Serial determination of glomerular filtration rate in conscious mice using FITC-inulin clearance.
Two nonradioactive methods for determining glomerular filtration rate (GFR) in conscious mice using FITC-labeled inulin (FITC-inulin) were evaluated. The first method measured GFR using clearance kinetics of plasma FITC-inulin after a single bolus injection. Based on a two-compartment model, estimated GFR was 236.69 +/- 16.55 and 140.20 +/- 22.27 microl/min in male and female C57BL/6J mice, respectively. Total or (5/6) nephrectomy reduced inulin clearance to 0 or 32.80 +/- 9.32 microl/min, respectively. Conversely, diabetes mellitus induced by streptozotocin was associated with increased GFR. The other approach measured urinary inulin clearance using intraperitoneal microosmotic pumps to deliver FITC-inulin and metabolic cages to collect timed urine samples. This approach yielded similar GFR values of 211.11 +/- 26.56 and 157.36 +/- 20.02 microl/min in male and female mice, respectively. These studies demonstrate the feasibility of repeated nonisotopic measurement of inulin clearance in conscious mice.


Cognitive dysfunction in multiple sclerosis: a review of recent developments.
Nearly half of all patients diagnosed with multiple sclerosis will develop cognitive dysfunction, a symptom associated with significant decline in activities of daily living. The purpose of this review is to discuss recent literature investigating issues related to cognitive dysfunction in multiple sclerosis. Recent studies, examined in this review, have provided increased understanding regarding specific cognitive processes affected in multiple sclerosis, as well as a characterization of its natural history. Studies have also continued to emphasize the extent to which cognitive deficits in the condition are associated with decline in daily living skills. Recent concerns regarding driving performance have been documented among cognitively impaired individuals. Studies have also examined correlates of cognitive dysfunction, with particular emphasis on neuroimaging techniques reflecting disease activity or lesion burden. With increased understanding of neurobiological correlates of cognitive deficits, investigators have begun to examine potential treatments for managing cognitive dysfunction. This area of research has suggested that disease modifying medications can have an impact on magnetic resonance imaging disease activity by altering the cerebral demyelinating process resulting in a slower decline in cognitive functions over time and improved activities of daily living for patients with multiple sclerosis.


Mexico: Determinants of the real exchange rate, 2001.01-2022.12.
We estimate the determinants (terms of trade, tradable to non-tradable price differentials, interest rate differentials, forward exchange rate and risk premium) of the Mexican bilateral real exchange rate (q) for the short and long run by using an Autoregressive Distributed Lag model (ARDL, Pesaran and Shin et al. (2001)) for Mexico (2001.01-2022.12). The inclusion of commercial and financial variables and finding empirical evidence of cointegration only for 2009.01-2022.12 are the main contributions. Our results indicate no cointegrating relationship either for the entire sample, or for 2001.01-2008.12. This finding has to do with the increasing international financialization process, after the 2008-2009 Great Financial Crisis. Using a double log model we find that: a) there is a strong short-run autoregressive effect of q of up to 4 lags (0.75), b) that the Balassa-Samuelson Effect is the largest in the model (-0.27 and -1.11 for short and long terms), c) the next most important factor is the terms of trade (-0.126 and -0.51, respectively), d) there are considerable, although lesser, effects of financial variables: forward exchange rate (0.0155 and 0.063, respectively) and risk-premium (0.009 and 0.036, respectively), e) there is a clear long-term trend of real depreciation expressed by the trend of 0.0020, which suggests that the PPP hypothesis applies.


[Regulation of the neuronal functional state by ultra low doses of different biologically active substances. Nonspecific effect ].
The role of biologically active substances in ultra-low doses (10(-15)-10(-27) mol/l) is discussed from the different points of view. The most detailed analysis of neurobiological effects produced by these doses can be studied on the preparate of completely isolated molluscan neurones. In this case the possibility arises to control the first modifications of action at the electrophysiological characteristics of neuronal activity. These changes of electrical activity can be regarded as a reaction to biologically active substance. The following characteristics were controlled: the level of membrane resting potential (MP), the electroexcitable membrane and pacemaker mechanism, chemical sensitivity of somatic membrane loci to neurotransmitter acetylcholine (Ach). Several substances were used in these experiments: two kinds of synthetic antioxidant, GABA, ethanol, serotonine, DSIP (delta-sleep inducing peptide), antibiotic ruboxil, nootrop GVS-111. The isolated neurones were placed into the special chamber. All these substances (0.35 ml) were added single dosing into this chamber with living physiological solution in concentration 10(-15)-10(-27) mol/l. The results demonstrated that all substances had initiated the development of prolonged neurophysiological responses. The intensities of neuronal reactions didn't depend in contact period on the concentration and on the type of substance. It is suggested that these data reveal the existence of unknown modes of regulation of neuronal functional states and presence of hidden channel for information transfer and receiving. This different way of regulation is extremely important influence living organisms.


Follow-up of women with previous GDM. Insulin, C-peptide, and proinsulin responses to oral glucose load.
Gestational diabetes mellitus (GDM) is a strong predictor of glucose intolerance later in life. Former GDM (n = 145) and control (n = 41) subjects were studied 3-4 yr after the index pregnancy. They were subjected to a 75-g oral glucose tolerance test (OGTT) with measurements of insulin, C-peptide, and proinsulin in the basal state and every 30 min for 180 min. In the former GDM group, 5 subjects (3.4%) had developed non-insulin-dependent diabetes mellitus (NIDDM), and 32 (22%) had developed impaired glucose tolerance (IGT; by World Health Organization criteria). In the control group, 2 (4%) had IGT. In the GDM group, IGT or NIDDM was significantly associated with obesity (body mass index [BMI] greater than or equal to 25 kg/m2) and earlier diagnosis of GDM during pregnancy (P less than 0.001). Nonobese (BMI less than 25 kg/m2) GDM subjects with normal glucose tolerance at follow-up had significantly higher mean glucose (P less than 0.01), insulin (P less than 0.05), and proinsulin (P less than 0.001) values during the OGTT than control subjects, whereas there was no significant difference in C-peptide values. A comparison between control subjects with normal OGTT and BMI less than 25 kg/m2 (n = 39) and GDM subjects (n = 39) selected to have a comparable area under the glucose curve, BMI, and age demonstrated no group differences in glucose, C-peptide, or insulin levels, whereas the proinsulin levels were significantly higher (P less than 0.001) during the glucose load. The molar ratio between proinsulin and insulin was also significantly higher among the former GDM subjects.(ABSTRACT TRUNCATED AT 250 WORDS)


Inverse association between birth weight, birth length and serum total cholesterol in adulthood.
To investigate whether impaired fetal growth, measured by low birth weight and short birth length, is linked with raised levels of serum lipids and increased risk and mortality of coronary heart disease. The association between birth length, birth weight, Ponderal Index and total serum cholesterol was examined in 545 Danish men and women aged 31 to 51 years who participated in the Ebeltoft Health Promotion Project in Denmark. No associations were found in women. For men, a negative association was found between birth weight and serum total cholesterol, with a fall in mean serum total cholesterol from 6.03 mmol/l at birth weight below 3300 g to 5.64 mmol/l at birth weight above 4000. A similar association was found between birth length and serum cholesterol, with a mean value of 6.23 mmol/l at birth length below 51 cm and a mean value of 5.56 mmol/l at birth length above 54 cm. No associations were found for Ponderal Index. Between 3% and 8% of the variance in serum total cholesterol could be explained by the statistical models used in this study. Our findings support the hypothesis of a negative association between birth weight, birth length and elevated serum cholesterol in adult life, but only in men.


A rhodamine B-based lysosomal pH probe.
A novel rhodamine B-based fluorescent probe (RML) for lysosomal pH was developed by integrating a 4-(2-aminoethyl)morpholine moiety, which is a lysosome-targetable group, into a rhodamine B fluorophore, which is associated with rhodamine B dyes possessing spirocyclic (non-fluorescent) and ring-opening (fluorescent) forms with response to pH. The probe responded to acidic pH at low concentration in a short amount of time. In addition, RML showed good membrane permeability and brilliant selectivity among various amino acids and metal cations. RML exhibited an 80-fold increase in fluorescence intensity at 583 nm throughout the pH range of 7.40-4.00 with a pKa of 5.16, which indicates that RML is valuable for studying intracellular acidic organelles. Moreover, RML has been successfully applied in HeLa cells, and the results demonstrated that RML could selectively stain lysosomes in living HeLa cells. Note that RML could be used to detect the pH increase in lysosomes induced by bafilomycin A1 within HeLa cells.


Effect of a sulfonated azo dye and sulfanilic acid on nitrogen transformation processes in soil.
Introduction of organic dyes into soil via wastewater and sludge applications has been of increasing concern especially in developing or under-developed countries where appropriate management strategies are scarce. Assessing the response of terrestrial ecosystems to organic dyes and estimating the inhibition concentrations will probably contribute to soil remediation studies in regions affected by the same problem. Hence, an incubation study was conducted in order to investigate the impact of a sulfonated azo dye, Reactive Black 5 (RB5) and sulfanilic acid (SA), a typical representative of aromatic sulfonated amines, on soil nitrogen transformation processes. The results apparently showed that nitrogen related processes in soil can be used as bioindicators of anthropogenic stress caused by organic dyes. It was found that urease activity, arginine ammonification rate, nitrification potential and ammonium oxidising bacteria numbers decreased by 10-20% and 7-28% in the presence of RB5 (> 20 mg/kg dry soil) and SA (> 8 mg/kg dry soil), respectively. Accordingly, it was concluded that organic dye pollution may restrict the nitrogen-use-efficiency of plants, thus further reducing the productivity of terrestrial ecosystems. Furthermore, the response of soil microbiota to SA suggested that inhibition effects of the organic dye may continue after the possible reduction of the parent dye to associated aromatic amines.


Recommendations for real-time speech MRI.
Real-time magnetic resonance imaging (RT-MRI) is being increasingly used for speech and vocal production research studies. Several imaging protocols have emerged based on advances in RT-MRI acquisition, reconstruction, and audio-processing methods. This review summarizes the state-of-the-art, discusses technical considerations, and provides specific guidance for new groups entering this field. We provide recommendations for performing RT-MRI of the upper airway. This is a consensus statement stemming from the ISMRM-endorsed Speech MRI summit held in Los Angeles, February 2014. A major unmet need identified at the summit was the need for consensus on protocols that can be easily adapted by researchers equipped with conventional MRI systems. To this end, we provide a discussion of tradeoffs in RT-MRI in terms of acquisition requirements, a priori assumptions, artifacts, computational load, and performance for different speech tasks. We provide four recommended protocols and identify appropriate acquisition and reconstruction tools. We list pointers to open-source software that facilitate implementation. We conclude by discussing current open challenges in the methodological aspects of RT-MRI of speech.


[Clinical course of acute coronary syndrome in dependence on containing of homozystein and С677Т methylenetetrahydrofolate reductase gene polymorphism].
Nowadays to a numerous factors of IHD development risks hyperhomocysteinemia (HHc), C-reactive protein, fibrogen, as well as genetic disorders are relating. With development of IHD and its complications associated methylentetrahudrofolate reductase gene mutation of С677Т polymorphism. The purpose of the investigation was studying the connection between acute coronary syndrome severity (ACS) in dependence on plasma homocysteine containing and genotype by С677Т polymorphism MTHFR gene. Examined: 161 patients with ACS and 87 almost healthy people. Identification of 4th exon allelic polymorphism MTHFR С677Т gene (rs1801133) was conducted with method of polymerase chain reaction, the investigation of homocysteine containing with immunoenzymated method. The statistic analyze was performed with using of SPSS - 17 programme. According to results of study patients with ACS of homozygote by minor allele T С677Т MTHFR gene polymorphism by main allele C and heterozygote were associated with high homocysteine containing in plasma. While frequencies of T/T genotype was reliably higher in patients with ACS with segment ST elevation and complicated course compare with patients with ACS with segment ST elevation and non-complicated course and ACS without climbs of segment ST. Also, statistically reliable difference in genotypes distribution by C677T MTHFR gene polymorphism in dependence on homocysteine plasma level and clinical course of ACS severity were established.


[Intravesical electrostimulation and magnetotherapy in chronic pyelonephritis and cystitis in children with urodynamic disorders].
The results of the treatment of 38 children (6 boys and 32 girls, age 6-14 years) with chronic pyelonephritis and/or cystitis complicated with neurogenic dysfunction of the urinary bladder (NDUB) and/or vesicoureteral reflux (VUR) of the first-third degree demonstrate efficacy of intravesical electrostimulation (IVES) and adrenal magnetotherapy. IVES was conducted with high-frequency current impulses (2.2 kHz) by means of INTRASTIM attachment to the device AMUS-01-INTRAMAG in the region of the urethrovesical anastomosis via solution of the drugs for instillation. As the result of exposure to both physical factors in the presence of standard medication, NDUB symptoms alleviated (by E.L. Vishnevsky's criteria) by 59.5% against 38.1% in the control group. Dopplerographic examination of renal vessels stated a 24.3% increase in blood flow in the major renal artery in the study group against 10.5% in the control. The proposed complex pharmacological plus physiotherapeutic treatment of chronic pyelonephritis and cystitis in abnormal urodynamics resulted in a 2.2-fold decrease in the number of recurrences compared to the standard treatment.


Transcription of the major neurospora crassa microRNA-like small RNAs relies on RNA polymerase III.
Most plant and animal microRNAs (miRNAs) are transcribed by RNA polymerase II. We previously discovered miRNA-like small RNAs (milRNAs) in the filamentous fungus Neurospora crassa and uncovered at least four different pathways for milRNA production. To understand the evolutionary origin of milRNAs, we determined the roles of polymerases II and III (Pol II and Pol III) in milRNA transcription. Our results show that Pol III is responsible for the transcription of the major milRNAs produced in this organism. The inhibition of Pol III activity by an inhibitor or by gene silencing abolishes the production of most abundant milRNAs and pri-milRNAs. In addition, Pol III associates with these milRNA producing loci. Even though silencing of Pol II does not affect the synthesis of the most abundant milRNAs, Pol II or both Pol II and Pol III are associated with some milRNA-producing loci, suggesting a regulatory interaction between the two polymerases for some milRNA transcription. Furthermore, we show that one of the Pol III-transcribed milRNAs is derived from a tRNA precursor, and its biogenesis requires RNase Z, which cleaves the tRNA moiety to generate pre-milRNA. Our study identifies the transcriptional machinery responsible for the synthesis of fungal milRNAs and sheds light on the evolutionary origin of eukaryotic small RNAs.


Cancer Biology or Ineffective Surveillance? A multicentre retrospective analysis of colitis-associated post-colonoscopy colorectal cancers.
Inflammatory bowel disease (IBD) is associated with high rates of post-colonoscopy colorectal cancer (PCCRC), but further in-depth qualitative analyses are required to determine whether they result from inadequate surveillance or aggressive IBD cancer evolution. All IBD patients who had a colorectal cancer (CRC) diagnosed between January 2015 to July 2019 and a recent (<4 years) surveillance colonoscopy at one of four English hospital trusts underwent root cause analyses as recommended by the World Endoscopy Organisation to identify plausible PCCRC causative factors. 61% (n=22/36) of the included IBD CRCs were PCCRCs. They developed in patients with high cancer risk factors (77.8%; n=28/36) requiring annual surveillance, yet 57.1% (n=20/35) had inappropriately delayed surveillance. Most PCCRCs developed in situations where (i) an endoscopically unresectable lesion was detected (40.9%; n=9/22), (ii) there was a deviation from the planned management pathway (40.9%; n=9/22) e.g. service, clinician or patient-related delays in acting on a detected lesion, or (iii) lesions were potentially missed as they were typically located within areas of active inflammation or post-inflammatory change (36.4%; n=8/22). IBD PCCRC prevention will require more proactive strategies to reduce endoscopic inflammatory burden, improve lesion optical characterisation, adherence to recommended surveillance intervals and patient acceptance of prophylactic colectomy. However, the significant proportion appearing to originate from non-adenomatous-looking mucosa which fail to yield neoplasia on biopsy yet display aggressive cancer evolution highlight the limitations of current surveillance. Emerging molecular biomarkers may play a role in enhancing cancer risk stratification in future clinical practice.


Human ontogenesis. I. Ultrastructural characteristics of developing human muscle.
Muscle cells of 25 humans fetuses 7, 9, 10, 14, 17, 20, and 24 weeks old were examined by electron microscopy to determine the structural characteristics of developing muscle. Three structurally different levels of maturation of muscle cells, the primitive myotube, the mature myotube, and the immature muscle fibers, have been observed in the process of human ontogenesis. The sequence of morphological changes and the timing of transformation of one form of fetal muscle into a more mature form are presented.


A Cotransformation Method To Identify a Restriction-Modification Enzyme That Reduces Conjugation Efficiency in Campylobacter jejuni.
Conjugation is an important mechanism for horizontal gene transfer in Campylobacter jejuni, the leading cause of human bacterial gastroenteritis in developed countries. However, to date, the factors that significantly influence conjugation efficiency in Campylobacter spp. are still largely unknown. Given that multiple recombinant loci could independently occur within one recipient cell during natural transformation, the genetic materials from a high-frequency conjugation (HFC) C. jejuni strain may be cotransformed with a selection marker into a low-frequency conjugation (LFC) recipient strain, creating new HFC transformants suitable for the identification of conjugation factors using a comparative genomics approach. To test this, an erythromycin resistance selection marker was created in an HFC C. jejuni strain; subsequently, the DNA of this strain was naturally transformed into NCTC 11168, an LFC C. jejuni strain, leading to the isolation of NCTC 11168-derived HFC transformants. Whole-genome sequencing analysis and subsequent site-directed mutagenesis identified Cj1051c, a putative restriction-modification enzyme (aka CjeI) that could drastically reduce the conjugation efficiency of NCTC 11168 (>5,000-fold). Chromosomal complementation of three diverse HFC C. jejuni strains with CjeI also led to a dramatic reduction in conjugation efficiency (∼1,000-fold). The purified recombinant CjeI could effectively digest the Escherichia coli-derived shuttle vector pRY107. The endonuclease activity of CjeI was abolished upon short heat shock treatment at 50°C, which is consistent with our previous observation that heat shock enhanced conjugation efficiency in C. jejuni Together, in this study, we successfully developed and utilized a unique cotransformation strategy to identify a restriction-modification enzyme that significantly influences conjugation efficiency in C. jejuniIMPORTANCE Conjugation is an important horizontal gene transfer mechanism contributing to the evolution of bacterial pathogenesis and antimicrobial resistance. Campylobacter jejuni, the leading foodborne bacterial organism, displays significant strain diversity due to horizontal gene transfer; however, the molecular components influencing conjugation efficiency in C. jejuni are still largely unknown. In this study, we developed a cotransformation strategy for comparative genomics analysis and successfully identified a restriction-modification enzyme that significantly influences conjugation efficiency in C. jejuni The new cotransformation strategy developed in this study is also expected to be broadly applied in other naturally competent bacteria for functional comparative genomics research.


Optimization of Arrhythmia-based ECG-lead Selection for Computer-interpreted Heart Rhythm Classification.
The 12-lead ECG only has 8 independent ECG leads, which leads to diagnostic redundancy when using all 12 leads for heart arrhythmias classification. We have previously developed a deep learning (DL)-based computer-interpreted ECG (CIE) approach to identify an optimal 4-lead ECG subset for classifying heart arrhythmias. However, the clinical diagnostic criteria of cardiac arrhythmia types are often lead-specific, so this study is going to explore the selection of arrhythmia-based ECG-lead subsets rather than one general optimal ECG-lead subset, which could improve the classification performance for the CIE. The DL-based CIE model previously developed was used to learn 4 common types of heart arrhythmias (LBBB, RBBB, AF, and I-AVB) for identifying corresponding optimal ECG-lead subsets. A public dataset that splits into training (approx. 70%), validation (approx. 15%), and test (approx. 15%) sets from the PhysioNet Cardiology Challenge 2020 was used to explore the study. The results demonstrated that the DL-based CIE model identified an optimal ECG-lead subset for each arrhythmia: I, II, aVR, aVL, V1, V3, and V5 for I-AVB; I, II, aVR, and V3 for AF; I, II, aVR, aVF, V1, V3, and V4 for LBBB; and I, II, III, aVR, V1, V4, and V6 for RBBB. For each arrhythmia classification, the DL-based CIE model using the optimal ECG-lead subset significantly outperformed the model using the full 12-lead ECG set on the validation set and on the external test dataset.The results support the hypothesis that using an optimal ECG-lead subset instead of the full 12-lead ECG set can improve the classification performance of a specific arrhythmia when using the DL-based CIE approach.Clinical Relevance- Using an arrhythmia-based optimal ECG-lead subset, the classification performance of a deep-learning-based model can be achieved without loss of accuracy in comparison with the full 12-lead set (p<0.05).


Transcranial direct current stimulation over the primary motor cortex improves speech production in post-stroke dysarthric speakers: A randomized pilot study.
The current study investigated the therapeutic potential of transcranial direct current stimulation (tDCS) on speech intelligibility, speech-related physiological and vocal functions among post-stroke dysarthric patients. Nine chronic post-stroke dysarthric patients were randomly assigned to the stimulation or sham group. The stimulation group received 2mA of anodal tDCS over the left inferior primary motor cortex for 15 minutes, while the sham group received 30s of stimulation under the same settings. All the participants received 10 daily 15 minutes of individualized speech therapy targeting their dominant phonological process or phonemes with the greatest difficulty. The outcome measures included (1) perceptual analysis of single words, passage reading and diadochokinetic rate, (2) acoustic analysis of a sustained vowel, and (3) kinematic analysis of rapid syllable repetitions and syllable production in sentence, conducted before and after the treatment. The results revealed that both the stimulation and sham groups had improved perceptual speech intelligibility at the word level, reduced short rushes of speech during passage reading, improved rate during alternating motion rate, AMR-kha1, and improved articulatory kinematics in AMR-tha1 and syllables /tha1/ and /kha1/ production in sentence. Compared to the sham group, the stimulation group showed significant improvement in articulatory kinematics in AMR-kha1 and syllable /kha1/ production in sentence. The findings also showed that anodal stimulation led to reduced shimmer value in sustained vowel /a/ phonation, positive changes in articulatory kinematics in AMR-tha1 and syllables /pha1/ and /kha1/ production in sentence at the post treatment measure. In addition to positive effects on articulatory control, reduced perturbation of voice amplitude documented in the stimulation group post treatment suggests possible tDCS effects on the vocal function. The current study documented the beneficial effects of anodal tDCS over the primary motor cortex on speech production and suggested that combined tDCS and speech therapy may promote recovery from post-stroke dysarthria.


Hyperbaric Oxygen Therapy Alleviates the Autoimmune Encephalomyelitis via the Reduction of IL-17a and GM-Csf Production of Autoreactive T Cells as Well as Boosting the Immunosuppressive IL-10 in the Central Nervous System Tissue Lesions.
Multiple sclerosis (MS) is a chronic autoimmune disease mainly caused by autoreactive T cells, followed by neuronal demyelination and disabling paralysis. Hyperbaric oxygen therapy (HBOT) is usually an adjunct to therapy for the treatment of neurological disorders. However, it remains still controversial whether HBOT is an effective option for the treatment of MS. Experimental autoimmune encephalomyelitis (EAE) is a well-studied mouse model investigated for the MS pathogenesis and the efficacy of the therapeutic intervention. Both encephalitogenic Th1 and Th17 are pivotal T cell subsets immunopathogenically producing several disease-initiating/modifying cytokines in the central nervous system (CNS) lesions to further exacerbate/ameliorate the progression of EAE or MS. However, it remains unclear whether HBOT modulates the context of T helper cell subsets in CNS lesions. We employed EAE in the presence of HBOT to assess whether disease amelioration is attributed to alterations of CNS-infiltrating T cell subsets. Our results demonstrated that semi-therapeutic HBOT significantly alleviated the progression of EAE, at least, via the suppression of Th17 response, the downregulation of CD4 T helper cells expressing GM-CSF or TNF-α, and the boosting of immunomodulatory IL-4 or IL-10-expressed CD4 T cells in the CNS lesions. Conclusively, HBOT attenuated EAE through the modulation of T cell responses in an earlier stage.


Radiation Risk of Cardiovascular Diseases in the Cohort of Russian Emergency Workers of the Chernobyl Accident.
This paper continues a series of publications that analyze the impact of radiation on incidence of circulatory system diseases in the cohort of Russian recovery operation workers (liquidators) and presents the results of the analysis of cardiovascular disease (CVD) incidence. The studied cohort consists of 53,772 liquidators who arrived in the Chernobyl accident zone within the first year after the accident (26 April 1986 to 26 April 1987). The individual doses varied from 0.0001 Gy to 1.42 Gy, and the mean external whole body dose in the cohort was 0.161 Gy. A total of 27,456 cases of CVD were diagnosed during the follow-up period 1986-2012 as a result of annual health examinations. A Poisson regression model was applied to estimate radiation risks and other risk factors associated with CVD. The following factors were identified as risk factors for CVD: the dose, duration of the liquidators' work in the Chernobyl zone, and concomitant diseases (diabetes mellitus, hypertension, overweight, and alcohol dependence). The baseline incidence of CVD is statistically significantly (p < 0.001) associated with all studied concomitant diseases. The incidence of CVD has revealed a statistically significant dose response with the lack of a latent period and with the average ERR Gy = 0.47, 95% CI = 0.31, 0.63, p < 0.001. Radiation risks of CVD statistically significantly (p = 0.01) varied with the duration of liquidators' stay in the Chernobyl zone; for those who stayed in the Chernobyl zone less than 6 wk, ERR/Gy = 0.80, 95% CI = 0.53; 1.08, p < 0.001.


Fc-comprising scDb-based trivalent, bispecific T-cell engagers for selective killing of HER3-expressing cancer cells independent of cytokine release.
Bispecific T-cell engagers are an established therapeutic strategy for the treatment of hematologic malignancies but face several challenges when it comes to their application for the treatment of solid tumors, including on-target off-tumor adverse events. Employing an avidity-mediated specificity gain by introducing an additional binding moiety for the tumor-associated antigen can be achieved using formats with a 2+1 stoichiometry. Besides biochemical characterization and validation of target cell binding to cancer cells with different HER3 expression, we used in vitro co-culture assays with human peripheral blood mononuclear cells (PBMCs) and HER3-expressing target cells to determine T-cell activation, T-cell proliferation and PBMC-mediated cancer cell lysis of HER3-positive cell lines by the trivalent, bispecific antibodies. In this study, we developed trivalent, bispecific antibodies comprising a silenced Fc region for T-cell retargeting to HER3-expressing tumor cells, combining a bivalent single-chain diabody (scDb) fused to a first heterodimerizing Fc chain with either an Fab or scFv fused to a second heterodimerizing Fc chain. All these HER3-targeting T-cell engagers comprising two binding sites for HER3 and one binding site for CD3 mediated target cell killing. However, format and orientation of binding sites influenced efficacy of target cell binding, target cell-dependent T-cell activation and T-cell-mediated target cell killing. Beneficial effects were seen when the CD3 binding site was located in the scDb moiety. These molecules showed efficient killing of medium HER3-expressing cancer cells with very low induction of cytokine release, while sparing target cells with low or undetectable HER3 expression. Our study demonstrates that these trivalent, bispecific antibodies represent formats with superior interdomain spacing resulting in efficient target cell killing and a potential advantageous safety profile due to very low cytokine release.


A novel semi-immersive virtual reality visuo-motor task activates ventrolateral prefrontal cortex: a functional near-infrared spectroscopy study.
In the last few years, the interest in applying virtual reality systems for neurorehabilitation is increasing. Their compatibility with neuroimaging techniques, such as functional near-infrared spectroscopy (fNIRS), allows for the investigation of brain reorganization with multimodal stimulation and real-time control of the changes occurring in brain activity. The present study was aimed at testing a novel semi-immersive visuo-motor task (VMT), which has the features of being adopted in the field of neurorehabilitation of the upper limb motor function. A virtual environment was simulated through a three-dimensional hand-sensing device (the LEAP Motion Controller), and the concomitant VMT-related prefrontal cortex (PFC) response was monitored non-invasively by fNIRS. Upon the VMT, performed at three different levels of difficulty, it was hypothesized that the PFC would be activated with an expected greater level of activation in the ventrolateral PFC (VLPFC), given its involvement in the motor action planning and in the allocation of the attentional resources to generate goals from current contexts. Twenty-one subjects were asked to move their right hand/forearm with the purpose of guiding a virtual sphere over a virtual path. A twenty-channel fNIRS system was employed for measuring changes in PFC oxygenated-deoxygenated hemoglobin (O2Hb/HHb, respectively). A VLPFC O2Hb increase and a concomitant HHb decrease were observed during the VMT performance, without any difference in relation to the task difficulty. The present study has revealed a particular involvement of the VLPFC in the execution of the novel proposed semi-immersive VMT adoptable in the neurorehabilitation field.


Effects on proprioception by Kinesio taping of the knee after anterior cruciate ligament rupture.
The use of Kinesio tape (KT) to improve proprioception is a matter of considerable debate. In comparison, the rupture of the anterior cruciate ligament is a sufficiently well-investigated injury with a proven compromise of proprioception. The objective of the present study was to assess a supportive effect on proprioception after KT application, taking the anterior cruciate ligament (ACL) rupture as an example. Forty-eight patients who had suffered an ACL rupture, confirmed clinically and by magnetic resonance imaging, and who were treated conservatively or were awaiting surgery were included in this study. In all patients, a gait analysis was performed on the affected leg before and after KT application. In addition, the IKDC score, the Lysholm score, stability using the Rolimeter, and the angle reproduction test were determined. Thirty-nine men and nine women who had had an ACL rupture for at least 3 weeks were included in the study. Significant improvements were achieved on the affected knee joint for the gait analysis parameters touchdown and unrolling, cadence, stability and stance phase as well as an extension of the hip joint. The Lysholm score improved from 79.3 to 85.8 (p < 0.001) and the IKDC score from 60.2 to 71.3 points (p < 0.001). Significant improvements were achieved in the Rolimeter and angle reproduction test. The use of KT has a positive effect on proprioception in patients with an anterior cruciate ligament rupture. Therefore, the application may improve gait pattern as well as the subjective function of the affected knee joint.


Lipid infiltration as a possible biologic cause of silicone gel breast implant aging.
The cause of silicone gel implant aging and rupture is not known. Recent reports indicate the failure rate is higher than previously published, and implant aging and rupture may be due to progressive mechanical deterioration of the outer vulcanized silicone shell. It is known that lipids are absorbed by the hydrophobic silicone elastomer, and lipid infiltration causes mechanical attenuation and possible failure of the elastomer. The purposes of this article are to analyze the silicone envelope/gel of explanted prostheses and the silicone elastomer of other medical grade silicone devices for lipid content and to suggest its possible role in implant aging and rupture. We assayed 33 ruptured silicone breast implant shells (mean age 13.1 years; range 8 to 26 years) and 8 medical grade silicone elastomer devices (mean age 3.7 years; range 3 months to 12 years) for evidence of lipid infiltration using thin layer chromatography. These were compared with control group assays from two nonimplanted silicone gel implants and one unused Silastic catheter. Ninety-eight percent of implants and other previously implanted silicone devices were found to have evidence of lipid infiltration compared with none in nonimplanted controls (p < 0.005). We conclude that lipids infiltrate the outer silicone shell and may be a factor related to breast implant aging and rupture due to progressive mechanical weakening of the outer silicone shell.


Expectancy bias in trait anxiety.
The ability of anxious and control participants to learn about signals for danger and safety was tested within an autonomic conditioned inhibition (A+/AB-) procedure. Only participants who could verbalize the differential contingencies between the stimuli and shock (aware participants) showed discrimination on electrodermal and shock expectancy measures. In Experiment 1, aware high-anxious participants showed similar responding to control participants. However unaware high-anxious participants showed heightened shock expectancy to all stimuli. Experiment 2 replicated this expectancy bias in anxious unaware participants controlling for shock intensity. In both experiments, expectancy bias was associated primarily with anxiety rather than depression. Results support the notion of an interpretive bias in anxious participants under ambiguous threat, consistent with recent findings from information-processing research on linguistic stimuli.


Lithium-induced renal toxicity in rats: protection by a novel antioxidant caffeic acid phenethyl ester.
Lithium carbonate used in the long-term treatment of manic-depressive illness has been reported to lead to progressive renal impairment in rats and humans. Caffeic acid phenethyl ester (CAPE), a component of honeybee propolis, protects tissues from reactive oxygene species mediated oxidative stress in ischemia-reperfusion and toxic injuries. The beneficial effect CAPE on lithium-induced nephrotoxicity has not been reported yet. The purpose of this study was to examine a possible renoprotective effect of CAPE against lithium-induced nephrotoxicity in a rat model. Twenty-two adult male rats were randomly divided into three experimental groups, as follows: control group, lithium-treated group (Li), and lithium plus CAPE-treated group (Li+CAPE). Li were treated intraperitoneally (i.p.) with 25 mg/kg Li2CO3 solution in 0.9% NaCl twice daily for 4 weeks. CAPE was co-administered i.p. with a dose of 10 microM/kg/day for 4 weeks. Serum Li, blood urea nitrogen and plasma creatinine, urinary N-acetyl-beta-D-glucosaminidase (NAG, a marker of renal tubular injury), and malondialdehyde (MDA, an index of lipid peroxidation), were used as markers of oxidative stress-induced renal impairment in Li-treated rats. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were studied to evaluate the changes of antioxidant status in renal tissue. Serum Li levels were found high in the Li and Li+CAPE groups. In Li-administrated rats, urinary NAG and renal MDA levels were increased according to control and Li+CAPE groups (p < 0.05). CAPE caused a significant reduction in the levels of these parameters. Likewise, renal SOD, CAT and GSH-Px activities were decreased in Li-administrated animals; CAPE caused a significant increase in the activities of these antioxidant enzymes. In conclusion, CAPE treatment has a protective effect against Li-induced renal tubular damage and oxidative stress in a rat model.


Reference point indentation is not indicative of whole mouse bone measures of stress intensity fracture toughness.
Bone fragility is a concern for aged and diseased bone. Measuring bone toughness and understanding fracture properties of the bone are critical for predicting fracture risk associated with age and disease and for preclinical testing of therapies. A reference point indentation technique (BioDent) has recently been developed to determine bone's resistance to fracture in a minimally invasive way by measuring the indentation distance increase (IDI) between the first and last indentations over cyclic indentations in the same position. In this study, we investigate the relationship between fracture toughness KC and reference point indentation parameters (i.e. IDI, total indentation distance (TID) and creep indentation distance (CID)) in bones from 38 mice from six types (C57Bl/6, Balb, oim/oim, oim/+, Phospho1(-/-) and Phospho1 wild type counterpart). These mice bone are models of healthy and diseased bone spanning a range of fracture toughness from very brittle (oim/oim) to ductile (Phospho1(-/-)). Left femora were dissected, notched and tested in 3-point bending until complete failure. Contralateral femora were dissected and indented in 10 sites of their anterior and posterior shaft surface over 10 indentation cycles. IDI, TID and CID were measured. Results from this study suggest that reference point indentation parameters are not indicative of stress intensity fracture toughness in mouse bone. In particular, the IDI values at the anterior mid-diaphysis across mouse types overlapped, making it difficult to discern differences between mouse types, despite having extreme differences in stress intensity based toughness measures. When more locations of indentation were considered, the normalised IDIs could distinguish between mouse types. Future studies should investigate the relationship of the reference point indentation parameters for mouse bone in other material properties of the bone tissue in order to determine their use for measuring bone quality.


Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol.
Cells employ regulated transport mechanisms to ensure that their plasma membranes (PMs) are optimally supplied with cholesterol derived from uptake of low-density lipoproteins (LDL) and synthesis. To date, all inhibitors of cholesterol transport block steps in lysosomes, limiting our understanding of post-lysosomal transport steps. Here, we establish the cholesterol-binding domain 4 of anthrolysin O (ALOD4) as a reversible inhibitor of cholesterol transport from PM to endoplasmic reticulum (ER). Using ALOD4, we: (1) deplete ER cholesterol without altering PM or overall cellular cholesterol levels; (2) demonstrate that LDL-derived cholesterol travels from lysosomes first to PM to meet cholesterol needs, and subsequently from PM to regulatory domains of ER to suppress activation of SREBPs, halting cholesterol uptake and synthesis; and (3) determine that continuous PM-to-ER cholesterol transport allows ER to constantly monitor PM cholesterol levels, and respond rapidly to small declines in cellular cholesterol by activating SREBPs, increasing cholesterol uptake and synthesis.


The ordering of XY spin glasses.
Ordering properties of XY-like spin-glass magnets with an easy-plane magnetic anisotropy are studied based on a symmetry consideration and the results of recent numerical simulations on the pure Heisenberg and XY spin-glass models. The effects of an easy-plane-type uniaxial anisotropy, a random magnetic anisotropy and an applied magnetic field are investigated. In the XY regime in zero field, the 'spin-chirality decoupling' persists even under the random magnetic anisotropy, escaping the 'spin-chirality recoupling' phenomenon which inevitably occurs in the Heisenberg regime. Contrast between the scalar chiral order and the vector chiral order is emphasized. Implications for experiments are discussed.


Population pharmacokinetics of ritonavir-boosted saquinavir regimens in HIV-infected individuals.
The aim of this study was to develop and validate a population pharmacokinetic model in order to describe ritonavir-boosted saquinavir concentrations dosed twice and once daily in human immunodeficiency virus (HIV)-infected patients from the UK, Uganda and Thailand and to identify factors that may influence saquinavir pharmacokinetics. Pharmacokinetic data from 10 clinical studies were combined. Non-linear mixed effects modelling (NONMEM version V) was applied to determine the saquinavir pharmacokinetic parameters, interindividual/interoccasion variability (IIV/IOV) and residual error. Various covariates potentially related to saquinavir pharmacokinetics were explored, and the final model was validated by means of 95% prediction interval and testing the predictive performance of the model with data not included in the model-building process. Ninety-seven patients were included from the UK (n = 52), Uganda (n = 18) and Thailand (n = 27), contributing 347 saquinavir profiles (1-14 profiles per patient). A one-compartment model with zero-order absorption and lag-time best described the data with IIV/IOV on apparent oral clearance (CL/F) and volume of distribution (V/F) and with IIV on duration and absorption lag-time. The ritonavir area under the curve over the dosing interval was significantly associated with saquinavir CL/F and V/F. A typical patient from the UK had approximately 1.5- and 3-fold higher saquinavir CL/F compared with patients from Uganda (89.0 versus 49.8 L/h) and Thailand (89.0 versus 26.7 L/h), respectively. A model to characterize ritonavir-boosted saquinavir pharmacokinetics in HIV-infected adults has been developed and validated. The model could be used for dosage adaptation following therapeutic drug monitoring and to assess patients' suitability for once-daily boosted saquinavir therapy.


Special critical care considerations in tracheostomy management.
The tracheotomized patient undergoing mechanical ventilation presents numerous challenges to the intensive care team. During the initial phase of respiratory failure, patient instability and risks of multiorgan failure focus efforts on an array of critical care management techniques designed to reverse the underlying process and prevent complications. During the stabilization phase, issues of tracheostomy care become equally important in improving patient outcome. These topics include the proper assistance in patient communication, initiation of enteral nutrition, weaning from airway cannulation, and anticipation of adverse reactions after airway decannulation. Failure in promoting a logically conceived and carefully applied treatment plan in any of these areas frequently delays patient recovery and risks serious complications of airway compromise.


Comments on a Method to Measure Sucralose Using UV Photodegradation Followed by UV Spectrophotometry.
A simple and quick method to measure sucralose in aqueous solution at concentrations in the order of 0.1-1.2 g·L-1 proposed by Idris et al. uses UV irradiation prior to UV spectrophotometry. The photolysis of sucralose forms a photoactive compound characterized by maximum absorbance at approximately 270 nm. The conditions required for sucralose photolysis, however, had not been completely reported. In this work, the procedure described by Idris et al. was replicated using a low-pressure UV lamp to irradiate sucralose samples with a wider range of initial concentrations (0.04-10 g·L-1) with known fluences. It was determined that care must be taken to ensure that the same fluence is applied for both calibration and measurement steps because the absorbance of the sucralose photolysis product is a function of the applied fluence. The way the samples are irradiated also has an impact on the results in that the method exhibits a greater linear range if an apparatus is used that maximizes the fluence rate (e.g., by placing samples closer to the UV source or using a higher-intensity lamp).


Risk factors and poor prognostic factors of preeclampsia in Ibn Rochd University Hospital of Casablanca: about 401 preeclamptic cases.
Preeclampsia is a gestational pathology that complicates 2 to 8% of pregnancies and is one of the major causes of maternal and fetal morbidity and mortality worldwide. The aim of this work was to study the epidemiological profile of preeclampsia in Casablanca and to identify risk factors as well as factors of poor maternal and fetal prognosis. 401 preeclamptic cases were collected in the gynecology-obstetrics "C" Service of Lalla Meryem Maternity of Ibn Rochd University Hospital of Casablanca (2010-2011) were included in this study and a statistical analysis with the SPSS software version (16.0) was performed. We used the Chi-2 test to analyze qualitative variables and Student's test and ANOVA (analysis of variance) for quantitative variables. The incidence of preeclampsia was (7.1%). The epidemiological profile was that of a primipara (57.6%), average age 30 years and (66.8%) of pregnancies were not followed. Multiparity was a factor of poor maternal prognosis (p = 0.007). The low gestational age and no prenatal care were factors of maternal as well as fetal prognosis. Risk factors frequently found in our patients were obesity (15.21%) and chronic hypertension (5.73%) as vascular-renal history; abortion (16.46%) and perinatal death (5.24%) as obstetric history. Preeclampsia is a common obstetric pathology in our context. Better prenatal care and early diagnosis could reduce its incidence.


[Adenylate cyclase system and structural modifications of nuclear proteins in organisms radioprotection].
The paper deals with modern ideas of ways and mechanisms for realization of the radioprotector antiradiation effect. The data on the effect of biogenic amines (serotonin in particular) and radiation on the cAMP system are analyzed. It is shown that one of the most important mechanisms of the radioprotective effect is realized by changing the levels of histones and nonhistone proteins modifications through the adenylate cyclase system which leads to regulation of the chromatin template activity.


Impact of specialist ataxia centres on health service resource utilisation and costs across Europe: cross-sectional survey.
Little is known about the costs of treating ataxia and whether treatment at a specialist ataxia centre affects the cost of care. The aim of this study was to investigate whether patients who attended specialist ataxia centres in three European countries reported differences in their health care use and costs compared with patients who did not attend a specialist ataxia centre. We compared mean resource use and health service costs per patient affected by ataxia in the United Kingdom, Italy and Germany over a 12-month period. Data were obtained from a survey distributed to people with ataxia in the three countries. We compared mean resource use for each contact type and costs, stratifying patients by whether they were currently attending a specialist ataxia centre or had never attended one. Responses were received from 181 patients from the United Kingdom, 96 from Italy and 43 from Germany. Differences in the numbers of contacts for most types of health service use between the specialist ataxia centre and non-specialist ataxia centre groups were non-significant. In the United Kingdom the mean total cost per patient was €2209 for non-specialist ataxia centre patients and €1813 for specialist ataxia centre patients (P = 0.59). In Italy these figures were €2126 and €1971, respectively (P = 0.84). In Germany they were €2431 and €4087, respectively (P = 0.19). Inpatient stays made the largest contribution to total costs. Within each country, resource use and costs were broadly similar for specialist ataxia centre and non-specialist ataxia centre groups. There were differences between countries in terms of health care contacts and costs.


Two Catastrophes in One Patient: Drug Reaction with Eosinophilia and Systemic Symptoms and Toxic Shock Syndrome.
A 70-year-old, immunocompromised patient presented to the emergency room (ER) five weeks after she was started on clopidogrel. She complained of skin eruption, mouth ulcers, fatigue, and myalgia over the past two weeks. Labs showed severe hyponatremia, acute kidney injury, rhabdomyolysis, hyperkalemia, and elevated liver enzymes. She was treated with steroids and discharged after her condition improved. However, a month later, she returned to the ER, complaining of nausea, vomiting, diarrhea, dizziness, chills, and shortness of breath over the past two days. She was lethargic and had orthostatic hypotension. She deteriorated clinically within a few days, with worsening lethargy and the development of respiratory distress along with profound hypotension. She needed mechanical ventilation and vasopressors. In addition, she had melena, severe thrombocytopenia, and hemolytic anemia. With supportive care, she improved and was discharged after a long stay in the intensive care unit. Retrospectively, the first hospitalization was believed to be caused by drug reaction with eosinophilia and systemic symptoms (DRESS). Treating that with steroids compromised her immune system beyond her pre-existing primary immunodeficiency status. At the time of her second hospitalization, she met the Centers for Disease Control and Prevention (CDC) criteria for a toxic shock syndrome (TSS) diagnosis. Her TSS started four days after a skin biopsy, which was done as part of her skin rash workup. It was thought that the source of the exotoxin that mediated her TSS was her skin, given the temporal relationship of the skin biopsy to her TSS. Another potential source of the exotoxin was the gastrointestinal tract, given the predominant gastrointestinal symptoms she had at the time of her second admission.


A homozygous deletion in the c-erbA beta thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance: isolation and characterization of the mutant receptor.
Different point mutations have been identified in the T3-binding domain of the c-erbA beta thyroid hormone receptor gene that are associated with variant phenotypes of generalized thyroid hormone resistance (GTHR). In most cases of GTHR, heterozygotes are affected; a single mutant allele results in the inhibition of the function of normal thyroid hormone receptors. We report here a novel genetic abnormality, a 3-basepair (bp) deletion in the T3-binding domain of the beta-receptor in a kindred, S, with GTHR. One patient, S1, was the product of a consanguineous union of two heterozygotes and was homozygous for this defect. Heterozygotes from kindred S harbored a CAC deletion at nucleotides 1295-1297, which resulted in the deduced loss of amino acid residue threonine at codon 332, and they displayed elevated free T4 levels and inappropriately normal TSH levels characteristic of other kindreds with GTHR. However, patient S1, who had two mutant alleles, had markedly elevated TSH and free T4 levels and displayed profound abnormalities in brain development and linear growth. A fibroblast c-erbA beta cDNA extending from codon 175 to stop codon 457 was cloned from patient S1, sequenced, and used to create a full-length mutant cDNA. The kindred S mutant receptor was synthesized in vitro and did not bind T3. This mutant receptor did bind with similar avidity as the wild-type human beta-receptor to thyroid hormone response elements of the human TSH beta (-12 to 43 bp) and rat GH (-188 to -160 bp) genes. Kindred S showed the effect in man of heterozygous and homozygous expression of a dominant negative form of c-erbA beta.


Elevated circulating PCSK-9 concentration in renal failure patients is corrected by renal replacement therapy.
A high level of circulating PCSK9 binds to the LDL receptor, reduces its cell's surface density and leads to hypercholesterolemia. The aim of this study was to examine the circulating PCSK9 level in patients with kidney disease. Out of the patients treated in our Departments we selected: (a) 44 patients with CKD stage 3 and 4 (b) 29 patients with CKD stage 5 on maintenance hemodialysis treatment; and (c) 20 patients after successful renal transplantation. Thirty-four subjects, without CKD formed the control group. Serum biochemical parameters' concentrations were assayed by a certified laboratory. Serum PCSK9 concentration was estimated by a commercially available ELISA kit. The mean serum concentration of PCSK9 in patients with kidney disease was higher than in the control group (238.7 ± 64.5 vs. 536.7 ± 190.4; p < 0.001). A strong negative correlation between serum PCSK9 concentration and eGFR was found (r = -0.66; p < 0.001), as well as between serum concentrations of PCSK9 and total- (r = 0.482; p < 0.05) or LDL-cholesterol (r = 0.533; p < 0.05), but exclusively in patients not receiving statins. The elevated serum concentration of PCSK9 in patients before hemodialysis session declined afterwards, reaching the values observed in patients after kidney transplantation and in the control group. The circulating PCSK9 concentration is increased in patients with CKD; however, this is not accompanied by hypercholesterolemia. The positive correlations between PCSK9/TCh and PCSK9/LDL-Ch have been found only in patients not treated with statins. The elevated circulating PCSK9 level is corrected by maintenance hemodialysis treatment and normalized by a successful kidney transplantation.


Synaptic organisation of lumbar sympathetic ganglia of guinea pigs: serial section ultrastructural analysis of dye-filled sympathetic final motor neurons.
The authors serially sectioned seven dye-filled neuronal somata and more than 1.6 mm of their dendrites from the lumbar sympathetic ganglia of guinea pigs and examined them ultrastructurally to determine the distribution of preganglionic synaptic inputs to their dendrites and cell bodies. Most of the surface of the neurons was covered with Schwann cells. Apposing boutons were rare, with an average density of one axosomatic bouton per 125 microm2 of somatic membrane and one axodendritic bouton per 25 microm of dendrite. Many dendritic segments that were more than 50 microm long completely lacked any apposing boutons. Although the average density of apposing boutons was low, local densities could be high, so that clusters of up to four adjacent boutons occurred on cell bodies and dendrites alike. The spatial arrangement of the apposing boutons for each of the cells examined here was not significantly different from a random distribution. Consequently, the number of apposing boutons observed for any neuron was simply proportional to the amount of neuronal surface sampled in the serial section run. About 50% of boutons directly apposing the neurons lacked any detectable presynaptic specialisations. When they were present, the presynaptic densities had a mean length of about 220 nm, with no difference between boutons that made axosomatic or axodendritic appositions. By applying these data to complete reconstructions of the dendritic trees of dye-filled sympathetic neurons at the light microscopic level, the authors estimated that few neurons in the lumbar sympathetic chain of guinea pigs would receive more than 200 synapses or apposing boutons and that many of them would receive less than 100 synapses. Up to 50% of these boutons would be predicted to make axosomatic contacts. These new observations provide a strong morphological framework for a better understanding of how sympathetic final motor neurons process their preganglionic synaptic inputs.


Uncoupling of pro- and anti-inflammatory properties of Staphylococcus aureus.
Staphylococcus aureus is a Gram-positive bacterium that is carried by a quarter of the healthy human population and that can cause severe infections. This pathobiosis has been linked to a balance between Toll-like receptor 2 (TLR2)-dependent pro- and anti-inflammatory responses. The relationship between these two types of responses is unknown. Analysis of 16 nasal isolates of S. aureus showed heterogeneity in their capacity to induce pro- and anti-inflammatory responses, suggesting that these two responses are independent of each other. Uncoupling of these responses was corroborated by selective signaling through phosphoinositol 3-kinase (PI3K)-Akt-mTOR and extracellular signal-regulated kinase (ERK) for the anti-inflammatory response and through p38 for the proinflammatory response. Uncoupling was also observed at the level of phagocytosis and phagosomal processing of S. aureus, which were required solely for the proinflammatory response. Importantly, the anti-inflammatory properties of an S. aureus isolate correlated with its ability to modulate T cell immunity. Our results suggest the presence of anti-inflammatory TLR2 ligands in the staphylococcal cell wall, whose identification may provide templates for novel immunomodulatory drugs.


Imaging of the nasopharynx and skull base.
The prerequisite for the correct diagnosis and accurate delineation of skull base lesions is familiarity with the complex anatomy of the skull base. Imaging plays a central role in the management of skull base disease because this region is often difficult to evaluate clinically. CT and MR imaging are complementary; they are often used together to demonstrate the full disease extent. This article focuses on the critical anatomy of theskull base and how this knowledge contributes to accurate disease assessment.


Design and functional testing of a multichamber perfusion platform for three-dimensional scaffolds.
Perfusion culture systems are widely used in tissue engineering applications for enhancing cell culture viability in the core of three-dimensional scaffolds. In this work, we present a multichamber confined-flow perfusion system, designed to provide a straightforward platform for three-dimensional dynamic cell cultures. The device comprises 6 culture chambers allowing independent and simultaneous experiments in controlled conditions. Each chamber consists of three parts: a housing, a deformable scaffold-holder cartridge, and a 7 mL reservoir, which couples water-tightly with the housing compressing the cartridge. Short-term dynamic cell seeding experiments were carried out with MC3T3-E1 cells seeded into polycaprolactone porous scaffolds. Preliminary results revealed that the application of flow perfusion through the scaffold favored the penetration of the cells to its interior, producing a more homogeneous distribution of cells with respect to dropwise or injection seeding methods. The culture chamber layout was conceived with the aim of simplifying the user operations under laminar flow hood and minimizing the risks for contamination during handling and operation. Furthermore, a compact size, a small number of components, and the use of bayonet couplings ensured a simple, fast, and sterility-promoting assembling. Finally, preliminary in vitro tests proved the efficacy of the system in enhancing cell seeding efficiency, opening the way for further studies addressing long-term scaffold colonization.


When linear stability does not exclude nonlinear instability.
We describe a mechanism that results in the nonlinear instability of stationary states even in the case where the stationary states are linearly stable. This instability is due to the nonlinearity-induced coupling of the linearization's internal modes of negative energy with the continuous spectrum. In a broad class of nonlinear Schrödinger equations considered, the presence of such internal modes guarantees the nonlinear instability of the stationary states in the evolution dynamics. To corroborate this idea, we explore three prototypical case examples: (a) an antisymmetric soliton in a double-well potential, (b) a twisted localized mode in a one-dimensional lattice with cubic nonlinearity, and (c) a discrete vortex in a two-dimensional saturable lattice. In all cases, we observe a weak nonlinear instability, despite the linear stability of the respective states.


A Narrative Review on Clinical Applications of fNIRS.
Functional near-infrared spectroscopy (fNIRS) is a relatively new imaging modality in the functional neuroimaging research arena. The fNIRS modality non-invasively investigates the change of blood oxygenation level in the human brain utilizing the transillumination technique. In the last two decades, the interest in this modality is gradually evolving for its real-time monitoring, relatively low-cost, radiation-less environment, portability, patient-friendliness, etc. Including brain-computer interface and functional neuroimaging research, this technique has some important application of clinical perspectives such as Alzheimer's disease, schizophrenia, dyslexia, Parkinson's disease, childhood disorders, post-neurosurgery dysfunction, attention, functional connectivity, and many more can be diagnosed as well as in some form of assistive modality in clinical approaches. Regarding the issue, this review article presents the current scopes of fNIRS in medical assistance, clinical decision making, and future perspectives. This article also covers a short history of fNIRS, fundamental theories, and significant outcomes reported by a number of scholarly articles. Since this review article is hopefully the first one that comprehensively explores the potential scopes of the fNIRS in a clinical perspective, we hope it will be helpful for the researchers, physicians, practitioners, current students of the functional neuroimaging field, and the related personnel for their further studies and applications.


Direct measurement of clathrin-coated vesicle formation using a cell-free assay.
Factors controlling the last stages of clathrin-coated vesicle formation were investigated using an assay allowing direct measurement of the detachment of these vesicles from the plasma membrane. Plasma membranes from cultured cells surface-labelled with 125I-alpha2-macroglobulin (a ligand that preferentially associates with clathrin-coated pits) were isolated by sonication of cells attached to a poly-L-lysine-coated substratum and incubated in the presence of nucleotide(s) +/- cytosol. A significant proportion of the membrane-associated radioactivity was released into the incubation medium in sedimentable form (14x10(6)g). The nucleotide and ligand specificities of this process together with the results of a series of biochemical, morphological and gradient analyses, led to the conclusion that measurement of the released sedimentable radioactivity provides a direct estimate of the formation of clathrin-coated vesicles from clathrin-coated pits. A morphological analysis of quick-frozen replicas of these membranes indicated that only the last stages of clathrin-coated vesicle formation were studied in the assay. Taking advantage of this cell-free system, we demonstrate that membrane-associated cytosolic factors and GTP-binding proteins, noteably dynamin, play a crucial role. Moreover, although these events can occur in the absence of ATP and Ca2+, optimal conditions for the formation of clathrin-coated vesicles require the presence of ATP, GTP and cytosol.


Differential influence of frequency, timing, and intensity cues in a complex acoustic categorization task.
Songbirds, which, like humans, learn complex vocalizations, provide an excellent model for the study of acoustic pattern recognition. Here we examined the role of three basic acoustic parameters in an ethologically relevant categorization task. Female zebra finches were first trained to classify songs as belonging to one of two males and then asked whether they could generalize this knowledge to songs systematically altered with respect to frequency, timing, or intensity. Birds' performance on song categorization fell off rapidly when songs were altered in frequency or intensity, but they generalized well to songs that were changed in duration by >25%. Birds were not deaf to timing changes, however; they detected these tempo alterations when asked to discriminate between the same song played back at two different speeds. In addition, when birds were retrained with songs at many intensities, they could correctly categorize songs over a wide range of volumes. Thus although they can detect all these cues, birds attend less to tempo than to frequency or intensity cues during song categorization. These results are unexpected for several reasons: zebra finches normally encounter a wide range of song volumes but most failed to generalize across volumes in this task; males produce only slight variations in tempo, but females generalized widely over changes in song duration; and all three acoustic parameters are critical for auditory neurons. Thus behavioral data place surprising constraints on the relationship between previous experience, behavioral task, neural responses, and perception. We discuss implications for models of auditory pattern recognition.


Robust metastable skyrmions and their triangular-square lattice structural transition in a high-temperature chiral magnet.
Skyrmions, topologically protected nanometric spin vortices, are being investigated extensively in various magnets. Among them, many structurally chiral cubic magnets host the triangular-lattice skyrmion crystal (SkX) as the thermodynamic equilibrium state. However, this state exists only in a narrow temperature and magnetic-field region just below the magnetic transition temperature Tc, while a helical or conical magnetic state prevails at lower temperatures. Here we describe that for a room-temperature skyrmion material, β-Mn-type Co 8Zn 8Mn 4, a field-cooling via the equilibrium SkX state can suppress the transition to the helical or conical state, instead realizing robust metastable SkX states that survive over a very wide temperature and magnetic-field region. Furthermore, the lattice form of the metastable SkX is found to undergo reversible transitions between a conventional triangular lattice and a novel square lattice upon varying the temperature and magnetic field. These findings exemplify the topological robustness of the once-created skyrmions, and establish metastable skyrmion phases as a fertile ground for technological applications.


Evidence of effectiveness of herbal medicinal products in the treatment of arthritis. Part 2: Rheumatoid arthritis.
Herbal medicinal products (HMPs) that interact with the mediators of inflammation are used in the treatment of rheumatoid arthritis (RA). The aim of this study was to update a previous systematic review published in 2000. We searched electronic databases (MEDLINE, EMBASE, CISCOM, AMED, CINAHL, Cochrane registers) to June 2007, unrestricted by date or language, and included randomized controlled trials that compared HMPs with inert (placebo) or active controls in patients with rheumatoid arthritis. Five reviewers contributed to data extraction. Disagreements were discussed and resolved by consensus with reference to Cochrane guidelines and advice from the Cochrane Collaboration. Twenty studies (10 identified for this review update, and 10 of the 11 studies of the original review) investigating 14 HMPs were included. Meta-analysis was restricted to data from previous seven studies with oils from borage, blackcurrant and evening primrose containing gamma linolenic acid (GLA). GLA doses equal or higher than 1400 mg/day showed benefit in the alleviation of rheumatic complaints whereas lower doses ( approximately 500 mg) were ineffective. Three studies compared products from Tripterygium wilfordii (thunder god vine) to placebos and returned favorable results but data could not be pooled because the interventions and measures differed. Serious adverse effects occurred in one study. In a follow-up study all side effects were mild to moderate and resolved after the intervention ceased, but time to resolution was variable. Two studies comparing Phytodolor NR to placebo were of limited use because some measures were poorly defined. The remaining studies, each considering differing HMPs, were assessed individually. For most HMPs used in the treatment of RA, the evidence of effectiveness was insufficient to either recommend or discourage their use. Interventions with HMPs containing GLA or Tripterygium wilfordii extract appear to produce therapeutic effects but further investigations are warranted to prove their effectiveness and safety.


Increased mortality in patients with differentiated thyroid cancer associated with Graves' disease.
We previously reported that differentiated thyroid cancer (DTC) has higher aggressiveness and poorer prognosis in patients with Graves' disease (GD) than DTC in euthyroid control patients. Subsequent studies on this issue reached controversial conclusions. Genetic and environmental factors, as well as the lack of appropriate control subjects and/or inadequate patient follow-up, may account for these discrepancies. The aim of this study was to investigate the long-term disease-specific mortality of nonoccult DTCs occurring in patients with GD compared with DTCs in matched euthyroid control patients. The previously described cohorts of nonoccult DTCs occurring in either patients with GD (DTC-GD, n = 21) or matched euthyroid DTC control patients (n = 70) were compared again after a longer follow-up (50-363.6 months; median, 165.6 months) to compare the major clinical endpoints of persistent/recurrent disease and overall survival. Both cohorts were recruited in 1982-1994 at a single institution. All patients had undergone total thyroidectomy and were followed up according to a standardized protocol. Persistent/recurrent disease was more frequent in DTC-GD patients than in control patients (P = .0119). Disease-specific mortality was also significantly higher in DTC-GD patients (6 of 21, 28.6%) than in euthyroid control patients (2 of 70, 2.9%) (P = .0001). At the last visit, the percentage of disease-free patients was 57.1% (12 of 21) in the DTC-GD group vs 87.1% (61 of 70) in the control group (P = .0025). Nonoccult DTCs occurring in patients with GD cause increased disease-specific mortality compared with DTCs in matched euthyroid control patients. These findings emphasize the need for early diagnosis and aggressive treatment of nonoccult DTCs in patients with GD.


Global climate anomalies and potential infectious disease risks: 2014-2015.
The El Niño/Southern Oscillation (ENSO) is a global climate phenomenon that impacts human infectious disease risk worldwide through droughts, floods, and other climate extremes. Throughout summer and fall 2014 and winter 2015, El Niño Watch, issued by the US National Oceanic and Atmospheric Administration, assessed likely El Niño development during the Northern Hemisphere fall and winter, persisting into spring 2015. We identified geographic regions where environmental conditions may increase infectious disease transmission if the predicted El Niño occurs using El Niño indicators (Sea Surface Temperature [SST], Outgoing Longwave Radiation [OLR], and rainfall anomalies) and literature review of El Niño-infectious disease associations. SSTs in the equatorial Pacific and western Indian Oceans were anomalously elevated during August-October 2014, consistent with a developing weak El Niño event. Teleconnections with local climate is evident in global precipitation patterns, with positive OLR anomalies (drier than average conditions) across Indonesia and coastal southeast Asia, and negative anomalies across northern China, the western Indian Ocean, central Asia, north-central and northeast Africa, Mexico/Central America, the southwestern United States, and the northeastern and southwestern tropical Pacific. Persistence of these conditions could produce environmental settings conducive to increased transmission of cholera, dengue, malaria, Rift Valley fever, and other infectious diseases in regional hotspots as during previous El Niño events. The current development of weak El Niño conditions may have significant potential implications for global public health in winter 2014-spring 2015. Enhanced surveillance and other preparedness measures in predicted infectious disease hotspots could mitigate health impacts.


[Suggestions for the teaching of public health nursing in undergraduate nursing programs].
The authors describe the role of the University in the preparation of human resources of nursing and present the bases for planning of the undergraduate curriculum, emphasizing the referencial, conceptual, structural and methodological frameworks. The principles which should guide nursing education as well as the introduction of public health nursing in the curriculum are discussed. At least there are formulated questions about the nursing teacher's role and the practitioner nursing's role in the actuality.


Temsirolimus is highly effective as third-line treatment in chromophobe renal cell cancer.
We report unexpectedly high efficacy of temsirolimus as third-line treatment in a patient with metastatic chromophobe renal cell carcinoma. After failure of two sequentially administered tyrosine kinase inhibitors, treatment with temsirolimus resulted in a prolonged partial remission of 14 months, and the response is still continuing. Up to now, no data from randomized clinical studies have been published addressing the question of efficacy of temsirolimus as third-line treatment after failure of tyrosine kinase inhibitors. The case presented here implies that temsirolimus could be a viable option for patients with metastatic chromophobe renal cell carcinoma.


[Inhibition in association cortex neurons upon direct and transcallosal stimulation in the cat].
The experiments were performed on cats immobilized with myorelaxants. Depression of background activity or IPSP was recorded in neurons of the associative cortex in response to direct cortical and transcallosal stimulation. With the intensification of stimulation the duration of inhibition increased up to a certain limit for each studied cell. After this it still could increase if the number of the stimuli increased. Prolonged inhibition (up to several seconds) in response to a series of stimuli had the same nature as short inhibition about 20 ms evoked by a single stimulus. It was due to a prolonged hyperpolarizing postsynaptic potential. A suggestion is made that neurons producing monosynaptical inhibition in the associative cortex cells can be situated in the contralateral hemisphere.


Mitochondrial complex I deficiency leads to inflammation and retinal ganglion cell death in the Ndufs4 mouse.
Mitochondrial complex I (NADH dehydrogenase) is a major contributor to neuronal energetics, and mutations in complex I lead to vision loss. Functional, neuroanatomical and transcriptional consequences of complex I deficiency were investigated in retinas of the Ndufs4 knockout mouse. Whole-eye ERGs and multielectrode arrays confirmed a major retinal ganglion cell functional loss at P32, and retinal ganglion cell loss at P42. RNAseq demonstrated a mild and then sharp increase in innate immune and inflammatory retinal transcripts at P22 and P33, respectively, which were confirmed with QRT-PCR. Intraperitoneal injection of the inflammogen lipopolysaccharide further reduced retinal ganglion cell function in Ndufs4 KO, supporting the connection between inflammatory activation and functional loss. Complex I deficiency in the retina clearly caused innate immune and inflammatory markers to increase coincident with loss of vision, and RGC functional loss. How complex I incites inflammation and functional loss is not clear, but could be the result of misfolded complex I generating a 'non-self' response, and induction of innate immune response transcripts was observed before functional loss at P22, including β-2 microglobulin and Cx3cr1, and during vision loss at P31 (B2m, Tlr 2, 3, 4, C1qa, Cx3cr1 and Fas). These data support the hypothesis that mitochondrial complex I dysfunction in the retina triggers an innate immune and inflammatory response that results in loss of retinal ganglion cell function and death, as in Leber's hereditary Optic Neuropathy and suggests novel therapeutic routes to counter mitochondrial defects that contribute to vision loss.


[Malignant reticuloendothelioses. Clinical variations influencing prognosis].
The relationship of age, sex, clinical findings and prognosis was studied among 30 children with malignant reticuloendotheliosis. A male predominance was found, but it was not possible to make any prognostic correlation regarding this parameter. A definitive worse prognosis was found in the early ages, thus 88% of less than 12 months-old children died. Although the visceral involvement degree signifies a poor prognosis, it was found that nevertheless, a solitary osteolytic lesion is in the accordance with good prognosis; all patients who did not have bone lesions died in less than three years. It is the first part of our purpose to enact the usefulness of the clinical findings toward a more precise prognosis in the malignant reticuloengotheliosis. Later on, we will report the possibility to obtain a numerical data from the clinical findings in order to establish an accurate prognosis.


[Ultrastructural changes in boar spermatozoa during freezing-thawing].
Using electron microscopy, no significant alteration were revealed in the boar spermatozoa suspended for 0.5-1 hour in the medium containing protective stuff except some desquamation and disruption in the spermatozoon head region. Similar picture was seen after a 3 hours' treatment in the medium. However, after freezing (-196 degrees C) and thawing more significant structural changes appear, at first part, in the head membrane structures. In addition, fragmentation and swelling of mitochondria is observed possibly accounting for the lack of spermatozoa motility after thawing.


Post-endodontic treatment of incisors and premolars among dental practitioners in Saarland: an interactive Web-based survey.
The aim of the present study was to evaluate the trend of dental practitioners in the federal state of Saarland in Germany in regard to restoring endodontically treated teeth using a Web-based survey. An interactive Web-based survey instrument was developed, including seven clinical scenarios, presented by photographs of natural incisor and premolar with different types of cavities. Following a decision tree adapted to the clinical treatment, questions on different aspects of the post-endodontic treatment were asked. All 615 members of the Saarland Dental Association (SDA) were asked to participate in the survey. A total of 33 % completed the survey. The majority of the participants believed in the reinforcement effect of the ferrule design, as well as the post placement. The vast majority of the responding practitioners (92 %) adapted their treatment strategies to a high extent to the destruction degree of the endodontically treated tooth. Fiber-reinforced composite (FRC) posts are the most popular prefabricated post type, regardless of the cavity size and tooth localization. Significant differences between the dentists according to the degree of experience were detected only for the use of glass-ionomer cements as core buildup material. The predominant post-endodontic treatment strategies of German dental practitioners are only partly in agreement with the current literature. There is a clear trend toward the increasing use of metal-free post and core materials. Although the participants showed a general adoption of modern materials and techniques, different patterns of post-endodontic treatment were revealed that were not consistent with approaches supported by the literature.


Fibronectin deficiency and intestinal transvascular fluid balance during bacteremia.
Reticuloendothelial (RE) clearance dysfunction, which can be induced by opsonic fibronectin deficiency, has been correlated with organ failure during sepsis. We investigate the role of opsonic fibronectin deficiency and RE blockade in modulating alterations in intestinal transvascular fluid balance induced by Pseudomonas bacteremia using an isolated, innervated, and autoperfused canine small intestinal segment. Intravenous infusion of gelatin-coated particles was used to induce fibronectin deficiency and RE blockade. Lymph flow and lymph/plasma (L/P) protein concentration ratios were stable following intravenous challenge with bacteria or gelatin-coated particles. In contrast, lymph flow increased and L/P ratio decreased significantly when bacteremia coexisted with particle-induced opsonic fibronectin deficiency and RE blockade. This elevation in lymph flow and decline in L/P ratio was associated with normal vascular permeability to albumin, IgG, and IgM. The increase in intestinal fluid flux during bacteremia with RE blockade appears to be due to an increase in microvascular hydrostatic pressure and not to an increase in vascular permeability. These findings emphasize a potentially important role for fibronectin and associated RE system function as determinants of fluid filtration during sepsis.


Dual-targeting GroEL/ES chaperonin and protein tyrosine phosphatase B (PtpB) inhibitors: A polypharmacology strategy for treating Mycobacterium tuberculosis infections.
Current treatments for Mycobacterium tuberculosis infections require long and complicated regimens that can lead to patient non-compliance, increasing incidences of antibiotic-resistant strains, and lack of efficacy against latent stages of disease. Thus, new therapeutics are needed to improve tuberculosis standard of care. One strategy is to target protein homeostasis pathways by inhibiting molecular chaperones such as GroEL/ES (HSP60/10) chaperonin systems. M. tuberculosis has two GroEL homologs: GroEL1 is not essential but is important for cytokine-dependent granuloma formation, while GroEL2 is essential for survival and likely functions as the canonical housekeeping chaperonin for folding proteins. Another strategy is to target the protein tyrosine phosphatase B (PtpB) virulence factor that M. tuberculosis secretes into host cells to help evade immune responses. In the present study, we have identified a series of GroEL/ES inhibitors that inhibit M. tuberculosis growth in liquid culture and biochemical function of PtpB in vitro. With further optimization, such dual-targeting GroEL/ES and PtpB inhibitors could be effective against all stages of tuberculosis - actively replicating bacteria, bacteria evading host cell immune responses, and granuloma formation in latent disease - which would be a significant advance to augment current therapeutics that primarily target actively replicating bacteria.


Racial disparities in metabolism, central obesity, and sex hormone-binding globulin in postmenopausal women.
Increased total and intraabdominal fat (IAF) obesity as well as other metabolic conditions associated with the insulin resistance syndrome (IRS) are related to low levels of sex hormone-binding globulin (SHBG) in young and older Caucasian (CAU) and young African-American (AA) women. We examined whether postmenopausal AA women, a population with a high incidence of obesity and IRS despite low IAF, would have higher levels of circulating SHBG compared with CAU women, and whether there would be negative relationships between indexes of obesity and risk factors associated with IRS and SHBG levels. We measured body composition, SHBG, free testosterone, leptin, glucose tolerance, insulin, and lipoprotein lipids in 55 CAU (mean +/- SD, 59 +/- 7 yr) and 35 AA (57 +/- 6 yr) sedentary women of comparable obesity (48% body fat, by dual energy x-ray absorptiometry). Compared with CAU women, AA women had larger waist (101 vs. 96 cm), larger fat mass (44.9 +/- 8.8 vs. 39.9 +/- 8.1 kg), larger sc fat area (552 +/- 109 vs. 452 +/- 109 cm(2)), and lower IAF/SC ratio (0.28 +/- 0.12 vs. 0.38 +/- 0.15; P < 0.01), but similar waist to hip ratio (0.83). Both groups had similar SHBG (117 vs. 124 nmol/L) and free testosterone (3.7 vs. 3.4 pmol/L) levels, but AA women had a 35% higher leptin, 34% higher fasting insulin, and 39% greater insulin response to a glucose load (P < 0.05) compared with CAU women. In CAU, but not AA, women SHBG correlated negatively with body mass index (r = -0.28; P < 0.05), waist (r = -0.36; P = 0.01), IAF (r = -0.34; P = 0.01), and insulin response to oral glucose (r = -0.37; P < 0.05) and positively with high density lipoprotein cholesterol (r = 0.30; P = 0.03). The relationship between insulin area and SHBG in CAU women disappeared after adjusting for IAF, whereas the relationship between high density lipoprotein cholesterol and SHBG persisted after adjusting for IAF, but not for fat mass. Leptin was positively related to fat mass (P < 0.05) in both groups, but it was related to insulin only in the Caucasian women (P< 0.01). There was a racial difference in the slopes (P< 0.05) of the relationships of leptin to fat mass (P < 0.05). Racial differences in leptin disappeared after adjustment for fasting insulin. These results suggest that the metabolic relationships between total and regional obesity, glucose, and lipid metabolism with SHBG in CAU women are different from those in postmenopausal obese AA women.


Cortical release signs in psychiatry.
To review the role of cortical release signs (CRS) in neuropsychiatry. A thorough literature review was conducted using Medline and Psychlit databases, and other relevant references available to the authors. A number of neurological abnormalities are reported at elevated rates in neuropsychiatric conditions. CRS are a group of primitive reflexes that are present in the neonate but become inhibited as the infant central nervous system (CNS) develops, only to later re-emerge in the context of CNS disease. The clinical elicitation and interpretation of each CRS is described with reference to its neurobiology. The prevalence of CRS in schizophrenia, affective disorder, obsessive-compulsive disorder, Alzheimer's disease, vascular dementia, frontotemporal dementia and other neuropsychiatric illness allows for their use in the clinical management of these patients, including diagnostic assessment, treatment monitoring and prognosis. A number of issues complicate their interpretation in neuropsychiatric illness, including the apparent high base rate of some CRS in non-clinical populations, their increasing prevalence with age, lack of specificity and uncertainty over what constitutes an 'abnormal' response. In some circumstances, CRS may assist in diagnostic differentiation and illness staging.


Inhibition of nuclear-protein phosphorylation in vitro by beryllium.
Endogenous cyclic-nucleotide-independent protein phosphorylation by ATP at pH 6.5 in adult rat liver nuclei in vitro is inhibited by beryllium (Be2+), but under the same conditions nuclear-protein dephosphorylation appears to be insensitive to Be2+. Prior incubation of nuclei with Be2+ is necessary to demonstrate the inhibition of phosphorylation, which increases as the pH is decreased from pH 8.0 to 6.5. The extent of inhibition can be related to the level of nuclear Be2+ binding and, evidence suggests, may be caused by direct or indirect interference by Be2+ with Mg2+ binding sites normally required to facilitate protein phosphorylation.


Under-diagnosed psychiatric syndrome. II: Pathologic skin picking.
Pathologic skin picking (PSP), previously known as neurotic excoriation, is characterised by habitual and repetitive self-excoriation of skin. Affecting mainly women with onset in the 20s and 30s, it can lead to significant distress, dysfunction and disfigurement. The extent and degree of self-excoriation is reported to be proportional to the distortion of the underlying personality. Because of the close similarity to obsessive compulsive disorder in phenomenology and pharmacological response to the serotonin re-uptake inhibitor (e.g. clomipramine, fluoxetine and sertraline), PSP has been considered as an obsessive compulsive spectrum disorder.


A dynamic model of gene expression in monocytes reveals differences in immediate/early response genes between adult and neonatal cells.
Neonatal monocytes display immaturity of numerous functions compared with adult cells. Gene expression arrays provide a promising tool for elucidating mechanisms underlying neonatal immune function. We used a well-established microarray to analyze differences between LPS-stimulated human cord blood and adult monocytes to create dynamic models for interactions to elucidate observed deficiencies in neonatal immune responses. We identified 168 genes that were differentially expressed between adult and cord monocytes after 45 min incubation with LPS. Of these genes, 95% (159 of 167) were over-expressed in adult relative to cord monocytes. Differentially expressed genes could be sorted into nine groups according to their kinetics of activation. Functional modelling suggested differences between adult and cord blood in the regulation of apoptosis, a finding confirmed using annexin binding assays. We conclude that kinetic studies of gene expression reveal potentially important differences in gene expression dynamics that may provide insight into neonatal innate immunity.


Dynamic role of the codon 72 p53 single-nucleotide polymorphism in mammary tumorigenesis in a humanized mouse model.
Female breast cancer (BrCa) is the most common noncutaneous cancer among women in the United States. Human epidemiological studies reveal that a p53 single-nucleotide polymorphism (SNP) at codon 72, encoding proline (P72) or arginine (R72), is associated with differential risk of several cancers, including BrCa. However, the molecular mechanisms by which these variants affect mammary tumorigenesis remain unresolved. To investigate the effects of this polymorphism on susceptibility to mammary cancer, we used a humanized p53 mouse model, homozygous for either P72 or R72. Our studies revealed that R72 mice had a significantly higher mammary tumor incidence and reduced latency in both DMBA-induced and MMTV-Erbb2/Neu mouse mammary tumor models compared to P72 mice. Analyses showed that susceptible mammary glands from E-R72 (R72 x MMTV-Erbb2/Neu) mice developed a senescence-associated secretory phenotype (SASP) with influx of proinflammatory macrophages, ultimately resulting in chronic, protumorigenic inflammation. Mammary tumors arising in E-R72 mice also had an increased influx of tumor-associated macrophages, contributing to angiogenesis and elevated tumor growth rates. These results demonstrate that the p53 R72 variant increased susceptibility to mammary tumorigenesis through chronic inflammation.


[Na]i modulates isoproterenol's effect on Ca permeability in cultured heart cells.
Isoproterenol (ISO) augments the slow inward Ca current in cardiac muscle cells. We examined the role of intracellular Na (Nai) on ISO-mediated alterations in Ca uptake in cultured chick heart cells. In 140 mM Na medium, 1 microM ISO did not measurably alter 45Ca uptake. When cells were first preincubated in Na-free medium for 5 min and then incubated in control medium with 45Ca, ISO increased 45Ca uptake by 30%. Nifedipine (10 microM), verapamil (1 microM), or dl-propranolol (1 microM) abolished the effect of ISO on 45Ca uptake. CGP 28392 (1 microM), a Ca channel agonist, increased Ca influx in a manner that was augmented by decreased Nai, similar to the ISO response. Neither ISO nor CGP 28392 altered 45Ca uptake when cells preincubated in Na-free medium were further incubated in Na-free medium containing 45Ca. Exposure of cells to Na-free medium or 25 mM K+ medium caused depolarization of the resting membrane potential to approximately -40 mV. In the absence of ISO, the 45Ca uptake in cells preincubated in Na-free or 25 mM extracellular K (Ko) medium was significantly greater than in cells preincubated in control medium. This appeared to be due partly to increased 45Ca uptake via nifedipine-sensitive pathways. These findings support the hypothesis that reduction in Nai concentration ([Na]i) enhances the ISO-induced augmentation of Ca uptake via nifedipine-sensitive pathways (presumably via slow Ca channels), probably by a direct effect on the channels.


17Beta-estradiol promotes aggressive laryngeal cancer through membrane-associated estrogen receptor-alpha 36.
17β-estradiol (E2) plays a key role in tumorigenesis by enhancing cell survivability and metastasis through its cytoplasmic receptors. Recently, a variant of estrogen receptor alpha, ERα36 has been implicated as a substantial mediator of E2's proliferative and antiapoptotic effects through rapid membrane-associated signaling, and cancers previously regarded as hormone-independent due to the absence of traditional receptors, may in fact be susceptible to E2. Despite rising from a secondary sex organ and having a clear gender disposition, laryngeal cancer is not uniformly accepted as hormone dependent, even in the face of compelling evidence of E2 responsiveness. The aim of this study was to further elucidate the role of E2 in the tumorigenesis of laryngeal cancer, both in vitro and in vivo. ERα36 presence was evaluated in membranes of the laryngeal carcinoma cell line, Hep2, as well as in laryngeal tumor samples. In vitro ERα36 was found to mediate rapid activation of protein kinase C and phospholipase D by E2, leading to increased proliferation and protection against chemotherapy-induced apoptosis. Furthermore, in response to E2 activation of ERα36, an upregulation of angiogenic and metastatic factors was observed. Clinical analysis of laryngeal tumors revealed a similar association between the amount of ERα36 and VEGF and indicated a role in lymph node metastasis. These findings present compelling evidence of ERα36-dependent E2 signaling in laryngeal cancer. Thus, targeting ERα36 may reduce the deleterious effects of E2 in laryngeal cancer, ultimately suggesting the importance of antiestrogen therapy or the production of novel drugs that specifically target ERα36.


[Determination of the quantitative composition of fecal microflora].
Shifts in the quantitative composition of fecal microflora may be assessed by estimating the summary share (in per cent) of the bacterial groups associated with fecal microbiocenosis, this share being estimated by the nonparametric statistics methods. The ratio between potentially dominating and concomitant groups of microorganisms in fecal microbiocenosis helps estimate the severity of disorders in the quantitative composition of fecal microflora.