imaging can aid in monitoring of intravascularly administered SPIO-labeled MSCs in vivo in kidney and liver.


Association of impaired immune responsiveness of lymphocytes from animals bearing large tumors with a membrane-bound suppressive substance.
The immunoreactivity of lymphocytes from mice bearing large tumors was investigated. As compared to normal lymphocytes, lymphocytes from tumor bearers manifested a lessened proliferative response to T-cell mitogens and were less capable of destroying syngeneic tumor target cells. However, the impaired reactivity of these lymphocytes was improved significantly after washing repeatedly in tissue culture medium in vitro. The increase in cytolytic activity was tumor specific. A membrane-associated suppressive substance was detected in the washing medium which inhibited the cytotoxicity of washed lymphocytes. The effect of suppressive substance was tumor specific and sensitive to treatment with protein A and anti-immunoglobulin antibody, indicating that the suppressive substance contained immunoglobulin. The present findings suggest that a membrane-associated suppressive substance(s) may be in part responsible for the diminished immune responsiveness of lymphocytes from animals bearing large tumors.


High quality RNA isolation from Aedes aegypti midguts using laser microdissection microscopy.
Laser microdissection microscopy (LMM) has potential as a research tool because it allows precise excision of target tissues or cells from a complex biological specimen, and facilitates tissue-specific sample preparation. However, this method has not been used in mosquito vectors to date. To this end, we have developed an LMM method to isolate midgut RNA using Aedes aegypti. Total RNA was isolated from Ae. aegypti midguts that were either fresh-frozen or fixed with histological fixatives. Generally, fresh-frozen tissue sections are a common source of quality LMM-derived RNA; however, our aim was to develop an LMM protocol that could inactivate pathogenic viruses by fixation, while simultaneously preserving RNA from arbovirus-infected mosquitoes. Three groups (10 - 15 mosquitoes per group) of female Ae. aegypti at 24 or 48-hours post-blood meal were intrathoracically injected with one of seven common fixatives (Bouin's, Carnoy's, Formoy's, Cal-Rite, 4% formalin, 10% neutral buffered formalin, or zinc formalin) to evaluate their effect on RNA quality. Total RNA was isolated from the fixed abdomens using a Trizol® method. The results indicated that RNA from Carnoy's and Bouin's fixative samples was comparable to that of fresh frozen midguts (control) in duplicate experiments. When Carnoy's and Bouin's were used to fix the midguts for the LMM procedure, however, Carnoy's-fixed RNA clearly showed much less degradation than Bouin's-fixed RNA. In addition, a sample of 5 randomly chosen transcripts were amplified more efficiently using the Carnoy's treated LMM RNA than Bouin's-fixed RNA in quantitative real-time PCR (qRT-PCR) assays, suggesting there were more intact target mRNAs in the Carnoy's fixed RNA. The yields of total RNA ranged from 0.3 to 19.0 ng per ~3.0 × 10(6) μm2 in the LMM procedure. Carnoy's fixative was found to be highly compatible with LMM, producing high quality RNA from Ae. aegypti midguts while inactivating viral pathogens. Our findings suggest that LMM in conjunction with Carnoy's fixation can be applied to studies in Ae. aegypti infected with arboviruses without compromising biosafety and RNA quality. This LMM method should be applicable to other mosquito vector studies.


Sex chromosome translocations in the evolution of reproductive isolation.
Haldane's rule states that in organisms with differentiated sex chromosomes, hybrid sterility or inviability is generally expressed more frequently in the heterogametic sex. This observation has been variously explained as due to either genic or chromosomal imbalance. The fixation probabilities and mean times to fixation of sex-chromosome translocations of the type necessary to explain Haldane's rule on the basis of chromosomal imbalance have been estimated in small populations of Drosophila melanogaster. The fixation probability of an X chromosome carrying the long arm of the Y(X.Y(L)) is approximately 30% greater than expected under the assumption of no selection. No fitness differences associated with the attached Y(L) segment were detected. The fixation probability of a deficient Y chromosome is 300% greater than expected when the X chromosome contains the deleted portion of the Y. It is suggested that sex-chromosome translocations may play a role in the establishment of reproductive isolation.


Trends in the demographic composition of poverty among working families in Germany and in Israel, 1991-2011.
While the working poverty rate in advanced economies is about 7%, the demographic composition of the working poor varies considerably across countries. Providing an in-depth look at the demographic composition of working poverty, this paper builds on a typology of three major antecedents of poverty among workers - age, household structure, and minority status - and documents their changing association with the likelihood of poverty in Germany and Israel for a 21-year span during which both countries underwent major labor market and welfare reforms. The paper utilizes data from the German Socio-Economic Panel and the Israeli Income Survey, 1991-2011, and includes logistics models and a decomposition analysis of the demographic components of trends in working poverty. Results document a pronounced increase in poverty risks among the Arab population and households with more than two children in Israel since 2000. Contrastingly, the most pronounced changes in Germany have occurred among single-headed households.


Training mode's influences on the relationships between training-load models during basketball conditioning.
To compare perceptual and physiological training-load responses during various basketball training modes. Eight semiprofessional male basketball players (age 26.3 ± 6.7 y, height 188.1 ± 6.2 cm, body mass 92.0 ± 13.8 kg) were monitored across a 10-wk period in the preparatory phase of their training plan. Player session ratings of perceived exertion (sRPE) and heart-rate (HR) responses were gathered across base, specific, and tactical/game-play training modes. Pearson correlations were used to determine the relationships between the sRPE model and 2 HR-based models: the training impulse (TRIMP) and summated HR zones (SHRZ). One-way ANOVAs were used to compare training loads between training modes for each model. Stronger relationships between perceptual and physiological models were evident during base (sRPE-TRIMP r = .53, P < .05; sRPE-SHRZ r = .75, P < .05) and tactical/game-play conditioning (sRPE-TRIMP r = .60, P < .05; sRPE-SHRZ r = .63; P < .05) than during specific conditioning (sRPE-TRIMP r = .38, P < .05; sRPE-SHRZ r = .52; P < .05). Furthermore, the sRPE model detected greater increases (126-429 AU) in training load than the TRIMP (15-65 AU) and SHRZ models (27-170 AU) transitioning between training modes. While the training-load models were significantly correlated during each training mode, weaker relationships were observed during specific conditioning. Comparisons suggest that the HR-based models were less effective in detecting periodized increases in training load, particularly during court-based, intermittent, multidirectional drills. The practical benefits and sensitivity of the sRPE model support its use across different basketball training modes.


Three-Qubit Randomized Benchmarking.
As quantum circuits increase in size, it is critical to establish scalable multiqubit fidelity metrics. Here we investigate, for the first time, three-qubit randomized benchmarking (RB) on a quantum device consisting of three fixed-frequency transmon qubits with pairwise microwave-activated interactions (cross-resonance). We measure a three-qubit error per Clifford of 0.106 for all-to-all gate connectivity and 0.207 for linear gate connectivity. Furthermore, by introducing mixed dimensionality simultaneous RB-simultaneous one- and two-qubit RB-we show that the three-qubit errors can be predicted from the one- and two-qubit errors. However, by introducing certain coherent errors to the gates, we can increase the three-qubit error to 0.302, an increase that is not predicted by a proportionate increase in the one- and two-qubit errors from simultaneous RB. This demonstrates the importance of multiqubit metrics, such as three-qubit RB, on evaluating overall device performance.


Unilateral primary or secondary retention of permanent teeth, and dental malformations.
The purpose of the present investigation was to describe the dentition in subjects with local primary or secondary unilateral retention of two or more permanent teeth, and to elucidate the aetiology by comparing the regions of retention with the innervation pattern of the jaws. The material comprised radiographic dental orthopantomograms (OTP) from 12 patients with an age range of 6-18 years (six females and six males). The locations of retention and the dental morphology in the affected regions were analysed. Comparison with contralateral teeth was undertaken and the innervation pattern of the affected field was considered. Varying degrees of dental root malformation were found to be associated with primary and secondary retention. More pronounced root malformations were observed in subjects with several affected teeth. A connection between unilateral retained permanent teeth and temporary or permanent disruption of the nerve supply to the affected region is suggested.


Potential Infection Control Risks Associated with Ultrasound Equipment - A Bacterial Perspective.
Ultrasound equipment used in trans-abdominal (TA) and trans-vaginal (TV) examination may carry bacterial contamination and pose risks to infection control during ultrasound examination. We aimed to describe the prevalence of bacterial contamination on ultrasound probes, gel, machine keyboard and cords and examined the effectiveness of low- and high-level disinfection techniques. This study was performed at a public hospital and a private practice. A total of 171 swabs were analyzed and bacterial species were identified using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) analysis and polymerase chain reaction (PCR). Sixty percent of TA probes and 14% of TV probes had evidence of bacterial contamination after an ultrasound examination. Low-level disinfection was partially effective, but 4% of probes were still contaminated by spore-forming species. Some heated gel samples were highly contaminated with the environmental bacterium Brevundimonas aurantiaca, suggesting the gel was conducive to bacterial growth. Ultrasound machines, probe cords and gels were identified as potential sources of bacterial contamination and need to be cleaned and changed regularly to minimize risks of infection.


Mass Spectrometry Imaging of In Vitro Cryptosporidium parvum-Infected Cells and Host Tissue.
Cryptosporidium parvum is a zoonotic-relevant parasite belonging to the phylum Alveolata (subphylum Apicomplexa). One of the most zoonotic-relevant etiologies of cryptosporidiosis is the species C. parvum, infecting humans, cattle and wildlife. C. parvum-infected intestinal mucosa as well as host cells infected in vitro have not yet been the subject of extensive biochemical investigation. Efficient treatment options or vaccines against cryptosporidiosis are currently not available. Human cryptosporidiosis is currently known as a neglected poverty-related disease (PRD), being potentially fatal in young children or immunocompromised patients. In this study, we used a combination of atmospheric pressure scanning microprobe matrix-assisted laser desorption/ionization (AP-SMALDI) mass spectrometry imaging (MSI) and liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to determine and locate molecular biomarkers in in vitro C. parvum-infected host cells as well as parasitized neonatal calf intestines. Sections of C. parvum-infected and non-infected host cell pellets and infected intestines were examined to determine potential biomarkers. Human ileocecal adenocarcinoma cells (HCT-8) were used as a suitable in vitro host cell system. More than a thousand different molecular signals were found in both positive- and negative-ion mode, which were significantly increased in C. parvum-infected material. A database search in combination with HPLC-MS/MS experiments was employed for the structural verification of markers. Our results demonstrate some overlap between the identified markers and data obtained from earlier studies on other apicomplexan parasites. Statistically relevant biomarkers were imaged in cell layers of C. parvum-infected and non-infected host cells with 5 µm pixel size and in bovine intestinal tissue with 10 µm pixel size. This allowed us to substantiate their relevance once again. Taken together, the present approach delivers novel metabolic insights on neglected cryptosporidiosis affecting mainly children in developing countries.


Hip fracture surgery: does type of anesthesia matter?
Hip fracture surgery is a common procedure, and the geriatric population with its multiple comorbid conditions is at most at risk of developing anesthesia-related complications. Data on the impact of type anesthesia on postoperative morbidity and mortality is limited. The effects of regional and general anesthesia on postoperative outcomes need to be clearly elucidated. In this study, all patients who underwent dynamic hip screw (DHS) fixation for intertrochanteric fractures, between January 2005 and December 2010, at the Aga Khan University Hospital, were included. Patients were divided into two groups; group A included those patients who received general anesthesia, and group B consisted of patients who had received regional anesthesia. The two groups were compared for differences in morbidity, mortality, and intraoperative complications based on the type of anesthesia administered. During this period, 194 patients underwent DHS fixation. One hundred and seven patients received general anesthesia whereas eighty-seven patients received regional anesthesia. The mean operative time was significantly lower in the group receiving regional anesthesia (1.25 ± 0.39 hrs) as compared to those who received general anesthesia (1.54 ± 0.6 hrs) (P < 0.05). There were no statistically significant differences in the rates of wound infections, length of hospital stay, postoperative ambulation status, intraoperative blood loss, postoperative complications, and mortality between the regional and general anesthesia groups. Even though administration of regional anesthesia was positively correlated with shorter operative duration, the type of anesthesia was not found to affect surgical outcomes in the two study groups. Based on these results, we recommend that anesthesia should be tailored to individual patient requirements.


[Children and adolescents with retarded growth due to hypopituitarism: a review of the psychosocial literature].
The research on the psychosocial development of children and adolescents with growth-retardation due to idiopathic hypopituitarism is reviewed. The results of this--scarce and not very recent--research appear to be far from consistent. There is disagreement, both as to the nature and to the seriousness of the psychosocial implications of the growth-retardation. Some research-workers stress the existence of psychological and social problems of a very serious nature and are convinced of the necessity of intensive psychotherapeutic help. The presence of such problems is denied by others and only occasionally some support should be needed. All authors agree, however, about adolescence being a psychosocially critical period. Furthermore in this review, the methodology of previous research is criticized.


Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance Registry Study.
Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) conditioning. The DEFIFrance post-marketing registry study evaluated effectiveness and safety in patients who received defibrotide. It collected retrospective/prospective patient data from 53 French HCT centres from July 2014 to March 2020. Primary endpoints were survival and complete response (CR; total serum bilirubin <2 mg/dL, multiorgan failure resolution) at Day 100 post-HCT among patients with severe/very severe VOD/SOS. A secondary endpoint was evaluation of treatment-emergent serious adverse events (TESAEs) of interest. Of 798 patients analysed, 251 and 81 received defibrotide treatment for severe/very severe VOD/SOS and mild/moderate VOD/SOS post-HCT, respectively; 381 received defibrotide for VOD/SOS prophylaxis. In patients with severe/very severe VOD/SOS post-HCT, Kaplan-Meier-estimated CR at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan-Meier-estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%. DEFIFrance represents the largest collection of real-world data on post-registration defibrotide use, supporting the real-world utility of defibrotide for patients with severe/very severe VOD/SOS post-HCT.


Newer immunosuppressive drugs: their potential role in rheumatoid arthritis therapy.
Rheumatoid arthritis (RA) is a chronic immune-mediated disease characterised by chronic synovitis, which leads to cartilage damage and joint destruction. It is generally a progressive disease with radiographic evidence of joint damage, functional status decline and premature mortality. Proinflammatory cytokines, such as interleukin 1 and tumour necrosis factor alpha, play an important role in maintaining the chronicity of RA and mediating tissue damage. New approaches in the therapy of RA with anticytokine biological agents, which neutralise or block cytokines or their receptors, are now the first generation antirheumatic drugs in clinical practice. A better understanding of the signal transduction systems and gene regulation by transcription factors involved in cytokine production has opened the way for the discovery of novel therapeutic compounds useful in treating patients with RA. Overactivation of selective kinases or aberrant function of downstream transcription factors could help convert a normal immune response to a chronic disease state. This provides a unique opportunity for novel therapeutic interventions, since specific signal transduction or transcription factor targets might interrupt the perpetuation mechanisms in RA. The availability of potent and selective p38 mitogen activated protein kinase inhibitors provide a means in further dissecting the pathways implicated in cytokine production, which in turn maintain the chronicity of RA. Many studies conclude that these compounds are very useful in the treatment of chronic synovitis and therefore are very promising for RA treatment.


Regulation of the DNA damage response and gene expression by the Dot1L histone methyltransferase and the 53Bp1 tumour suppressor.
Dot1L, a histone methyltransferase that targets histone H3 lysine 79 (H3K79), has been implicated in gene regulation and the DNA damage response although its functions in these processes remain poorly defined. Using the chicken DT40 model system, we generated cells in which the Dot1L gene is disrupted to examine the function and focal recruitment of the 53Bp1 DNA damage response protein. Detailed kinetic and dose response assays demonstrate that, despite the absence of H3K79 methylation demonstrated by mass spectrometry, 53Bp1 focal recruitment is not compromised in these cells. We also describe, for the first time, the phenotypes of a cell line lacking both Dot1L and 53Bp1. Dot1L⁻/⁻ and wild type cells are equally resistant to ionising radiation, whereas 53Bp1⁻/⁻/Dot1L⁻/⁻ cells display a striking DNA damage resistance phenotype. Dot1L and 53Bp1 also affect the expression of many genes. Loss of Dot1L activity dramatically alters the mRNA levels of over 1200 genes involved in diverse biological functions. These results, combined with the previously reported list of differentially expressed genes in mouse ES cells knocked down for Dot1L, demonstrates surprising cell type and species conservation of Dot1L-dependent gene expression. In 53Bp1⁻/⁻ cells, over 300 genes, many with functions in immune responses and apoptosis, were differentially expressed. To date, this is the first global analysis of gene expression in a 53Bp1-deficient cell line. Taken together, our results uncover a negative role for Dot1L and H3K79 methylation in the DNA damage response in the absence of 53Bp1. They also enlighten the roles of Dot1L and 53Bp1 in gene expression and the control of DNA double-strand repair pathways in the context of chromatin.


Optimizing Clinical Interpretation of Distortion Product Otoacoustic Emissions in Infants.
The purpose of this study was to analyze distortion product otoacoustic emission (DPOAE) level and signal to noise ratio in a group of infants from birth to 4 months of age to optimize prediction of hearing status. DPOAEs from infants with normal hearing (NH) and hearing loss (HL) were used to predict the presence of conductive HL (CHL), sensorineural HL (SNHL), and mixed HL (MHL). Wideband ambient absorbance was also measured and compared among the HL types. This is a prospective, longitudinal study of 279 infants with verified NH and HL, including conductive, sensorineural, and mixed types that were enrolled from a well-baby nursery and two neonatal intensive care units in Cincinnati, Ohio. At approximately 1 month of age, DPOAEs (1-8 kHz), wideband absorbance (0.25-8 kHz), and air and bone conduction diagnostic tone burst auditory brainstem response (0.5-4 kHz) thresholds were measured. Hearing status was verified at approximately 9 months of age with visual reinforcement audiometry (0.5-4 kHz). Auditory brainstem response air conduction thresholds were used to assign infants to an NH or HL group, and the efficacy of DPOAE data to classify ears as NH or HL was analyzed using receiver operating characteristic (ROC) curves. Two summary statistics of the ROC curve were calculated: the area under the ROC curve and the point of symmetry on the curve at which the sensitivity and specificity were equal. DPOAE level and signal to noise ratio cutoff values were defined at each frequency as the symmetry point on their respective ROC curve, and DPOAE results were combined across frequency in a multifrequency analysis to predict the presence of HL. Single-frequency test performance of DPOAEs was best at mid to high frequencies (3-8 kHz) with intermediate performance at 1.5 and 2 kHz and chance performance at 1 kHz. Infants with a conductive component to their HL (CHL and MHL combined) displayed significantly lower ambient absorbance values than the NH group. No differences in ambient absorbance were found between the NH and SNHL groups. Multifrequency analysis resulted in the best prediction of HL for the SNHL/MHL group with poorer sensitivity values when infants with CHL were included. Clinical interpretation of DPOAEs in infants can be improved by using age-appropriate normative ranges and optimized cutoff values. DPOAE interpretation is most predictive at higher F2 test frequencies in young infants (2-8 kHz) due to poor test performance at 1 to 1.5 kHz. Multifrequency rules can be used to improve sensitivity while balancing specificity. Last, a sensitive middle ear measure such as wideband absorbance should be included in the test battery to assess possibility of a conductive component to the HL.


Serotonin has kinin-like activity in stimulating secretion by Malpighian tubules of the house cricket Acheta domesticus.
Serotonin stimulates secretion by Malpighian tubules (MT) of a number of insects, and functions as a diuretic hormone in Rhodnius prolixus and in larval Aedes aegypti. Serotonin is here shown to be a potent stimulant of secretion by MT of the house cricket, Acheta domesticus, with an apparent EC(50) of 9.4 nmol L(-1), although its diuretic activity is just 25% of the maximum achievable with either the native CRF-related peptide, Achdo-DH, or a crude extract of the corpora cardiaca. In this respect, the diuretic activity of serotonin is similar to that of the cricket kinin Achdo-KI, and when tested together their actions are not additive, which suggests they target the same transport process. Consistent with this suggestion, the activity of serotonin is chloride-dependent and is associated with a non-selective stimulation of NaCl and KCl transport. In common with Achdo-KI, serotonin has no effect on cAMP production by isolated MT, and both act synergistically with exogenous 8bromo-cAMP in stimulating fluid secretion, most likely by promoting the release of Ca(2+) from intracellular stores. A number of serotonin agonists and antagonists were tested to determine the pharmacological profile of receptors on cricket MT. The results are consistent with the diuretic activity of serotonin being mediated through a 5-HT(2)-like receptor.


Accumulative difference image protocol for particle tracking in fluorescence microscopy tested in mouse lymphonodes.
The basic research in cell biology and in medical sciences makes large use of imaging tools mainly based on confocal fluorescence and, more recently, on non-linear excitation microscopy. Substantially the aim is the recognition of selected targets in the image and their tracking in time. We have developed a particle tracking algorithm optimized for low signal/noise images with a minimum set of requirements on the target size and with no a priori knowledge of the type of motion. The image segmentation, based on a combination of size sensitive filters, does not rely on edge detection and is tailored for targets acquired at low resolution as in most of the in-vivo studies. The particle tracking is performed by building, from a stack of Accumulative Difference Images, a single 2D image in which the motion of the whole set of the particles is coded in time by a color level. This algorithm, tested here on solid-lipid nanoparticles diffusing within cells and on lymphocytes diffusing in lymphonodes, appears to be particularly useful for the cellular and the in-vivo microscopy image processing in which few a priori assumption on the type, the extent and the variability of particle motions, can be done.


D-aspartate: an atypical amino acid with neuromodulatory activity in mammals.
Within the pool of endogenous amino acids, serine and aspartate are the only two residues occurring at significant concentrations in free D-form in mammalian tissues. D-Serine (D-Ser) is mainly localized in the forebrain structures of the CNS throughout embryonic development and postnatal phase. Compelling evidence demonstrates that D-Ser has a functional role as an endogenous co-agonist at N-methyl-D-aspartate receptors (NMDARs) and shows its beneficial involvement in psychiatric disorders including schizophrenia. On the other hand, knowledge concerning the role of free D-Asp in mammals has so far been less extensive. D-Asp occurs in the brain as well as in peripheral tissues including the endocrine glands. In endocrine glands, D-Asp levels increase during the postnatal period in concomitance with their functional maturation. The involvement of D-Asp in the regulation of the synthesis and/or release of different hormones has been clearly demonstrated. However, its biological significance in the brain is still obscure. D-Asp appears with a peculiar temporal pattern of localization, being abundant during embryonic development and strongly decreasing after birth. This phenomenon is the result of the postnatal onset of D-Asp oxidase (DDO) expression, the only known enzyme that strictly controls the endogenous levels of D-Asp. The pharmacological affinity of D-Asp for the glutamate site of NMDARs has raised the intriguing question whether this D-amino acid may have some in vivo influence on responses mediated by this subclass of glutamate receptors. In order to unveil the physiological function of D-Asp and of its metabolizing enzyme, genetic and pharmacological approaches have been recently developed. It has now become possible to generate animal models with abnormally elevated levels of D-Asp in adulthood based on the targeted deletion of the Ddo gene and on the oral administration of D-Asp. These animal models have thus highlighted that D-Asp has a neuromodulatory role at NMDARs in brain areas where they regulate crucial nervous functions. Indeed, abnormally high D-Asp levels in the hippocampus are able to strongly enhance NMDAR-dependent LTP and, in turn, to facilitate spatial memory of mice. Moreover, in both mutant and treated animals, this deregulated D-Asp content completely suppresses striatal LTD, most likely via overactivation of NMDARs. The later synaptic plasticity alteration resembles that produced by chronic administration of haloperidol and is probably the neurobiological substrate responsible for the attenuation of prepulse inhibition deficits induced by amphetamine and MK-801 in Ddo knockout and D-Asp-treated mice. These in vitro and in vivo findings, together with others reported in this review, support a neuromodulatory action for D-Asp at glutamatergic synapses. In addition, they suggest that this D-amino acid may play a potential beneficial role in conditions related to a pathological hypofunctioning of NMDARs in the mammalian brain.


[Protein catabolism and malnutrition in liver cirrhosis - impact of oral nutritional therapy].
Malnutrition with loss of muscle is common in patients with liver cirrhosis and has negative impact on morbidity and mortality. The aetiology of malnutrition is multifactorial and includes inflammation, early onset of gluconeogenesis due to impaired glycogen storage and sometimes hypermetabolism. Reduced nutritional intake, however, plays the most important role in the pathogenesis of malnutrition. There is, however, ample evidence that nutritional intake and therapy are inadequate in liver cirrhosis although studies have clearly shown that dietary counselling and nutritional therapy with oral supplements improve intake in these patients. Protein requirement is considered to be increased in liver cirrhosis and high protein intake has been shown to be well tolerated and associated with an improvement of liver function and nutritional status. Protein intolerance on the other hand is uncommon and hepatic encephalopathy can thus rarely be attributed to high protein consumption. Recommendations for general protein restriction must therefore be considered obsolete and rather a risk factor for an impaired clinical outcome. Furthermore, the administration of late evening meals is highly beneficial in patients with liver disease since the rapid onset of the overnight catabolic state is counteracted. The serum concentration of branched-chain amino acids (BCAA) is decreased in patients with liver cirrhosis and long-term supplementation of BCAA has been shown to improve nutritional status and prolong event-free survival and quality of life.


A Heparin Purification Process Removes Spiked Transmissible Spongiform Encephalopathy Agent.
In 2000, bovine heparin was withdrawn from the US market for fear of contamination with bovine spongiform encephalopathy (BSE) agent, the cause of variant Creutzfeldt-Jakob disease in humans. Thus, US heparin is currently sourced only from pig intestines. Availability of alternative sources of crude heparin, a life-saving drug, would benefit public health. Bovine heparin is an obvious option, but BSE clearance by the bovine heparin manufacturing process should be evaluated. To this end, using hamster 263K scrapie as a surrogate for BSE agent, we applied a four-step bench-scale heparin purification protocol resembling a typical heparin manufacturing process to investigate removal of the spiked scrapie agent. We removed aliquots from each step and analyzed them for residual abnormal prion protein (PrPTSE) using a sensitive in vitro method, real-time quaking-induced conversion (RT-QuIC) assay, and for infectivity using animal bioassays. The purification process reduced infectivity by 3.6 log10 and removed PrPTSE, measured as seeding activity, by 3.4 log10. NaOH treatment was the most effective removal step tested. We also investigated NaOH at different concentrations and pH: the results showed that as much as 5.2 log10 of PrPTSE seeding activity was removed at pH 12.5. Thus, changes to the concentration, treatment time, and temperature of alkaline extraction might further improve removal. Our results, using a basic heparin manufacturing process, inform efforts to reintroduce safe bovine heparin in the USA.


Transcriptomic Leaf Profiling Reveals Differential Responses of the Two Most Traded Coffee Species to Elevated [CO2].
As atmospheric [CO2] continues to rise to unprecedented levels, understanding its impact on plants is imperative to improve crop performance and sustainability under future climate conditions. In this context, transcriptional changes promoted by elevated CO2 (eCO2) were studied in genotypes from the two major traded coffee species: the allopolyploid Coffea arabica (Icatu) and its diploid parent, C. canephora (CL153). While Icatu expressed more genes than CL153, a higher number of differentially expressed genes were found in CL153 as a response to eCO2. Although many genes were found to be commonly expressed by the two genotypes under eCO2, unique genes and pathways differed between them, with CL153 showing more enriched GO terms and metabolic pathways than Icatu. Divergent functional categories and significantly enriched pathways were found in these genotypes, which altogether supports contrasting responses to eCO2. A considerable number of genes linked to coffee physiological and biochemical responses were found to be affected by eCO2 with the significant upregulation of photosynthetic, antioxidant, and lipidic genes. This supports the absence of photosynthesis down-regulation and, therefore, the maintenance of increased photosynthetic potential promoted by eCO2 in these coffee genotypes.


Striatum morphometry is associated with cognitive control deficits and symptom severity in internet gaming disorder.
Internet gaming disorder (IGD), identified in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) Section III as a condition warranting more clinical research, may be associated with impaired cognitive control. Previous IGD-related studies had revealed structural abnormalities in the prefrontal cortex, an important part of prefrontal-striatal circuits, which play critical roles in cognitive control. However, little is known about the relationship between the striatal nuclei (caudate, putamen, and nucleus accumbens) volumes and cognitive control deficit in individuals with IGD. Twenty-seven adolescents with IGD and 30 age-, gender- and education-matched healthy controls participated in this study. The volume differences of the striatum were assessed by measuring subcortical volume in FreeSurfer. Meanwhile, the Stroop task was used to detect cognitive control deficits. Correlation analysis was used to investigate the relationship between striatal volumes and performance in the Stroop task as well as severity in IGD. Relative to controls, the IGD committed more incongruent condition response errors during the Stroop task and showed increased volumes of dorsal striatum (caudate) and ventral striatum (nucleus accumbens). In addition, caudate volume was correlated with Stroop task performance and nucleus accumbens (NAc) volume was associated with the internet addiction test (IAT) score in the IGD group. The increased volumes of the right caudate and NAc and their association with behavioral characteristics (i.e., cognitive control and severity) in IGD were detected in the present study. Our findings suggest that the striatum may be implicated in the underlying pathophysiology of IGD.


Correlation of cumulative ST elevation with left ventricular ejection fraction and 30-day outcome in patients with ST elevation myocardial infarction.
The electrocardiogram (ECG) is the first and often the only investigation available prior to definitive therapy in patients with ST elevation myocardial infarction (STEMI). A good prognostic marker is the left ventricular ejection fraction (LVEF) on ECG. Our aim was to assess the correlation between ST elevation (STE) in ECG and the LVEF and thereby aid the prognosis of patients with STEMI. This was a prospective cohort study of 230 patients with STEMI. A baseline 12-lead ECG was taken to calculate the sum of STE at the J point in all the leads showing elevation. The STE was measured 90 min after revascularization to calculate the ST resolution percentage (STR%). All patients underwent echocardiography, and the LVEF was measured using biplane Simpson's method. A total of 136 patients with anterior myocardial infarction (MI), 35 with inferior MI, and 59 with inferoposterior MI were included in the study. Mean STE was 13 mm and was significantly higher among patients with anterior MI. There was a good inverse correlation between the STE and the LVEF with a correlation coefficient of -0.64. STR% had a correlation coefficient of 0.59 to the LVEF. A formula was generated to calculate the LVEF based on the STE as follows: LVEF = (37.34 - STE)/0.567. An STE ≥15 mm predicted an LVEF <35% with a sensitivity and specificity of 70%. The STE and STR% are useful surrogate markers in prognosticating patients irrespective of the type of STEMI.


Haematological Alterations Associated with Selected Vector-Borne Infections and Exposure in Dogs from Pereira, Risaralda, Colombia.
Infections due to Ehrlichia, Anaplasma, Dirofilaria, Mycoplasma, Babesia and Hepatozoon continue to be highly prevalent in dogs, especially in tropical and subtropical areas, where vectors of many of them are present. However, many clinical aspects of dogs have not been characterized in detail, including assessing the haematological alterations associated with them, particularly in Colombia and Latin America. A group of 100 dogs with Ehrlichia, Anaplasma, Dirofilaria, Mycoplasma, Babesia and Hepatozoon infections/exposure were assessed by blood smear serology (SNAP4DX) and PCR in Pereira, Colombia. We performed blood counts to evaluate anaemia, leukopenia/leukocytosis, neutropenia, neutrophilia, lymphopenia/lymphocytosis, monocytosis, eosinophilia, and thrombocytopenia, among other alterations. Bivariate analyses were performed on Stata®14, with significant p < 0.05. From the total, 85% presented ≥1 infection (past or present), 66% with coinfections (≥2 pathogens) (Ehrlichia 75%), and 89% presented clinical alterations. A total of 100% showed anaemia, 70% thrombocytopenia, 61% monocytosis, and 47% neutropenia, among other alterations. Additionally, 11% presented pancytopenia and 59% bicytopenia. The median platelet count was lower in infected dogs (126,000 cells/μL) versus non-infected (221,000 cells/μL) (p = 0.003). Thrombocytopenia was higher among infected dogs (75%) versus non-infected (40%) (p = 0.006), with a 91% positive predictive value for infection. Median neutrophil count was lower in infected dogs (6591 cells/μL) versus non-infected (8804 cells/μL) (p = 0.013). Lymphocytosis occurred only among those infected (27%) (p = 0.022). Leukopenia was only observed among infected dogs (13%). Pancytopenia was only observed among infected dogs. Ehrlichiosis and other hematic infections have led to a significant burden of haematological alterations on infected dogs, including pancytopenia in a tenth of them, most with thrombocytopenia and all anemic.


CIGAR-seq, a CRISPR/Cas-based method for unbiased screening of novel mRNA modification regulators.
Cellular RNA is decorated with over 170 types of chemical modifications. Many modifications in mRNA, including m6 A and m5 C, have been associated with critical cellular functions under physiological and/or pathological conditions. To understand the biological functions of these modifications, it is vital to identify the regulators that modulate the modification rate. However, a high-throughput method for unbiased screening of these regulators is so far lacking. Here, we report such a method combining pooled CRISPR screen and reporters with RNA modification readout, termed CRISPR integrated gRNA and reporter sequencing (CIGAR-seq). Using CIGAR-seq, we discovered NSUN6 as a novel mRNA m5 C methyltransferase. Subsequent mRNA bisulfite sequencing in HAP1 cells without or with NSUN6 and/or NSUN2 knockout showed that NSUN6 and NSUN2 worked on non-overlapping subsets of mRNA m5 C sites and together contributed to almost all the m5 C modification in mRNA. Finally, using m1 A as an example, we demonstrated that CIGAR-seq can be easily adapted for identifying regulators of other mRNA modification.


Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency?
Ketamine, administered in subanesthetic doses, is an effective off-label treatment for severe and even treatment-refractory depression; however, despite dozens of studies across nearly 2 decades of research, there is no definitive guidance on matters related to core practice issues. This article presents a qualitative review and summary about what is known about ketamine dosing, rate of administration, route of administration, duration of treatment, and frequency of sessions. Ketamine is most commonly administered in the dose of 0.5 mg/kg, but some patients may respond to doses as low as 0.1 mg/kg, and others may require up to 0.75 mg/kg. The ketamine dose is conventionally administered across 40 minutes; however, safety and efficacy have been demonstrated in sessions ranging between 2 and 100 minutes in duration. Bolus administration is safe and effective when the drug is administered intramuscularly or subcutaneously. Whereas the intravenous route is the most commonly employed, safety and efficacy have been described with other routes of administration, as well; these include oral, sublingual, transmucosal, intranasal, intramuscular, and subcutaneous routes. Patients may receive a single session of treatment or a course of treatment during the acute phase, and treatment may rarely be continued for weeks to years to extend and maintain treatment gains in refractory cases. When so extended, the ideal frequency is perhaps best individualized wherein ketamine is dosed a little before the effect of the previous session is expected to wear off. There is likely to be a complex interaction between ketamine dose, session duration, route of administration, frequency of administration, and related practice. Until definitive studies comparing different doses, rates of administration, routes of administration, and other considerations are conducted, firm recommendations are not possible. From the point of view of clinical practicability, subcutaneous, intranasal, and oral ketamine warrant further study. If domiciliary treatment is considered, the risk of abuse must be kept in mind.


Effect of Zingiber officinale on some biochemical parameters and cytogenic analysis in lead-induced toxicity in experimental rats.
Exposure to toxic elements is greatly unavoidable in our daily activities due to several routes of coming in contact with these elements. Thus lead (Pb), is one of the major causes of health hazard in human. In this study, evaluation of Zingiber officinale as mitigating measure against Pb induced biochemical and cytogenic toxicity in albino rats was investigated. Experimental rats were grouped into five with five animals per group, group I serves as control and groups 2-5 were induced intraperitoneal with lead acetate dissolved in distilled water at 3 mg/kg body weight whereas group 3-5 were orally administered with 200 mg/kg vitamin C, 200 mg/kg, and 100 mg/kg of Z. officinale, respectively for 7 d. The obtained results show that aspartate aminotransferase (AST), alkaline phosphatase (ALP), lipid peroxidation, urea, creatinine, bilirubin, and gamma-glutamyl transferase (GGT) were significantly increased (p < 0.05) and catalase (CAT) were reduced progressively in Pb alone induced rats. Hematological parameters showed a progressive reduction (p < 0.05) in lead acetate alone rats. There were significant changes in micronuclei (MN), chromosomal aberrations (CA) frequency, and oxidative damages in the bone marrow cells from lead acetate alone induced rats, although, mitotic index scores in these cells were reduced gradually (p < 0.05). The altered parameters were significantly reversed toward the levels observed in normal control rats administered with vitamin C and aqueous extract of Z. officinale. Hence, these results suggest that Z. officinale roots might contain therapeutic potential that can ameliorate the hazard effect of lead acetate poison.


Female gender predicts lower access and adherence to antiretroviral therapy in a setting of free healthcare.
Barriers to HIV treatment among injection drug users (IDU) are a major public health concern. However, there remain few long-term studies investigating key demographic and behavioral factors--and gender differences in particular--that may pose barriers to antiretroviral therapy (ART), especially in settings with universal healthcare. We evaluated access and adherence to ART in a long-term cohort of HIV-positive IDU in a setting where medical care and antiretroviral therapy are provided free of charge through a universal healthcare system. We evaluated baseline antiretroviral use and subsequent adherence to ART among a Canadian cohort of HIV-positive IDU. We used generalized estimating equation logistic regression to evaluate factors associated with 95% adherence to antiretroviral therapy estimated based on prescription refill compliance. Between May 1996 and April 2008, 545 IDU participants were followed for a median of 23.8 months (Inter-quartile range: 8.5-91.6), among whom 341 (63%) were male and 204 (37%) were female. Within the six-month period prior to the baseline interview, 133 (39%) men and 62 (30%) women were on ART (p=0.042). After adjusting for clinical characteristics as well as drug use patterns measured longitudinally throughout follow-up, female gender was independently associated with a lower likelihood of being 95% adherent to ART (Odds Ratio [OR]=0.70; 95% Confidence Interval: 0.53-0.93). Despite universal access to free HIV treatment and medical care, female IDU were less likely to access and adhere to antiretroviral therapy, a finding that was independent of drug use and clinical characteristics. These data suggest that interventions to improve access to HIV treatment among IDU must be tailored to address unique barriers to antiretroviral therapy faced by female IDU.


Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications.
Intranasal corticosteroids (INSs) are effective treatments for allergic rhinitis, rhinosinusitis, and nasal polyposis. In recent years, increased understanding of corticosteroid and glucocorticoid receptor pharmacology has enabled the development of molecules designed specifically to achieve potent, localized activity with minimal risk of systemic exposure. Pharmacologic potency studies using affinity and other assessments have produced similar rank orders of potency, with the most potent being mometasone furoate, fluticasone propionate, and its modification, fluticasone furoate. The furoate and propionate ester side chains render these agents highly lipophilic, which may facilitate their absorption through nasal mucosa and uptake across phospholipid cell membranes. These compounds demonstrate negligible systemic absorption. Systemic absorption rates are higher among the older corticosteroids (flunisolide, beclomethasone dipropionate, triamcinolone acetonide, and budesonide), which have bioavailabilities in the range of 34-49%. Studies, including 1-year studies with mometasone furoate, fluticasone propionate, and budesonide that evaluated potential systemic effects of INSs in children have generally found no adverse effects on hypothalamic-pituitary-adrenal axis function or growth. Clinical data suggest no significant differences in efficacy between the INSs. Theoretically, newer agents with lower systemic availability may be preferable, and may come closer to the pharmacokinetic/pharmacologic criteria for the ideal therapeutic choice.


Lipoprotein-associated phospholipase A2 does not predict mortality or new ischaemic events in acute coronary syndrome patients.
Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been suggested as an independent predictor of cardiovascular events in epidemiological studies. We sought to evaluate Lp-PLA(2) as a risk factor for future cardiovascular events in patients with acute coronary syndromes (ACS) and to elucidate the relationship between Lp-PLA(2) and other known risk markers in ACS patients and healthy control subjects. Blood samples were obtained at randomization in a random subset of ACS patients in the FRISC II (n = 1362) and GUSTO IV (n = 904) studies and in 435 apparently healthy controls of similar age and gender. Median Lp-PLA(2) (mass) levels were 305 ng/mL (FRISC II), 373 ng/mL (GUSTO IV), and 254 ng/mL (healthy controls). Time delay from symptom onset did not influence Lp-PLA(2) levels. In the FRISC II patients and healthy controls, Lp-PLA(2) was significantly correlated with cholesterol (r = 0.3), low-density lipoprotein (r = 0.4 and r = 0.3, respectively), and C-reactive protein (r = 0.08 and r = 0.1, respectively), all P < 0.01. Lp-PLA(2) was not correlated with age, interleukin-6, troponin T, or NT-proBNP in any of the three cohorts. There was no difference in the composite of death and myocardial infarction at 30 days (GUSTO IV) or 180 days (FRISC II) in relation to low, middle, and top tertiles of Lp-PLA(2) at randomization. In FRISC II, the 1 year mortality was 4.2, 4.2, and 4.8% in the low, middle, and top Lp-PLA(2) tertiles, respectively, P = 0.8. In GUSTO IV, 1 year mortality was 7.0, 8.3, and 9.6% in the low, middle, and top Lp-PLA(2) tertiles, respectively, P = 0.5. ACS patients had higher Lp-PLA(2) levels than healthy controls. Lp-PLA(2) was significantly correlated to lipid levels but only weakly correlated or unrelated to other well-established risk markers in ACS. The risk of future cardiovascular events or mortality was not related to Lp-PLA(2) levels in ACS patients. The biological role of Lp-PLA(2) and its role as a risk marker in ACS patients still remain unclear.


Defective dendrite elongation but normal fertility in mice lacking the Rho-like GTPase activator Dbl.
Dbl is the prototype of a large family of GDP-GTP exchange factors for small GTPases of the Rho family. In vitro, Dbl is known to activate Rho and Cdc42 and to induce a transformed phenotype. Dbl is specifically expressed in brain and gonads, but its in vivo functions are largely unknown. To assess its role in neurogenesis and gametogenesis, targeted deletion of the murine Dbl gene was accomplished in embryonic stem cells. Dbl-null mice are viable and did not show either decreased reproductive performances or obvious neurological defects. Histological analysis of mutant testis showed normal morphology and unaltered proliferation and survival of spermatogonia. Dbl-null brains indicated a correct disposition of the major neural structures. Analysis of cortical stratification indicated that Dbl is not crucial for neuronal migration. However, in distinct populations of Dbl-null cortical pyramidal neurons, the length of dendrites was significantly reduced, suggesting a role for Dbl in dendrite elongation.


Phosphorylation influences the translation state of FMRP-associated polyribosomes.
Fragile X mental retardation protein, FMRP, is absent in patients with fragile X syndrome, a common form of mental retardation. FMRP is a nucleocytoplasmic RNA binding protein that is primarily associated with polyribosomes. FMRP is believed to be a translational repressor and may regulate the translation of certain mRNAs at the base of dendritic spines in neurons. However, little is known about the regulation of FMRP. Using mass spectrometry and site-directed mutagenesis, we show that FMRP is phosphorylated between residues 483 and 521, N-terminal to the RGG box, both in murine brain and in cultured cells. Primary phosphorylation occurs on the highly conserved serine 499, which triggers hierarchical phosphorylation of nearby serines. FMRP is phosphorylated within 2-4 h of synthesis, however, phosphorylation has no effect on the half-life of the protein. In contrast to the Drosophila ortholog dFxr, the phosphorylation status of mammalian FMRP does not influence its association with specific mRNAs in vivo. However, we find unphosphorylated FMRP associated with actively translating polyribosomes while a fraction of phosphorylated FMRP is associated with apparently stalled polyribosomes. Our data suggest that the phosphorylation may regulate FMRP and that the release of FMRP-induced translational suppression may involve a dephosphorylation signal.


Expression of Oct4 in HCC and modulation to wnt/β-catenin and TGF-β signal pathways.
Hepatocellular carcinoma (HCC) is considered as a disease of dysfunction of the stem cells. Studies on stem cells have demonstrated that Oct4 plays a pivotal role in embryo regulation. In order to understand the role of Oct4 in HCC and the relationship among Oct4 and wnt/β-catenin and TGF-β signal pathways, we have detected the expression of Oct4, Nanog, Sox2, STAT3 as well as the genes in wnt/β-catenin, and TGF-β families in HCC cell lines and in tumor specimens from HCC patients. The authors found that Oct4 was expressed in all of the four HCC cell lines and the tumor specimens from HCC patients. Some other genes were also expressed in them with different level including Nanog, Sox2, STAT3 and TCF3, wnt10b, β-catenin, ELF, Smad3 and Smad4. The ability of the clone formation and migration of the HepG2 decreased after Oct4 was knockdowned. Silencing of Oct4 and TCF3 in HCC cell line HepG2 revealed that there were complicated relationships among Oct4, wnt/β-catenin family and TGF-β family genes. Knockdowning Oct4 reduced the expression of TGF-β family genes ELF, Smad3, Smad4 and wnt/β-catenin family genes, wnt10b, and β-catenin but increased TCF3. In reverse, knockdowning TCF3 led to the increased expression of Oct4 and TGF-β family genes. In conclusion, the expression of Oct4 in HCC may play an important role as in stem cell. Because Oct4 improves not only the function of wnt/β-catenin, but also the TGF-β signal pathways, the significance of its expression in HCC might be more complicated than we evinced before.


Carotid artery stenosis in patients with chronic kidney disease undergoing dialysis: epidemiological aspects, main risk factors and appropriate diagnostic criteria.
Knowledge of the epidemiology and risk profile of peripheral vascular disease among patients with chronic kidney disease (CKD) has a potential role for determining its outcome. This study assessed the epidemiological aspects and risk factors of carotid artery stenosis (CAS), assessed by clinical ankle brachial index (ABI), in patients on dialysis. This study was performed on 84 patients with CKD undergoing hemodialysis (HD; n = 65) or peritoneal dialysis (PD; n = 19). The ABI was measured using a concurrent oscillometric method and Color Doppler sonography. An ABI value >0.9 was defined as normal. Severity of the stenosis was determined using B-Mode sonography. Overall, CAS was seen in 51.2% of the study patients. No significant difference was found in the overall prevalence of CAS between the HD and PD groups (50.8% vs. 52.6%, P = 0.552). The mean ABI in the HD and PD groups was 1.13 and 1.06, respectively. Among patient characteristics, advanced age was found to be a predictor of CAS in the study patients. Gender, type of dialysis or underlying risk factors could not predict CAS. ABI measurement was an acceptable predictor of CAS, with a receiver operator characteristic of 0.645. The optimal cut-off for ABI for predicting CAS was identified at 1.0; this yielded a sensitivity of 70.8% and a specificity of 63.6% for the test. In conclusion, a notable number of patients undergoing dialysis for CKD had CAS. The main predictive factor was advanced age. ABI measurement seems to be an acceptable tool to diagnose CAS.


A mass balance approach to investigate arsenic cycling in a petroleum plume.
Natural attenuation of organic contaminants in groundwater can give rise to a series of complex biogeochemical reactions that release secondary contaminants to groundwater. In a crude oil contaminated aquifer, biodegradation of petroleum hydrocarbons is coupled with the reduction of ferric iron (Fe(III)) hydroxides in aquifer sediments. As a result, naturally occurring arsenic (As) adsorbed to Fe(III) hydroxides in the aquifer sediment is mobilized from sediment into groundwater. However, Fe(III) in sediment of other zones of the aquifer has the capacity to attenuate dissolved As via resorption. In order to better evaluate how long-term biodegradation coupled with Fe-reduction and As mobilization can redistribute As mass in contaminated aquifer, we quantified mass partitioning of Fe and As in the aquifer based on field observation data. Results show that Fe and As are spatially correlated in both groundwater and aquifer sediments. Mass partitioning calculations demonstrate that 99.9% of Fe and 99.5% of As are associated with aquifer sediment. The sediments act as both sources and sinks for As, depending on the redox conditions in the aquifer. Calculations reveal that at least 78% of the original As in sediment near the oil has been mobilized into groundwater over the 35-year lifespan of the plume. However, the calculations also show that only a small percentage of As (∼0.5%) remains in groundwater, due to resorption onto sediment. At the leading edge of the plume, where groundwater is suboxic, sediments sequester Fe and As, causing As to accumulate to concentrations 5.6 times greater than background concentrations. Current As sinks can serve as future sources of As as the plume evolves over time. The mass balance approach used in this study can be applied to As cycling in other aquifers where groundwater As results from biodegradation of an organic carbon point source coupled with Fe reduction.


Amino ketone synthesis in avian erythrocytes.
1. The relative rates of synthesis of aminolaevulate and aminoacetone by particles prepared from avian erythrocytes were measured under various conditions. 2. The production of both amino ketones by fresh particles was about three times greater in anaemia caused by phenylhydrazine and acetylphenylhydrazine than in anaemia caused by removal of 20-30ml. of blood. 3. The synthesis of aminolaevulate by freeze-dried particles decreased more than that of aminoacetone in the absence of added pyridoxal phosphate, in the presence of cyanide and of tris buffer, and after preincubation of the erythrocyte particles. Other differences in the rates of synthesis of the two amino ketones were observed after (a) incubation of particles at different temperatures and (b) storage of homogenized freeze-dried particles at different pH values. 4. It is suggested that these differences in the production of the two amino ketones are due to the presence of two amino ketone synthetases or to two or more isoenzymes of aminolaevulate synthetase. 5. The metabolic significance of aminoacetone in erythrocytes is discussed.


The correlative triad among aging, dopamine, and cognition: current status and future prospects.
The brain neuronal systems defined by the neurotransmitter dopamine (DA) have since long a recognized role in the regulation of motor functions. More recently, converging evidence from patient studies, animal research, pharmacological intervention, and molecular genetics indicates that DA is critically implicated also in higher-order cognitive functioning. Many cognitive functions and multiple markers of striatal and extrastriatal DA systems decline across adulthood and aging. Research examining the correlative triad among adult age, DA, and cognition has found strong support for the view that age-related DA losses are associated with age-related cognitive deficits. Future research strategies for examining the DA-cognitive aging link include assessing (a) the generality/specificity of the effects; (b) the relationship between neuromodulation and functional brain activation; and (c) the release of DA during actual task performance.


A polyphenol-enriched diet and Ascaris suum infection modulate mucosal immune responses and gut microbiota composition in pigs.
Polyphenols are a class of bioactive plant secondary metabolites that are thought to have beneficial effects on gut health, such as modulation of mucosal immune and inflammatory responses and regulation of parasite burdens. Here, we examined the interactions between a polyphenol-rich diet supplement and infection with the enteric nematode Ascaris suum in pigs. Pigs were fed either a basal diet or the same diet supplemented with grape pomace (GP), an industrial by-product rich in polyphenols such as oligomeric proanthocyanidins. Half of the animals in each group were then inoculated with A. suum for 14 days to assess parasite establishment, acquisition of local and systemic immune responses and effects on the gut microbiome. Despite in vitro anthelmintic activity of GP-extracts, numbers of parasite larvae in the intestine were not altered by GP-supplementation. However, the bioactive diet significantly increased numbers of eosinophils induced by A. suum infection in the duodenum, jejunum and ileum, and modulated gene expression in the jejunal mucosa of infected pigs. Both GP-supplementation and A. suum infection induced significant and apparently similar changes in the composition of the prokaryotic gut microbiota, and both also decreased concentrations of isobutyric and isovaleric acid (branched-chain short chain fatty acids) in the colon. Our results demonstrate that while a polyphenol-enriched diet in pigs may not directly influence A. suum establishment, it significantly modulates the subsequent host response to helminth infection. Our results suggest an influence of diet on immune function which may potentially be exploited to enhance immunity to helminths.


Effects of observing eye contact on gaze following in high-functioning autism.
Observing eye contact between others enhances the tendency to subsequently follow their gaze and has been suggested to function as a social signal that adds meaning to an upcoming action or event. The present study investigated effects of observed eye contact in high-functioning autism (HFA). Two faces on a screen either looked at or away from each other before providing congruent or incongruent gaze cues to one of two target locations. In contrast to control participants, HFA participants did not depict enhanced gaze following after observing eye contact. Individuals with autism, hence, do not seem to process observed mutual gaze as a social signal indicating the relevance of upcoming (gaze) behaviour. This may be based on the reduced tendency of individuals with HFA to engage in social gaze behavior themselves, and might underlie some of the characteristic deficiencies in social communicative behaviour in autism.


Gray scale ultrasound in obstetrics and gynecology.
Ultrasound can provide significant information in the fields of obstetrics and gynecology, Fetal presentation, presence of multiple gestation, and gross fetal abnormalities are easily determined. Measurement of the biparietal diameter correlates more closely with gestational age than does use of the fetogram. In addition, there is no evidence of fetal toxicity by this method, and the placenta is easily located. Ultrasound is the preferred method for diagnosis of placenta previa. Abnormalities of the early gestational period including missed abortion, ectopic pregnancy, and molar pregnancy also can be diagnosed by ultrasound. The cystic or solid nature of pelvic masses can be assessed as well as their relationship to the uterus and adnexa.


On the strength-safety factor (SSF) for load-bearing skeletal organs.
The strength of healthy postnatal mammalian load-bearing bones, growth plates, joints, fascia, ligaments and tendons exceeds the minimum strength needed to keep voluntary mechanical usage from breaking or rupturing them or from causing arthroses. Thus, they have a strength-safety factor (SSF). Some general features of the physiology in the Utah paradigm of skeletal physiology can explain two things: (i) Why load-bearing bones should have an SSF, (ii) and why its numerical value should approximately 6 in healthy young adult mammals. The number and kinds of studies and facts that revealed those two things for load-bearing bones do not yet exist for the extraosseous load-bearing organs that are made with cartilage and collagenous tissue. However, clinical-pathologic observations suggest the latter organs' SSFs should depend on features analogous to those that create SSFs for load-bearing bones. If so, the physiology on which bone's SSF depends could suggest directions for future studies of the SSF determinants of load-bearing extraosseous organs. Biomechanicians currently favor strain above stress when discussing biomechanical roles in the functional adaptations of bones to mechanical loading. However, an SSF is best expressed in stress terms, so a Table in this article provides corresponding strain/stress/unit-load values for bone's three important thresholds, and for its ultimate strength.


Incremental cost of implementing residual insecticide treatment with delthametrine on top of intensive routine Aedes aegypti control.
Information on the cost of implementing residual insecticide treatment (RIT) for Aedes control is scarce. We evaluated the incremental cost on top of intensive conventional routine activities of the Aedes control programme (ACP) in the city of Santiago de Cuba, Cuba. We conducted the cost analysis study in 2011-2012, from the perspective of the ACP. Data sources were bookkeeping records, activity registers of the Provincial ACP Centre and the accounts of an RIT implementation study in 21 clusters of on average four house blocks comprising 5180 premises. The annual cost of the routine ACP activities was 19.66 US$ per household. RIT applications in rounds at 4-month intervals covering, on average, 97.2% and using 8.5 g of delthametrine annually per household, cost 3.06 US$ per household per year. Delthametrine comprised 66.5% of this cost; the additional cost for deploying RIT comprised 15.6% of the total ACP routine cost and 27% of the cost related to routine adult stage Aedes control. The incremental cost of implementing RIT is high. It should be weighed against the incremental effect on the burden caused by the array of pathogens transmitted by Aedes. The cost could be reduced if the insecticide became cheaper, by limiting the number of yearly applications or by targeting transmission hot spots.


INFLUENCE OF SEROLOGICAL MARKERS OF BLOOD GROUPS ON THE DEVELOPMENT OF VISUAL MEMORY FUNCTION IN YOUNG FEMALE ATHLETES AGED 13-15 YEARS.
The article investigates the influence of serological markers of blood groups on the development of the mental function of visual memory of young female athletes aged 13-15 years. The study involved girls of a specialised sports institution (n=168), who were divided into two groups: group A - speed and power sports (n=83); group B - endurance sports (n=85). The control group consisted of female students of secondary schools aged 13-15 years (n=113) and female students of higher education institutions aged 17-20 years (n=213) who do not engage in sports. The study of short-term visual memory function was conducted using the method of "memory for geometric shapes", which was proposed by Makarenko M.V. in co-authorship. The person had to memorise the location of 7 figures within 30 s and then reproduce them on a blank registration form within 45 s. The number of figures correctly drawn and placed in the form (correct answers) and the number of errors made by the person during the entire period of work were counted. The fact of possible use of blood groups in genetic prediction of the development of visual memory of the subjects was established. It was found that female students with blood group 0(I) who do not engage in sports have the best associative relationships with the properties of the mentioned function, while the worst relationship remains unclear. In female athletes with blood group 0(I), there is only a tendency towards improved development of the above function. The factor of sexual dimorphism does not make significant adjustments to the specifics of changes in visual memory function.


Jugular approach for percutaneous closure of atrial septal defect.
One hundred and forty-two consecutive procedures of percutaneous closure or atrial septal defect were approached by cannulation of the right femoral vein. In 3 of them, the internal jugular vein approach was also necessary because of azygos continuation or unsuccessful device implantation due to inadequate septal alignment. In all of them, device implantation was successfully performed through this alternative percutaneous vascular approach.


Spectrum of coronary artery disease in idiopathic hypertrophic subaortic stenosis.
The spectrum of coronary arterial involvement is described in 42 patients with hemodynamically proved idiopathic hypertrophic subaortic stenosis. Of nine patients with significant coronary arterial involvement, six had atheromatous disease and three had coronary arterial anomalies. The hemodynamic and clinical features of patients with coronary arterial involvement did not differ significantly from those of patients with normal coronary arteries. Neither the severity nor the character of the chest pain distinguished those patients with coronary disease. The diagnostic electrocardiographic features of myocardial infarction classically seen in patients with idiopathic hypertrophic subaortic stenosis were not present in the 9 patients with coronary arterial involvement but were found in 8 of the 33 patients with normal coronary arteries. The data demonstrate a significant incidence of coronary arterial involvement in patients with idiopathic hypertrophic subaortic stenosis after age 45 years.


Personality disorder and public mental health.
The diagnosis of personality disorder often appears to tell as much about the diagnoser as the diagnosed. For many it describes those who are deemed personally offensive, and as such it is not so much a diagnosis as a value judgment, the product of a negative interaction between two people that is given spurious respectability by a medical label. It is argued that these attitudes constitute a disastrous misperception of the truth, as personality disturbance (diathesis) in its many forms, including the unsatisfactory term 'disorder', is a highly significant contributor to human misery and handicap and a major cost to public mental health. It achieves this sorry record largely through stealth, because the current categorical system fails to embrace the breadth and heterogeneity of abnormal personality and the notion of offensive immutability makes the diagnosis a stigmatic one. This can be avoided by recoding personality in terms of severity. New treatments are now beginning to show evidence of efficacy and it is not unreasonable to hope that a condition that has been muttered about for years in parentheses will now be better recognised and defined, exposed without misunderstanding, and managed appropriately and well.


Long-term effects of CPAP on daytime functioning in patients with sleep apnoea syndrome.
Daytime sleepiness, impaired cognitive performance and dysphoric mood are often present in patients with obstructive sleep apnoea syndrome (SAS). This prospective controlled study evaluates the effects of treatment with continuous positive airway pressure (CPAP) during 1 yr on daytime functioning in a large group of patients with SAS. The authors studied 80 patients (mean+/-sem 49+/-1 yrs) with SAS with a mean apnoea-hypopnoea index of 60+/-2 h-1, and 80 healthy control subjects matched for sex and age (46+/-1 yrs.). Measurements were obtained at the beginning of the study and 12+/-1 months later, and included: daytime sleepiness (Epworth scale), depression and anxiety (Beck tests), vigilance (Steer-Clear) and reaction time (Psychometer Vigilance Test 192). Drug, coffee and alcohol intake, as well as the sleep schedule, were also recorded. Results showed that, before treatment, patients were more somnolent (p<0.001), anxious (p<0.01) and depressed (p<0.001) than control subjects. Also, they had a longer reaction time (p<0.05) and poorer vigilance (p<0.01). The use of CPAP improved significantly the levels of somnolence (p<0.0001) and vigilance (p<0.01), but failed to modify anxiety and depression. Reaction time changes were minor. Variables with a potential confounding effect did not change during the study. These results provide firm evidence to substantiate the use of continuous positive airway pressure in patients with sleep apnoea syndrome.


Embracing Biological and Methodological Variance in a New Approach to Pre-Clinical Stroke Testing.
High-profile failures in stroke clinical trials have discouraged clinical translation of neuroprotectants. While there are several plausible explanations for these failures, we believe that the fundamental problem is the way clinical and pre-clinical studies are designed and analyzed for heterogeneous disorders such as stroke due to innate biological and methodological variability that current methods cannot capture. Recent efforts to address pre-clinical rigor and design, while important, are unable to account for variability present even in genetically homogenous rodents. Indeed, efforts to minimize variability may lessen the clinical relevance of pre-clinical models. We propose a new approach that recognizes the important role of baseline stroke severity and other factors in influencing outcome. Analogous to clinical trials, we propose reporting baseline factors that influence outcome and then adapting for the pre-clinical setting a method developed for clinical trial analysis where the influence of baseline factors is mathematically modeled and the variance quantified. A new therapy's effectiveness is then evaluated relative to the pooled outcome variance at its own baseline conditions. In this way, an objective threshold for robustness can be established that must be overcome to suggest its effectiveness when expanded to broader populations outside of the controlled environment of the PI's laboratory. The method is model neutral and subsumes sources of variance as reflected in baseline factors such as initial stroke severity. We propose that this new approach deserves consideration for providing an objective method to select agents worthy of the commitment of time and resources in translation to clinical trials.


Review: formation and properties of amyloid-like fibrils derived from alpha-synuclein and related proteins.
Synucleinsare small proteins that are highly expressed in brain tissue and are localised at presynaptic terminals in neurons. alpha-Synuclein has been identified as a component of intracellular fibrillar protein deposits in several neurodegenerative diseases, and two mutant forms of alpha-synuclein have been associated with autosomal-dominant Parkinson's Disease. A fragment of alpha-synuclein has also been identified as the non-Abeta component of Alzheimer's Disease amyloid. In this review we describe some structural properties of alpha-synuclein and the two mutant forms, as well as alpha-synuclein fragments, with particular emphasis on their ability to form beta-sheet on ageing and aggregate to form amyloid-like fibrils. Differences in the rates of aggregation and morphologies of the fibrils formed by alpha-synuclein and the two mutant proteins are highlighted. Interactions between alpha-synuclein and other proteins, especially those that are components of amyloid or Lewy bodies, are considered. The toxicity of alpha-synuclein and related peptides towards neurons is also discussing in relation to the aetiology of neurodegenerative diseases.


Falls and falls efficacy: the role of sustained attention in older adults.
Previous evidence indicates that older people allocate more of their attentional resources toward their gait and that the attention-related changes that occur during aging increase the risk of falls. The aim of this study was to investigate whether performance and variability in sustained attention is associated with falls and falls efficacy in older adults. 458 community-dwelling adults aged ≥ 60 years underwent a comprehensive geriatric assessment. Mean and variability of reaction time (RT), commission errors and omission errors were recorded during a fixed version of the Sustained Attention to Response Task (SART). RT variability was decomposed using the Fast Fourier Transform (FFT) procedure, to help characterise variability associated with the arousal and vigilance aspects of sustained attention.The number of self-reported falls in the previous twelve months, and falls efficacy (Modified Falls Efficacy Scale) were also recorded. Significant increases in the mean and variability of reaction time on the SART were significantly associated with both falls (p < 0.01) and reduced falls efficacy (p < 0.05) in older adults. An increase in omission errors was also associated with falls (p < 0.01) and reduced falls efficacy (p < 0.05). Upon controlling for age and gender affects, logistic regression modelling revealed that increasing variability associated with the vigilance (top-down) aspect of sustained attention was a retrospective predictor of falling (p < 0.01, OR = 1.14, 95% CI: 1.03-1.26) in the previous year and was weakly correlated with reduced falls efficacy in non-fallers (p = 0.07). Greater variability in sustained attention is strongly correlated with retrospective falls and to a lesser degree with reduced falls efficacy. This cognitive measure may provide a novel and valuable biomarker for falls in older adults, potentially allowing for early detection and the implementation of preventative intervention strategies.


All-fiber acousto-optic polarization monitor.
We describe the operational principle of and experimentally demonstrate a narrowband, wavelength-tunable polarization monitor based on a fiber acousto-optic tunable filter. Two orthogonally vibrating acoustic waves are used to create a variable polarizer that can be used to measure the state of polarization of an incident narrowband light source. The accuracy of the polarization monitor is measured at two different wavelengths in reference to a commercial polarimeter and is shown to be within 5%.


Birth weight discordance in very and extremely preterm twins and the risk of neonatal hearing loss.
Birth weight (BW) discordant twins have an increased risk of mortality and morbidity. We aimed to study the effect of BW discordance on the risk of neonatal hearing loss (NHL) in very and extremely preterm twins. Results of the nationwide newborn hearing screening program in Dutch Neonatal Intensive Care Units and diagnostic examination were centrally registered between 2003 and 2021 and included in this study. We selected twins and singletons with a gestational age (GA) 24- < 32 weeks. Logistic regression analyses were applied to study the effect of BW discordance on the risk of NHL adjusted for BW, GA and sex. Singletons and concordant twins, defined as a BW discordance of ≤20 %, were used as two reference groups. BW discordance was further categorized as medium (>20-30 %) and high (>30 %). In total, 3430 twins (2694 concordant, 428 medium and 308 high BW discordant), and 23,114 singletons were available. Smaller newborns of high BW discordant twins showed an increased risk of NHL compared to singletons (adjusted odds ratio with 95 % confidence interval was 3.56 (2.26-5.60)). Also, smaller newborns of medium and high BW discordant twins showed an increased risk of NHL compared to concordant twins (adjusted odds ratio with 95 % confidence interval were 1.97 (1.13-3.44) and 4.17 (2.56-6.82), respectively). No other statistically significant differences were found. BW discordance increased the risk of NHL in the smaller of the twin born very or extremely preterm. This risk increased as the weight difference increased.


The Vulnerability of Qilian Juniper to Extreme Drought Events.
Identifying which trees are more vulnerable to extreme climatic events is a challenging problem in our understanding of forest and even ecosystem dynamics under climate change scenarios. As one of the most widely distributed tree species across the arid and semi-arid northeastern Tibetan Plateau, Qilian juniper (Juniperus przewalskii Kom.), is the main component of the local forest ecosystem, providing critical insurance for the ecological security of the surrounding areas. However, this species's ability to cope with climate extremes (especially drought) has not been adequately assessed. Here, we apply a dendroecological approach that considers indices of resistance and resilience to quantify the vulnerability of Qilian junipers to the extreme drought events of 1957, 1966, 1979, and 1995. A total of 532 Qilian juniper trees from different age stages (100-1,100 years) and altitudes [3,500-4,000 m above sea level (a.s.l.)] were studied to assess their response characteristics during these four drought extremes. We conclude that drought extremes have a significant negative impact on the growth of Qilian juniper. The oldest Qilian junipers at the lower altitudes constituted the most vulnerable populations across the northeastern Tibetan Plateau and were characterized by the lowest resistance values, the narrowest annual rings, and the highest proportion of missing rings during the four drought years. Tree resilience after droughts was strongly related to the intensity of the drought event and did not change with tree age or elevation. A threshold of tree tolerance to drought may exist, with the more vulnerable tree individuals (e.g., the oldest Qilian junipers from lower altitudes) being exposed to the highest mortality risk when drought intensity exceeds the threshold value. Such a threshold needs further consideration, through the study of trees that have died (or are about to die) due to extreme droughts.