Physiopathological mechanisms involved in the development of hypertension associated with gut dysbiosis and the effect of nutritional/pharmacological interventions.
The gut microbiota dysbiosis represents a triggering factor for cardiovascular diseases, including hypertension. In addition to the harmful impact caused by hypertension on different target organs, gut dysbiosis is capable of causing direct damage to critical organs such as the brain, heart, blood vessels, and kidneys. In this sense, it should be noted that pharmacological and nutritional interventions may influence gut microbiota composition, either inducing or preventing the development of hypertension. Some of the most important nutritional interventions at this level are represented by pro-, pre-, post- and/or syn-biotics, as well as polysaccharides, polyunsaturated fatty acids ω-3, polyphenols and fiber contained in different foods. Meanwhile, certain natural and synthetic active pharmaceutical ingredients, including antibiotics, antihypertensive and immunosuppressive drugs, vegetable extracts and vitamins, may also have a key role in the modulation of both gut microbiota and cardiovascular health. Additionally, gut microbiota may influence drugs and food-derived bioactive compounds metabolism, positively or negatively affecting their biological behavior facing established hypertension. The understanding of the complex interactions between gut microbiome and drug/food response results of great importance to developing improved pharmacological therapies for hypertension prevention and treatment. The purpose of this review is to critically outline the most relevant and recent findings on cardiovascular, renal and brain physiopathological mechanisms involved in the development of hypertension associated with changes in gut microbiota, besides the nutritional and pharmacological interventions potentially valuable for the prevention and treatment of this prevalent pathology. Finally, harmful food/drug interventions on gut microbiota are also described.


TLX is an intrinsic regulator of the negative effects of IL-1β on proliferating hippocampal neural progenitor cells.
Hippocampal neurogenesis is a lifelong process whereby new neurons are produced and integrate into the host circuitry within the hippocampus. It is regulated by a multitude of extrinsic and intrinsic regulators and is believed to contribute to certain hippocampal-dependent cognitive tasks. Hippocampal neurogenesis and associated cognition have been demonstrated to be impaired after increases in the levels of proinflammatory cytokine IL-1β in the hippocampus, such as that which occurs in various neurodegenerative and psychiatric disorders. IL-1β also suppresses the expression of TLX (orphan nuclear receptor tailless homolog), which is an orphan nuclear receptor that functions to promote neural progenitor cell (NPC) proliferation and suppress neuronal differentiation; therefore, manipulation of TLX represents a potential strategy with which to prevent the antiproliferative effects of IL-1β. In this study, we assessed the mechanism that underlies IL-1β-induced changes in TLX expression and determined the protective capacity of TLX to mitigate the effects of IL-1β on embryonic rat hippocampal neurosphere expansion. We demonstrate that IL-1β activated the NF-κB pathway in proliferating NPCs and that this activation was responsible for IL-1β-induced changes in TLX expression. In addition, we report that enhancing TLX expression prevented the IL-1β-induced suppression of neurosphere expansion. Thus, we highlight TLX as a potential protective regulator of the antiproliferative effects of IL-1β on hippocampal neurogenesis.-Ó'Léime, C. S., Kozareva, D. A., Hoban, A. E., Long-Smith, C. M., Cryan, J. F., Nolan, Y. M. TLX is an intrinsic regulator of the negative effects of IL-1β on proliferating hippocampal neural progenitor cells.


Precursors to rape: pressuring behaviors and rape proclivity.
We developed measures assessing personal and normative attitudes toward two types of behaviors that are symptomatic of rape culture. We conceptualize sexual violence as existing on a continuum and argue that two types of behaviors may be potential antecedents to (and consequences of) sexual violence: attempts to pressure, which mimic the power dynamics of rape in a less aggressive fashion, and benevolent dating behaviors, which are accepted dating scripts in which men initiate action. We examined individuals' acceptance of these behaviors in relation to their attitudes toward rape victims and among men to rape proclivity. This initial work suggests that these constructs and measures may be useful to investigate in future research.


Why metabolic syndrome criteria have not made prime time: a view from the clinic.
Much has been written on the metabolic syndrome and related recent criteria. However, it remains unclear whether such criteria help clinical practice. This review will evaluate the usefulness of metabolic syndrome criteria to enhance risk prediction for either cardiovascular disease or diabetes. This is a narrative review that is based on the author's experience from relevant publications from his group and from other related research. Although the presence of metabolic syndrome, however defined, is clearly associated with higher risk for vascular disease, the criteria do not enhance coronary heart disease (CHD) prediction from simpler Framingham-based risk scores. The dichotomous nature of metabolic syndrome criteria-either you have it or you do not-combined with the lack of age, low-density lipoprotein cholesterol and smoking account for their inferior predictive value. Metabolic syndrome criteria are, in fact, more strongly associated with incident diabetes, an observation demonstrated in the West of Scotland Coronary Prevention Study (WOSCOPS). This is because three of the five parameters within metabolic syndrome criteria (waist, glucose and triglyceride) are more closely linked to risk for diabetes than risk for CHD. However, screening for prevalent or high risk of incident diabetes is a complex and debated issue and is by no means guaranteed to be widely adopted. Metabolic syndrome criteria do not offer benefits beyond established methods of vascular risk assessment. Thus, the focus in clinical practice should remain on established risk factors (for example, smoking, lipids, blood pressure) both to determine CHD risk, through established charts, and to reduce it.


Effects of some metabolic intermediates on AMP-deaminase activity in denervation atrophy.
Effects in vitro of glutamate, aspartate, fumarate and malate on substrate activation kinetics of AMP-deaminase in denervated and contralateral gastrocnemius muscles of the frog, Rana hexadactyla were studied. Glutamate increase the enzyme activity of both muscles by increasing maximal velocity (V) and decreasing Michaelis-Menten constant (Km), whereas, aspartate did not show any significant effect. Fumarate and malate exerted mixed type of inhibition by decreasing V and increasing Km of enzymes in both muscle preparations. The inhibitor constant (Ki) values suggest that the denervated muscle enzyme was more sensitive to fumarate and malate as compared to the contralateral muscle enzyme.


Acamprosate in alcohol dependence: a randomized controlled efficacy study in a standard clinical setting.
This study was undertaken to evaluate the efficacy and safety of acamprosate in the treatment of alcohol dependence. The investigation was a double-blind, placebo-controlled, 24-week study carried out at the University of São Paulo, Brazil. The sample comprised 75 patients, 18-60 years of age, with an International Classification of Diseases (ICD-10) diagnosis of alcohol dependence. After a 1-week detoxification period the patients were randomly divided into two groups: the first received acamprosate (1.998 mg/day) and the second received placebo. After the first 12 weeks, the patients continued follow-up for a similar length of time without medication. The main outcome measures were relapse rates, side effects and time to first relapse. On an intention-to-treat basis, the Kaplan-Meier survival curve showed an advantage in relapse rates for acamprosate over placebo (log-rank test, p = .02), and acamprosate was well tolerated. Acamprosate seems to be an effective treatment for alcohol dependence in a Brazilian population.


Genetic diversity and antiretroviral resistance-associated mutation profile of treated and naive HIV-1 infected patients from the Northwest and Southwest regions of Cameroon.
Antiretroviral therapy (ART) has improved the survival of HIV infected persons. However, rapid scale-up of ART and the high HIV-1 genetic variability, has greatly influenced the emergence of drug-resistant strains. This constitutes a potential threat to achieving the UNAIDS' 90-90-90 goals by 2020. We investigated the prevalent HIV-1 genotypes, drug resistance-associated mutations and assessed some predictors of the occurrence of these mutations. This was a hospital-based cross-sectional study conducted between October 2010 and June 2012. Participants were consecutively enrolled from selected HIV treatment centers of the Southwest and Northwest regions of Cameroon. Viral load was determined with the automated Abbott Real-time HIV-1 m2000rt System. HIV genotyping and antiretroviral resistance mutations analysis were performed using Bayer's HIV-1 TRUGENE™ Genotyping Kit and OpenGene DNA Sequencing system. The drug resistance mutation was interpreted with the Stanford HIV database. Epidemiological data were obtained using pre-tested semi-structured questionnaires. Of the 387 participants, 239 were successfully genotyped. The median age of these participants was 33 years (interquartile range, IQR: 28-40 years), and a majority (65.7%) were female. A total of 29.3% of the participants were receiving ART. The median duration of ART was 10.5 months (IQR: 4-17.25 months). The median CD4 count and log10 viral load of study participants were 353.5 cells/ml (IQR:145-471) and 4.89 copies/ml (IQR: 3.91-5.55) respectively. CRF02 (A/G) (69%) was the most prevalent subtype followed by G (8.2%) and F (6.7%). Overall, resistance mutations were present in 37.1% of ART-experienced and 10.7% of ART-naive patients. Nucleoside reverse transcriptase inhibitors (NRTI) mutations occurred in 30% of ART-experienced and 2.4% of ART-naïve patients, while non-nucleoside reverse transcriptase inhibitors (NNRTI) mutations occurred in 34.2% of ART-experienced and 10.1% of -naïve patients. M184V (8.4%, 20/239) and K103N (5.4%, 13/239) were the most prevalent mutations. Major protease inhibitor mutations occurred in 3 (1.3%) out of the 239 sequences. The duration of ART independently predicted the occurrence of resistance mutation among ART-experienced patients. The high resistance to NNRTIs, which are the main support to the backbone (NRTIs) first-line antiretroviral regimen in Cameroon, has prompted the need to rollout an integrase strand transfer inhibitor regimen (containing Dolutegravir) with a higher genetic barrier to resistance as the preferred first line regimen.


Coordination of Mucosal Immunity by Innate Lymphoid Cells.
Mucosal barrier surfaces of the mammalian body are frequent sites of pathogen colonization or entry and are also densely colonized with trillions of normally beneficial microbes, termed the microbiota. Therefore, it is paramount that the host immune system recognizes these microbes and is capable of differentiating between them. To this end, a multitude of mechanisms have evolved to carefully balance the need for immune activation in the face of infections while maintaining an appropriate level of tolerance to protect both the host and the beneficial microbes from hyperactivation. These mechanisms include the deployment of an emerging class of tissue-resident innate immune cells, innate lymphoid cells (ILCs), that are enriched at mucosal barriers such as the lungs and intestines, and are critical mediators of tissue homeostasis, tolerance, repair, and innate immunity. Recent findings have provided insight into the regulation of these cells and their interactions, not only with microbes, both commensal and foreign, but also with other systems of the body to prevent disease and promote tissue health. Here, we discuss recent findings in the regulation and function of ILCs, including a focus on their interactions with bodily systems, such as the nervous system, and how these interactions affect their functionality in states of health, infection, and disease.


Differential contribution of complement receptor C5aR in myeloid and non-myeloid cells in chronic ethanol-induced liver injury in mice.
Complement is implicated in the development of alcoholic liver disease. C3 and C5 contribute to ethanol-induced liver injury; however, the role of C5a receptor (C5aR) on myeloid and non-myeloid cells to progression of injury is not known. C57BL/6 (WT), global C5aR-/-, myeloid-specific C5aR-/-, and non-myeloid-specific C5aR-/- mice were fed a Lieber-DeCarli diet (32%kcal EtOH) for 25 days. Cultured hepatocytes were challenged with ethanol, TNFα, and C5a. Chronic ethanol feeding increased expression of pro-inflammatory mediators in livers of WT mice; this response was completely blunted in C5aR-/- mice. However, C5aR-/- mice were not protected from other measures of hepatocellular damage, including ethanol-induced increases in hepatic triglycerides, plasma alanine aminotransferase and hepatocyte apoptosis. CYP2E1 and 4-hydroxynonenal protein adducts were induced in WT and C5aR-/- mice. Myeloid-specific C5aR-/- mice were protected from ethanol-induced increases in hepatic TNFα, whereas non-myeloid-specific C5aR-/- displayed increased hepatocyte apoptosis and inflammation after chronic ethanol feeding. In cultured hepatocytes, cytotoxicity induced by challenge with ethanol and TNFα was completely eliminated by treatment with C5a in cells from WT, but not C5aR-/- mice. Further, treatment with C5a enhanced activation of pro-survival signal AKT in hepatocytes challenged with ethanol and TNFα. Taken together, these data reveal a differential role for C5aR during ethanol-induced liver inflammation and injury, with C5aR on myeloid cells contributing to ethanol-induced inflammatory cytokine expression, while non-myeloid C5aR protects hepatocytes from death after chronic ethanol feeding.


Regulation of IL-1 gene expression: differential responsiveness of murine macrophage lines.
In order to begin to define the mechanisms by which lipopolysaccharide (LPS) regulates IL-1 gene expression, we have examined IL-1 RNA levels, the transcription rate of the IL-1 genes, and IL-1 mRNA stabilities in P388D1/C, RAW264.7, and murine peritoneal exudate cells (PEC). These experiments showed that total cellular IL-1 RNA levels and IL-1 transcription rates were dramatically upregulated in all three cell types. In all cases, IL-1 alpha and IL-1 beta cellular RNA levels and gene transcription rates were regulated in parallel. However, the profiles of IL-1 gene activation during the 24 h after LPS treatment differed in these three cell types. Additionally, culture in the presence of actinomycin D (Act D) showed differential stabilities of the IL-1 alpha and IL-1 beta RNAs in these cells. In peritoneal exudate cells, the half-lives (t1/2) of the IL-1 alpha and IL-1 beta RNAs were each > 8 h. In RAW264.7 cells, the stability of the IL-1 beta RNA was greater than the IL-1 alpha RNA (t1/2 > 8 h and approximately 6 h, respectively). In P388D1/C cells, the t1/2's of the IL-1 alpha and beta RNAs varied depending on the time of addition of actinomycin D. This and other data suggest that components of the IL-1 RNA catabolic pathway are labile and sensitive to treatment with actinomycin D. Together these data indicate that the two IL-1 genes show a diverse regulatory repertoire, even within related mononuclear phagocytic cells.


Maximum duration of phonation: objective tool for assessment of voice.
30 male and 30 female adults sustained the vowel /a/ under specified conditions. Analysis of the data for 10 trials suggests that four trials produced at a comfortable pitch and loudness level and interrupted by a 60-sec. rest would reliably evaluate prolonged vocalization. Males' superior performance was noted. Clinical applications and research implications are discussed.


Pediatric Sickle Cell Disease and Parent and Child Catastrophizing.
Pain catastrophizing is poorly understood in children and adolescents with sickle cell disease (SCD) and their parents. The objectives of this study were twofold: 1) to evaluate the interplay between parent and child pain catastrophizing and its effect on disability among youth with SCD, and 2) to evaluate whether child pain catastrophizing served as a mechanism that explained the relation between pain and functional disability within the context of varying levels of parent pain catastrophizing. One hundred youth (8-18 years old) with SCD and parents completed measures of pain characteristics (pain frequency and intensity), catastrophizing (Pain Catastrophizing Scale), and the outcome of functional disability (Functional Disability Inventory) in a cross-sectional study. Youth with low levels of catastrophizing showed high levels of disability in the presence of high levels of parent catastrophizing. Additionally, child pain catastrophizing was a significant mechanism that partially explained the effect of higher pain frequency and pain intensity on greater levels of disability, but only at low levels of parent pain catastrophizing. High levels of parent catastrophizing and incongruence between child and parent catastrophizing contributes to poorer functional outcomes in youth with SCD. Youth with SCD and parents with high levels of catastrophic thinking about child pain or incongruent levels of catastrophizing are at increased risk for greater child disability. Clinicians treating youth with SCD should focus on targeting worried thinking about pain in patients and parents to facilitate improved function.


Macromolecular synthesis and stability in growth-arrested BALB/c-3T3 cells.
Concentrations of methylglyoxal bis-(guanylhydrazone) (mGBG) that inhibited serum-stimulated BALB/c-3T3 cells in late G1 caused a marked inhibition of 3H-leucine incorporation during a 20-min incubation. No decrease was observed in the incorporation of 3H-uridine during a 20-min incubation; however, the amount of acid-insoluble 3H-uridine in mGBG-treated cultures was decreased when the incubation period was longer than 20 min. The amount of the decrease in the accumulation of incorporated 3H-uridine was directly proportional to the length of the incorporation time. Between 10 and 12 h after quiescent BALB/c-3T3 cells were serum-stimulated in mGBG no additional 3H-uridine was accumulated. The stability of the incorporated 3H-uridine, as determined by acid-insoluble radioactivity remaining after the addition of actinomycin D, was less in cells cultured in mGBG. Exogenous spermine or spermidine reversed the inhibition of 3H-uridine accumulation in acid-insoluble material produced by mGBG as well as the decrease in stability of the incorporated 3H-uridine in acid-insoluble material. The effects of mGBG on both the incorporation of 3H-uridine and the stability of the incorporated 3H-uridine can apparently be accounted for by an effect on ribosomal RNA.


Spontaneous splenic rupture following stem cell mobilization with G-CSF and plerixafor in AL amyloidosis.
AL amyloidosis is a rare plasma cell dyscrasia with multiorgan involvement. Good risk patients are candidate to high dose chemotherapy and autologous stem cell transplantation. However both transplantation and stem cell collection entail significant risk in such patients. Plerixafor is a novel mobilizing agent approved for use in "poor mobilizer" patients with lymphoma and multiple myeloma; experience in systemic amyloidosis patients is limited. We describe a case of spontaneous splenic rupture following administration of G-CSF and plerixafor in a patient with AL amyloidosis who previously underwent heart transplantation due to amyloid heart involvement. This is the first report of spontaneous splenic rupture following stem cell mobilization with G-CSF and plerixafor in AL amyloidosis. The role of plerixafor has to be established. AL amyloidosis patients undergoing stem cell mobilization need careful monitoring of signs and symptoms of spontaneous splenic rupture.


Robust, ECG-based detection of Sleep-disordered breathing in large population-based cohorts.
Up to 5% of adults in Western countries have undiagnosed sleep-disordered breathing (SDB). Studies have shown that electrocardiogram (ECG)-based algorithms can identify SDB and may provide alternative screening. Most studies, however, have limited generalizability as they have been conducted using the apnea-ECG database, a small sample database that lacks complex SDB cases. Here, we developed a fully automatic, data-driven algorithm that classifies apnea and hypopnea events based on the ECG using almost 10 000 polysomnographic sleep recordings from two large population-based samples, the Sleep Heart Health Study (SHHS) and the Multi-Ethnic Study of Atherosclerosis (MESA), which contain subjects with a broad range of sleep and cardiovascular diseases (CVDs) to ensure heterogeneity. Performances on average were sensitivity(Se)=68.7%, precision (Pr)=69.1%, score (F1)=66.6% per subject, and accuracy of correctly classifying apnea-hypopnea index (AHI) severity score was Acc=84.9%. Target AHI and predicted AHI were highly correlated (R2 = 0.828) across subjects, indicating validity in predicting SDB severity. Our algorithm proved to be statistically robust between databases, between different periodic leg movement index (PLMI) severity groups, and for subjects with previous CVD incidents. Further, our algorithm achieved the state-of-the-art performance of Se=87.8%, Sp=91.1%, Acc=89.9% using independent comparisons and Se=90.7%, Sp=95.7%, Acc=93.8% using a transfer learning comparison on the apnea-ECG database. Our robust and automatic algorithm constitutes a minimally intrusive and inexpensive screening system for the detection of SDB events using the ECG to alleviate the current problems and costs associated with diagnosing SDB cases and to provide a system capable of identifying undiagnosed SDB cases.


Amyloid beta and the longest-lived rodent: the naked mole-rat as a model for natural protection from Alzheimer's disease.
Amyloid beta (Aβ) is implicated in Alzheimer's disease (AD) as an integral component of both neural toxicity and plaque formation. Brains of the longest-lived rodents, naked mole-rats (NMRs) approximately 32 years of age, had levels of Aβ similar to those of the 3xTg-AD mouse model of AD. Interestingly, there was no evidence of extracellular plaques, nor was there an age-related increase in Aβ levels in the individuals examined (2-20+ years). The NMR Aβ peptide showed greater homology to the human sequence than to the mouse sequence, differing by only 1 amino acid from the former. This subtle difference led to interspecies differences in aggregation propensity but not neurotoxicity; NMR Aβ was less prone to aggregation than human Aβ. Nevertheless, both NMR and human Aβ were equally toxic to mouse hippocampal neurons, suggesting that Aβ neurotoxicity and aggregation properties were not coupled. Understanding how NMRs acquire and tolerate high levels of Aβ with no plaque formation could provide useful insights into AD, and may elucidate protective mechanisms that delay AD progression.


Impact factors for difficult cecal intubation during colonoscopy.
There are no accepted means of identifying patients in whom colonoscopy is likely to be more difficult and allocate time accordingly. To identify patient-related, endoscopist-related, and procedure-related factors associated with difficult cecal intubation. This was a prospective study performed at the Kaohsiung Chang Gung Memorial Hospital, Kaohsiung Medical Center, from January to December 2009. Data pertaining to patient information (age, sex, weight, waist circumference and buttock girth, bowel habit, and abdomen surgery history) were recorded prospectively. Procedure-specific information including the need to alter patient position, application of external compression, and cecal intubation time (CIT) was documented. A total of 859 consecutive patients were enrolled. The mean age of the patients was 50.5 ± 11.4 years. CIT was longer in women compared with men (410 ± 195 vs. 376 ± 224 s; P = 0.021). Older patients had longer CITs--an additional 2.1 seconds for each incremental year (P = 0.001), and poor bowel preparation increased CIT (P = 0.019). Patients who required a position change or abdominal compression took longer to reach the cecum (P<0.001). Our findings emphasize the importance of colon preparation and the need for abdominal compression and a change of position when performing a difficult colonoscopy.


In vitro pathogenicity assay for anti-desmoglein autoantibodies in pemphigus.
Patients with pemphigus have circulating anti-desmoglein (Dsg) 1 and/or Dsg3 autoantibodies that induce blister formation on the skin and mucous membrane. We describe here two assays that measure the pathogenic strength of autoantibodies in blister formation: an in vitro dissociation assay using primary human epidermal keratinocytes to assess pathogenicity of anti-Dsg3 autoantibodies, and an alternative method whereby anti-Dsg3 and Dsg1 autoantibodies are injected into organ-cultured human skin specimen.


Role of stereotactic biopsy in the surgical treatment of cerebral tumors.
Out of 664 intracranial tumors subjected to surgical procedures since 1980, 163 underwent stereobiopsy. On the basis of this experience, we devised a scheme to help decide whether and why stereobiopsy is advisable.


Optic disc interpretation in glaucoma: is confidence misplaced?
A photographic questionnaire has been used to investigate whether or not clinicians have realistic expectations of their ability to distinguish optic discs associated with glaucomatous visual field loss from discs of healthy eyes. The questionnaire consisting of 30 non-stereoscopic fundus photographs from 15 patients was administered to 40 ophthalmologists of varying experience and 10 optometrists. Each group displayed large discrepancies between their expected and achieved scores suggesting that clinicians may overestimate their ability to recognize the glaucomatous optic disc. This could lead to diagnostic errors especially in cases where tonometric and visual field parameters are considered equivocal. An over-reliance on the cup/disc ratio appeared to be the most likely cause of error.


Fungal Endocarditis: Update on Diagnosis and Management.
Fungal endocarditis is an extremely debilitating disease associated with high morbidity and mortality. Candida spp. are the most common isolated organisms in fungal endocarditis. It is most prevalent in patients who are immunosuppressed and intravenous drug users. Most patients present with constitutional symptoms, which are indistinguishable from bacterial endocarditis, hence a high index of suspicion is required for pursuing diagnosis. Diagnosis of fungal endocarditis can be very challenging: most of the time, blood cultures are negative or take a long time to yield growth. Fungal endocarditis mandates an aggressive treatment strategy. A medical and surgical combined approach is the cornerstone of therapy.


Preschool children involve a third party in a dyadic sharing situation based on fairness.
To investigate whether preschool children would involve third parties in dyadic sharing situations, we created unequal sharing situations in which one agent had no resources and a child participant and a third-party individual had unequal resources. We analyzed children's tendency to share with the indigent agent and to involve the wealthy agent, whereas the indigent agent elicited sharing from them by means of progressive levels of request. The results showed that 5-year-olds involved the third party to a greater extent than 3.5-year-olds when they had fewer resources than the third party (Experiment 1). Yet, when 5-year-olds had the largest amount of resources, they were less likely to involve a third party but more likely to share themselves (Experiment 2). This study provides the first evidence that the tendency to involve third-party individuals in resource allocation situations develops at the preschool age and that it is based on fairness considerations.


Characterization of dissociated monolayer cultures of human spinal cord.
Embryonic human spinal cord cells have been grown in dissociated monolayer cultures for 1 to 7 weeks. Using cell type specific markers, it was possible to show that the cultures contain neurons, astrocytes and fibroblasts. Electrical membrane properties were studied with patch electrodes using the whole cell recording technique. Neurons had short duration action potentials that could be blocked by tetrodotoxin. The membrane currents in these neurons were studied in voltage clamp experiments. Three types of voltage-dependent currents were observed: a sodium current; a potassium current made up of two components, IA and IK; and a calcium current. Both cholinergic and GABAergic neurons are present in the cultures. There is more choline acetyltransferase activity in cultures prepared from the anterior as compared to the posterior part of the spinal cord, suggesting that the cultures contain motoneurons. This tissue culture preparation was developed for the study of amyotrophic lateral sclerosis; we have been unable to detect the presence of any toxic agent from the serum of these patients on the cultured cells. Experiments are in progress to purify the motoneurons using Percoll gradients.


Parallel multiple instance learning for extremely large histopathology image analysis.
Histopathology images are critical for medical diagnosis, e.g., cancer and its treatment. A standard histopathology slice can be easily scanned at a high resolution of, say, 200,000×200,000 pixels. These high resolution images can make most existing imaging processing tools infeasible or less effective when operated on a single machine with limited memory, disk space and computing power. In this paper, we propose an algorithm tackling this new emerging "big data" problem utilizing parallel computing on High-Performance-Computing (HPC) clusters. Experimental results on a large-scale data set (1318 images at a scale of 10 billion pixels each) demonstrate the efficiency and effectiveness of the proposed algorithm for low-latency real-time applications. The framework proposed an effective and efficient system for extremely large histopathology image analysis. It is based on the multiple instance learning formulation for weakly-supervised learning for image classification, segmentation and clustering. When a max-margin concept is adopted for different clusters, we obtain further improvement in clustering performance.


Equilenin: a specific fluorescent probe for steroid-protein interactions in sex steroid-binding protein.
Equilenin, a naturally fluorescent steroid, has high binding affinity for human sex steroid-binding protein (SBP). At 4 degrees C the equilibrium association constant is approximately 6 X 10(7) M-1. The fluorescence excitation and emission spectra of the steroid-protein complex indicate that both hydrophobic interactions and hydrogen bonding of the 3'-hydroxyl group of the estrogen are important in its binding to the protein. Equilenin has a substantially different 3-dimensional spatial configuration compared with the normally bound androgens, and yet exhibits very tight binding to SBP. This suggests that SBP undergoes a conformational change to accomodate equilenin.


The T-shaped FST pharyngoplasty step-by-step closure technique.
Pharyngocutaneous fistula is one of the most common and serious complications associated with total laryngectomy. Numerous studies tried to evaluate causative and predisposing factors associated with this complication, but data are considerably variable and there is still no international consensus. Incidence rate varies considerably between studies, with reported rates from 3% to 65%. This 4K video presents our T-shaped four-step technique (FST) for closing the pharyngeal mucosa after total laryngectomy in a step-by-step manner. All sutures were performed by braided absorbable 3/0 26 mm 1/2c (Vicryl plus 3.0; Ethicon, Somerville, NJ, USA). Recordings were performed using a Karl Storz 4K 3D VITOM® exoscope (Karl Storz SE & Co. KG, Tuttlingen, Germany). We have been described this technique through a high-definition video, showing each step, and tips from the authors. Our T-shaped pharyngoplasty closure technique can be divided into four steps: 1. "Key Stitches"; 2. "Area Refinement Stitches"; 3. "Modified Connell Suture"; 4. "Modified Purse String Suture." Our T-shaped FST closure technique proved to be an effective and reproducible method, which we feel could be the preferred choice for primary pharyngoplasty closure.


Anesthesia for the horse with colic.
This article discusses anesthesia for horses with colic from acute gastrointestinal disease. Emphasis is placed on new developments in pre-, intra-, and immediate postoperative management over the last decade, including early goal-directed therapy (EGDT) in the resuscitation of septic patients, the controversy over the optimal fluid type to administer, and the management of complications, such as cardiovascular depression, hypoventilation and hypoxemia, and decreased colloid oncotic pressure (COP). An update on analgesia is also provided; older drugs such as ketamine and lidocaine are increasingly being recognized both for their analgesic properties and other potentially beneficial effects in endotoxemic horses.


Phorbol ester inhibition of current responses and simultaneous protein phosphorylation in Xenopus oocyte injected with brain mRNA.
The role of protein kinase C activation in a coupling of Ca2+-mobilizing receptors/GTP-binding protein/phospholipase C was examined using Xenopus oocytes before and after microinjection of mRNA purified from rat brains. Under voltage-clamp conditions, although the phorbol ester TPA per se never elicited any changes in ionic conductance, chloride current responses of mRNA-injected cells to 5-hydroxytryptamine and acetylcholine (ACh) were suppressed by an 8-min pretreatment of 12-O-tetradecanoyl-4 beta-phorbol-13-acetate (TPA), at nanomolar concentrations. Native ACh response in intact follicular oocytes was also inhibited by the TPA treatment. However, similar current responses triggered by the direct activation of their intracellular signalling pathway with guanosine-5'-O-(3-thio)triphosphate or Ca2+ were not affected by TPA. Biochemical analyses indicated that phosphorylation of 33,000- and 45,000-dalton proteins was markedly enhanced by TPA in vivo, and that stimulation of receptors with agonists as well as TPA treatment increased phosphoproteins in the membrane fraction of mRNA-injected oocytes. These observations suggest that protein kinase C may switch off the signal transduction from receptors to GTP-binding proteins and may participate in the negative feedback modulation of receptor-operated ion channel responses.


The role of closed circuit television in the teaching of operative dentistry.
Closed circuit television has been used in the Department of Operative Dental Surgery of the University of Newcastle-upon-Tyne since 1966. The medium has played an increasingly important role in the teaching of technique courses, especially after 1978 when the large 80-place teaching laboratory of the newly-built Dental School was commissioned.


A novel class of apical sodium-dependent bile acid transporter inhibitors: the amphiphilic 4-oxo-1-phenyl-1,4-dihydroquinoline derivatives.
A series of 4-oxo-1-phenyl-1,4-dihydroquinolines possessing a linker and an ammonio moiety were synthesized and found to inhibit the apical sodium-dependent bile acid transporter (ASBT). The potency of ASBT inhibition varied with the position and length of the linking tether. Compound 21e effectively lowered the total serum cholesterol levels in hamsters.


Calibrated fMRI in the medial temporal lobe during a memory-encoding task.
Prior measures of the blood oxygenation level-dependent (BOLD) and cerebral blood flow (CBF) responses to a memory-encoding task within the medial temporal lobe have suggested that the coupling between functional changes in CBF and changes in the cerebral metabolic rate of oxygen (CMRO(2)) may be tighter in the medial temporal lobe as compared to the primary sensory areas. In this study, we used a calibrated functional magnetic resonance imaging (fMRI) approach to directly estimate memory-encoding-related changes in CMRO(2) and to assess the coupling between CBF and CMRO(2) in the medial temporal lobe. The CBF-CMRO(2) coupling ratio was estimated using a linear fit to the flow and metabolism changes observed across subjects. In addition, we examined the effect of region-of-interest (ROI) selection on the estimates. In response to the memory-encoding task, CMRO(2) increased by 23.1+/-8.8% to 25.3+/-5.7% (depending upon ROI), with an estimated CBF-CMRO(2) coupling ratio of 1.66+/-0.07 to 1.75+/-0.16. There was not a significant effect of ROI selection on either the CMRO(2) or coupling ratio estimates. The observed coupling ratios were significantly lower than the values (2 to 4.5) that have been reported in previous calibrated fMRI studies of the visual and motor cortices. In addition, the estimated coupling ratio was found to be less sensitive to the calibration procedure for functional responses in the medial temporal lobe as compared to the primary sensory areas.


Further validation of the expanded auditory verbal learning test for detecting poor effort and response bias: data from temporal lobectomy candidates.
The present study aimed to further examine the specificity of the Exaggeration Index of the expanded Auditory Verbal Learning Test procedure for detecting inadequate effort or response bias in a nonlitigating sample with unequivocal brain damage. Data from 56 patients with intractable epilepsy undergoing presurgical evaluation for temporal lobectomy were analyzed. In this sample, specificity was excellent at the recommended cut-off (94%), and comparable to that of another well-researched instrument for detecting inadequate effort, the Recognition Memory Test. Findings strongly support the generalizability of the specificity estimates obtained by Barrash et al. and, more broadly, the clinical utility of the Exaggeration Index. To facilitate diagnostic decision-making, the probability of invalid performances associated with each score on the Exaggeration Index, based on all clinical cross-validation samples reported to date, is also presented.


Creating Age-Friendly Health Systems - A vision for better care of older adults.
Safe and effective care of older adults is a crucial issue given the rapid growth of the aging demographic, many of whom have complex health and social needs. At the same time, the health care delivery environment is rapidly changing, offering a new set of opportunities to improve care of older adults. We describe the background, evidence-based changes, and testing, scale-up, and spread strategy that are part of the design of the Creating Age-Friendly Health Systems initiative. The goal is to reach 20% of U.S. hospitals and health systems by 2020, with plans to reach additional hospitals and health systems in subsequent years.


Cognitive Impairment and Associated Factors among Older Adults with Diabetes in a Suburban Primary Health Center in Thailand.
Thailand is a rapidly aging society. The percentage of older adults with diabetes has also been increasing. Since diabetes mellitus is documented as a risk factor for dementia, it is important to address cognitive impairment in older adults with diabetes. Thus, this study aimed to evaluate the prevalence and associated factors of cognitive impairment among older adults with diabetes in a suburban primary health center in Thailand. A cross-sectional study in 244 diabetic patients aged 60 years or older was conducted in a primary health care unit in Pathum Thani, Thailand. Cognitive function was assessed with the validated Thai version of the Mini-Addenbrooke's Cognitive Examination Test. Sociodemographic and health characteristic data were obtained. The prevalence of cognitive impairment was 54.5% (133 out of 244). Multivariate logistic regression disclosed that factors significantly associated with cognitive impairment were ages 70-79 years compared to ages 60-69 years (odds ratio [OR] 1.90, 95% confidence interval [CI]: 1.01-3.62, p value 0.048), ages ≥80 years compared to ages 60-69 years (OR 3.65, 95% CI: 1.19-11.24, p value 0.024), education ≤ primary school (OR 7.28, 95% CI: 3.56-14.89, p value <0.001), and medication managed by caregiver compared to self-management of medication (OR 13.40, 95% CI: 1.55-116.10, p value 0.019). We revealed that approximately half of older adults with diabetes had cognitive impairment. This finding strongly suggests the need to include cognitive assessment in a standard clinical practice guideline for diabetic patients and to focus more on individuals who are very old, have low education, or are unable to manage their drugs by themselves.


A structured literature synthesis of wrist outcome measures: An evidence-based approach to determine use among common wrist diagnoses.
Structured literature synthesis. Hand therapists and researchers have numerous options when selecting outcome measures for patients with wrist pathologies. An evidence-based approach to determining which measures are used most often can inform choices. To describe how frequently outcome measures are used in recent randomized controlled trials of patients with wrist diagnoses. Identifying assessment design and related International Classification of Functioning, Disability and Health (ICF) domains provides additional consideration for selection. Systematic PubMed and Cumulative Index to Nursing and Allied Health Literature searches for the time frame between January 2005 and March 2015 captured measures used in randomized controlled trials researching wrist-specific fractures, ligament injuries, nerve injuries, arthritis/arthroplasty, or stress injuries/wrist pain. Three most frequent measures used within each diagnostic category are detailed with assessment design described and ICF domain identified. Across diagnoses, grip/pinch strength and Disabilities of Arm, Shoulder and Hand were the most frequently used physical and patient-reported outcome measures, respectively. The Jebsen-Taylor Hand Function Test was the most frequently used performance measure. Consideration of the evidence, ICF domains, wrist diagnoses, and assessment design can help hand therapists select the measure most appropriate for use. 2a.


Genetic architecture and key regulatory genes of fatty acid composition in Gushi chicken breast muscle determined by GWAS and WGCNA.
Fatty acids composition in poultry muscle is directly related to its tenderness, flavour, and juiciness, whereas its genetic mechanisms have not been elucidated. In this study, the genetic structure and key regulatory genes of the breast muscle fatty acid composition of local Chinese chicken, Gushi-Anka F2 resource population by integrating genome-wide association study (GWAS) and weighted gene co-expression network analysis (WGCNA) strategies. GWAS was performed based on 323,306 single nucleotide polymorphisms (SNPs) obtained by genotyping by sequencing (GBS) method and 721 chickens from the Gushi-Anka F2 resource population with highly variable fatty acid composition traits in the breast muscle. And then, according to the transcriptome data of the candidate genes that were obtained and phenotypic data of fatty acid composition traits in breast muscle of Gushi chickens at 14, 22, and 30 weeks of age, we conducted a WGCNA. A total of 128 suggestive significantly associated SNPs for 11 fatty acid composition traits were identified and mapped on chromosomes (Chr) 2, 3, 4, 5, 13, 17, 21, and 27. Of these, the two most significant SNPs were Chr13:5,100,140 (P = 4.56423e-10) and Chr13:5,100,173 (P = 4.56423e-10), which explained 5.6% of the phenotypic variation in polyunsaturated fatty acids (PUFA). In addition, six fatty acid composition traits, including C20:1, C22:6, saturated fatty acid (SFA), unsaturated fatty acids (UFA), PUFA, and average chain length (ACL), were located in the same QTL intervals on Chr13. We obtained 505 genes by scanning the linkage disequilibrium (LD) regions of all significant SNPs and performed a WGCNA based on the transcriptome data of the above 505 genes. Combining two strategies, 9 hub genes (ENO1, ADH1, ASAH1, ADH1C, PIK3CD, WISP1, AKT1, PANK3, and C1QTNF2) were finally identified, which could be the potential candidate genes regulating fatty acid composition traits in chicken breast muscle. The results of this study deepen our understanding of the genetic mechanisms underlying the regulation of fatty acid composition traits, which is helpful in the design of breeding strategies for the subsequent improvement of fatty acid composition in poultry muscle.


GA-binding protein regulates KIS gene expression, cell migration, and cell cycle progression.
The cyclin-dependent kinase inhibitor p27(Kip1) arrests cell cycle progression through G1/S phases and is regulated by phosphorylation of serine/threonine residues. Recently, we identified the serine/threonine kinase, KIS, which phosphorylates p27(Kip1) on serine 10 leading to nuclear export of p27(Kip1) and protein degradation. However, the molecular mechanisms of transcriptional activation of the human KIS gene and its biological activity are not known. We mapped the transcription initiation site approximately 116 bp 5' to the translation start site, and sequences extending to -141 were sufficient for maximal promoter activity. Mutation in either of two Ets-binding sites in this region resulted in an approximately 75-80% decrease in promoter activity. These sites form at least 3 specific complexes, which contained GA-binding protein (GABP). Knocking down GABPalpha by siRNA in vascular smooth muscle cells (VSMCs) diminished KIS gene expression and reduced cell migration. Correspondingly, in serum stimulated GABPalpha-deficient mouse embryonic fibroblasts (MEFs), KIS gene expression was also significantly reduced, which was associated with an increase in p27(Kip1) protein levels and a decreased percentage of cells in S-phase. Consistent with these findings, following vascular injury in vivo, GABPalpha-heterozygous mice demonstrated reduced KIS gene expression within arterial lesions and these lesions were significantly smaller compared to GABP+/+ mice. In summary, serum-responsive GABP binding to Ets-binding sites activates the KIS promoter, leading to KIS gene expression, cell migration, and cell cycle progression.


Enhanced cardioprotective effects by coexpression of two isoforms of hepatocyte growth factor from naked plasmid DNA in a rat ischemic heart disease model.
The therapeutic potential of pCK-HGF-X7, a naked DNA designed to express two isoforms of hepatocyte growth factor (HGF(723) and HGF(728) ), was studied in the rat ischemic heart disease model. First, the kinetics of gene expression was examined by injecting pCK-HGF-X7 DNA into the rat heart. Second, the cardioprotective effects were compared between the two naked DNA constructs, expressing a single (HGF(728) ) or both isoforms (HGF(728) and HGF(723) ) of HGF, in the rat ischemic heart disease model. The ischemic injury to the rat heart was created by ischemia-reperfusion in the anterior descending artery. The respective naked DNA constructs were injected into the anterior wall of the rat heart with the ischemia-reperfusion injury. Cardiac function, capillary density and anti-fibrotic activity were compared between the two naked DNA constructs. The intramyocardial administration of pCK-HGF-X7 resulted in transient and localized HGF expression for 3 weeks. At its peak, approximately 678 pg (per mg of tissue protein) of HGF was produced in the injected heart without an increase of HGF protein level in other tissues, and serum. pCK-HGF-X7 more efficiently improved the left ventricular ejection fraction and the systolic anterior wall thickness, increased the capillary density, and inhibited myocardial fibrosis, in a statistically significant manner, compared to the identical vector encoding HGF(728) only. These results demonstrate that transfer of the genomic-cDNA hybrid expressing both isoforms of the HGF gene might provide higher therapeutic effects than the cDNA sequence producing HGF(728) alone in the treatment of ischemic heart disease.


SGLT2 and cancer.
Glycolysis plays a central role in tumor metabolism and growth, and this is reflected in a high rate of glucose uptake. It is commonly assumed that the upregulation of the facilitated glucose transporter GLUT1 meets the tumor's demand for sugar. This underlies the success in using 2FDG PET imaging in the clinic to identify and stage many tumors. However, 2FDG is not a substrate for a second class of glucose transporters, the sodium-dependent glucose cotransporters, SGLTs, and so 2FDG PET may not provide a complete picture. A specific new radiotracer to detect SGLT activity has been introduced, Me4FDG, and this provides an opportunity to explore the potential role of SGLTs in supporting tumor glycolysis. In this brief review, I highlight the development of Me4FDG and our preliminary studies of Me4FDG PET in cancer patients. We find that the renal isoform, SGLT2, is expressed in pancreatic and prostate tumors and glioblastomas, and Me4FDG PET introduces a new method to image tumors. As SGLT2 drugs are successful in treating type 2 diabetes mellitus, they may also provide a new therapy.


Hypervirulent Klebsiella pneumoniae clones causing bacteraemia in adults in a teaching hospital in Barcelona, Spain (2007-2013).
Virulent hypermucoviscous Klebsiella pneumoniae strains associated with the magA and rmpA genes have mainly emerged in Asia. We analysed the frequency and the clinical and molecular epidemiology of K. pneumoniae bacteraemia isolates obtained over a 7-year period (2007-2013). Fifty-three of 878 K. pneumoniae invasive isolates (5.4%) showed a hypermucoviscous phenotype (by the string test). Of these, 16 (30.2%) were magA(+)/rmpA(+), 12 (22.6%) were magA(-)/rmpA(+), and the remaining 25 (47.2%) were magA(-)/rmpA(-). After multilocus sequence typing and wzi sequencing, all magA(+)/rmpA(+) isolates were serotype K1 and sequence type (ST)23. Of the 12 magA(-)/rmpA(+) isolates, nine were K2 (ST380, ST86, ST65, ST25 and ST493), and three magA(-)/rmpA(+) isolates had the new wzi allele 122, an unknown serotype, and the new ST1013. The remaining isolates, which were magA(-)/rmpA(-), showed different serotypes and STs. Patients with magA(+)/rmpA(+) or magA(-)/rmpA(+)K. pneumoniae bacteraemia more frequently had pyogenic liver abscesses (PLAs) and pneumonia than patients with magA(-)/rmpA(-)K. pneumoniae bacteraemia (respectively: 21.4% vs. 8%, p 0.26; and 17.9% vs. 0%, p 0.05). In fact, magA(-)/rmpA(-) isolates were similar to the those termed 'classic' K. pneumoniae isolates causing bacteraemia, the urinary and biliary tracts being the main foci of infection. In conclusion, hypervirulent clones (CC23K1, CC86K2, CC65K2, and CC380K2) were infrequent among K. pneumoniae isolates causing bacteraemia in our geographical area. A hypermucoviscous phenotype as determined with the string test is not enough to recognize these clones; additional molecular studies are needed. Patients with magA(+) and/or rmpA(+)K. pneumoniae bacteraemia more frequently had PLAs and pneumonia than patients without hypermucoviscosity genes.


Nanoscaled Materials for Drug Delivery into Cells/Stem Cells.
The successful and efficient transport and delivery of drugs and biomolecules to cells/stem cells have revealed the main challenge in clinical therapy development. Special materials and systems are used in smart drug delivery to improve the effectiveness by controlling drug release and decreasing the side effects. Synthesized water-dispersible polymer-covalent organic framework nanocomposites are integrated via the assembly of PEG-modified monofunctional curcumin derivatives and amine-functionalized covalent organic frameworks for in vitro and in vivo drug delivery. The smart delivery system exhibits an efficient targeting strategy for cancer therapy and also demonstrates an important promise on the improvement of a smart system for cancer cell-/stem cell-targeted drug delivery.


Modelling airway smooth muscle passive length adaptation via thick filament length distributions.
We present a new model of airway smooth muscle (ASM), which surrounds and constricts every airway in the lung and thus plays a central role in the airway constriction associated with asthma. This new model of ASM is based on an extension of sliding filament/crossbridge theory, which explicitly incorporates the length distribution of thick sliding filaments to account for a phenomenon known as dynamic passive length adaptation; the model exhibits good agreement with experimental data for ASM force-length behaviour across multiple scales. Principally these are (nonlinear) force-length loops at short timescales (seconds), parabolic force-length curves at medium timescales (minutes) and length adaptation at longer timescales. This represents a significant improvement on the widely-used crossbridge models which work so well in or near the isometric regime, and may have significant implications for studies which rely on crossbridge or other dynamic airway smooth muscle models, and thus both airway and lung dynamics.


[Beneficial effect of oral retinoid in psoriatic hyperproliferation. Autoradiographic studies on involved and non involved skin (author's transl)].
In 16 patients with generalized psoriasis treated with oral retinoid (Ro 10-9359; 1 mg/kg body weight/(day) autoradiographic studies were performed before, and 24 h, 48 h, 1 week and 3 weeks after beginning of treatment on involved and non involved epidermis. During the first week no significant changes of all cellular parameters were found. However, after 3 weeks of continuing medication the increased 3H-thymidine labelling index was markedly lowered and the prolonged DNA synthesis time was shortened; whereas, the cell cycle time remained unaffected. The findings revealed that oral retinoid has a distinct influence on epidermal cell proliferation towards normalization in both involved and non involved epidermis in psoriasis. The time needed for this effect indicates that the drug does not directly interfere with the cell cycle. It seems reasonable, therefore, to combine oral retinoids as a basic adjuvant drug with other antipsoriatic techniques, such as retinoid + anthralin, retinoid + PUVA, retinoid + UVB.


Molecular cytogenetic characterization of an interstitial deletion of chromosome 21 (21q22.13q22.3) in a patient with dysmorphic features, intellectual disability and severe generalized epilepsy.
We report on a de novo interstitial deletion of chromosome 21q in a patient presenting with characteristic facial features, intellectual disability, and epilepsy. The deletion extent was about 4.9 Mb from position 37713441 bp (21q22.13) to position 42665162 bp (21q22.3) (NCBI36/hg18 map). Patients with partial monosomy 21 are quite rare; this anomaly has been associated with a wide spectrum of clinical signs, ranging from very mild to quite severe phenotypes. This variability results from variability in the deleted regions, thus accurate molecular definition of the chromosomal breakpoints is necessary to make better genotype-phenotype correlations. We compared our patient's phenotype with the few other patients reported in the literature and found to have similar deletion when analyzed by array CGH. The minimal overlapping region contains only two genes, DYRK1A and KCNJ6, which may play a major role in these patients' phenotype.


Performance enhancement of polyaniline-based polymeric wire biosensor.
We demonstrate here the performance enhancement of polyaniline-based biosensor using screen-printing technology and pulse mode measurement technique. Screen-printed silver electrodes were made on a nitrocellulose membrane and the distance between the two electrodes was approximately 550 microm. Resistance of the electrodes had an average of 1.4 Omega with a standard deviation of +/-0.4 Omega. The surface of nitrocellulose membrane was modified by glutaraldehyde to immobilize streptavidin. Biotinylated anti-mouse IgG was conjugated with polyaniline-coated magnetic nanoparticles. Formation of polyaniline-coated magnetic nanoparticles was confirmed by a transmission electron microscope image. The polyaniline was used as an electric signal transducer for the monitoring of the biospecific binding event. An electrical response induced by the streptavidin-biotin interaction was measured by pulse mode measurement. This measurement method reduced the resistance caused by interfacial capacitance. Dose-dependent resistance changes were also successfully analyzed by the pulse mode polymeric wire biosensor. Results showed that the pulse mode measurement technique enhanced the performance of the polyaniline-based polymeric wire biosensor by reducing the interfacial effects. This approach could be helpful in samples with high interfering background materials, such as food and clinical specimens.


White matter integrity in patients with classic trigeminal neuralgia: a multi-node automated fiber tract quantification study.
To study the characteristics of point-by-point destruction of white matter tracts in patients using automated fiber tract quantification (AFQ). Thirty-four classic trigeminal neuralgia (CTN) patients and 34 healthy control (HC) subjects underwent 3.0 T diffusion tensor magnetic resonance imaging and T1-weighted imaging. The fractional anisotropy (FA) and mean diffusivity (MD) of 100 nodes of 20 fiber tracts were analyzed by AFQ, and the correlations of the FA and MD with the visual analogue scale (VAS) pain score were assessed. The FA values of the left thalamic radiation (middle segment), left corticospinal tract, callosum forceps minor, and right uncinate fasciculus were significantly lower in CTN patients than in the HC group. The MD of the left thalamic tract (middle segment), left corticospinal tract, right superior longitudinal fasciculus, and left superior longitudinal fasciculus (anterior segment) were significantly higher in the CTN group. Additionally, the VAS pain score in CTN patients was positively correlated with FA and negatively correlated with MD. Specific fiber tract nodes were damaged in CTN patients, which was related to the VAS pain score. Multi-node quantitative studies of fiber tract damage are valuable for understanding the white matter tract damage pattern in CTN patients.


Life-threatening respiratory failure due to cranial dystonia after dental procedure in a patient with multiple system atrophy.
We report on a woman with a an 8-year history of multiple system atrophy with predominance of parkinsonism who developed jaw-locking oromandibular dystonia within hours after insertion of ill-fitting dentures. Dystonia spread rapidly to involve other facial muscles and the larynx causing stridor with respiratory failure necessitating crush intubation.


ACTH response to LPS in the first stages of development of the fish Dicentrarchus labrax L.
ACTH and ACTH receptor-like molecules were found at the examined stages of development (2, 4, 8, 12, 18, and 24 days post-hatching) in yolk sac, pronephros tubules, interrenal tissue, thymus, liver, spleen, cardinal veins, and skin of the teleost fish Dicentrarchus labrax. ACTH and the related receptor-like molecules show a similar distribution. LPS treatment at two different stages (8 and 24 days post-hatching) provoked both a release and an induction of ACTH-like molecules, suggesting an important role of this peptide to control the modifications in body homeostasis during the first period of the sea bass' life, i.e., 30 days post-hatching, before the lymphoid cells have reached complete maturation.


Nitrogen-fixing trees in mixed forest systems regulate the ecology of fungal community and phosphorus cycling.
The fungal community plays an important role in forest ecosystems via the provision of resources to plant nutrition and productivity. However, the ecology of the fungal network and its relationship with phosphorus (P) dynamics remain poorly understood in mixed forest plantations. Here, we analyzed the fungal community using the amplicon sequencing in plantations of pure Eucalyptus grandis, with (E + N) and without N fertilization (E), besides pure Acacia mangium (A), and in a consortium of E. grandis and A. mangium (E + A), at 27 and 39 months after planting. We analyzed chemical, physical and biochemical soil and litter attributes related to P cycling, and the fungal community structure to find out if mixed plantations can increase fungal connections and to identify their role in the P dynamics in the soil-litter system. Soil organic fraction (OF), phosphorus in OF, total-P and acid phosphatase activity were significantly higher in E + A and A treatments regardless of the sampling period. Total N and P, richness, and Shannon diversity of the fungi in the litter was significantly higher in the treatments E + A and A. The fungal community structure in litter differed between treatments and sampling periods, and E + A showed an intermediate structure between the two pure treatments (E) and (A). E + A correlated highly with P dynamics when evaluated by both Pearson and redundancy analyses, particularly in the litter layer. Co-occurrence networks of fungal taxa became simpler in pure E. grandis plantations, whereas mixed system (E + A) showed a more connected and complex network. Our findings provide novel evidence that mixed forest plantations promote positive responses in the fungal community connections, which are closely related to P availability in the system, prominently in the litter layer. This indicates that the litter layer represents a specific niche to improve nutrient cycling by fungi in mixed forest ecosystems.


Analysis of phellinus igniarius effects on gastric cancer cells by atomic force microscopy.
Gastric cancer is one of the common malignant tumors in the world, which originates from the gene mutation of human cells. In this work, an atomic force microscope was used to quantitatively detect the changes of multiple physical parameters such as the cell morphology, surface roughness, elasticity modulus and adhesion force before and after Phellinus linteus stimulation. The experimental results show that Phellinus linteus can change the shape of gastric cancer cells (SGC-7901) from flat to spherical, and increase their height and surface roughness values. The adhesion force of cells is reduced and the elasticity modulus is increased. But there are no significant differences in the morphology and mechanical properties of gastric epithelial cells (GES-1). The results indicate that Phellinus linteus has a high anticancer effect on the gastric cancer cells, but has less toxic side effects on the gastric epithelial cells. This work proves that Phellinus linteus can be used as a preferred anticancer drug for the treatment of gastric cancer cells.


Sleep biosignature of Type 2 diabetes: a case-control study.
To determine whether or not the sleep disturbances associated with Type 2 diabetes affect the structure of sleep. We designed a case-control study in 76 patients with Type 2 diabetes and 76 control subjects without Type 2 diabetes, matched by age, gender, BMI and waist and neck circumferences. A subgroup of 32 patients with Type 2 diabetes was also matched with 64 control subjects without Type 2 diabetes according to apnoea-hypopnoea index score. Examination included an overnight full polysomnography. No differences in the percentage of time spent in either rapid eye movement or non-rapid eye movement sleep were observed between groups; however, patients with Type 2 diabetes had more microarousal events during sleep than control subjects [41.4 (total range 4.0-104.4) vs 20.7 (total range 1.3-94.5) events/h; P < 0.001]. These differences were mainly observed during the non-rapid eye movement sleep [7.4 (total range 0-107.2) vs 0.2 (total range 0-65.2) events/h; P < 0.001]. In addition, sleep variables related to oxygen saturation measures, such as the percentage of time spent with oxygen saturation ≤90%, were significantly greater during the rapid eye movement sleep in patients with Type 2 diabetes [20.3 (total range 0-99.2) vs. 10.5 (total range 0-94.0)%; P = 0.047]. This pattern was maintained in the subgroup of patients matched by apnoea-hypopnaea index. Finally, stepwise regression analyses showed that apnoea-hypopnoea index, the presence of Type 2 diabetes and fasting plasma glucose value were independently associated with the number of microarousals (R2 =0.667). Type 2 diabetes is associated with an altered sleep structure, with different effects according to rapid eye movement (increase in nocturnal hypoxia) or non-rapid eye movement (increase in sleep fragmentation) sleep.


Substitution of pyridoxal 5'-phosphate in the O-acetylserine sulfhydrylase from Salmonella typhimurium by cofactor analogs provides a test of the mechanism proposed for formation of the alpha-aminoacrylate intermediate.
O-Acetylserine sulfhydrylase (OASS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the final step in the de novo synthesis of L-cysteine in Salmonella typhimurium. Complementary cofactor mutagenesis in which the active site PLP is substituted with cofactor analogs is used to test the mechanism proposed for the OASS. Data obtained with the pyridoxal 5'-deoxymethylenephosphonate-substituted enzyme suggest that the binding of OAS as it forms the external Schiff base is such that the acetate side chain is properly positioned for elimination (orthogonal to the developing alpha,beta-double bond) only about 1% of the time. Data support the assignment of an enzyme group with a pK of 6.7 that interacts with the acetyl side chain, maintaining it orthogonal to the developing alpha,beta-double bond. Similar studies of the 2'-methylpyridoxal 5'-phosphate-substituted enzyme suggest that, although the mechanism is identical to that catalyzed by native OASS, the reaction coordinate for alpha-proton abstraction may be decreased compared with that observed for the native enzyme.


Synthesis of some purine and pyrimidine nucleosides of 3-amino-2,3,6-trideoxy-L-lyxo-hexopyranose (daunosamine).
The daunosaminyl analogue of the antibiotic puromycin and the nucleoside derivatives of daunosamine with adenine, thymine, and cytosine have been synthesised. The nucleoside derivatives of 6-dimethylaminopurine, thymine, and cytosine were prepared by melting the protected daunosamine with the protected base in vacuo. Daunosaminyladenine was obtained by condensing N-trifluoroacetyl-O-trifluoroacetyl-alpha-daunosaminyl chloride either with N6-benzoyl-9-chloromercuryadenine in boiling xylene or with N6-benzoyladenine in dichloromethane at room temperature in the presence of a molecular sieve. In each reaction, the beta-anomeric nucleoside was obtained, as shown by p.m.r. data. The protecting groups were removed with barium hydroxide or methanolic ammonia to give the free aminonucleosides in good yield. 9-beta-Daunosaminyl-6-dimethylaminopurine was coupled to N-benzylocyxcarbonyl-O-methyltyrosine, giving, after hydrogenolysis, the daunosaminyl analogue of puromycin.


Effects of a Theory-Based Educational Program on Health Behaviors and Cardiovascular Health Outcomes Among Overweight Postmenopausal Women: A Randomized Controlled Trial.
With the natural cessation of estrogen, after menopause, women, especially those who are overweight, are at a high risk for cardiovascular disease. Diet control and adequate physical activity (PA) are recommended as the essence of promoting cardiovascular health for women after menopause. The aim of this study was to examine the effects of a theory-based educational program on health behaviors and cardiovascular health outcomes among overweight postmenopausal Chinese women compared with conventional didactic education. In this randomized controlled trial, 288 participants were randomly allocated to intervention (n = 144) or control (n = 144) groups. The control group received conventional didactic education. The intervention group received a 3-month theory-based educational program. Primary outcomes were PA and dietary behavior. Secondary outcomes included cardiovascular health knowledge, self-efficacy in PA and diet, and cardiovascular health outcomes. Data were collected at baseline (T0), 3 months (T1), 6 months (T2), and 12 months (T3). The intervention group demonstrated significantly greater improvements in PA, dietary behavior, self-efficacy in PA and diet, and several cardiovascular health outcomes (body weight, body mass index, waist circumference, blood pressure, and Framingham risk score [body mass index]) at postintervention compared with the control group (all P s < .05). These significant effects maintained at T2, and the effects on self-efficacy in PA and diet also were maintained at T3. A theory-based educational program may be an effective strategy for improving PA, dietary behavior, self-efficacy in PA and diet, and several cardiovascular health outcomes for overweight postmenopausal Chinese women. However, further strategies are needed to enhance the sustainability of the positive changes.


Preparation and electrochemical properties of Ce-Ru-SnO2 ternary oxide anode and electrochemical oxidation of nitrophenols.
A cerium doped ternary SnO(2) based oxides anode that is CeO(2)-RuO(2)-SnO(2) (Ce-Ru-SnO(2)) anode, was prepared by facile thermal decomposition technique. XRD was used to characterize the crystal structures of modified SnO(2) anodes. Electrochemical impedance spectroscopy (EIS) and accelerated life test were also utilized to study the electrochemical property of Ce-Ru-SnO(2) anode. The results indicated that Ce-Ru-SnO(2) anode possessed smaller charge transfer resistance and longer service life than other modified SnO(2) anodes. Oxidants, such as hydroxyl radicals, hydrogen peroxide and hypochlorite ions were determined. Electrochemical oxidation of nitrophenols (NPs) were conducted and compared with previous studies. The degradation of nitrophenols revealed two distinguishing laws for mononitrophenol and multinitrophenols. The Ce-Ru-SnO(2) anode is considered to be a promising material for the treatment of organic pollutants due to its high electrochemical activity and benign stability.


Microbial glycosylation of four free anthraquinones by Absidia coerulea.
Absidia coerulea transformed four anthraquinones from rhubarb, chrysophanol, physcion, emodin and aloe-emodin to their corresponding glycosylated metabolites. The structures of the products were characterized as chrysophanol 8-O-beta-D-glucoside, physcion 8-O-beta-D-glucoside, emodin 6-O-beta-D-glucoside, and aloe-emodin 1-O-beta-D-glucoside, respectively.


Prognostic Value of Different Computed Tomography Scoring Systems in Patients With Severe Traumatic Brain Injury Undergoing Decompressive Craniectomy.
In this study, we investigate the preoperative and postoperative computed tomography (CT) scores in severe traumatic brain injury (TBI) patients undergoing decompressive craniectomy (DC) and compare their predictive accuracy. Univariate and multivariate logistic regression analyses were used to determine the relationship between CT score (preoperative and postoperative) and mortality at 30 days after injury. The discriminatory power of preoperative and postoperative CT score was assessed by the area under the receiver operating characteristic curve (AUC). Multivariate logistic regression analysis adjusted for the established predictors of TBI outcomes showed that preoperative Rotterdam CT score (odds ratio [OR], 3.60; 95% confidence interval [CI], 1.13-11.50; P = 0.030), postoperative Rotterdam CT score (OR, 4.17; 95% CI, 1.63-10.66; P = 0.003), preoperative Stockholm CT score (OR, 3.41; 95% CI, 1.42-8.18; P = 0.006), postoperative Stockholm CT score (OR, 4.50; 95% CI, 1.60-12.64; P = 0.004), preoperative Helsinki CT score (OR, 1.44; 95% CI, 1.03-2.02; P = 0.031), and postoperative Helsinki CT score (OR, 2.55; 95% CI, 1.32-4.95; P = 0.005) were significantly associated with mortality. The performance of the postoperative Rotterdam CT score was superior to the preoperative Rotterdam CT score (AUC, 0.82-0.97 vs 0.71-0.91). The postoperative Stockholm CT score was superior to the preoperative Stockholm CT score (AUC, 0.76-0.94 vs 0.72-0.92). The postoperative Helsinki CT score was superior to the preoperative Helsinki CT score (AUC, 0.88-0.99 vs 0.65-0.87). In conclusion, assessing the CT score before and after DC may be more precise and efficient for predicting early mortality in severe TBI patients who undergo DC.


Isolation of Thogoto virus from ticks in Portugal.
An agent pathogenic for mice was isolated from Rhipicephalus sanguineus ticks collected from goats from Vila Vicosa , Portugal. The virus was shown serologically to be closely related to or identical with Thogoto virus, which had previously been isolated from ticks over a wide geographic area including Sicily, the African continent, and Iran.


Characterization of competitive interactions in the coexistence of Bt-transgenic and conventional rice.
Transgene flow through pollen and seeds leads to transgenic volunteers and feral populations in the nature, and consumer choice and economic incentives determine whether transgenic crops will be cultivated in the field. Transgenic and non-transgenic plants are likely to coexist in the field and natural habitats, but their competitive interactions are not well understood. Field experiments were conducted in an agricultural ecosystem with insecticide spraying and a natural ecosystem, using Bt-transgenic rice (Oryza sativa) and its non-transgenic counterpart in pure and mixed stands with a replacement series. Insect damage and competition significantly decreased plant growth and reproduction under the coexistence of transgenic and conventional rice. Insect-resistant transgenic rice was not competitively superior to its counterpart under different densities in both agricultural and natural ecosystems, irrespective of insect infection. Fitness cost due to Bt-transgene expression occurred only in an agroecosystem, where the population yield decreased with increasing percentage of transgenic rice. The population yield fluctuated in a natural ecosystem, with slight differences among pure and mixed stands under plant competition or insect pressure. The presence of Chilo suppressalis infection increased the number of non-target insects. Plant growth and reproduction patterns, relative competition ability and population yield indicate that Bt-transgenic and non-transgenic rice can coexist in agroecosystems, whereas in more natural habitats, transgenic rice is likely to outcompete non-transgenic rice.


[Electron microscopic and morphometric investigations of the integument of Acanthocephala (Aschelminthes) (author's transl)].
The integument of the acanthocephalans Echinorhynchus gadi, Acanthocephalus lucii, Polymorphus minutus and Macracanthorhynchus hirudinaceus have been investigated by stereoscan and transmission electron microscopy. The absorptive surface is considerably increased by invaginations of the outer plasma membrane (pore canals and vesicles). The rate of this enlargement has been calculated using morphometric methods. The values range from 20 to 62. The values are compared to values obtained from other gutless parasitic helminths and from the free-living rotifers which are presumably to be regarded as closely related to the acanthocephalans.


"NMDA receptor spectrum disorder" in the differential diagnosis of demyelinating disorders of the CNS: optic neuritis and myelitis.
The aim of this study was to investigate the frequency of anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibody positivity in patients presenting with transverse myelitis (TM) and/or optic neuritis (ON), to describe their neurologic and radiological characteristics, and to compare these characteristics with those reported in previous studies. This study included 179 patients (ON: 96, TM: 74, ON and TM: 9) who visited Isfahan Multiple Sclerosis Center from January 2017 to September 2019, for approximately 32 months. The respective neurological examinations were performed. Demographic data of the patients, as well as findings from radiological and serological investigations were obtained. Frequencies of anti-NMDAR seropositivity in patients with TM, ON, and concurrent TM and ON were approximately 3.4%, 1.4%, and 11.1%, respectively. None exhibited any psychiatric symptoms. Based on the frequency of seropositivity for anti-NMDAR antibody in our patients, positivity for this antibody appears to be more frequent than previously anticipated in patients presenting with these conditions. We recommend that the anti-NMDAR antibody presence in CSF/serum be checked and considered in addition to the routine examinations performed upon confronting demyelinating conditions such as TM and ON. We suggest considering the term "NMDAR spectrum disorder" to more clearly distinguish the potentially overlapping conditions with different etiologies in patients with CNS disorders.


Local anesthesia with lidocaine and prilocaine, using the tumescent technique, for the radiofrequency ablation of lower extremity varicose veins.
To demonstrate the possible use of a tumescent solution containing lidocaine and prilocaine for radiofrequency-assisted segmental thermal ablation and to reduce the need for postoperative analgesics. Fifty patients (51 limbs) underwent radiofrequency-assisted segmental thermal ablation (VNUS Closure FAST(™) ) of insufficient great and small saphenous veins and phlebectomy. The amount of tumescent fluid injected was noted, and evaluation of pain reported on visual analog scale (VAS) and quantity of the postoperative analgesics used and their side effects were recorded one day and six weeks after the procedure. The average amount of a tumescent fluid injected was 852 ml/patient (250-1470 ml). One day after surgery, 65% of the patients reported no pain (VAS 0), 27% reported a VAS of 1, and 4% reported a VAS of 2 on a scale of 0-10. Overall, 4% of the total patient population used analgesics after the procedure. Six weeks after the procedure, 84% of the patients reported no pain. Local anesthesia with lidocaine and prilocaine, and the tumescent technique, were found to be effective and safe modalities for radiofrequency ablation of varicose veins of the lower extremities.


Deamidated lipocalin-2 induces endothelial dysfunction and hypertension in dietary obese mice.
Lipocalin-2 is a proinflammatory adipokine upregulated in obese humans and animals. A pathogenic role of lipocalin-2 in hypertension has been suggested. Mice lacking lipocalin-2 are protected from dietary obesity-induced cardiovascular dysfunctions. Administration of lipocalin-2 causes abnormal vasodilator responses in mice on a high-fat diet (HFD). Wild-type and lipocalin-2 knockout mice were fed with standard chow or HFD. Immunoassays were performed for evaluating the circulating and tissue contents of lipocalin-2. The relaxation and contraction of arteries were studied using a wire myograph. Blood pressure was monitored with implantable radio telemetry. Dietary obesity promoted the accumulation of lipocalin-2 protein in blood and arteries. Deficiency of this adipokine protected mice from dietary obesity-induced elevation of blood pressure. Mass spectrometry analysis revealed that human and murine lipocalin-2 were modified by polyamination. Polyaminated lipocalin-2 was rapidly cleared from the circulation. Adipose tissue was a major site for lipocalin-2 deamidation. The circulating levels and the arterial accumulation of deamidated lipocalin-2 were significantly enhanced by treatment with linoleic acid (18:2n-6), which bound to lipocalin-2 with high affinity and prevented its interactions with matrix metalloproteinase 9 (MMP9). Combined administration of linoleic acid with lipocalin-2 caused vascular inflammation and endothelial dysfunction and raised the blood pressure of mice receiving standard chow. A human lipocalin-2 mutant with cysteine 87 replaced by alanine (C87A) contained less polyamines and exhibited a reduced capacity to form heterodimeric complexes with MMP9. After treatment, C87A remained in the circulation for a prolonged period of time and evoked endothelial dysfunction in the absence of linoleic acid. Polyamination facilitates the clearance of lipocalin-2, whereas the accumulation of deamidated lipocalin-2 in arteries causes vascular inflammation, endothelial dysfunction, and hypertension.


Tracheostomy and home ventilation in children.
The last 30 years have brought a significant emphasis on home care for ventilator-dependent children. While the movement was driven by the desire to minimize healthcare costs, the advancements in medical knowledge and technology, and the change in the perception of a ventilator-dependent child have offered a fertile environment for the development of programs that support the chronic care of ventilator-dependent children at home (N. Engl. J. Med. 309(21) (1983) 1319; J. Pediatr. 106(5) (1985) 850; N. Engl. J. Med. 310(17) (1984) 1126; JAMA 258(23) (1987) 3398). In addition, the advances in medical and nursing care have led to the steady increase in the number of children with chronic respiratory failure and development of multi-disciplinary teams experienced and dedicated to the care of these children. Another trend that has also contributed to the rise in the number of pediatric patients using long-term mechanical ventilation is the parental expectation of long-term survival of their child. This parental expectation continues to grow as the effect of long-term mechanical ventilation on quality of life and longer survival becomes more evident. The primary indication for use of home mechanical ventilation is chronic respiratory failure (CRF) as indicated by hypoxemia and or hypercapnia. CRF is considered to be a condition persisting for greater than 1 month and requiring mechanical ventilation during part or all of the day to provide adequate gas exchange for the support of vital function (Chest 103(5) (1993) 1463).


Increased intracellular [dATP] enhances cardiac contraction in embryonic chick cardiomyocytes.
Although ATP is the physiological substrate for cardiac contraction, cardiac contractility is significantly enhanced in vitro when only 10% of ATP substrate is replaced with 2'-deoxy-ATP (dATP). To determine the functional effects of increased intracellular [dATP] ([dATP](i)) within living cardiac cells, we used hypertonic loading with varying exogenous dATP/ATP ratios, but constant total nucleotide concentration, to elevate [dATP](i) in contractile monolayers of embryonic chick cardiomyocytes. The increase in [dATP](i) was estimated from dilution of dye added in parallel with dATP. Cell viability, average contractile amplitude, rates of contraction/relaxation, spontaneous beat frequency, and Ca2+ transient amplitude and kinetics were examined. At total [dATP](i) above approximately 70 microM, spontaneous contractions ceased, and above approximately 100 microM [dATP](i), membrane blebbing was also observed, consistent with apoptosis. Interestingly, [dATP](i) of approximately 60 microM ( approximately 40% increase over basal [dATP](i) levels) enhanced both amplitude of contraction and the rates of contraction and relaxation without affecting beat frequency. With total [dATP](i) of approximately 60 microM or less, we found no significant change in Ca2+ transients. These data indicate that there is an "optimal" concentration of exogenously loaded [dATP](i) that under controlled conditions can enhance contractility in living cardiomyocytes without affecting beat frequency or Ca2+ transients.


Double-hyperbolic force-velocity relation in frog muscle fibres.
1. The relationship between force and velocity of shortening was studied at 2.10 micron sarcomere length during fused tetani (1-3 degrees C) in single fibres isolated from the anterior tibialis muscle of Rana temporaria. The speed of shortening was recorded from the whole fibre and, in some experiments, simultaneously from a short (ca. 0.6 mm) segment, while the preparation was released to shorten isotonically at selected force levels ('load-clamp' recording). The segment was defined by opaque markers of hair that were placed on the fibre surface. The distance between the markers was recorded by means of a photo-electric detector system. 2. The force-velocity relation had two distinct regions, each one exhibiting an upwards concave shape, that were located within the ranges 0-78 and 78-100% of the measured isometric force (P0), respectively. The two portions of the force-velocity relation could be fitted well by hyperbolic functions or by single-exponential functions. The curvature was more pronounced in the high-force region than at low-intermediate loads. The transition between the two portions of the force-velocity relation (the 'break point' of the force-velocity curve) occurred at 78.4 +/- 0.4% of P0 (mean +/- S.E. of mean, n = 12) corresponding to 10.9 +/- 0.4% of maximum velocity of shortening (Vmax). The general shape of the force-velocity curve, and the appearance of a break point near 78% of P0, was the same when measurements were made from the whole fibre and from a short segment along the same fibre. 3. The 'negative' branch of the force-velocity relation was delineated for loads ranging from P0 to 1.6-1.8 P0 in five experiments. The negative branch formed a smooth continuation of the force-velocity relation recorded between 0.78 P0 and P0. The force-velocity relation was nearly flat between 0.90 P0 and 1.20 P0, the difference in speed of shortening or elongation being 1.8 +/- 0.3% (mean +/- S.E. of mean, n = 5) of Vmax over this range. 4. An increase in sarcomere length from 1.85 to 2.60 micron did not affect Vmax but caused a steady decrease in curvature of the force-velocity relation, both at low-intermediate loads and in the high-force range. Similar changes in shape of the force-velocity relation were produced by osmotic compression of the fibre in a Ringer solution made hypertonic by addition of 98 mM-sucrose.(ABSTRACT TRUNCATED AT 400 WORDS)


[Skin changes as demonstrated in art. II. Examples from the Germanisches Nationalmuseum in Nürnberg].
An attempt was made to diagnose the alternations of skin lesions shown in three works of art in the Germanic National Museum, Nürnberg. Evidently, these are a tumour, a naevus pigmentosus and some lepromatous processes.


Bone Mineral Density Response to Long-Term Bisphosphonate Treatment and Discontinuation in a Real-World Clinical Service.
Bisphosphonate treatment does not increase bone mineral density (BMD) in all subjects particularly at the femoral neck (FN). Our aim was to evaluate the relationship between response to oral bisphosphonate (oBP) at the FN and change in BMD following discontinuation. Data were collected retrospectively from postmenopausal women on oBP for ≥3 years, attending a real-world metabolic clinic at initiation of oBP, discontinuation, and 1 to 2 years post discontinuation. Improvement in BMD ≥4% in the FN and ≥5% for the lumbar spine (LS) were deemed clinically meaningful and used as least significant change (LSC) values. We divided subjects based on FN BMD response and compared outcomes between responders and non-responders after oBP discontinuation. Of the 213 subjects, 32.1% showed an increase ≥LSC at the FN compared to 57.1% at the LS on treatment (P < .0001). FN responders had lower BMD levels at pretreatment baseline than non-responders both at the FN (0.58 vs 0.62 g/cm2; P = .003) and LS (0.76 vs 0.79 g/cm2; P = .044). Off-treatment, more subjects lost BMD ≥LSC at FN in the responder group than in the non-responder group (37.5% vs 14.2%; P < .001). BMD remained above pre-treatment levels in responders after a median follow-up of 1.52 years. BMD response at FN is suboptimal in patients on oBP and is much less common than LS response. FN responders tend to lose the accumulated bone quickly off-treatment, though BMD remains above pretreatment levels. These observations suggest that new approaches may be needed to optimize osteoporosis management in real-world patients.


Continuous spark plasma synthesis of Au/Co binary nanoparticles with tunable properties.
We present here a scalable and environmentally friendly gas phase technique employing atmospheric pressure electrical spark discharge plasmas for the production of Au/Co binaries, an effective catalyst system for the decomposition of hydrogen-rich compounds, such as ammonium borane. We demonstrate that Au/Co alloy nanoparticles can be produced via the spark plasma-based technique. The possibility of varying the morphology and phase structure via real time heat treatment of the generated aerosol to form Au/Co/CoO particles with continuous control over a wide particle compositional range (from 24 to 64 at.% [Co]/([Co] + [Au]) content) is also demonstrated. Since our spark-based approach is proven to be capable of providing reasonable particle yields, these results may contribute to the transition of lab-scale, nanocatalyst-based hydrogen storage systems to real world applications.


Decrease of serum folates in healthy male volunteers taking phenytoin.
The effect of phenytoin (PHT) on serum folate and the effect of additional oral folic acid (FA) on serum folate during continued treatment with PHT were studied in 13 healthy male subjects 20-35 years of age. The study was divided into two phases: Phase I determined Vmax (mg/kg/day) and Km (microgram/ml) of PHT in order to calculate the PHT doses needed for the second phase. Phase II was a four-way cross-over study to examine the effect of 1 and 5 mg FA on total serum PHT concentrations 1 microgram/ml less and 5 micrograms/ml greater than the subject's Km, Km-1 and Km+5, respectively. Both phases examined the effect of PHT on serum folate. In Phase I, serum folate decreased by a mean and standard deviation of 42.15 +/- 21.44% after an average of 24.15 +/- 5.63 days of PHT administration, with a mean steady-state total serum PHT concentration of 8.45 +/- 2.70 micrograms/ml. Mean percentage decreases in serum folate before the addition of 1 and 5 mg FA in Phase II were 12.80 +/- 31.45% and 23.24 +/- 21.24% for Km-1 and Km+5, respectively. The average numbers of days of PHT administration and total serum PHT concentrations before FA administration were 9.52 +/- 3.34 and 15.84 +/- 7.02 days, and 2.60 +/- 2.18 and 8.64 +/- 3.44 micrograms/ml, for Km-1 and Km+5, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Monensin induces secretory granule-mediated cell death in eosinophils.
Eosinophils contribute to the pathology of several types of disorders, in particular of allergic nature, and strategies to limit their actions are therefore warranted. We sought to evaluate the possibility of targeting the acidic, lysosome-like eosinophil granules as a potential means of inducing eosinophil cell death. To this end, we used monensin, an ionophoric drug that has previously been shown to permeabilize the secretory granules of mast cells, thereby inducing cell death. Our findings reveal that monensin induces cell death in human eosinophils, whereas neutrophils were less affected. Blockade of granule acidification reduced the effect of monensin on the eosinophils, demonstrating that granule acidity is an important factor in the mechanism of cell death. Furthermore, monensin caused an elevation of the granule pH, which was accompanied by a decrease of the cytosolic pH, hence indicating that monensin caused leakage of acidic contents from the granules into the cytosol. In agreement with a granule-targeting mechanism, transmission electron microscopy analysis revealed that monensin caused extensive morphological alterations of the eosinophil granules, as manifested by a marked loss of electron density. Eosinophil cell death in response to monensin was caspase-independent, but dependent on granzyme B, a pro-apoptotic serine protease known to be expressed by eosinophils. We conclude that monensin causes cell death of human eosinophils through a granule-mediated mechanism dependent on granzyme B.


A half-century of research on tuberculosis: Successes and challenges.
Great progress has been made over the past half-century, but TB remains a formidable global health problem, particularly in low- and middle-income countries. Understanding the mechanisms of pathogenesis and necessary and sufficient conditions for protection are critical. The need for inexpensive and sensitive point-of-care diagnostic tests for earlier detection of infection and disease, shorter and less-toxic drug regimens for drug-sensitive and -resistant TB, and a more effective vaccine than BCG is immense. New and better tools, greater support for international research, collaborations, and training will be required to dramatically reduce the burden of this devastating disease which still kills 1.6 million people annually.


Development of specific PCR assays for the detection of Cryptocaryon irritans.
Cryptocaryon irritans is one of the most important protozoan pathogens of marine fish, causing the "white spot" disease and posing a significant problem to marine aquaculture. In the present study, a C. irritans-specific reverse primer (S15) was designed based on the published sequence of the second internal transcribed spacer (ITS-2) of ribosomal DNA (rDNA) of C. irritans and used together with the conserved forward primer P1 to develop a specific polymerase chain reaction (PCR) assay for direct, rapid, and specific detection of C. irritans. The specificity of these primers was tested with both closely and distantly related ciliates (Pseudokeroronpsis rubra, Pseudokeroronpsis carnae, Euplotes sp. 1, Ichthyophthirius multifiliis, Pseudourostyla cristata, and Paramecium caudaium), and only C. irritans was detected and no product was amplified from any other ciliates examined in this study using the specific primer set P1-S15. The specific PCR assay was able to detect as low as 45 pg of C. irritans DNA and a nested PCR assay using two primer sets (P1/NC2, P1/S15) increased the sensitivity, allowing the detection of a single C. irritans. The species-specific PCR assays should provide useful tools for the diagnosis, prevention, and molecular epidemiological investigations of C. irritans infection in marine fish.


Targeting regions with highest lipid content on MR spectroscopy may improve diagnostic yield in stereotactic biopsy.
Gliomas are heterogeneous brain tumors and prognosis and treatment are dependent on the highest histological grade present. Stereotactic biopsy is associated with an inherent risk of sampling error. Magnetic resonance spectroscopy (MRS) uses clinical MR scanners to provide chemical in addition to conventional information. MRS studies in brain tumors have found increased levels of choline-containing compounds (Cho) and decreased levels of N-acetylaspartate (NAA), creatine (Cr) and phosphocreatine (PCr) which are all associated with increased grade of glioma. We propose the use of MRS-guided stereotactic biopsy of astrocytomas to increase diagnostic yield and reduce the sampling error rate. MRS was performed on two patients undergoing stereotactic biopsy for suspected astrocytoma. Spectral peak heights of the metabolites Cho at 3.2 parts per million (ppm) chemical shift, NAA at 2.0 ppm and lipid (Lip) at 1.2 ppm, were measured. Biopsy targets were selected from the voxels with the highest Cho/NAA and normalised against Cho levels in the contralateral normal tissue, as well as those with highest lipid content. The biopsies were taken and tissue diagnosis was obtained via standard histological techniques. Histological grade was found to be different in one case: the region with a high Lip/Cr and Cho/NAA ratios showed glioblastoma, whereas the region with high Cho/NAA but low Lip/Cr ratios showed anaplastic astrocytoma. The second patient had high Cho/NAA ratio but low Lip/Cr ratio in both targets and the histology revealed anaplastic astrocytoma in both samples. MRS is a useful biomedical imaging tool for diagnosing and grading astrocytomas. Targeting regions with highest lipid content can potentially improve the diagnostic yield and minimize sampling error in stereotactic biopsy.


[Iodine status in historically iodine deficiency area].
The median urinary iodine concentration (UIC) for schoolchildren was 90 microg/L in Biella and 136 microg/L in Novara in survey carried out in 1995-1996. Biella resulted as iodine deficiency area and Novara as iodine sufficient area. Aim of our study was to assess goiter prevalence by ultrasonography in Biella and Novara schoolchildren and to evaluate median UIC in Biella schoolchildren. A total of 829 Biella schoolchildren and 310 Novara schoolchildren, aged 7-15 years, were submitted to thyroideal ultrasonography. Biella schoolchildren were submitted to morning-spot urine sample's collection for UIC's determination. The ultrasound goiter prevalence as function of age resulted 15.7% in Biella and 14.8% in Novara (P = 0.7, chi 2 test). The ultrasound goiter prevalence as function of body surface area resulted 17.1% in Biella and 7.1% in Novara (P < 0.0001, chi 2 test). UIC (25-75 degrees ) for Biella schoolchildren who attended third and fifth year of primary school was 159 microg/L (107-228 microg/L) while for Biella schoolchildren who attended second year of secondary school was 150 microg/L (92-218 microg/L). Based on the results of UIC, Biella is considered as iodine sufficient area. Based on the results of goiter prevalence by ultrasonography, both Biella and Novara resulted as iodine deficiency area. UIC and goiter prevalence, however, provide different informations about iodine status: UIC supplies informations about present iodine status while goiter prevalence assesses past iodine status.


Contribution to knowledge of the biosynthesis of cyclosporin A.
3H- and 13C-NMR spectroscopic investigations on the structure of labeled cyclosporin A were performed after feeding of appropriate precursors. The 6 N-methyl groups and the methyl group in position 4 of the epsilon, zeta-unsaturated amino acid No. 1 (Mebmt) are introduced as intact CH3-units from methionine. Four head-to-tail acetate units are involved in the biosynthesis of the 8-carbon chain of the olefinic amino acid.