A clinicopathological approach to the diagnosis of dementia.
The most definitive classification systems for dementia are based on the underlying pathology which, in turn, is categorized largely according to the observed accumulation of abnormal protein aggregates in neurons and glia. These aggregates perturb molecular processes, cellular functions and, ultimately, cell survival, with ensuing disruption of large-scale neural networks subserving cognitive, behavioural and sensorimotor functions. The functional domains affected and the evolution of deficits in these domains over time serve as footprints that the clinician can trace back with various levels of certainty to the underlying neuropathology. The process of phenotyping and syndromic classification has substantially improved over decades of careful clinicopathological correlation, and through the discovery of in vivo biomarkers of disease. Here, we present an overview of the salient features of the most common dementia subtypes - Alzheimer disease, vascular dementia, frontotemporal dementia and related syndromes, Lewy body dementias, and prion diseases - with an emphasis on neuropathology, relevant epidemiology, risk factors, and signature signs and symptoms.


Oxygen influences benzyladenine and 2,4-dichlorophenoxyacetic acid levels in cultured embryogenic tissue of Norway spruce.
It is known that reducing the partial pressure of O2 influences the induction of somatic embryogenesis. We tested the hypothesis that O2 causes changes in the endogenous levels of exogenously supplied benzyladenine (BA) or 2,4-dichlorophenoxyacetic acid (2,4-D). Embryogenic tissue of Picea abies was incubated under reduced (2.5, 5 kPa) and ambient (21 kPa) levels of O2 for 1, 3, 7 and 11 days and the endogenous concentrations of BA and 2,4-D were measured. For all treatments the concentration of BA in the tissue increased until the third day. At day 3, the ratio of BA in the tissue relative to the initial concentration in the medium, was 3.9, 2.8 and 1.9 for tissue incubated under 2.5, 5 and 21 kPa O2 , respectively. The BA concentration then declined gradually. Uptake of 2,4-D was inhibited at low O2 levels. However, 2,4-D gradually accumulated in tissue grown under hypoxia, so that high levels were reached by day 11. These shifts in the BA and 2,4-D levels also caused a transient increase in the BA to 2,4-D ratio in tissue incubated under hypoxia. Although relevant for the previously reported effects of oxygen on induction of embryogenic tissue, it is unlikely that oxygen-induced alterations in BA and 2,4-D levels alone suffice to explain these findings.


Proteomics-driven identification of SCO4677-dependent proteins in Streptomyces lividans and Streptomyces coelicolor.
AfsR2 is a global regulatory protein which stimulates antibiotic biosynthesis in both Streptomyces lividans and S. coelicolor. Previously, various afsR2-dependent genes including a putative abaA-like regulatory gene, SCO4677, were identified through comparative DNA microarray analysis. To further identify the putative SCO4677-dependent proteins, the comparative proteomics-driven approach was applied to the SCO4677-overexpressing strains of S. lividans and S. coelicolor along with the wild-type strains. The 2D gel-electrophoresis gave approximately 277 protein spots for S. lividans and 207 protein spots for S. coelicolor, showing different protein expression patterns between the SCO4677-overexpressing strains and the wild-type strains. Further MALDI-TOF analysis revealed that only 18 proteins exhibited similar expression patterns in both S. lividans and S. coelicolor, suggesting that the SCO4677 could encode an abaA-like regulator which controls a few cross-species proteins as well as many species-specific proteins in Streptomyces species.


Transposon accumulation at xenobiotic gene family loci in aphids.
The evolution of resistance is a major challenge for the sustainable control of pests and pathogens. Thus, a deeper understanding of the evolutionary and genomic mechanisms underpinning resistance evolution is required to safeguard health and food production. Several studies have implicated transposable elements (TEs) in xenobiotic-resistance evolution in insects. However, analyses are generally restricted to one insect species and/or one or a few xenobiotic gene families (XGFs). We examine evidence for TE accumulation at XGFs by performing a comparative genomic analysis across 20 aphid genomes, considering major subsets of XGFs involved in metabolic resistance to insecticides: cytochrome P450s, glutathione S-transferases, esterases, UDP-glucuronosyltransferases, and ABC transporters. We find that TEs are significantly enriched at XGFs compared with other genes. XGFs show similar levels of TE enrichment to those of housekeeping genes. But unlike housekeeping genes, XGFs are not constitutively expressed in germline cells, supporting the selective enrichment of TEs at XGFs rather than enrichment owing to chromatin availability. Hotspots of extreme TE enrichment occur around certain XGFs. We find, in aphids of agricultural importance, particular enrichment of TEs around cytochrome P450 genes with known functions in the detoxification of synthetic insecticides. Our results provide evidence supporting a general role for TEs as a source of genomic variation at host XGFs and highlight the existence of considerable variability in TE content across XGFs and host species. These findings show the need for detailed functional verification analyses to clarify the significance of individual TE insertions and elucidate underlying mechanisms at TE-XGF hotspots.


A multiparametric approach to assessing residual pain experienced by dairy cows undergoing digestive tract surgery under multimodal analgesia.
This study assessed residual pain responses of dairy cows undergoing fistulation surgery under multimodal analgesia using a multiparametric method combining behavioural and physiological indicators. A longitudinal study was conducted on five dairy cows, each acting as her own control. The surgery consisted of implanting a ruminal and a duodenal cannula in each cow. The multimodal drug protocol consisted of a combination of N-Methyl-D aspartic Acid antagonists, α2-agonists, and local anaesthetic during surgery, and non-steroidal anti-inflammatory drugs (NSAIDs) and opioid treatment postsurgery. Cow responses to surgery were monitored by direct behavioural observation, physiological assay indicators, and milk production from day (D) -6 days before surgery (D-6) to D13 postsurgery. From the data recorded, the variables that contributed most to the discrimination of days pre- and postsurgery were identified using factorial discriminant analysis. Components 1 and 2 of the factorial discriminant analysis explained 68.2% and 17.9%, respectively, of the total variance. Component 1 was mainly explained by haptoglobin (contribution to axis: 0.885), oxidative stress (ratio of oxidized gluthatione to reduced glutathione (GSH/GSSG), -0.746; vitamin E, -0.683; vitamin A, -0.597; malondialdehyde (MDA), 0.416), and behavioural indicators (general attitude, 0.594). On this axis, the higher the score, the higher were the apathy and haptoglobin and MDA concentrations, and the lower were the GSH/GSSG ratio and concentrations of vitamins A and E. This axis opposed cows on D-6 to cows on D3 and D5; cows on D1 and D13 were intermediate. Component 2 was mainly explained by the Hypothalamic-pituitary-adrenal axis (non-esterified fatty acid (NEFA), 0.686; cortisol, 0.669), milk yield (-0.725), oxidative stress (MDA, -0.584; nitric oxide (NO), 0.454), and behavioural indicators of pain (ear position, 0.467; leg postures, 0.431). On this axis, the higher the score, the higher the NEFA, cortisol, and nitric oxide concentrations; the more the ear and leg pain postures; and the lower the milk production and MDA concentrations. This axis opposed cows on D13 to cows on D1. These results suggest that cows may experience some pain only on D1, whereas on subsequent days, the inflammatory response and oxidative stress did not seem to be associated with pain. Our results should be considered for different surgeries to improve analgesia immediately after surgery, and to provide antioxidants along with NSAIDs to promote recovery.


Factors associated with different types of birth attendants for home deliveries: an analysis of the cross-sectional 2010 South Sudan household survey.
In South Sudan, birth deliveries attended by unskilled birth attendants put the mothers and their newborns at increased risk of perinatal morbidity and mortality. The aim of this study was to identify factors associated with delivery by unskilled birth attendants or by unassisted delivery. We examined data for 2,767 (weighted total) women aged 15-49 years who delivered at home 2 years prior to the South Sudan Household Health Survey 2010. Multinomial logistic regression analyses were used to identify factors associated with delivery by unskilled birth attendants or by unassisted delivery. The prevalence of delivery by unskilled birth attendants was 19% [95% confidence interval (CI) 17.0, 20.5], by skilled birth attendants (SBAs) was 45% (95% CI 42.4, 47.0), and by unassisted delivery was 36% (95% CI 34.2, 38.6). After adjusting for potential confounders, the following factors were associated with the increased odds for unassisted delivery or delivery by an unskilled birth attendant: mothers with no schooling, who did not attend antenatal care (ANC) during pregnancy, who had lower quality of ANC services, from poor households, or who had no prior knowledge about obstetric danger signs. We found that non-utilization of maternal health care services, such as ANC, was significantly associated with unattended birth delivery or delivery by unskilled health providers. The increased uptake of SBAs at delivery will require easier access to ANC services, health promotion on the importance and benefits of SBAs for delivery, targeting both mothers and their families, and the training and deployment of more SBAs across the country.


Unraveling the Gordian knot: red blood cell storage lesion and transfusion outcomes.
What is following the impressive progress that has been made? During the last couple of years several tremors have shaken the field of Transfusion Medicine. The epicentres of those tremors were located on novel insights into the RBC storage lesion, on emerging connections between storage lesion and post-transfusion performance and effects, and on acknowledging that storage time is only one (rather than the most prominent) of the parameters which contribute to the progression of storage lesion in any given unit of blood. The optimisation of bio-preservation conditions emerged at the same time with all-new scientific knowledge gained by advances in research tools, implementation of technological innovations, and application of elegant in vitro and in vivo models of transfusion. Simultaneously, one after another, all the reported randomised clinical trials concluded, with spectacular consensus, that there is no significant difference in the rate of adverse clinical events (including death) among patients who underwent transfusion with fresh (and presumably good) or standard of care (and presumably bad) blood. The comparative analysis and comprehension of the aforementioned data would set the context for the next generation of research in blood transfusion science, since the need for safer and more efficient transfusions remains.


Identification of metabolites in human and rat urine after oral administration of Xiao-Qing-Long-Tang granule using ultra high performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry.
Xiao-Qing-Long-Tang is a traditional Chinese formula used for the treatment of cold syndrome, bronchitis, and nasal allergies for thousands of years. However, the in vivo integrated metabolism of its multiple components and the active chemical constituents of Xiao-Qing-Long-Tang remain unknown. In this study, a method using ultra high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry was established for the detection and identification of the metabolites in human and rat urine after oral administration of Xiao-Qing-Long-Tang. A total of 19 compounds were detected or tentatively identified in human urine samples, including eight prototypes and 11 metabolites. Also, a total of 50 compounds were detected or tentatively identified in rat urine samples, including 15 prototypes and 35 metabolites detected with either a highly sensitive extracted ion chromatogram method or the MSE determination using Mass Fragment software. Our results indicated that phase Ⅱ reactions (e.g. glucuronidation and sulfation) were the main metabolic pathways of flavones, while phase I reactions (e.g. demethylation and hydroxylation) were the major metabolic reaction for alkaloids, lignans, and ginger essential oil. This investigation provided important structural information on the metabolism of Xiao-Qing-Long-Tang and provided evidence to obtain a more comprehensive metabolic profile.


All-optical logic gates based on unidirectional surface plasmon polaritons.
Optical logic gates are important elements in optical computing and optical circuits. In this study, all-optical logic gates, including OR, XOR, XNOR, NAND, and NOT gates, are obtained in a composite structure composed of gyroelectric material and metal based on the interference and absorption of surface waves. In the composite structure, a Y-shaped channel through which surface plasmon polaritons propagate unidirectionally is formed. Through the ingenious one-way surface plasmon polaritons, backscattering and side-scattering generated by the composite structure and influencing the surrounding devices are prohibited effectively. The precisely controlled optical phase difference ensures the realization of five different logic gates with high contrast ratios. The maximum contrast ratios for XOR, XNOR, NAND, and NOT gates are 31.64 dB, 43.47 dB, 31.47 dB, and 43.47 dB, respectively. The output logic states "1"or "0" obtained by different logic inputs have nearly the same light intensity. Our research results provide the possibility for constructing all-optical integrated logic devices.


Monopolar electrosurgical flash fire.
A 78-year-old man underwent ectropion repair with a monopolar electrosurgical unit. A flash fire occurred, resulting in a loss of eyelashes of the left upper and lower eyelids. A retrospective analysis of the case was conducted, including a review of the relevant literature. Although rare, the possibility of a flash fire should be considered when performing surgery with an electrosurgical unit. Minimizing supplemental oxygen and electrosurgical power settings may help to avoid such an incident.


Effect of Illness Perception Correction - Based Educational Program on Quality Of Life and Self- Care in Patients with Heart Failure: a Randomized Controlled Trial.
Introduction: Because of the chronic nature of Heart Failure (HF), low Quality of Life (QoL) and poor self-care are prevalent among patients with HF. Thus, the aim of this study was to evaluate the effect of illness perception correction- based educational program on QoL,and self- care in patients with HF. Methods: In this randomized controlled trial, 78 eligible patients were included in the study from Rajaei Heart Center (Tehran, Iran) and randomly assigned into intervention and control group with 1:1 allocation ratio. The intervention was a combination of illness perception correction- based education program (30- minute sessions over 3 consecutive days) and 10-minute phone calls made once a week in the course of 8 weeks. The control group received usual care. The primary outcome was quality of life and secondary outcomes were self- care and illness- perception which were measured at baseline and at the end of the study. SPSS version 13 was used for the analysis. Results: Out of 76 eligible patients, 70 patients with HF finished the study. Although the mean of quality of life, self-care, and illness perception were not different at baseline, QoL (45.2 (8.3) VS 66.8 (15.4); P<0.001), self-care (18.5 (4.5) VS 37.1 (7.2); P<0.001), and illness- perception (183.6 (8.4) VS 151.2 (24.5); P<0.001) improved following the program in the intervention group in comparison to the control group. Conclusion: According to the study findings, this program can be applied by nurses for patients with HF as a discharge plan in order to improve their QoL, self-care, and their illness perception.


What to Do in the Next Pandemic Outbreak: Natural Herd Immunity Versus Lockdown (Lessons Learned from COVID-19).
The purpose of this article is to analyse non-pharmaceutical approaches to control pandemics. Currently vaccines are our best hope to control the COVID-19 pandemic, but before the appearance of the first vaccines the available possibilities were much more limited. While most people worldwide were confined to their homes to slow the spread of the new coronavirus, some countries (most notably the United Kingdom) advocated infecting the majority of the community, aiming to achieve what has been called "herd immunity". This article focuses on two non-therapeutic strategies for dealing with deadly viruses and points out their respective problems: natural herd immunity and quarantines/lockdowns. It analyses these strategies from three perspectives: legal, ethical and social. The article concludes that in the absence of therapeutic alternatives (vaccines), short-term lockdowns are necessary, but long-term lockdowns are legally, ethically, socially and financially impossible to sustain.


[Comparison of lansoprazole (30 mg) and omeprazole (20 mg) in the treatment of duodenal ulcer. A multicenter double-blind comparative trial].
The efficacy of lansoprazole (30 mg/d) and omeprazole (20 mg/d) has been assessed in active duodenal ulcer disease in 144 patients included in a multicentric, randomized, double-blind trial. After two weeks, the healing rates were 74% and 58% in the lansoprazole and omeprazole groups, respectively (P = 0.049). After 4 weeks, the healing rates were 94% in each group (NS). The delay to pain relief was 2 days for lansoprazole and 3 days for omeprazole (NS). Minor side effects occurred in 12% of the lansoprazole treated patients and in 13% of the omeprazole treated patients. No severe adverse events were reported. A slight increase in serum gastrin level was observed, similar in both groups (+35 UI/L and +19 UI/L for lansoprazole and omeprazole respectively). This study confirms previous results concerning the efficacy of both treatments in duodenal ulcer disease. The statistical difference observed for healing rates after 2 weeks could correspond to a faster efficacy for lansoprazole (30 mg) than for omeprazole (20 mg).


Molecular characterization reveals the complexity of previously overlooked coral-exosymbiont interactions and the implications for coral-guild ecology.
Several obligate associate crabs and shrimps species may co-occur and interact within a single coral host, leading to patterns of associations that can provide essential ecological services. However, knowledge of the dynamics of interactions in this system is limited, partly because identifying species involved in the network remains challenging. In this study, we assessed the diversity of the decapods involved in exosymbiotic assemblages for juvenile and adult Pocillopora damicornis types α and β on reefs of New Caledonia and Reunion Island. This approach revealed complex patterns of association at regional and local scales with a prevalence of assemblages involving crab-shrimp partnerships. Furthermore, the distinction of two lineages in the snapping shrimp Alpheus lottini complex, rarely recognized in ecological studies, reveals a key role for cryptic diversity in structuring communities of mutualists. The existence of partnerships between species that occurred more commonly than expected by chance suggests an increased advantage for the host or a better adaptation of associated species to local environmental conditions. The consideration of cryptic diversity helps to accurately describe the complexity of interaction webs for diverse systems such as coral reefs, as well as the functional roles of dominant associated species for the persistence of coral populations.


Adverse response to pegylated interferon therapy in two patients with chronic hepatitis C.
Pegylated interferons have recently been approved for treatment of hepatitis C. The safety of these formulations is reported to be similar to that of non-pegylated interferon. We present two patients who experienced exacerbations of their liver disease following administration of pegylated interferon alfa-2b. Vigilant monitoring of patients treated with these new agents is recommended.


Striving for equity in academia: embracing the power of no in decision-making.
In academia, saying "yes" to opportunities and "no" to distractions is crucial for effective decision-making. Here, we emphasize the importance of carefully considering commitments and courageously declining those that may lead to overextension. We highlight that discernment is vital, particularly for junior faculty/scientists and those with marginalized identities, as overcommitment can hinder career advancement. The "Fame, Fortune, and Fun test" offers a practical heuristic for evaluating opportunities, enabling academics to make informed choices. Saying "no" effectively involves preserving personal and professional integrity by declining tasks that do not align with one's abilities or interests. However, challenges in saying "no" are multifaceted, including fear of missing career advancements, pressures to please superiors or peers, and perceived negative consequences. This decision can be even more complex for individuals with minoritized identities, as additional expectations and responsibilities may arise due to implicit biases. The article provides a scheme for academics when deciding whether to accept or decline opportunities. The "Fame, Fortune, and Fun test" is a simplified scheme based on the Japanese concept of Ikigai, which comes from two words that mean life's purpose. The concept allows an individual to determine their reason for being and aim to align their time spent with as many components that satisfy the following four categories: what one loves, what one is good at, what one can be paid for, and what the world needs. The more overlap, the more alignment with Ikigai, and the more compelling reason to say yes. Once one has determined that they can say no, effectively saying "no" involves clear and direct communication, offering alternatives, expressing gratitude, and considering a "not now" approach if unable to commit immediately. To promote inclusivity, we suggest recommending individuals from diverse backgrounds for opportunities. By amplifying underrepresented voices, we can foster a healthier academic environment. Saying "no" empowers academics to prioritize meaningful contributions and maintain work-life balance. Embracing the power of "no" is essential for maintaining integrity and well-being in academia. Junior faculty/scientists and individuals with marginalized identities may face additional challenges in their decision-making. By carefully evaluating commitments and effectively declining non-aligning opportunities, academics can focus on what truly matters, fostering a supportive and thriving academic environment.


Toxicity of myristic acid analogs toward African trypanosomes.
New drugs are needed for treatment of diseases caused by African trypanosomes. One possible target for chemotherapy is the biosynthesis of the glycosyl phosphatidyl-inositol (GPI) of this parasite's variant surface glycoprotein (VSG). Unlike mammalian GPIs, the diacylglycerol moiety of the VSG anchor contains only myristate (tetradecanoate), added in unique remodeling reactions. We previously found that 11-oxatetradecanoic acid [i.e., 10-(propoxy)decanoic acid] is selectively toxic to trypanosomes. We have now assayed 244 different fatty acid analogs, most with chain lengths comparable to that of myristate, for trypanocidal effects. In these assays we surveyed the effects on toxicity of systematic alterations in the analogs' steric, conformational, and hydrophobic properties. We also used three 3H-labeled oxatetradecanoic acids to explore the mechanism of analog action. Their incorporation into VSG correlated roughly with toxicity, although they also were incorporated into phospholipids and other proteins. Myristate analogs are useful for studying the mechanism of GPI myristolyation, and they are candidates for antitrypanosomal chemotherapy.


Post-pneumonic thoracic empyema in children: a continued surgical challenge.
The optimal treatment of post-pneumonic thoracic empyema in children is controversial. In this retrospective study, we review our seven-year experience with open surgical drainage in this condition. Between July 1, 1989, and June 30, 1996, 20 children (median age 2.7 years, range 1-8 years) underwent thoracotomy for post-pneumonic empyema in our department. The diagnosis of thoracic empyema was established by the combination of exudate in a pleural tap and the demonstration of multi-loculated pleural effusion by either chest ultrasound or computerized tomography of the chest. The surgical approach was through a posterolateral mini-thoracotomy under general anesthesia. Intrapleural debris, gelatinous, and fibrinous material were evacuated and drains were placed, under vision, at the most dependent pleural locations. The mean length of pre-hospital illness was 5 days (S.D. 3.1 days) and the mean hospital length of stay in a pediatric ward prior to surgery, during which all children received intravenous antibiotics, was 9.4 days (S.D. 7.7 days). A causative pathogen was identified in 8 cases: Streptococcus pneumoniae in 6 cases, Streptococcus group A, and H. influenzae each in one case. Cultures from the pus removed during surgery were sterile for all 19 children who received antibiotics for more than 24 hours prior to surgery. Within 48 hours after surgery, fever dropped to < 37.5 degrees C in 85% of the cases. The postoperative course was uneventful in all cases and the children were discharged home 9 days (S.D. 2.8 days) after surgery. We conclude that open mini-thoracotomy and removal of the entire empyema sac is a safe and curative procedure for children with thoracic empyema.


Draft Genome Sequence of Bacillus pumilus Strain GM3FR, an Endophyte Isolated from Aerial Plant Tissues of Festuca rubra L.
Here, we report the draft genome sequence of Bacillus pumilus GM3FR, an endophytic bacterium isolated from aerial plant tissues of Festuca rubra L. The draft genome consists of 3.5 Mb and harbors 3,551 predicted protein-encoding genes. The genome provides insights into the biocontrol potential of B. pumilus GM3FR.


Carbon-bound diazeniumdiolates from the reaction of nitric oxide with amidines.
[reaction: see text] The enediamine tautomer of a variety of substituted amidine free bases reacts with nitric oxide (NO) to produce compounds containing a carbon-bound diazeniumdiolate [R1R2R3C-N(O)=NO-] functional group (previously called "nitrosohydroxylamines"). The new reaction has been shown to be quite general, although the nature of the products does vary. Amidines containing more than one replaceable hydrogen produce polydiazeniumdiolates as intermolecular salts, while those in which only one diazeniumdiolation can occur provide zwitterionic salts. These diazeniumdiolated amidines are shown to be useful NO donor compounds which undergo very slow spontaneous dissociation on dissolution in pH 7.4 phosphate buffer to produce mixtures of NO and nitrous oxide containing mostly NO. The most advantageous manifestation of the new discovery is the preparation of the monodiazeniumdiolated amidine zwitterions. Reaction of the medically relevant alpha-adrenergic agonists tetrahydrozoline and idazoxan produced monodiazeniumdiolated amidine zwitterions from which NO release was observed for up to 28 days and showed little sign of ending. The reaction should be applicable to a variety of pharmaceutical agents, including NO synthase inhibitors, antitumor agents, and antibacterials.


The impact of COVID-19 pandemic lockdowns on air quality index: a systematic review.
During the outbreak of the novel coronavirus disease 2019 (COVID-19), many countries implemented lockdown policies to control its transmission. These restrictions provided an opportunity to rest and recover the environment. This systematic review (SR) aimed to evaluate the impact of COVID-19 lockdowns on the Air Quality Index (AQI) in countries worldwide. ScienceDirect and PubMed were searched using relevant keywords to identify studies published until March 2020. Overall, 20 studies were included in the SR based on the eligibility criteria. The results show that COVID-19-related lockdown policies positively affect AQI by restricting air-polluting activities, such as transportation, industry, and construction. However, it is important to note that these policies are ineffective in controlling sources of natural air pollution and local dust. The findings of this study emphasize the need for policymakers to approve legislation limiting the sources of air pollutants.


The canine sodium/myo-inositol cotransporter gene: structural organization and characterization of the promoter.
The sodium/myo-inositol cotransporter (SMIT) is a plasma membrane protein catalyzing transfer of myo-inositol into cells against a considerable concentration gradient using the electrochemical potential of sodium across the cell membrane. Transcription of the SMIT gene is markedly stimulated when cells are exposed to a hypertonic environment resulting in increased abundance of SMIT mRNA and increased SMIT activity. The increased accumulation of myo-inositol protects cells from the deleterious effects of hypertonicity. In an effort toward understanding transcriptional regulation, we cloned canine genomic DNA fragments containing the SMIT gene. The gene is 37 kb in size consisting of 2 exons and a large intron of 25 kb. The entire open reading frame is in the second exon. The promoter of the gene is highly active due to a GC-rich sequence. Ribonuclease protection assay using a riboprobe complementary to the 5' end of the gene confirmed that the promoter of the gene is stimulated by hypertonicity. The promoters and regulatory sequences of the SMIT gene and the betaine transporter gene, another gene regulated by hypertonicity, appear to be different.


Synthesis and biological evaluation of an orally active glycosylated endomorphin-1.
The endogenous opioid peptide endomorphin-1 (1) was modified by attachment of lactose to the N-terminus via a succinamic acid spacer to produce compound 2. The carbohydrate modification significantly improved the metabolic stability and membrane permeability of 2 while retaining μ-opioid receptor binding affinity and agonist activity. Analogue 2 produced dose-dependent antinociceptive activity following intravenous administration in a chronic constriction injury (CCI) rat model of neuropathic pain with an ED(50) of 8.3 (± 0.8) μmol/kg. The corresponding ED(50) for morphine was 2.6 (± 1.4) μmol/kg. Importantly, compound 2 produced dose-dependent pain relief after oral administration in CCI rats (ED(50) = 19.6 (± 1.2) μmol/kg), which was comparable with that of morphine (ED(50) = 20.7 (±3.6) μmol/kg). Antineuropathic effects of analogue 2 were significantly attenuated by pretreatment of animals with the opioid antagonist naloxone, confirming opioid receptor-mediated analgesia. In contrast to morphine, no significant constipation was produced by compound 2 after oral administration.


Sulfide as a signaling molecule in autophagy.
Hydrogen sulfide is already recognized as an important signaling molecule in mammalian systems, and emerging data suggest that H2S is a signaling molecule just as important as nitric oxide (NO) and H2O2 in plants. Although sulfide is generated in chloroplasts and mitochondria, it is present predominantly in the charged HS (-) form due to the basic pH inside both organelles, thus requiring an active transporter, which is yet to be identified, to be released. In Arabidopsis, we found that the cytosolic L-cysteine desulfhydrase DES1 is involved in the degradation of cysteine, and therefore responsible for the generation of H2S in this cellular compartment. DES1 deficiency leads to the induction of autophagy. Moreover, we have demonstrated that sulfide in particular exerts a general effect on autophagy through negative regulation, in a way unrelated to nutrient deficiency. The mechanisms of H2S action and its molecular targets are largely unknown, although in animal systems, protein S-sulfhydration has been proposed as a mechanism for sulfide-mediated signaling.


Frequentist analysis of basket trials with one-sample Mantel-Haenszel procedures.
Recent substantial advances of molecular targeted oncology drug development is requiring new paradigms for early-phase clinical trial methodologies to enable us to evaluate efficacy of several subtypes simultaneously and efficiently. The concept of the basket trial is getting of much attention to realize this requirement borrowing information across subtypes, which are called baskets. Bayesian approach is a natural approach to this end and indeed the majority of the existing proposals relies on it. On the other hand, it required complicated modeling and may not necessarily control the type 1 error probabilities at the nominal level. In this article, we develop a purely frequentist approach for basket trials based on one-sample Mantel-Haenszel procedure relying on a very simple idea for borrowing information under the common treatment effect assumption over baskets. We show that the proposed Mantel-Haenszel estimator for the treatment effect is consistent under two limiting models of the large strata and sparse data limiting models (dually consistent) and propose dually consistent variance estimators. The proposed estimators are interpretable even if the common treatment effect assumptions are violated. Then, we can design basket trials in a confirmatory matter. We also propose an information criterion approach to identify effective subclasses of baskets.


Severe hypernatraemia due to nephrogenic diabetes insipidus - a life-threatening side effect of chronic lithium therapy.
Renal toxicity of long-term lithium therapy is a common problem. Nephrogenic diabetes insipidus is the most frequently encountered complication, but often remains unrecognised because of the rather benign symptoms. We present a patient with long-term lithium therapy who developed life-threatening hypernatraemia due to insufficient oral fluid intake after elective spinal surgery. Careful daily substitution of up to 25 l of hypotonic fluids led to full recovery within 9 days. Nephrogenic diabetes insipidus should always be considered in lithium-treated patients undergoing elective surgery in order to avoid severe hypernatraemia.


Elevation of NMDAR after transplantation of neural stem cells.
Cognitive deficits could be alleviated by transplantation of neural stem cells in animals. Grafted cells may differentiate into neurons, thereby improving animal cognition. Alternatively, grafted cells may provide neurotrophic factors to modify neuronal functions and to alleviate cognitive deficits. To test which mechanism is underlying this recovery process, senescence-accelerated mice were transplanted with human neural stem cells into the hippocampus. The effect of cell transplantation was assessed in the Morris water maze. The survival and differentiation of grafted cells and the expression of NMDA receptors were examined. The data suggested that in addition to the neural differentiation of grafted neural stem cells, up-regulation of NMDA receptors after transplantation also contributed to the alleviation of cognitive deficits in this animal model.


Implications of maraviroc and/or rapamycin in a mouse model of fragility.
As age increases, the risk of developing fragility also increases. Improving the knowledge of frailty could contribute to maintaining the functional ability of elderly people. Interleukin (IL)-10 homozygous knockout mice (IL-10tm/tm [IL10KO]) constitute an excellent tool for the study of frailty. Because patients with frailty demonstrate an overexpression of CCR5, rapamycin (RAPA) and/or maraviroc (MVC), two molecules able to decrease CCR5 expression, were evaluated. Muscle myostatin was reduced in all the therapeutic groups but the MVC group (p <0.001 for RAPA and MVC-RAPA) and in serum samples (p <0.01 for all the groups). Serum CK levels were also significantly lower in MVC and RAPA groups (p <0.01 in both cases). Lower AST levels were observed in all the therapeutic groups (p <0.05 for all of them). The apoptotic effector caspase-3 was significantly lower in MVC and RAPA groups (p<0.05 in both cases). Combined treatment with MVC-RAPA showed a synergistic increase in p-AKT, p-mTOR and SIRT1 levels. MVC and RAPA show a protective role in some factors involved in frailty. More studies are needed to prove their clinical applications. Eighty male homozygous IL10KOs were randomly assigned to one of 4 groups (n= 20): i) IL10KO group (IL10KO); ii) IL10KO receiving MVC in drinking water (MVC group), iii) IL10KO receiving RAPA in drinking water (RAPA group), and finally, iv) MVC-RAPA group that received MVC and RAPA in drinking water. Blood and muscle samples were analysed. Survival analysis, frailty index calculation, and functional assessment were also performed.


Neural control of cochlear blood flow.
Effects of intraarterial and intravenous injections of autonomic nervous system agents on cochlear blood flow were studied in order to investigate the neural control of the inner ear vessels. Blood flow changes in the inner ear of the guinea pig were measured with an electrical impedance plethysmograph. Rather weak control of the vertebrobasilar and labyrinthine arteries by the sympathetic nervous system of the alpha-receptor type did appear to exist. Beta-receptors of the sympathetic nerve appeared to be non-existent in the cochlear vessels, and parasympathetic modulation was not evident.


The tea weevil, Myllocerinus aurolineatus, is attracted to volatiles induced by conspecifics.
The tea weevil, Myllocerinus aurolineatus (Voss) (Coleoptera: Curculionidae), is a leaf-feeding pest of Camellia sinensis (O.Ktze.) with aggregative behaviors that can seriously reduce tea yield and quality. Although herbivore-induced host plant volatiles have been shown to attract conspecific individuals of some beetle pests, especially members of the Chrysomelidae family, little is known about the volatiles emitted from tea plants infested by M. aurolineatus adults and their roles in mediating interactions between conspecifics. The results of behavioral bioassays revealed that volatile compounds emitted from tea plants infested by M. aurolineatus were attractive to conspecific weevils. Volatile analyses showed that infestations dramatically increased the emission of volatiles, (Z)-3-hexenal, (Z)-3-hexenol, (E)-beta-ocimene, linalool, phenylethyl alcohol, benzyl nitrile, indole, (E, E)-alpha-farnesene, (E)-nerolidol, and 31 other compounds. Among the induced volatiles, 12 chemicals, including gamma-terpinene, benzyl alcohol, (Z)-3-hexenyl acetate, myrcene, benzaldehyde, (Z)-3-hexenal, and (E, E)-alpha-farnesene, elicited antennal responses from both sexes of the herbivore, whereas (E)-beta-ocimene elicited antennal responses only from males. Using a Y-tube olfactometer, we found that six of the 13 chemicals, gamma-terpinene, benzyl alcohol, (Z)-3-hexenyl acetate, myrcene, benzaldehyde, and (Z)-3-hexenal, were attractive to both males and females; two chemicals, (E/Z)-beta-ocimene and (E, E)-alpha-farnesene, were attractive only to males; and four chemicals, (E)-4,8-dimethyl-1,3,7-nonatriene, phenylethyl alcohol, linalool, and (Z)-3-hexenol, were attractive only to females. The findings provide new insights into the interactions between tea plants and their herbivores, and may help scientists develop new strategies for controlling the herbivore.


Integrative Acupuncture and Spinal Manipulative Therapy Versus Either Alone for Low Back Pain: A Randomized Controlled Trial Feasibility Study.
The objective of this study was to assess the feasibility of conducting a large-scale randomized controlled trial (RCT) examining whether an integrative care model combining spinal manipulative therapy (SMT) and acupuncture can lead to better outcomes for low back pain (LBP) than either therapy alone. This study was conducted at a complementary and alternative medicine university health center. Participants with acute or chronic LBP were randomized to (1) acupuncture, (2) SMT, or (3) integrative acupuncture and SMT groups. Treatments were provided over 60 days by licensed doctors of chiropractic and acupuncturists. Acupuncture treatments consisted of needling of acupoints combined with electrotherapy, moxibustion, cupping, and Tui Na. SMT used specific contact points on vertebral processes, along with soft tissue therapy and physiotherapy. Primary outcome measures were the Roland-Morris LBP Disability Questionnaire and 0 to 10 Numeric Rating Scale for LBP. Participants in all 3 groups experienced clinically meaningful improvements in the primary outcome measures; however, no between-group differences in outcomes were apparent. This study indicated that it is feasible to conduct an RCT to compare the effectiveness of integrative acupuncture and SMT for LBP to either therapy alone. Future studies should include a larger sample to increase the power for detecting clinically meaningful differences between groups.


Knockdown of Salusin-β Improves Cardiovascular Function in Myocardial Infarction-Induced Chronic Heart Failure Rats.
Salusin-β is a biologically active peptide with 20 amino acids that exerts several cardiovascular activity-regulating effects, such as regulating vascular endothelial function and the proliferation of vascular smooth muscle cells. However, the regulatory effects of salusin-β in myocardial infarction-induced chronic heart failure (CHF) are still unknown. The current study is aimed at investigating the effects of silencing salusin-β on endothelial function, cardiac function, vascular and myocardial remodeling, and its underlying signaling pathways in CHF rats induced by coronary artery ligation. CHF and sham-operated (Sham) rats were subjected to tail vein injection of adenoviral vectors encoding salusin-β shRNA or a control-shRNA. The coronary artery (CA), pulmonary artery (PA), and mesenteric artery (MA) were isolated from rats, and isometric tension measurements of arteries were performed. Compared with Sham rats, the plasma salusin-β, leptin and visfatin levels and the salusin-β protein expression levels of CA, PA, and MA were increased, while the acetylcholine- (ACh-) induced endothelium-dependent vascular relaxation of CA, PA, and MA was attenuated significantly in CHF rats and was improved significantly by salusin-β gene knockdown. Salusin-β knockdown also improved cardiac function and vascular and myocardial remodeling, increased endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) levels, and decreased NAD(P)H oxidase activity, NOX-2 and NOX-4 expression, and reactive oxygen species (ROS) levels in arteries in CHF rats. The effects of salusin-β knockdown in CHF rats were attenuated significantly by pretreatment with the NOS inhibitor L-NAME. These results indicate that silencing salusin-β contributes to the improvement of endothelial function, cardiac function, and cardiovascular remodeling in CHF by inhibiting NAD(P)H oxidase-ROS generation and activating eNOS-NO production.


Identification and sequence analysis of prolactin receptor and its differential expression profile at various developmental stages in striped hamsters.
Prolactin (PRL) plays critical roles in regulation of biological functions with the binding of specific prolactin receptor (PRLR). Revealing the expression patterns of PRLR at different developmental stages is beneficial to better understand the role of PRL and its mechanism of action in striped hamsters. In this study, the cDNA sequence of PRLR (2866-base-pairs) was harvested from the pituitary of mature female striped hamsters (Cricetulus barabensis) that contains an 834-base-pair 5'-untranslated region (1-834 bp), a 1848-base-pair open reading frame (835-2682 bp), and a 184-base-pair 3'-untranslated region (2683-2866). The 1848-base-pair open reading frame encodes a mature prolactin-binding protein of 592 amino acids. In the mature PRLR, two prolactin-binding motifs, 12 cysteines, and five potential Asn-linked glycosylation sites were detected. Our results showed that the PRLR mRNA quantity in the hypothalamus, pituitary, ovaries, or testis was developmental-stage-dependent, with the highest level at sub-adult stage and the lowest level at old stage. We also found that PRLR mRNAs were highest in pituitary, medium level in hypothalamus, and lowest in ovaries or testis. PRLR mRNAs were significantly higher in males than in females, except in the hypothalamus and pituitary from 7-week-old striped hamsters. Moreover, the PRLR mRNAs in the hypothalamus, pituitary, and ovaries or testis were positively correlated with the expression levels of GnRH in the hypothalamus. These results indicated that the PRLR has conserved domain in striped hamster, but also possesses specific character. PRLR has multiple biological functions including positively regulating reproduction in the striped hamster.


The needs of patients requiring home enteral tube feeding.
A report by the British Artificial Nutrition Survey of the British Association for Parenteral and Enteral Nutrition has highlighted the needs of patients using home enteral tube feeding. Many are frail and elderly and require careful discharge planning from hospital and co-ordinated, multidisciplinary care in nursing homes or their own homes on return to the community.


Results of colectomy for severe idiopathic constipation in women (Arbuthnot Lane's disease).
Twenty-one women with slow-transit constipation have been treated by bowel resection. All had a normal barium enema, but an increased colonic transit time. Pathological examination of the resected colons showed no evidence of aganglionosis. Some of the patients were treated by segmental colonic resection, anorectal myectomy, anal stretch or internal sphincterectomy but were not helped. Colectomy with ileorectal or caecorectal anastomosis gave the best results; on balance, ileorectal anastomosis seems preferable. Of sixteen patients who underwent colectomy, ten subsequently had normal bowel function and four were markedly improved. The spontaneous bowel frequency in this group rose from 0.3 +/- 0.1 (s.e.m.) to 21.7 +/- 8.3 weekly (P less than 0.001).


Microwave-assisted derivatisation and LC-MS/MS determination of nitrofuran metabolites in farm-raised prawns (Penaeus monodon).
A new microwave-assisted derivatisation and LC-MS/MS method has been developed for the analysis of nitrofuran metabolites - 3-amino-5-morpholino-methyl-1,3-oxa-zolidinone (AMOZ), 3-amino-2-oxazolidinone (AOZ), 1-aminohydantoin (AHD) and semicarbazide (SEM) - in farm-raised prawns (Penaeus monodon) from the coastal regions of South India. Analysis was carried out by reverse-phase column (Phenomenex Luna C18) with gradient elution using mobile phase A (0.02% acetic acid in water) and mobile phase B (0.02% acetic acid in acetonitrile), at a flow rate of 200 μl min(-1) and an injection volume of 20 μl. Microwave-assisted derivatisation was achieved in 6 min with good recovery. The results showed that the samples collected from Andhra Pradesh and Karnataka contained residues of nitrofuran metabolites in the range from 5.0 to 40 ng g(-1). This work emphasises the importance of ensuring the safety of seafood and that a new method of derivatisation is applicable for the analysis of nitrofuran metabolites in seafood.


Bioreactor considerations for secondary metabolite production from plant cell tissue culture: Indole alkaloids from Catharanthus roseus.
Batch shake flask studies with Catharanthus roseus demonstrated that alkaloid production commenced only after growth had slowed or ceased. To obtain high alkaloid productivities for extended periods, a hormone-free production medium was used. To develop a readily scalable process, both immobilized and suspended cell systems were studied. In the immobilized cell systems, growth, glucose utilization, and alkaloid production were suppressed; for the case of membrane entrapped cells this suppression was observed to be reversible. Based on the oxygen requirements of the cells, and the oxygen transfer capabilities of a pneumatically agitated bubble column, conditions were established that allowed the growth and production dynamics observed in shake flasks to be reproduced in the air sparged column reactor. The requirement for the aseptic exchange of growth for production medium was satisfied by using a coarse cotton filter and coupling filtration to aeration. With this filtration system, media can be rapidly and completely exchanged and the filter can be quickly and effectively backwashed. By coupling filtration to aeration, a two-stage batch operation can be employed while requiring only a single bioreactor. Studies with this system demonstrated its capabilities for alkaloid production.


Circulating levels of insulin-like growth factor (IGF) binding protein-1 and -3 in aging men: relationships to insulin, glucose, IGF, and dehydroepiandrosterone sulfate levels and anthropometric measures.
Reduced secretion of GH and production of insulin-like growth factor I (IGF-I) contribute to altered body composition in human aging. IGF-binding proteins (IGFBPs) are important modulators of IGF action, yet little is known regarding their role and regulation in aging. Accordingly, we measured levels of IGFBP-1, an important short term modulator of IGF bioavailability that is suppressed by insulin, and levels of IGFBP-3, the major circulating IGF carrier protein, and examined their relationships to insulin, glucose, IGF, and dehydroepiandrosterone sulfate levels and anthropometric measures in old (63-89 yr) and young (23-39 yr) men. Serum levels of IGFBP-1 were increased 3-fold in old vs. young men despite high insulin levels in elders. Nevertheless, IGFBP-1 and insulin levels correlated in old and young men (r = - 0.49; P < 0.002 and r = -0.42; P < 0.025), suggesting that insulin continues to play an important role in the regulation of IGFBP-1 in aging. Glucose levels also were significantly inversely related to IGFBP-1 in old and young men (r = 0.37; P = 0.02 and r = -0.49; P < 0.01), and this relationship was not accounted for by the effect of insulin. IGF-I levels were reduced by 33% in elders (P < 0.001) and correlated with IGFBP-1 levels among old (r = -0.40; P < 0.01), but not young, men, indicating that low GH secretion and/or IGF-I production may contribute to the elevation of IGFBP-1 levels in aging. IGFBP-3 levels were reduced among elders, but not to the same extent as IGF-I, resulting in a relative excess of IGFBP-3 in elders (IGFBP-3/IGF-I ratio, 20.1 +/- 0.9 vs. 15.4 +/- 1.0; P < 0.001). The IGFBP-3/IGF-I ratio correlated with IGF-I levels in young and old men (r = -0.79; P < 0.001 and r = -0.82; P < 0.001), indicating that diminished GH secretion also may contribute to a relative excess of IGFBP-3 among elders. Dehydroepiandrosterone sulfate levels were low in elders, but did not correlate with IGF, IGFBP, insulin, or glucose levels in either age group. Serum levels of IGFBP-1 (but not IGF-I or -II or IGFBP-3) correlated with body mass index and upper arm fat and muscle areas in elders. These relationships were accounted for by the effects of insulin, suggesting that regulation of IGFBP-1 by insulin may play a role in determining body composition in aging. We conclude that insulin remains an important determinant of IGFBP-1 levels in elders, that the fasting glucose level is also a significant determinant of IGFBP-1 in both old and young subjects, and that reduced secretion of GH may contribute to impaired anabolism in aging through multiple mechanisms, including reduced production of IGF-I and alterations in circulating levels of both IGFBP-1 and -3. These findings are consistent with the concept that alterations in IGFBP levels may contribute to changes in IGF bioavailability and body composition in aging.


[Does fetal oxytocin initiate human labour? A hypothesis].
The concentration of specific oxytocin receptors increases during pregnancy and reaches a maximum at term after the onset of spontaneous labour. This constitutes a biochemical explanation for the well-known increase of oxytocin sensitivity during pregnancy. Oxytocin receptors were also found in human decidua and their concentration increased similarly. Based on these results the hypothesis was set up that oxytocin leads to an increase in prostaglandin production though specific receptors in decidua. Under specific incubation circumstances oxytocin indeed increased prostaglandin E and prostaglandin F synthesis of decidual tissue. In induction of labour with oxytocin PGF-levels in the maternal peripheral plasma increased significantly in all women in whom induction was successful. Since it is known that the fetus secretes considerable amounts of oxytocin in case of labour of spontaneous onset the hypothesis was set up that fetal oxytocin may initiate human labour by the mechanisms described above.


Interaction of SPIN90 with dynamin I and its participation in synaptic vesicle endocytosis.
SH3 protein interacting with Nck, 90 kDa (SPIN90) is an Nck-binding protein that contains one Src homology 3 (SH3) domain, three proline-rich domains (PRDs), a serine/threonine-rich region, and a hydrophobic C-terminal region. Previously, we have shown that SPIN90 plays roles in the sarcomere assembly in cardiac muscles and in the formation of focal contacts in HeLa cells. Besides in heart, SPIN90 is also highly expressed in the brain, but its role in the neuronal system is completely unknown. Here, we found that SPIN90 is expressed in the presynaptic compartment in which it binds dynamin I, a key component of the endocytic machinery, and that it participates in synaptic vesicle endocytosis. Pull-down analysis and coimmunoprecipitation proved the associations of SPIN90 with dynamin I through SH3-PRD interaction. Overexpression of SPIN90 or knocking down SPIN90 by small interfering RNA impaired synaptic vesicle endocytosis. We further confirmed by the rescue experiments that the endocytic defects by SPIN90 expression come from its interaction with dynamin I. Exocytosis kinetics was not affected by SPIN90 expression. Together, our findings suggest that SPIN90 could modulate the interactions of dynamin I with other endocytic proteins that cooperate in the coated vesicle formation, thus regulating synaptic vesicle endocytosis.


Salt-induced formation of the molten globule state of cytochrome c studied by isothermal titration calorimetry.
Although the molten globule state has been proposed as a major intermediate of protein folding, it has proven difficult to obtain thermodynamic data characterizing this state. To explore another approach for characterizing the molten globule state, salt-induced formation of the molten globule state of horse cytochrome c at pH 1.8 was studied by isothermal titration calorimetry. By titrating the acid-unfolded cytochrome c with sodium perchlorate, an exothermic reaction was observed. The titration curve obtained from the heat was cooperative and agreed well with the conformational transition curve measured by CD at 222 nm. This result indicated that the salt-induced conformation change is well approximated by a two-state transition between the acid-unfolded and molten globule states. The heat for formation of the molten globule state estimated by isothermal titration calorimetry was consistent with the enthalpy change for unfolding of the sodium perchlorate-stabilized molten globule state at pH 1.8, which was measured by differential scanning calorimetry and CD. These results indicate that the heat of titration largely reflects the enthalpy change of the conformational transition. From these results, we consider that isothermal titration calorimetry will become a useful approach for investigating the molten globule state.


Effects of uniform vertical inflow perturbations on the performance of flapping wings.
Flapping wings have attracted significant interest for use in miniature unmanned flying vehicles. Although numerous studies have investigated the performance of flapping wings under quiescent conditions, effects of freestream disturbances on their performance remain under-explored. In this study, we experimentally investigated the effects of uniform vertical inflows on flapping wings using a Reynolds-scaled apparatus operating in water at Reynolds number ≈ 3600. The overall lift and drag produced by a flapping wing were measured by varying the magnitude of inflow perturbation from J Vert = -1 (downward inflow) to J Vert = 1 (upward inflow), where J Vert is the ratio of the inflow velocity to the wing's velocity. The interaction between flapping wing and downward-oriented inflows resulted in a steady linear reduction in mean lift and drag coefficients, C ¯ L and C ¯ D , with increasing inflow magnitude. While a steady linear increase in C ¯ L and C ¯ D was noted for upward-oriented inflows between 0 < J Vert < 0.3 and J Vert > 0.7, a significant unsteady wing-wake interaction occurred when 0.3 ≤ J Vert < 0.7, which caused large variations in instantaneous forces over the wing and led to a reduction in mean performance. These findings highlight asymmetrical effects of vertically oriented perturbations on the performance of flapping wings and pave the way for development of suitable control strategies.


ModuleBlast: identifying activated sub-networks within and across species.
Identifying conserved and divergent response patterns in gene networks is becoming increasingly important. A common approach is integrating expression information with gene association networks in order to find groups of connected genes that are activated or repressed. In many cases, researchers are also interested in comparisons across species (or conditions). Finding an active sub-network is a hard problem and applying it across species requires further considerations (e.g. orthology information, expression data and networks from different sources). To address these challenges we devised ModuleBlast, which uses both expression and network topology to search for highly relevant sub-networks. We have applied ModuleBlast to expression and interaction data from mouse, macaque and human to study immune response and aging. The immune response analysis identified several relevant modules, consistent with recent findings on apoptosis and NFκB activation following infection. Temporal analysis of these data revealed cascades of modules that are dynamically activated within and across species. We have experimentally validated some of the novel hypotheses resulting from the analysis of the ModuleBlast results leading to new insights into the mechanisms used by a key mammalian aging protein.


Characterization of iso-CF2I2 in frequency and ultrafast time domains.
The photolysis of diiododifluoromethane (CF(2)I(2)) in condensed phases was studied by a combination of matrix isolation and ultrafast time-resolved spectroscopy, in concert with ab initio calculations. Photolysis at wavelengths of 355 or 266 nm of CF(2)I(2):Ar samples (1:5000) held at approximately 8 K yielded iso-CF(2)I(2) (F(2)C-I-I), a metastable isomer of CF(2)I(2), characterized here for the first time. The infrared (IR) spectra of this isomer were recorded in matrix experiments, and the derived positions of the C-F stretching modes are in very good agreement with the predictions of high level ab initio calculations, which show that the iso-form is a minimum on the CF(2)I(2) ground state potential energy surface. The formation of this isomer following 350 nm excitation of CF(2)I(2) in room temperature CCl(4) solutions was monitored through its intense C-F stretching mode by means of ultrafast time-resolved IR absorption. Together, matrix isolation and ultrafast IR absorption experiments suggest that the formation of iso-CF(2)I(2) occurs via recombination of CF(2)I radical and I atom. Ultrafast IR experiments detect a delayed rise of iso-CF(2)I-I absorption, placing an upper limit of 400 fs for the C-I bond dissociation and primary geminate recombination processes. The product absorption spectrum recorded 1 ns after 350 nm excitation of CF(2)I(2) in solution is virtually identical to the visible absorption spectrum of iso-CF(2)I(2) trapped in matrix isolation experiments [with subtracted I(2)(X) absorption]. The formation of this isomer in solution at room temperature has direct dynamic implications for the ultrafast production of molecular iodine from electronically excited CF(2)I(2).


On the need for standardization in panic disorder treatment research: survey of the literature, 1980-1992.
A retrospective literature survey (1980-1992) was conducted to chronicle the development of panic disorder treatment research. Based on a National Institute of Mental Health conference on assessment standardization in this area (Shear and Maser, 1994), the results and implications of the survey are presented in terms of eight domains of measurement recommended as essential for high quality research.


A novel form of necrosis, TRIAD, occurs in human Huntington's disease.
We previously reported transcriptional repression-induced atypical cell death of neuron (TRIAD), a new type of necrosis that is mainly regulated by Hippo pathway signaling and distinct from necroptosis regulated by RIP1/3 pathway. Here, we examined the ultrastructural and biochemical features of neuronal cell death in the brains of human HD patients in parallel with the similar analyses using mutant Htt-knock-in (Htt-KI) mice. LATS1 kinase, the critical regulator and marker of TRIAD, is actually activated in cortical neurons of postmortem human HD and of Htt-KI mouse brains, while apoptosis promoter kinase Plk1 was inactivated in human HD brains. Expression levels of YAP/YAPdeltaC were decreased in cortical neurons of human HD brains. Ultra-structural analyses revealed extreme enlargement of endoplasmic reticulum (ER), which characterizes TRIAD, in cortical neurons of human HD and those of Htt-KI mice. These biochemical and morphological results support that TRIAD occurs in human and mouse neurons under the HD pathology.


In vitro activation of the human Harvey-ras proto-oncogene by aflatoxin B1.
Activation of ras proto-oncogenes occurs frequently in vivo in chemically induced rodent tumours, including rat hepatomas induced by aflatoxin B1. This study examines the in vitro activation of a human ras gene by this mycotoxin. A plasmid containing the human Ha-ras proto-oncogene, together with a neomycin resistance gene (pECneo), was incubated in vitro with a microsomal system generating aflatoxin B1 8,9-epoxide. Subsequent transfection of the plasmid into mouse NIH 3T3 fibroblasts, followed by G418 selection and s.c. injection of surviving cells into immunodeficient mice demonstrated that the proto-oncogene had acquired transforming capacity. Although a single tumour resulted from similar treatment of incubated unconjugated plasmid, no tumours were produced by a secondary round of transfections using DNA from this tumour. Selective PCR amplification of the human Ha-ras gene in extracted tumour DNA followed by sequencing demonstrated the presence of G-->T transversions either at the first or middle base of codon 12 in tumours resulting from transfection with the aflatoxin-B1-modified pECneo plasmid, but this was not detected in the single tumour resulting from transfection with the unmodified plasmid. Thus, although a mutation in the Ha-ras gene has not been reported for human primary hepatomas occurring in aflatoxin-exposed populations, metabolically activated aflatoxin B1 is capable of mutating this proto-oncogene to its oncogenic form in vitro. No mutations were observed in codon 61. It appears that, in contrast to the frequently reported G-->T transversions in codon 249 of the p53 gene in primary hepatomas in aflatoxin-exposed humans, the failure to detect Ha-ras mutations in these tumours is not due to an inability of aflatoxin B1 to activate this proto-oncogene. The G-->T transversions observed in this study contrast with the most frequent aflatoxin B1 in vivo induced mutations, G-->A transitions in the rat Ki-ras gene. Possible mechanisms for these differences are discussed.


Numerical realization of diffuse sound pressure fields using prolate spheroidal wave functions.
A diffuse sound field is conventionally defined as a zero-mean circularly symmetric complex Gaussian random field. A more recent, generalized definition is that of a sound field having mode shapes that are diffuse in the conventional sense, and eigenfrequencies that conform to the Gaussian orthogonal ensemble. Such a generalized diffuse sound field can represent a random ensemble of sound fields that share gross features, such as modal density and total absorption, but otherwise have any possible arrangement of local wave scattering features. The problem of generating realizations or Monte Carlo samples of a conventional diffuse sound field or, equivalently, of the mode shapes of a generalized diffuse sound field, is addressed here. Such realizations can be obtained from an eigenvalue decomposition of the spatial correlation function. A discrete decomposition is numerically expensive when the sound pressures at many locations are of interest, so a fast analytical decomposition based on prolate spheroidal wave functions is developed. The approach is numerically validated by comparison with a detailed room model, where random wave scatterers are explicitly modeled as acoustic point masses with random positions, and good correspondence is observed. Furthermore, applications involving correlated sound sources and sound-structure interaction are presented.


Scurvy in a patient with presumptive oral lichen planus.
Scurvy is a disease caused by vitamin C deficiency. In this study, a patient with scurvy is presented with soreness and ulcerations of the mouth that were previously diagnosed as oral lichen planus. This disease is relatively more common than scurvy in the United States. Physicians should be aware that even in developed countries, soreness of the mouth and ulceration can be seen in patients with scurvy and potentially be misdiagnosed as oral lichen planus.


Factors associated with falls among hospitalized and community-dwelling older adults: the APPCARE study.
Falls are a leading cause of disability. Previous studies have identified various risk factors for falls. However, contemporary novel research is needed to explore these and other factors associated with falls among a diverse older adult population. This study aims to identify the factors associated with falls among hospitalized and community-dwelling older adults. Cross-sectional data from the 'Appropriate care paths for frail elderly people: a comprehensive model' (APPCARE) study were analyzed. The study sample consisted of hospitalized and community-dwelling older adults. Falling was assessed by asking whether the participant had fallen within the last 12 months. Multivariable logistic regression models were used to evaluate associations between socio-demographic characteristics, potential fall risk factors and falls. The sample included 113 hospitalized (mean age = 84.2 years; 58% female) and 777 community-dwelling (mean age = 77.8 years; 49% female) older adults. Among hospitalized older adults, loneliness was associated with an increased risk of falls. Associations between female sex, secondary education lever or lower, multimorbidity, a higher score on limitations with activities of daily living (ADL), high risk of malnutrition and falling were found among community-dwelling participants. The results of this study confirm the multi-factorial nature of falling and the complex interaction of risk factors. Future fall prevention programs could be tailored to the needs of vulnerable subpopulations at high risk for falls.


Parcas, a regulator of non-receptor tyrosine kinase signaling, acts during anterior-posterior patterning and somatic muscle development in Drosophila melanogaster.
We have isolated parcas (pcs) in a screen to identify novel regulators of muscle morphogenesis. Pcs is expressed in the ovary and oocyte during oogenesis and again in the embryo, specifically in the developing mesoderm, throughout muscle development. pcs is first required in the ovary during oogenesis for patterning and segmentation of the early Drosophila embryo due primarily to its role in the regulation of Oskar (Osk) levels. In addition to the general patterning defects observed in embryos lacking maternal contribution of pcs, these embryos show defects in Wingless (Wg) expression, causing losses of Wg-dependent cell types within the affected segment. pcs activity is required again later during embryogenesis in the developing mesoderm for muscle development. Loss and gain of function studies demonstrate that pcs is necessary at distinct times for muscle specification and morphogenesis. Pcs is predicted to be a novel regulator of non-receptor tyrosine kinase (NRTK) signaling. We have identified one target of Pcs regulation, the Drosophila Tec kinase Btk29A. While Btk29A appears to be regulated by Pcs during its early role in patterning and segmentation, it does not appear to be a major target of Pcs regulation during muscle development. We propose that Pcs fulfils its distinct roles during development by the regulation of multiple NRTKs.


How Czech and Slovak vascular surgeons and nephrologists accept recommendations of the European Society of Vascular Surgery - survey study.
Arteriovenous access (AVA) is the cornerstone for the long-term haemodialysis treatment in the patient with end-stage kidney disease. Nowadays, European Society of Vascular Surgery (ESVS) has presented clinical guidelines regarding all aspects of AVA. The aim of the study was to identify acceptance rate of selected ESVS recommendations among Czech and Slovak vascular surgeons and nephrologists. We carried out a prospective analysis of 7 questions from an online survey collected from January to February 2020. 211 (33 %) of 646 participants responded to the survey. Questions were divided into two groups, general and surgical. General questions were for both nephrologist and vascular surgeons. Surgical questions were evaluated only for vascular surgeons. In the first group 190 (90 %) respondents accept, that extremity dominance is important for location of AVA, 186 (89 %) agree that clinically suspected venous hypertension/central vein occlusion is an indication for fistulography, 111 (53 %) agree, that indwelling central venous catheter/pacemaker is an indication for AVA creation in the opposite side. In the second group, 50 (57 %) agree that patients before AVA creation should be examined with a tourniquet prior to surgery, 45 (51 %) agree, that pre-operative ultrasonography mapping is recommended, 66 (75 %) agree, that the inner radial artery and the cephalic vein should be more than 2.0 mm, and only 9 (10 %) respondents agree that regional anaesthesia is preferred over local anaesthesia for AVA creation. In both Czech and Slovak Republic, preoperative planning is not uniform and ESVS recommendations for AVA are accepted at the level of 57 %.


Resveratrol Promotes Osteogenic Differentiation of Canine Bone Marrow Mesenchymal Stem Cells Through Wnt/Beta-Catenin Signaling Pathway.
Bone marrow mesenchymal stem cells (BMSCs) can transdifferentiate into different types of cells and may serve as a cell source for tissue engineering. Resveratrol has been shown to possess many benefits, including activation of osteogenesis. Furthermore, Wnt/β-catenin signaling has been known to promote osteogenic differentiation in many cells. In this study, we investigated the role of resveratrol in osteoblastic differentiation of canine BMSCs. Resveratrol treatment of canine BMSCs remarkably increased alkaline phosphatase activity and calcium nodules, inhibited the function of glycogen synthase kinase 3β, led to an increase in stabilization and nuclear accumulation of β-catenin, and upregulated expression of osteoblast-related marker gene expression. In addition, resveratrol caused rapid activation of ERK1/2. Collectively, our results indicate that resveratrol promotes osteoblastic differentiation of canine BMSCs by activating the Wnt/β-catenin; ERK/MAPK signaling pathways are also involved in osteogenic differentiation of canine BMSCs.


A theoretical approach to the link between oxidoreductions and pyrite formation in the early stage of evolution.
There are two fundamental axioms of surface metabolism theory: (i) pyrite formation from H2S and FeS is proposed as a source of energy for life, and (ii) archaic reductive citric acid cycle is put into the center of a metabolic network. However, the concept fails to indicate how sulfide oxidation ought to be coupled to processes driven by free energy change occurring during pyrite production, and secondly, how reductive citric acid cycle ought to be supplied with row material(s). Recently, the non-enzymatic methylglyoxalase pathway has been recommended as the anaplerotic route for the reductive citric acid cycle. In this paper a mechanism is proposed by which the oxidation of lactate, the essential step of the anaplerotic path, becomes possible and a coupling system between sulfide oxidation and endergonic reaction(s) is also presented. Oxidoreduction for other redox pairs is discussed too. It is concluded that the S(o)/H2S system may have been the clue to energy production at the early stage of evolution, as hydrogen sulfide produced by the metabolic network may have functioned as a coupling molecule between endergonic and exergonic reactions.


Regio- and stereoselectivity of various forms of purified cytochrome P-450 in the metabolism of benzo[a]pyrene and (-) trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene as shown by product formation and binding to DNA.
Highly purified cytochromes P-450(LM2) and P-450(LM4) and partially purified P-450(LM1), P-450(LM3b), and P-450(LM7) from rabbit liver microsomes exhibit different catalytic activities in the metabolism of benzo[a]pyrene (BzP) and (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene [(-)trans-7,8-diol] in a reconstituted enzyme system. The two highly purified cytochromes also exhibit differences in the activation of BzP and (-)trans-7,8-diol to intermediates that bind to DNA, as well as in the stereoselective conversion of (-)trans-7,8-diol to the highly mutagenic and carcinogenic diol-epoxides r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10- tetrahydrobenzo[a]pyrene (diol-epoxide I) and r - 7,t - 8 - dihydroxy - c - 9,10 - oxy - 7,8,9,10 - tetrahydrobenzo[a]pyrene (diol-epoxide II). P-450(LM2) is more active than P-450(LM4) in the metabolism of BzP and in its conversion to products that bind to DNA. In contrast, P-450(LM4) is more active than P-450(LM2) in the metabolism of (-)trans-7,8-diol and in its conversion to products that bind to DNA. The ratio of activity (percent substrate metabolized) with BzP relative to that with (-)trans-7,8-diol is 21 for P-450(LM2) and 0.3 for P-450(LM4); P-450(LM1), P-450(LM3b), and P-450(LM7) gave intermediate ratios. Marked stereoselectivity in the oxygenation of the (-)trans-7,8-diol to the highly mutagenic and putatively carcinogenic diol-epoxides I and II was observed with P-450(LM4), whereas the other preparations showed less selectivity. The ratio of diolepoxide I to diol-epoxide II ranges from 0.3 for P-450(LM7) to 11 for P-450(LM4). The substrate specificity and regio- and stereo-selectivity of the different forms of cytochrome P-450 may regulate the balance between activation and detoxification pathways of BzP and therefore determine the susceptibility of individual tissues, strains, and species to the carcinogenic action of BzP.


[1,3-Bis(4-nitrophenyl)triazenido](triphenylphosphine)gold(I).
In the title complex, [Au(C(12)H(8)N(5)O(4))(C(18)H(15)P)], the coordination geometry about the Au(I) ion is linear, with one deprotonated 1,3-bis(4-nitrophenyl)triazenide ion, [O(2)NC(6)H(4)N=N-NC(6)H(4)NO(2)](-), acting as a monodentate ligand (two-electron donor), and one neutral triphenylphosphine molecule completing the metal coordination. The triazenide ligand is almost planar (r.m.s. deviation = 0.0767 A), with the largest interplanar angle being 11.6 (7) degrees between the phenyl ring of one of the terminal 4-nitrophenyl substituents and the plane defined by the N=N-N triad. The Au-N and Au-P distances are 2.108 (5) and 2.2524 (13) A, respectively. Pairs of molecules generated by centrosymmetry are associated into a supramolecular array via intermolecular C-H...O interactions, and N...C and N...O pi-pi interactions.


Deletion of HIF-1α partially rescues the abnormal hyaloid vascular system in Cited2 conditional knockout mouse eyes.
Cited2 (CBP/p300-interacting transactivators with glutamic acid (E) and aspartic acid (D)-rich tail 2) is a member of a new family of transcriptional modulators. Cited2 null embryos exhibit hyaloid hypercellularity consisting of aberrant vasculature in the eye. The purpose of the study is to address whether abnormal lenticular development is a primary defect of Cited2 deletion and whether deletion of hypoxia inducible factor (HIF)-1α or an HIF-1α target gene, vascular endothelial growth factor (VEGF), could rescue abnormal hyaloid vascular system (HVS) in Cited2 deficient adult eyes. Le-Cre specific Cited2 knockout (Cited2(CKO)) mice with or without deletion of HIF-1α or VEGF were generated by standard Cre-Lox methods. Eyes collected from six-eight weeks old mice were characterized by Real Time PCR and immunohistological staining. Cited2(CKO) mice had smaller lenses, abnormal lens stalk formation, and failed regression of the HVS in the adult eye. The eye phenotype had features similar to persistent hyperplastic primary vitreous (PHPV), a human congenital eye disorder leading to abnormal lenticular development. Deletion of HIF-1α or VEGF in Cited2 knockout eyes partially rescued the abnormal HVS but had no effect on the smaller lens and abnormal lens stalk differentiation. Intravitreal injection of Topotecan (TPT), a compound that inhibits HIF-1α expression, partially eliminated HVS defects in Cited2(CKO) lenses. Abnormal HVS is a primary defect in Cited2 knockout mice, resulting in part from dysregulated functions of HIF-1 and VEGF. The Cited2(CKO) mouse line could be used as a novel disease model for PHPV and as an in vivo model for testing potential HIF-1 inhibitors.


Sperm transport and storage and its relation to the annual sexual cycle of the female red-sided garter snake, Thamnophis sirtalis parietalis.
Female red-sided garter snakes (Thamnophis sirtalis parietalis) store sperm from both late-summer and spring matings. Before winter dormancy, sperm are stored in specialized furrows in the vaginal portion of the oviduct, 3-6 cm anterior to the vent. After 6 weeks in dormancy, the epithelial cells lining this vaginal region hypertrophy and stain strongly with periodic acid-Schiff (PAS). This PAS+ epithelial border sloughs and associates with sperm. These aggregations of PAS+ material, which will be referred to as carrier matrices, move anteriorly through the oviduct. After 20 weeks in dormancy, most sperm are found in specialized infundibular storage regions. Spring mating induces a rapid degeneration of winter-stored sperm. Stored sperm are evacuated from infundibular storage receptacles within 6 hours after mating. Yet sperm from the spring mating are not evident in the oviduct until 24 hours after mating. Carrier matrices begin to form at this time. At 48 hours after mating, sperm, often associated with carrier matrices, appear in the infundibulum. At 40 days after mating, most sperm have moved into infundibular storage receptacles. Evidence suggests that carrier matrices not only facilitate the transport of sperm anteriorly from vaginal to infundibular regions, but also function as nutritional stores.


Thermodiffusion of Monovalent Organic Salts in Water.
The ionic Soret effect induced by temperature gradients is investigated in organic electrolytes (tetramethylammonium and tetrabutylammonium hydroxides) dispersed in water using a holographic grating experiment. We report the influences of temperature and salt concentrations on the Soret, diffusion, and thermal diffusion coefficients. Experimental results to the thermal diffusion coefficient are compared with a theoretical description for thermodiffusion of Brownian particles in liquids based in the thermal expansion of the liquid solution. It is observed that the obtained thermal diffusion coefficients for the organic electrolytes present a similar temperature dependence as the theoretical prediction. Comparing the experimental results for the organic and common inorganic salts it is proposed an additional physical mechanism as the cause to the different thermal diffusion coefficients in both types of salt. We propose that the temperature dependence of hydration free energy gives rise to a force term that also leads to ion migration in a temperature gradient. We describe the thermal diffusion results as a competition between thermal expansion and hydration effects. The specific structure each type of ion cause in water molecules is considered in the heat of transport theory to describe thermal diffusion of electrolytes. A qualitative agreement is seen between our results and the classical heat of transport theory.


Referred shoulder pain preceding abdominal pain in a teenage girl with gastric perforation.
Referred shoulder pain is an important yet potentially distracting sign of serious intra-abdominal illness. A case is presented wherein shoulder pain preceded by several hours the onset of abdominal pain in a teenage girl with gastric perforation. The range of causes of gastric perforation and the pathophysiology of referred shoulder pain are discussed.


Improvement of the stability of hydroxyapatite through glass ceramic reinforcement.
Hydroxyapatite has achieved significant application in orthopedic and dental implants due to its excellent biocompatibility. Sintered hydroxyapatites showed significant dissolution, however, after their immersion in water or simulated body fluid (SBF). This grain boundary dissolution, even in pure hydroxyapatites, resulted in grain separation at the surfaces, and finally, in fracture. In this study, hydroxyapatite ceramics containing apatite-wollastonite (AW) or calcium silicate (SG) glass ceramics as additives were prepared to prevent the dissolution. AW and SG glass ceramics were added at 0-7 wt% and powder-compacted uniaxially followed by firing at moisture conditions. The glass phase was incorporated into the hydroxyapatite to act as a sintering aid, followed by crystallization, to improve the mechanical properties without reducing the biocompatibility. As seen in the results of the dissolution test, a significant amount of damage was reduced even after more than 14 days. TEM and SEM showed no decomposition of HA to the secondary phase, and the fracture toughness increased, becoming even higher than that of the commercial hydroxyapatite.


Evening primrose oil attenuates oxidative stress, inflammation, fibrosis, apoptosis, and ultrastructural alterations induced by metanil yellow in the liver of rat: a histological, immunohistochemical, and biochemical study.
The food color metanil yellow (Myl) is hazardous to several body systems. Evening primrose oil (EPO) was reported to have anti-inflammatory and anti-oxidant properties. The present work investigated the impact of Myl on the hepatic structure and function of rats and evaluated the protective effect of EPO. Forty adult male rats were divided into four groups: control, EPO (5 g/kg/day), Myl (200 mg/kg/day), and EPO- Myl group. Myl significantly increased liver enzymes, advanced glycation end products (AGE), oxidative stress parameters, pro-inflammatory cytokines, nuclear factor kappa B (NF-κB), and inducible nitric oxide synthase (iNOS). Blood vessels in the liver were dilated and congested, with cellular infiltration around them and associated with fibrosis. The hepatocytes were vacuolated and had dark nuclei. The immunohistochemical expression of iNOS, glial fibrillary acidic protein (GFAP), and Bax was significantly elevated. Ultrastructurally, the hepatocytes showed lipid droplets, irregular condensed nuclei with widened perinuclear space, dilated rER, mitochondria with destructed cristae, and multiple vacuoles. Dilated congested blood sinusoids and collagen fiber bundles were seen between hepatocytes. Interestingly, these alterations were less pronounced in rats co-administrated with EPO and Myl. In conclusion, EPO can protect liver against the toxic effects of Myl due to its anti-inflammatory and anti-oxidant activities.


Curcumin Can be Acts as Effective agent for Prevent or Treatment of Alcohol-induced Toxicity in Hepatocytes: An Illustrated Mechanistic Review.
Previous studies have shown that alcohol abuse can cause serious liver damage and cirrhosis. The main pathway for these types of hepatocellular cell neurodegeneration is mitochondrial dysfunction, which causes lipid peroxidation and dysfunction of the glutathione ring and the defect of antioxidant enzymes in alcoholic hepatic cells. Alcohol can also initiate malicious inflammatory pathways and trigger the initiation and activation of intestinal and extrinsic apoptosis pathways in hepatocellular tissues that lead to cirrhosis. Previous studies have shown that curcumin may inhibit lipid peroxidation, glutathione dysfunction and restore antioxidant enzymes. Curcumin also modulates inflammation and the production of alcohol-induced biomarkers. Curcumin has been shown to play a critical role in the survival of alcoholic hepatocellular tissue. It has been shown that curcumin can induce and trigger mitochondrial biogenesis and, by this mechanism, prevent the occurrence of both intrinsic and extrinsic apoptosis pathways in liver cells that have been impaired by alcohol. According to this mechanism, curcumin may protect hepatocellular tissue from alcohol-induced cell degeneration and may therefore survive alcoholic hepatocellular tissue. . Based on these mechanisms, the protective functions of curcumin against alcohol-induced cell degeneration due to oxidative stress, inflammation, and apoptosis events in hepatocellular tissue have been recorded. Hence, in this research, we have attempted to evaluate and analyze the main contribution mechanism of curcumin cell defense properties against alcohol-induced hepatocellular damage, according to previous experimental and clinical studies, and in this way we report findings from major studies.


Evaluation of learning outcomes in Web-based continuing medical education.
There has been significant growth in use of Web-based continuing medical education (CME) by physicians. A number of evaluation and metareview studies have examined the effectiveness of Web-based CME to varying degrees. One of the main limitations of this literature has been the lack of systematic evaluation across different clinical subject matter areas using standardized Web-based CME learning formats. One group of pretest-postest designs were used to evaluate knowledge and self-reported confidence change across multiple Web-based courses using a standardized instructional format but comprising distinct clinical subject matter. Participants also completed a participant satisfaction survey and a self-reported retrospective skill/ability change survey. The majority of courses evaluated demonstrated significant pre to post knowledge and confidence effect size change, as well as significant self-reported retrospective practice change. A Web-based CME instructional format comprising multimedia-enhanced learning tutorials supplemented by asynchronous computer-mediated conferencing for case-based discussions was found to be effective in enhancing knowledge, confidence, and self-reported practice change outcomes across a variety of clinical subject matter areas.


An improved ultra-high-performance liquid chromatography-tandem mass spectrometric method for the quantitation of dexmedetomidine in small volume of pediatric plasma.
Dexmedetomidine (Dex), a highly selective α2 -adrenergic agonist, is used primarily for the sedation and anxiolysis of adults and children in the intensive care setting. A sensitive and selective assay for Dex in pediatric plasma was developed by employing ultra-high-performance liquid chromatography-tandem mass spectrometry with d4-Dex as an internal standard. Dex was extracted from 0.1 mL of plasma by micro-elution solid-phase extraction. Separation was achieved with a Waters XBridge C18 column with a flow rate of 0.3 mL/min using a mobile phase comprising 5 mm ammonium acetate buffer with 0.03% formic acid in water and methanol-acetonitrile (50:50, v/v). The intra-day precision (coefficient of variation) and accuracy for quality control samples ranged from 1.32 to 8.91% and from 92.8 to 108%, respectively. The inter-day precision and accuracy ranged from 2.13 to 8.45% and from 97.0 to 104%, respectively. The analytical method showed excellent sensitivity using a small sample volume (0.1 mL) with a lower limit of quantitation of 5 pg/mL. This method is robust and has been successfully employed in a pharmacokinetic study of Dex in neonates and infants postoperative from cardiac surgery.


Mediators and non-specific bronchial hyperreactivity.
Bronchial hyperreactivity is a major if not an essential characteristic of bronchial asthma. The relation between mediators and non-specific bronchial reactivity is an essential question in the pathogenesis of bronchial asthma. This is reflected in the different hypotheses on pathogenesis. The bronchial reaction to mediators is determined by the pre-existing degree of non specific bronchial reactivity. Bronchial reactivity to histamine or prostaglandin F2 alfa is related to the bronchial metacholine-reactivity. The bronchial lability to exercise or cold air and the immediate bronchoconstriction after allergen inhalation are also determined by the non specific bronchial reactivity. On the other hand, several observations support the concept that mediators modify the non specific bronchial reactivity. The non specific bronchial reactivity increases during the pollen season. Disodiumcromoglycate, a known inhibitor of mediator release, prevents the seasonal increase in bronchial reactivity. The increased bronchial reactivity in patients with allergic rhinitis may also be related to local mediator release. Exposure to ozone and viral upper respiratory tract infections enhance the bronchial reactivity. Avoidance of house dust mite exposure in mite sensitive asthmatics decreases the bronchial reactivity. The same observation has been made after withdrawal from occupational exposure. In experimentally induced asthma, the late asthmatic reaction after allergen inhalation is followed by an increase in nonspecific bronchial reactivity. Mediator release may enhance non specific bronchial reactivity in several ways. Increase of mucosal permeability, modification of sensory nerve endings, alteration of the efferent vagal motor pathway, enhancement of the effect of other mediators, influx of secondary cells, modification of cell receptors and changes in smooth muscle contractility have all been suggested. Mediator release and non specific bronchial reactivity thus appear to be interrelated characteristics of bronchial asthma. Individual differences in the clinical importance of the two characteristics may have therapeutic significance.


Dual-time-point F-18 FDG PET/CT for evaluation in patients with malignant lymphoma.
The aim of this study was to evaluate the usefulness of F-18 fluorodeoxyglucose (FDG) dual-time-point (DTP) positron emission tomography (PET)/computed tomography (CT) with semiquantitative analyses for the initial staging in patients with malignant lymphoma. Forty-three patients had DTP PET/CT, with 60-min and 2-h scan [n = 8, Hodgkin's lymphoma (HL); n = 12, indolent non-Hodgkin lymphoma (NHL); n = 23, aggressive NHL]. A total of 524 lesions were evaluated (406 lymph nodes and 118 extra-nodal lesions). The maximum standardized uptake value (SUV(max)) on 2-h delayed scan (SUV(2)) was significantly higher than those on 1-h early scan (SUV(1)) for all groups (P < 0.0001 for HL; P < 0.0001 for indolent NHL; P < 0.0001 for aggressive NHL). Significant differences were detected between HL and indolent NHL, between indolent NHL and the aggressive NHL for both SUV(1) and SUV(2) (each P < 0.0001). No significant differences were detected between HL and aggressive NHL for both SUV(1) and SUV(2) (P = 0.6891 for SUV(1); P = 0.8828 for SUV(2)); however, significant differences were detected for the retention index of SUV(max) between these groups (P = 0.0238). DTP F-18 FDG PET/CT with a semiquantitative technique may have the potential to provide the more accurate diagnoses for the staging of malignant lymphoma and the more important role in predicting the histological grades of malignancy compared with single-time-point F-18 FDG-PET scan.


Managing acute pain in opioid tolerant patients.
Managing acute pain in opioid tolerant patients can be a significant challenge. This article will provide an overview of the terminology used when managing acute pain in these patients. This understanding is essential to ensure adequate pain relief while avoiding opioid withdrawal. It is also crucial that these patients are identified and that sufficient peri- and postoperative pain management plans are formulated. This article will present an overview of the terms tolerance, physical dependence and addiction. The literature on the management of acute pain in opioid tolerant patients will be considered. Finally an audit that explores and compares the practises of a group of London hospitals, with regard to managing postsurgical pain in opioid-dependent patients will be discussed.


DDAVP therapy controls bleeding in Ehlers-Danlos syndrome.
Patients with Ehlers-Danlos syndrome (EDS), especially types IV, VI, and VIII, are at increased risk of bleeding, and most do not have specific hemostatic deficiencies that would be amenable to replacement therapy. We have investigated the ability of DDAVP (desmopressin acetate) to control bleeding in EDS. Two children with EDS, types VIII and VI, presented with hemorrhagic symptoms and scheduled surgical procedures. Ivy bleeding times (BTs) were measured before and after intravenous (i.v.) DDAVP challenge, and i.v. DDAVP was used prophylactically for their procedures. Laboratory testing was performed to rule out other hemostatic disorders. Both patients had prolonged BTs that corrected following i.v. DDAVP therapy; all other laboratory values were normal. Both patients had excellent clinical hemostasis with surgery, and one has continued to use intranasal DDAVP to control epistaxis and gingival bleeding. The bleeding time in both patients was corrected with DDAVP, and the patients did not have any postoperative bleeding. DDAVP should be considered in other patients who have EDS with bleeding tendencies.


Gender Differences in Risk Factors for Delayed Diagnosis of HIV/AIDS in a Midsized City of Brazil.
Patients treated in the specialized service at a midsized city in Brazil participated in a cross-sectional study that aimed to identify the risk factors for delayed diagnosis of HIV/AIDS. Through interviews and review of medical records, information was collected on sociodemographic and clinical characteristics and diagnoses. The study included 403 patients, of whom 216 (53.6%) were male and 311 (77.1%) had ≤8 years of education. According to the criteria adopted in this study, 162 (40.2%) of the participants had a late diagnosis of AIDS. Only 19 (4.7%) were diagnosed by routine examinations and 45 (11.2%) presented with AIDS-defining disease at the time of diagnosis. After adjustments, the results showed that having more education was protective against a late diagnosis for women. With the advance of the AIDS epidemic to small town and rural Brazil, vulnerable populations now include low-income and less educated women, most of whom have had monogamous relationships throughout their lives.


A comparison of biochemical and histopathologic staging in cats with chronic kidney disease.
Chronic kidney disease (CKD) is prevalent in elderly cats. Frequently, a diagnosis is made in later stages of disease, by which time many renal lesions are irreversible. As such, little headway has been made in identifying an etiology and preventing this common disease. The aim of this study was to evaluate the presence and severity of both reversible and irreversible histopathologic changes in the kidneys of cats at each stage of CKD and, in addition, to determine if lesion prevalence and character were different between stages. A total of 46 cats with CKD were classified according to the International Renal Interest Society (IRIS) as stage I (3 cats), stage II (16 cats), stage III (14 cats), and stage IV (13 cats). Eleven young, nonazotemic and 10 geriatric, nonazotemic cats were included as controls. The severity of tubular degeneration, interstitial inflammation, fibrosis, and glomerulosclerosis was significantly greater in later stages of CKD compared with early stages of disease. Proteinuria was associated with increased severity of tubular degeneration, inflammation, fibrosis, tubular epithelial single-cell necrosis, and decreased normal parenchyma. Presence of hyperplastic arteriolosclerosis, fibrointimal hyperplasia, or other vascular lesions were not found to be significantly different between hypertensive and normotensive cats. The greater prevalence and severity of irreversible lesions in stage III and IV CKD implies that therapeutic interventions should be targeted at earlier stages of disease.