Spectroscopic analysis of [Trp3]-beta-casomorphin analogs. Comparative structure conformation-activity studies.
A series of [3-tryptophan]-beta-casomorphin-5([Trp3]-beta-CM-5) analogs were investigated by circular dichroism (CD) and fluorescence spectroscopy to explore their structure-conformation properties in solution. In addition, the comparative opioid activities of these compounds were evaluated using the in vitro guinea pig ileum (GPI) and mouse vas deferens (MVD) assays. Specifically, the pentapeptide sequence of [Trp3]-beta-CM-5, H-Tyr-Pro-Trp-Pro-Gly-OH (I) was modified at Pro-2 and Pro-4 by D-Pro substitutions to provide two diastereometric analogs, [Trp3-D-Pro-4]-beta-CM-5 (II) and [D-Pro2,4,Trp3]-beta-CM-5 (III). In the GPI and MVD assays, beta-CM-5 effected IC50 values of 1.3 microM and 8.9 microM, respectively, which confirmed its known mu/delta-selectivity on these two peripheral opioid receptor subtypes. The potencies of compounds I, II, and III were 0.2, 2.0, and less than 0.005 relative to beta-CM-5 on the GPI assay. Compounds I and II exhibited pronounced mu/delta-selectivities (greater than 18.9- and 12.4-fold respectively), whereas compound III was essentially inactive in both the GPI and MVD assays. CD studies of beta-CM-5 and its [Trp3]-beta-CM-5 analogs showed striking differences in their near-UV and far-UV spectra in aqueous or organic solvents. In the far UV CD spectra, weak (20%) alpha-helicity (maximum at 193 nm and minima at 208 and 222 nm) for beta-CM-5 was obtained in trifluoroethanol (TFE); however, none of the [Trp3]-beta-CM-5 analogs showed such CD bands. Of potential relevance to gamma-turn or C7 secondary structure was the observation of a strong negative band at 245 nm for compounds II and III which was not solvent-dependent in H2O or TFE, whereas compound I showed this CD band exclusively in TFE. In the near-UV CD at 275 nm (Trp electronic transition), the relative order of intensities of this band were determined for the [Trp3]-beta-CM-5 compounds to be II greater than I greater than III, which was identical to their relative biological potencies in both the GPI and MVD assays. Fluorescence energy transfer (FET) experiments of compounds I-III provided the intramolecular distances (r) between their Tyr (donor) to Trp (acceptor) side-chains, by the Förster method, and were as follows: [Trp3]-beta-CM-5, r = 10.6 A; [Trp3, D-Pro4]-beta-CM-5, r = 9.6 A; and [D-Pro2,4,Trp3]-beta-CM-5, r = 11.0 A.(ABSTRACT TRUNCATED AT 400 WORDS)


On one approach to health protection: Music of the brain.
This review presents the current status of a method for prevention and timely correction of human functional disturbances that was first proposed by Russian neurologist Ya.I. Levin in 1998 and further developed by the authors. The approach is named "Music of the Brain" and is based on musical or music-like stimulation organized in strict accordance with the biopotentials of a patient's brain. Initial studies on the music of the brain approach were analyzed, and its limitations were noted. To enhance the efficiency and usability of the approach, several combinations of music therapy with neurofeedback technique - musical neurofeedback - were developed. Enhanced efficiency of the approach has been shown for correction of functional disturbances during pregnancy and for elimination of stress-induced states in high technology specialists. The use and advantages of musical neurofeedback technology for increasing human cognitive activity, correcting sleep disturbances and treatment of disorders of attention were verified. After further development and testing the approach may be suited for a wide range of therapeutic and rehabilitation procedures in the protection of public health.


Cervical facet dislocation: techniques for ventral reduction and stabilization.
To demonstrate the safety and utility of one surgical approach, the authors reviewed their experience with the ventral surgical approach for decompression, reduction, and stabilization in 10 patients with either unilateral or bilateral cervical facet dislocation. Six patients presented with unilateral cervical facet dislocation and four patients with bilateral cervical facet dislocation. There were six male and four female patients who ranged in age from 17 to 72 years (average 37.1 years). The level of facet dislocation was C4-5 in one, C5-6 in four, and C6-7 in five patients. Three patients presented with a complete spinal cord injury (SCI), three patients with an incomplete SCI, three with radicular symptoms or myeloradiculopathy, and one patient was neurologically intact. All patients underwent plain radiography, magnetic resonance imaging, and computerized tomography evaluation of the cervical spine. All patients had sustained significant ligamentous injury with minimum or no bone disruption. All patients underwent ventral decompressive surgery, reduction of the dislocation, and stabilization of the cervical spine. Techniques for performing ventral reduction of unilateral or bilateral cervical facet dislocation are described. Decompression, reduction, and stabilization of the cervical spine via the ventral approach was accomplished in all but one patient. This patient underwent a ventral decompressive procedure and an attempt at ventral reduction and subsequent dorsal reduction and fusion in which a lateral mass screw plate fixation system was used; this was followed by ventral placement of instrumentation and fusion. There were no surgery-related complications. Postoperative neurological status was unchanged in four patients and improved in six patients. No patient experienced neurological deterioration after undergoing this surgical approach. The authors conclude that a ventral surgical decompression, reduction, and stabilization procedure provides a safe and effective alternative for the treatment of patients with unilateral or bilateral cervical facet dislocation without significant bone disruption.


Adaptability and evolution.
The capacity of organisms to respond in their own lifetimes to new challenges in their environments probably appeared early in biological evolution. At present few studies have shown how such adaptability could influence the inherited characteristics of an organism's descendants. In part, this has been because organisms have been treated as passive in evolution. Nevertheless, their effects on biological evolution are likely to have been important and, when they occurred, accelerated the pace of evolution. Ways in which this might have happened have been suggested many times since the 1870s. I review these proposals and discuss their relevance to modern thought.


Transcription of alpha-specific genes in Saccharomyces cerevisiae: DNA sequence requirements for activity of the coregulator alpha 1.
Transcription activation of alpha-specific genes in Saccharomyces cerevisiae is regulated by two proteins, MCM1 and alpha 1, which bind to DNA sequences, called P'Q elements, found upstream of alpha-specific genes. Neither MCM1 nor alpha 1 alone binds efficiently to P'Q elements. Together, however, they bind cooperatively in a manner that requires both the P' sequence, which is a weak binding site for MCM1, and the Q sequence, which has been postulated to be the binding site for alpha 1. We analyzed a collection of point mutations in the P'Q element of the STE3 gene to determine the importance of individual base pairs for alpha-specific gene transcription. Within the 10-bp conserved Q sequence, mutations at only three positions strongly affected transcription activation in vivo. These same mutations did not affect the weak binding to P'Q displayed by MCM1 alone. In vitro DNA binding assays showed a direct correlation between the ability of the mutant sequences to form ternary P'Q-MCM1-alpha 1 complexes and the degree to which transcription was activated in vivo. Thus, the ability of alpha 1 and MCM1 to bind cooperatively to P'Q elements is critical for activation of alpha-specific genes. In all natural alpha-specific genes the Q sequence is adjacent to the degenerate side of P'. To test the significance of this geometry, we created several novel juxtapositions of P, P', and Q sequences. When the Q sequence was opposite the degenerate side, the composite QP' element was inactive as a promoter element in vivo and unable to form stable ternary QP'-MCM1-alpha 1 complexes in vitro. We also found that addition of a Q sequence to a strong MCM1 binding site allows the addition of alpha 1 to the complex. This finding, together with the observation that Q-element point mutations affected ternary complex formation but not the weak binding of MCM1 alone, supports the idea that the Q sequence serves as a binding site for alpha 1.


Self-reinnervated cat medial gastrocnemius muscles. I. comparisons of the capacity for regenerating nerves to form enlarged motor units after extensive peripheral nerve injuries.
1. The aims of this study are to determine 1) whether regenerating motor axons have the capacity to form enlarged motor units (MUs) in muscles reinnervated by few motoneurons and 2) whether the type of nerve injury, repair, and/or growth environment affects this capacity. 2. MU innervation ratio (IR) was estimated by measuring isometric unit tetanic force in reinnervated cat medial gastrocnemius muscles 3-16 mo after denervation by either 1) crushing its nerve, 2) transecting the nerve and suturing the proximal end to the distal stump (N-N suture), or 3) transecting the nerve and suturing the proximal end directly to the muscle fascia (N-M suture). In addition, the number of regenerating axons was experimentally reduced by cutting one of two contributing ventral roots. 3. Muscles were reinnervated by 2-88% of their normal complement of MUs. Mean unit tetanic force increased as the number of reinnervated MUs decreased in reinnervated muscles after nerve crush or N-N suture, but not after N-M suture, even when few axons made functional connections. When the number of MUs was < 20% of normal, mean unit force was significantly higher in reinnervated muscles after nerve crush compared with muscle reinnervated after N-N suture. 4. The cross-sectional areas (CSAs) of all muscle fiber types were similar to normal in reinnervated muscles after nerve crush, but the CSAs of type IIa and IIb fibers were significantly smaller in muscles reinnervated after complete nerve transections (i.e., N-N or N-M sutures). 5. When MU force was normalized to mean muscle fiber CSA, cut motor axons displayed the same capacity to form enlarged MUs as crushed motor axons. The force of the MUs increased by as much as 5-8 times that of normal, provided the axons grew along the distal nerve stump (N-N suture). 6. Tetanic force increased in the normal order slow < fast-fatigue resistant < fast-fatigue intermediate = fast-fatigable. However, the increase in tetanic force of the slow (S) units was significantly larger than the corresponding increase of the more forceful fast (F) units. The disproportional increase in S and not F unit force, was primarily due to a significant decline in CSA of the type IIa and IIb muscle fibers. 7. The technique of glycogen depletion was used to count MU fibers to estimate the IR of MUs in 5 normal and 11 reinnervated muscles (7 N-N sutures, 4 N-M sutures). Unit tetanic force covaried with IR in both normal and reinnervated muscles. 8. These results show that regenerating axons have the same capacity as intact axons in partially denervated muscles to form enlarged MUs to compensate for a reduced number of functioning MUs. Only when axons regenerate in the absence of the distal nerve sheath is this capacity compromised.


Intestinal dermoid cyst in a German shepherd dog.
A two-year-old male German shepherd dog was admitted to Shahid Bahonar Veterinary Hospital with clinical signs that included lethargy, anorexia, vomiting, abdominal pain and dehydration. Physical examination revealed nothing significant. Routine paraclinical tests only revealed a stress leukogram. Radiography revealed a mass in the stomach. Whilst performing a laparotomy, the surgeon observed an unusual mass in the subserosal layer of the proximal part of the jejunum. The histopathology of the mass revealed some scattered sebaceous and sweat glands associated with the cyst wall that confirmed the diagnosis of a dermoid cyst. Intestinal dermoid cysts are very rare and to our knowledge this is the first report of an intestinal dermoid cyst in a dog.


Effect of Microfibrillated Cellulose on Microstructure and Properties of Poly(vinyl alcohol) Foams.
Poly(vinyl alcohol) foams, containing different amounts of microfibrillated cellulose, were prepared through an eco-friendly procedure based on high-speed mixing and freeze-drying. The effect of filler amount on cell shape and regularity was studied by scanning electron microscopy (SEM) and the evolution of the microstructure was assessed through dynamic cryo-SEM. Fourier Transformed Infrared Analysis and Differential Scanning Calorimetry measurements revealed the presence of hydrogen bond interaction among cellulosic filler and the matrix. The modulus and compression deflection of neat PVA were significantly improved by increasing the amount of microfibrillated cellulose content with respect to foams realised with pulp cellulose fibers.


Suppression of translation frameshift by upstream termination codon.
Retroviruses employ translation frameshift for gene expression. Translation frameshift takes place at the slippery heptanucleotide sequence on mRNA. A downstream stem-loop structure (and a pseudoknot formed by the stem-loop) enhances the level of ribosomal frameshifting. Here, we describe that an upstream termination codon suppresses the ribosomal frameshifting, leading to reduction in the expression of downstream genes.


Anti-Diabetic Potential of Ocimum gratissimum Leaf Fractions in Fortified Diet-Fed Streptozotocin Treated Rat Model of Type-2 Diabetes.
Background: Ocimum gratissimum (OG) is used in the traditional management of diabetes in Nigeria. This study investigated the anti-diabetic potential of OG leaf fractions (OGLF) in a rat model of Type-2 diabetes (T2D). Method: Methanol crude extract of OG leaf was fractionated with solvents of increasing order of polarity (n-hexane, chloroform, ethyl-acetate, n-butanol and water). The anti-diabetic potential of the fractions was evaluated in vivo. T2D was induced in Albino Wistar rats and treated with OGLF. Result: The T2D rats showed significant elevation in serum levels of fasting blood glucose (FBG), liver and kidney function biomarkers. At 4-weeks of intervention with OGLF, the untreated diabetic control group maintained severe hyperglycaemia in the presence of 61.7% serum insulin, 17.3% pancreatic β-cell function (HOMA-β) and 51.5% Insulin sensitivity. The glucose tolerance ability was enhanced in the n-butanol-fraction (OGb) treated group. With 74.8% available serum insulin and 38.6% improvement in insulin sensitivity, the OGb treated group had a 63.5% reduction in FBG and it was found to be most effective as it ameliorates a majority of the changes caused in the studied parameters in diabetic rats. Conclusions: The data from this study suggest that OGb fraction is a potential candidate for the development of an effective drug for the management of T2D.


Magnitude and factors associated with intimate partner violence against pregnant women in Ethiopia: a multilevel analysis of 2016 Ethiopian demographic and health survey.
Intimate partner violence (IPV) is defined as acts of physical aggression, sexual coercion, psychological/emotional abuse, or controlling behaviors by a current or former partner or spouse. IPV has a special concern for pregnant women since it leads to higher rates of miscarriage, several complications including adverse birth outcomes. So far, the effect of contextual factors on IPV was largely overlooked. Therefore, this study aimed to assess the magnitude and factors associated with IPV among pregnant women in Ethiopia. Data from the 2016 Ethiopian Demographic and Health Survey was used for this study. A total of 4167 (weighted sample) pregnant women were included in the analysis. The multi-level logistic regression model was fitted to identify factors associated with IPV. Finally, the adjusted odds ratio (AOR) with 95% CI and random effects for the multilevel logistic regression model was reported. In this study, the overall magnitude of IPV among pregnant women was 28.74 (95% CI 27.38, 30.13) with emotional violence being the most common (24.09%) type. In the multi-level analysis, women with no education (AOR = 2.07; 95%CI 1.23, 3.48), primary education (AOR = 2.04; 95%CI:1.24, 3.38), and secondary education (AOR = 1.53; 95%CI:126.96.36.199), women from households with poorest (AOR = 1.72; 95%CI: 1.16, 2.56), poorer (AOR = 1.62;95% CI:1.09, 2.41), middle (AOR = 1.74;95%CI:1.17, 2.56), and richer (AOR = 1.58;95%CI: 1.08, 2.33) wealth index, women aged 35-39 years (AOR = 1.28;95%CI:1.01, 1.63) and 40-49 years (AOR = 1.78;95%CI:1.28, 2.45) and those from pastoral (AOR = 1.47;95%CI:1.04, 1.93) and agrarian regions (AOR = 1.32;95%CI 1.02, 1.88) had a higher likelihood of having IPV. Of the partner-related factors, women with husbands who drink alcohol (AOR = 2.94; 95%CI: 2.36, 3.42) and secondary educational level (AOR = 1.47; 95%CI 1.02, 2.12) had higher odds of experiencing IPV during pregnancy. Intimate partner violence during pregnancy is a public health problem in Ethiopia. Therefore, improving the educational status of women and their husbands, improving the economic capacity of women, and promoting the healthy behavior of husbands by reducing the alcohol consumption in those agrarian and pastoral regions of Ethiopia is vital to reduce the magnitude of IPV.


The emerging role of 5-ALA-PDT in dermatology: is PDT superior to standard treatments?
Several open studies report the efficacy of topical photodynamic therapy (PDT) in the treatment of non-melanoma skin cancer and pre-cursor lesions. For a new therapy to change clinical practice, comparison studies with standard therapies are required, assessing efficacy, adverse events and cosmetic outcome. This review considers the evidence for using topical PDT over standard therapies in non-melanoma skin cancer. Limited data indicates topical PDT to be superior to cryotherapy and equivalent to topical 5-fluorouracil in clearing non-hyperkeratotic actinic keratoses, and to achieve a superior cosmetic outcome. Topical PDT is superior to topical 5-fluorouracil, and equivalent to cryotherapy, in the treatment of squamous cell carcinoma in situ (Bowen's disease), again with fewer adverse reactions. Similarly, PDT is as effective as cryotherapy for basal cell carcinoma, but with superior healing and cosmesis. PDT may be particularly advantageous for large and/or multiple lesions and for those in sites where disfigurement or poor healing from conventional therapies is a particular risk. There remains a lack of comparison data concerning routine surgery, curettage, and radiotherapy, but topical PDT would appear as effective as, and in certain aspects superior to, standard therapies in the treatment of non-melanoma skin cancer.


[A toxicological study on ammonium oxofluoromolybdate [(NH4)2MoO2F4]].
(NH4)2MoO2F4 is a new effective anticarious agent. In order to ensure the safety in clinical application of (NH4)2MoO2F4, six toxicity tests were conducted. Results indicated that: (1) The LD50 was 203. 6 mg/kg after oral administration, which showed that the toxicity of (NH4)2MoO2F4 wasn't higher than that of silver ammounium fluoride which was used routinely. (2) After 90 days of oral administration, no toxicity reaction was found in the lowest dosage group (25 mg/kg), but gastric mucosa was found to have slight injury in the highest dosage group (100 mg/kg), which was conformable to the result of the cumulative toxicity test. (3) Injuries of mucosa, allergic reactions and pulp damages were not observed when (NH4)2MoO2F4 contacted with mucosa, skin and surface of dental crown. Therefore, clinical application of (NH4)2MoO2F4 is safe while using it in the stipulated dosage.


Kinetic mechanism of Tritrichomonas foetus inosine 5'-monophosphate dehydrogenase.
IMP dehydrogenase (IMPDH) catalyzes the oxidation of IMP to XMP with conversion of NAD+ to NADH. This reaction is the rate-limiting step in de novo guanine nucleotide biosynthesis. IMPDH is a target for antitumor, antiviral, and immunosuppressive chemotherapy. We have determined the complete kinetic mechanism for IMPDH from Tritrichomonas foetus using ligand binding, isotope effect, pre-steady-state kinetic, and rapid quench kinetic experiments. Both substrates bind to the free enzyme, which suggests a random mechanism. IMP binds to the enzyme in two steps. Two steps are also involved when IMP binds to a mutant IMPDH in which the active site Cys is substituted with a Ser. This observation suggests that this second step may be a conformational change of the enzyme. No Vm isotope effect is observed when [2-2H]IMP is the substrate which indicates that hydride transfer is not rate-limiting. This result is confirmed by the observation of a pre-steady-state burst of NADH production when monitored by absorbance. However, when NADH production was monitored by fluorescence, the rate constant for the exponential phase is 5-10-fold lower than when measured by absorbance. This observation suggests that the fluorescence of enzyme-bound NADH is quenched and that this transient represents NADH release from the enzyme. The time-dependent formation and decay of [14C]E-XMP intermediates was monitored using rapid quench kinetics. These experiments indicate that both NADH release and E-XMP hydrolysis are rate-limiting and suggest that NADH release precedes hydrolysis of E-XMP.


Uptake of 1-methyl-4-phenylpyridinium ion (MPP+) and ATP content in synaptosomes.
Symptoms such as those in Parkinson's disease are known to be induced by the neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). We tried to quantitatively measure synaptosomal MPP+ uptake using an MPP+ selective electrode to study the correlation between MPP+ uptake and respiratory inhibition. Synaptosomal MPP+ uptake was low but could be increased by the addition of glucose as an energy substrate, or increased with an increase in the concentration of MPP+. The rate of uptake was 0.2 nmol/mg protein/min at 50 microM MPP+. Tetraphenylboron (TPB+), which enhances cation permeability, increased MPP+ uptake, and the increase was proportional to the TPB+ concentration. When external MPP+ concentration was increased above 200 microM, ATP was depleted and the uptake of MPP+ decreased, which resulted in the release of intrasynaptosomal MPP+. MPP+ uptake was also decreased by depolarization of the membrane potential in synaptosomes. MPP+ was presumed to be distributed across both the synaptosomal and inner mitochondrial membranes, and to be affected by membrane potential as a lipophilic cation. When respiration of the inner mitochondria was inhibited by increasing the intrasynaptosomal MPP+ concentration, the concentration of MPP+ in cytosol was presumed to increase by the release of MPP+ from the mitochondria, and synaptosomal MPP+ uptake would then be decreased.


The influence of the leaf gauge and anterior jig on jaw muscle electromyography and condylar head displacement: a pilot study.
A leaf gauge and an anterior jig may be used to assist the recording of a reproducible jaw position for restorative and prosthodontic treatment. This study investigated possible condylar displacement using an opto-electronic jaw-tracking device and a leaf gauge or anterior jig. The effect of a leaf gauge and anterior jig on jaw muscle electromyography was also examined. Five healthy adults without symptoms of temporomandibular disorders were selected. Condylar displacement during clenching were recorded simultaneously with electromyographic activity of superior and inferior heads of the lateral pterygoid, anterior and posterior temporalis, masseter, and suprahyoid muscles. Subjects were trained to bite at maximum and half-maximum bite-force using an anterior jig incorporating a force transducer. No consistent condylar displacement was observed in x, y and z axes between different bite-forces although there was a trend towards superior displacement. Comparison of maximum intercuspal clench and maximum clench on a leaf gauge and an anterior jig produced significant decrease in anterior temporalis activity (p < 0.05), whilst an anterior jig with maximum clench significantly decreased posterior temporalis muscle activity. Within the limits of this pilot study, no consistent change in condylar position was identified with these appliances.


[Interregional migration and net migration: comments on the Italian case].
"After having examined the relations between the partial net migration and the corresponding total net migration, an attempt is made to identify some indicators...of inter-regional mobility, considering the size of the total net migration in relation to all the net migrations with other territorial units. Attention is particularly focused on two indicators: the index of net regional migratory interchange, and the index of net total migratory interchange...." Data are for regions in Italy during the period 1955-1989. (SUMMARY IN ENG AND FRE)


Catalytic Reductive Alkylation of Amines in Batch and Microflow Conditions Using a Silicon-Wafer-Based Palladium Nanocatalyst.
We describe the development of the catalytic reductive alkylation of amines with aldehydes under the atmospheric pressure of H2 using a brush-like silicon-nanostructure-supported palladium nanoparticle composite (SiNS-Pd) as a silicon-wafer-based reusable heterogeneous catalyst. The present reaction of primary and secondary amines with various aliphatic and aromatic aldehydes in the presence of the catalyst (0.02-0.05 mol % Pd) gave the corresponding secondary and tertiary amines including Lomerizine and Aticaprant in a 68% quantitative yield without overalkylation. We also designed and fabricated a flow device equipped with SiNS-Pd for microflow reactions, which was applied to the gas-liquid-solid triphasic reaction system (i.e., H2 gas, a substrate solution, and a solid catalyst). A multigram-scale reaction of aniline and benzaldehyde was demonstrated to obtain N-benzylaniline (ca. 4 g/day), in which the internal volume of the flow channel was 43 μL, the residence time was approximately 1 s, and the turnover number (TON) reached 4.0 × 104 in a continuous 24 h run (1.7 × 103 h-1; 0.50 s-1).


A novel P-type Cl(-)-stimulated ATPase: phosphorylation and specificity.
Utilizing a proteoliposomal preparation containing Cl(-)-ATPase, it was demonstrated that [gamma-32P]ATP-induced phosphorylation of this pump is by way of a relatively low binding affinity while protein dephosphorylation was accelerated by increasing concentrations of unlabeled ATP. Ca2+ and Mn2+ were also shown to stimulate phosphorylation of the enzyme, but to a much lesser extent than Mg2+. Orthovanadate inhibition of enzyme phosphorylation was directly related to its concentration. These results suggested that the Cl(-)-pump was a P-type ATPase similar to that found in plants and fungi based upon its low-affinity phosphorylation kinetics.


The oxygen uptake efficiency slope: what do we know?
To summarize what is currently known about the oxygen uptake efficiency slope (OUES) as an objective and independent submaximal measure of cardiorespiratory fitness in health and disease. A literature search was performed within the following electronic databases--PubMed, Cochrane Library, Embase, Web of Science, CINAHL, PsycINFO, Scopus, and MEDLINE--using the search terms "OUES," "oxygen uptake efficiency slope," and "ventilatory efficiency." The search identified 51 articles. Selection, evaluation, and data extraction were accomplished independently by 2 authors. Twenty-four studies satisfied all inclusion criteria: 17 cross-sectional studies and 7 intervention studies. The results indicated that the OUES is relatively independent of exercise intensity, correlates highly with other exercise parameters, appears to have discriminative value, and is sensitive to the effects of physical training in patients with cardiac disease. Oxygen uptake efficiency slope values are considerably influenced by anthropometric variables and show large interindividual variation. Oxygen uptake efficiency slope is an independent and reproducible measure of cardiorespiratory function that does not require maximal exercise. It greatly reduces test variability because of motivational and subjective factors and is reliable and easily determinable in all subjects. Although OUES appears not interchangeable with maximal parameters of cardiopulmonary function, it seems to be a useful submaximal alternative in subjects unable to perform maximal exercise.


Enhancement of the immune response to sheep erythrocytes in mice by phosphodiesterase-inhibiting dipyridamole derivatives.
Some potent phosphodiesterase (PDE)-inhibiting dipyridamole derivatives are able to increase the primary immune response in mice immunized with sheep red blood cells (SRBC). 10mg/kg/day of the most potent substance administered in the drinking water increased the number of plaque forming cells (PFC) in spleens of these mice by a factor of about 2 when the treatment was started after immunization. Pretreating the animals did not result in an enhancement of numbers of plaque forming cells. There was no increase in the background number of PFC.


Influence of a constant magnetic field on human lymphocyte cultures.
The growing exposure to magnetic fields of a certain intensity could represent a serious hazard for our health. In the present note we analyze the effect of a 740 Gauss magnetic field on human lymphocyte cell cultures. From the analysis of our data it is possible to point out that this field produces an inhibition of the cell growth, while does not affect at all the sister chromatid exchange frequency of the chromosomes. Conversely we found a significant increase of chromosome aberrations in the exposed cells. The chromosome aberrations found were mostly gaps and breaks.


To evaluate the status and need for dental prosthesis among the geriatric population of Central India reporting to the dental colleges.
The study aimed at evaluating the dental prosthetic status and its need among the geriatric population of Central India reporting to the dental colleges. A descriptive cross-sectional study was carried out to evaluate prosthetic status and needs among geriatric individuals in Wardha city, Maharashtra reporting to dental colleges. A detailed inspection of the oral cavity of the study subjects was done using Basic Oral Health Surveys, World Health Organization (WHO) 1997. A total of 110 individuals were evaluated for the study. A total of 26.36% study participants had some prosthesis at the time of examination, whereas 79.99% needed prosthesis. A total of 51.82% needed complete dentures. About 12.71% of the participants needed combination prosthesis. The result of this study concluded that the prosthetic status of the geriatric individuals in Wardha city (MH) of Central India is poor and needs prosthetic rehabilitation. A well-structured approach is required to fulfill these needs.


The ubiquitin-proteasome pathway is important for dengue virus infection in primary human endothelial cells.
Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) are the most severe forms of dengue virus infection with hemorrhage and plasma leakage. However, pathogenic mechanisms of DHF and DSS remain poorly understood. We therefore investigated host responses as determined by changes in the cellular proteome of primary human endothelial cells upon infection with dengue virus serotype 2 (DEN-2) at a multiplicity of infection (MOI) of 10 for 24 h. Two-dimensional PAGE and quantitative intensity analysis revealed 38 significantly altered protein spots (16 upregulated and 22 downregulated) in DEN-2-infected cells compared to mock controls. These altered proteins were successfully identified by mass spectrometry, including those involved in oxidative stress response, transcription and translation, cytoskeleton assembly, protein degradation, cell growth regulation, apoptosis, cellular metabolism, and antiviral response. The proteomic data were validated by Western blot analyses [upregulated ubiquitin-activating enzyme E1 (UBE1) and downregulated annexin A2] and an immunofluorescence study (upregulated MxA). Interestingly, we found that MxA was colocalized with DEN-2 viral capsid protein, strengthening its role as an antiviral protein. Moreover, we also identified upregulation of a proteasome subunit. Our functional study revealed the significant role of ubiquitination in dengue infection and UBE1 inhibition by its specific inhibitor (UBEI-41) caused a significant reduction in the level of viral protein synthesis and its infectivity. Our findings suggest that various biological processes were triggered in response to dengue infection, particularly antiviral IFN and ubiquitin-proteasome pathways.


Different Withering Times Affect Sensory Qualities, Chemical Components, and Nutritional Characteristics of Black Tea.
The present study emphasizes the effect of withering time set at 4 ± 0.5 h (WT4), 6 ± 0.5 h (WT6), 8 ± 0.5 h (WT8), 10 ± 0.5 h (WT10), and 12 ± 0.5 h (WT12) on the sensory qualities, chemical components, and nutritional characteristics of black tea. The sensory evaluation revealed high total quality scores at WT8 and WT10. Polysaccharides, amino acids, and soluble sugars significantly increased with an increase in withering time, and an apparent peak value was obtained at WT10. However, polyphenols, flavonoids, glycosides, organic acids, catechins, alkanoids, and theaflavins decreased with an increase in withering time. With an increase in withering time, the content of aromatic substances showed a trend of increasing first and then decreasing. The peaks of alcohols, aldehydes, and acids appeared at 10 ± 0.5 h, 10 ± 0.5 h, and 8 ± 0.5 h, respectively. The content of esters, ketones, and hydrocarbons showed a downward trend with an increase in withering time. Aroma analysis revealed that withering time could not exceed 10 ± 0.5 h. Black tea withered up to WT10 showed enhanced inhibition of α-glucosidase and α-amylase activity with good sensorial attributes. Glucose uptake inhibition capacity increased up 6 ± 0.5 h and then decreased, while antioxidant capacity decreased with an increase in withering time. The overall results show that the 8 ± 0.5 h to 10 ± 0.5 h withering time could improve black tea quality and nutritional characteristics.


Oral tolerance and allergic responses to food proteins.
The default response to protein antigens in the intestine is the induction of systemic and local hyporesponsiveness, ensuring the prevention of coeliac disease and food allergies. Interest is increasing in the role of dietary manipulation and probiotics in treating allergic and other diseases, but less is known about how these regimens might influence systemic and local immune responses. This paper addresses the mechanisms at the interface of innate and adaptive immunity that determine how the body responds to orally administered proteins and how local bacteria modify these. This paper discusses evidence that dendritic cells in the intestinal mucosa are the critical cells that take up dietary proteins and migrate to the draining mesenteric lymph node, where they induce regulatory CD4 T-cell differentiation. The properties of tolerized T cells are discussed and it is proposed that the gut microenvironment maintains homeostasis by conditioning dendritic cells to remain in a quiescent state. Inhibitory signalling by commensal bacteria possibly contributes to this process. A regulatory network controls how dietary antigens are taken up and presented to T lymphocytes by specialized antigen-presenting cells. Elucidating their nature and how they are influenced by external factors such as probiotics may help develop novel therapies for allergy and help understand diseases such as coeliac disease.


Captopril inhibits the hydroosmotic effect of ADH in the cortical collecting tubule.
Previous studies have shown that captopril (CP) inhibits ADH-stimulated osmotic water permeability (Pf) in the toad bladder by potentiating endogenous bradykinin (BK). The present studies examine the effect of CP on ADH-stimulated Pf in isolated, perfused rabbit cortical collecting tubules (CCT). CP (10(-4) M) reversibly inhibited Pf, stimulated by maximal concentrations of ADH (10 microU/ml). Pretreatment of CCT's with 5 microM indomethacin, however, abolished the effect of CP. Inhibition of BK production by the kallikrein inhibitors, aprotinin and benzamidine, failed to enhance Pf stimulated by submaximal concentrations of ADH (2.5 microU/ml). Since ADH exerts its effects by activation of adenylyl cyclase (AC), further experiments were performed to identify the site at which CP inhibits this cascade. CP significantly inhibited forskolin (10(-4) M) stimulated Pf; however, it had no effect on cyclic AMP (10(-5) M) stimulated Pf, suggesting that the site of action is on the catalytic subunit or one of the GTP regulatory proteins of AC. To further localize the site of CP's action, CCT's were pre-incubated with pertussis toxin (0.5 microgram/ml) to inactivate the inhibitory, guanosine triphosphate (GTP) regulatory protein, Gi. In these tubules, CP failed to inhibit the action of ADH. We conclude that CP stimulates prostaglandin production which in turn activates Gi and inhibits AC activity. We further suggest that CP stimulates PG's directly, not via BK.


The K-complex in thalamic depth recordings.
K-complexes were recorded from the thalamus in a patient having stereotaxic surgery for intractable stump pain. Two insertions were performed, one in the lateral and the other in the medial thalamus. It was found that, (1) very prominent K-complex activity was present at the depth electrode with relatively meager representation of these forms at the scalp; (2) the trailing spindle component of the K-complex was well displayed on the scalp, but the sharp and slow components were not readily visible in the scalp recordings, suggesting a multiple system response; (3) insertion into the lateral thalamus revealed much K-complex activity in contrast to the relatively little amount found with the insertion into the medial thalamus. These findings support earlier hypotheses of a subcortical origin, and specifically thalamic participation, in the K-complex formations.


Antibiotic prescribing for upper respiratory tract infections in sarawak district hospitals.
Upper respiratory tract infection (URTI) is mostly viral in aetiology, but patients presenting with such complaints are frequently prescribed antibiotics. This may result in increased development of antimicrobial resistance. The objectives of this study are to determine the choice and proportion of oral antibiotics prescribed in patients with URTI, in a Sarawak district hospital setting. All outpatient prescriptions received in July 2011 in 10 hospitals with relevant diagnoses were analysed. A total of 6747 URTI prescriptions met the inclusion criteria, and 64.8% (95% CI 63.7%, 65.9%) had antibiotic prescribed. Medical Assistants (MAs) were significantly more likely to prescribe antibiotics compared to Medical Officers (MOs) (p < 0.001). Prescribers were significantly influenced by the patient's age and specific diagnosis when prescribing antibiotics for URTI (p < 0.001). Antibiotic choices differed between MOs and MAs, where some of the antibiotic choices were inappropriate. There is a need for multi-faceted interventions to improve antibiotic prescribing rate and choice.


A Phase I Clinical Trial of CHT-25 a 131I-Labeled Chimeric Anti-CD25 Antibody Showing Efficacy in Patients with Refractory Lymphoma.
PURPOSE: There is a need for new treatments for Hodgkin and T-cell lymphoma due to the development of drug resistance in a proportion of patients. This phase I study of radioimmunotherapy used CHT-25, a chimeric antibody to the alpha-chain of the interleukin-2 receptor, CD25, conjugated to iodine-131 ((131)I) in patients with refractory CD25-positive lymphomas. EXPERIMENTAL DESIGN: Fifteen patients were treated (Hodgkin lymphoma, 12; angioimmunoblastic T-cell lymphoma, 1; adult T-cell leukemia/lymphoma, 2). Tumor was monitored by computed tomography and in all but two patients by (18)F-fluorodeoxyglucose positron emission tomography. RESULTS: There were no grade 3 or 4 infusion reactions. At the maximum tolerated dose of 1,200 MBq/m(2), the major side effect was delayed myelotoxicity with the nadir for platelets at 38 days and for neutrophils at 53 days. One patient treated with 2,960 MBq/m(2) developed prolonged grade 4 neutropenia and thrombocytopenia and died of Pneumocystis jiroveci pneumonia. Nonhematologic toxicity was mild. Single photon emission computer tomography imaging showed tumor-specific uptake and retention of (131)I and no excessive retention in normal organs. Of nine patients receiving >/=1,200 MBq/m(2), six responded (three complete response and three partial response); one of six patients with administered radioactivity of </=740 MBq/m(2) had a complete response. CONCLUSIONS: CHT-25 is well tolerated with 1,200 MBq/m(2) administered radioactivity and shows clinical activity in patients who are refractory to conventional therapies. Phase II studies are justified to determine efficacy and toxicity in a broader range of clinical scenarios. (Clin Cancer Res 2009;15(24):7701-10).


[Host factors influencing the clinical outcome of chronic hepatitis B virus infection].
The clinical outcomes of chronic HBV infection are influenced by the interaction between virus, host and environmental factors. Several factors of host include age, sex, individual behavior, host genetic polymorphism and intestinal microflora, directly or indirectly affect the clinical outcome of chronic HBV infection. Therefore, in the management of chronic HBV infection, more attention need to be paid not only to antiviral therapy, but also to the impact of host factors in order to maximally improve the prognosis of patients.


Preparation, purification and morphology of polymeric nanoparticles as drug carriers.
The aim of this work was to prepare biodegradable poly(D,L-lactic acid-co-glycolic acid) copolymer (PLAGA) nanoparticles by the solvent evaporation process and to incorporate an antifungal antibiotic, amphotericin B. Blank nanoparticles obtained were 130 +/- 27 nm in diameter. When amphotericin B was added in the organic phase, the final suspension showed two populations due to unbound drug. Free amphotericin B was removed by contacting the nanoparticle suspension with an adsorbent polymer. Amberlite XAD16, and subsequently ultrafiltering the medium. The drug payload was between 0.7 and 1.3%. To gain more insight in the cause of this low loading, we studied progesterone-loaded nanoparticles using PLAGA and polystyrene as models because progesterone and these polymers exhibit a degree of miscibility. In the case of polystyrene, nanoparticle drug content reached 8%.


[Differential therapeutic topics in antihypertensive therapy. What can angiotensin-converting enzyme inhibitors accomplish?].
The results of large epidemiological studies dealing with the prognosis and unfavourable outcome of essential hypertension, clearly show that the pharmacological reduction of the elevated blood pressure of hypertensive patients significantly reduces the risk of at least some major cardiovascular complications. Satisfactory antihypertensive efficacy reflects, nevertheless, merely a minimal requirement for a modern antihypertensive drug. Additional pharmacological properties, which counteract the typical concomitant diseases like CHD, heart failure and other cardiovascular complications would be desirable. In this respect, the oral CE-inhibitors captopril and enalapril offer an exciting new approach to the treatment of arterial hypertension. As the most predictive international studies on prevention of hypertension were conducted before CE-inhibitors were available, the present review evaluates the pharmacological profile of this new class of antihypertensive compounds in the light of previously available baseline drugs, including the calcium channel antagonists. Until now, captopril and enalapril have been the best investigated and documented representatives. Besides new experimental results concerning the molecular mechanism of these drugs, clinical and experimental approaches to verify protective effects on the cardiovascular and the renal system are addressed. These offer a rational basis for the preferential treatment of hypertensive patients with reduced renal function, diabetes and chronic heart failure. In addition, some distinct advantages of enalapril over captopril, resulting mainly from the long-term reduction of high blood pressure, are discussed.


Plant mitochondrial DNA.
Plants possess mitochondrial genomes that are large and complex compared to animals. Nearly all animal mitochondrial genomes are about 16.5. kbp in length, whereas plant mitochondrial genomes range between 200-2,000 kbp. This is curious if we assume modern mitochondria originated from a common alpha-proteobacterial ancestor. Despite their size, plant mitochondrial genomes do not contain significantly more genes than their animal counterparts. Most of the additional DNA found in plant mitochondrial genomes consists of large introns, repeats and non-coding regions. Furthermore, plant mtDNA does not exist as large circular DNA molecules but mostly as a collection of linear DNA with combinations of smaller circular and branched molecules. Studies into these highly fragmented genomes heavily imply that recombination is the main mechanism driving replication of plant mtDNA.


Crystallization of Ice in Aqueous Solutions of Glycerol and Dimethyl Sulfoxide. 1. A Comparison of Mechanisms
The crystallization of ice from aqueous solutions of glycerol and dimethyl sulfoxide (Me2SO) has been studied using differential scanning calorimetry. In particular, the ice crystallization behavior of glycerol and Me2SO solutions containing approximately the same mole percent solute concentration (i.e., approximately 16 mol%) has been compared. These solutions (45 w/w% Me2SO (15.9 mol%) and 50 w/w% glycerol (16.4 mol%)) were shown to exhibit markedly different ice crystallization properties. For example, the peak homogeneous nucleation temperature of the Me2SO solution was observed to be 3°C above Tg, whereas the peak homogeneous nucleation temperature of the glycerol solution was shown to be 20°C above Tg. Further, the 50 w/w% glycerol solution was shown to devitrify at temperatures close to those of the peak nucleation rate, whereas the Me2SO solution was found to devitrify at temperatures much higher than the peak nucleation temperature. This, along with evidence from emulsion-based calorimetry experiments, indicates that the nucleation leading to devitrification in 45 w/w% Me2SO solutions is largely heterogeneous in nature.


Peripheral blood CD4+ cell counts but not CD3+ and CD8+ cell counts are reduced in SARS-CoV-2 infection.
The world is facing the global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). T cell-induced immune responses during acute SARS-CoV-2 infection have rarely been reported. We use cell counting chips and PCR arrays to offer the first insights into the T cell involved in the course of acute SARS-CoV-2 infection. All consecutive patients with suspected SARS-CoV-2 infection treated at the designated hospital between January 2020 and February 2020 were recruited for the study, and cases were confirmed by real-time RT-PCR. Baseline characteristics for inpatients were prospectively collected and analyzed. 96 patients with suspected SARS-CoV-2 infection in our center were screened for inclusion in the study. The median age of the patients was 39.0 years, and 47 (49.0%) were female. Multivariate logistic regression analysis showed that only the CD4+ cell counts were significantly lower in the infection group and slightly higher in the control group. Receiver operating characteristic curve analysis showed good discrimination power between subjects with and subjects without infection. This is a single-center study of patients with a specific ethnic background and lacks a mechanism. These findings imply the importance of CD4+ T cells (but not CD8+ and CD3+ T cells) in SARS-CoV-2 infection associated pneumonia and indicate that CD4+ T cells might be important for the control of SARS-CoV-2.


Urbanization, urbanicity, and health.
A majority of the world's population will live in urban areas by 2007. The most rapidly urbanizing cities are in less-wealthy nations, and the pace of growth varies among regions. There are few data linking features of cities to the health of populations. We suggest a framework to guide inquiry into features of the urban environment that affect health and well-being. We consider two key dimensions: urbanization and urbanicity. Urbanization refers to change in size, density, and heterogeneity of cities. Urbanicity refers to the impact of living in urban areas at a given time. A review of the published literature suggests that most of the important factors that affect health can be considered within three broad themes: the social environment, the physical environment, and access to health and social services. The development of urban health as a discipline will need to draw on the strengths of diverse academic areas of study (e.g., ecology, epidemiology, sociology). Cross-national research may provide insights about the key features of cities and how urbanization influences population health.


Genome data on the extinct Bison schoetensacki establish it as a sister species of the extant European bison (Bison bonasus).
The European bison (Bison bonasus), now found in Europe and the Caucasus, has been proposed to originate either from the extinct steppe/extant American bison lineage or from the extinct Bison schoetensacki lineage. Bison schoetensacki remains are documented in Eurasian Middle Pleistocene sites, but their presence in Upper Pleistocene sites has been questioned. Despite extensive genetic studies carried out on the steppe and European bison, no remains from the fossil record morphologically identified as Bison schoetensacki has been analyzed up to now. In this paper, we analyzed a 36,000-year-old Bison schoetensaki bone sample from the Siréjol cave (France) and a cave hyena coprolite (fossilized feces) found in a nearby cave and containing large amounts of Bovinae DNA. We show that the Bovinae mitochondrial DNA sequences from both samples, including a complete mitochondrial genome sequence, belong to a clade recently reported in the literature. This clade only includes ancient bison specimens without taxonomic identification and displays a sister relationship with the extant European bison. The genetic proximity of Bison schoetensacki with specimens from this clade is corroborated by the analysis of nuclear DNA single nucleotide polymorphisms. This work provides genetic evidence supporting the continuing presence of Bison schoetensacki up to the Upper Pleistocene. Bison schoetensacki turns out to be a sister species of Bison bonasus, excluding the steppe bison Bison priscus as a direct ancestor of the European bison.


Pluralistic and singular causal attributions for epilepsy in Uganda.
In Uganda, causal attributions for epilepsy reflect a variety of beliefs and impact care-seeking behavior, perpetuate stigma, and undermine the effectiveness of interventions to narrow the epilepsy treatment gap. The objective of this study was to characterize beliefs about seizure etiology to gain a better understanding of how epilepsy is conceptualized in the community in order to inform culturally appropriate educational policies and interventions. In a community-based study, 15,383 participants were surveyed about beliefs related to 15 potential causes for epilepsy. Principal axis factor analysis (PFA) was performed to identify causative factors and then utilized to classify singular versus pluralistic belief systems related to epilepsy etiology. Analysis of variance (ANOVA) and Mann-Whitney U-tests were conducted to examine the differences in background characteristics across the etiology belief groups. Three main causative factors emerged from the PFA: biological, sociospiritual, and biospiritual. Among those endorsing at least one factor (n = 13,036), the biological factor was endorsed most frequently as a potential cause for epilepsy (88.0%), followed by the sociospiritual (63.4%), then biospiritual (47.6%). Review of the patterns of endorsement found that only 22.2% endorsed the biological factor alone, 6.7% the sociospiritual factor alone, and 2.8% the biospiritual factor alone (total 31.7%). The remainder endorsed a combination of two or all three factors as being potentially causal, and most (65.7%) endorsed a pluralistic combination inclusive of a biological etiology. Group comparisons showed that endorsing only the biological factor was associated with the highest levels of education (p < 0.01), the pluralistic group had the highest ratio of people in the household who needed assistance to those that could provide aid (p < 0.01), and there were significant differences in income across specific groups (p < 0.01). Pluralistic attributions for epilepsy are common in Uganda, with the majority of community members drawing from biomedical and traditional concepts to construct complex explanations for seizures that transcend discrete belief categories traditionally depicted in the literature. These findings emphasize the need to understand cultural beliefs about epilepsy in order to design contextually specific interventions and education programs, which respect the fundamental beliefs and values of the community. This article is part of the Special Issue "The Intersection of Culture, Resources, and Disease: Epilepsy Care in Uganda".


Factors affecting the viscosity in high concentration solutions of different monoclonal antibodies.
The viscosity profiles of four different IgG(1) molecules were studied as a function of concentration at pH 6.0. At high concentrations, MAb-H and -A showed significantly higher viscosities as compared to MAb-G and -E. Zeta Potential (ξ) measurements showed that all the IgG(1) molecules carried a net positive charge at this pH. MAb-G showed the highest positive zeta potential followed by MAb-E, -H, and -A. A consistent interpretation of the impact of net charge on viscosity for these MAbs is not possible, suggesting that electroviscous effects cannot explain the differences in viscosity. Values of k(D) (dynamic light scattering) indicated that the intermolecular interactions were repulsive for MAb-E and -G; and attractive for MAb-H and -A. Solution storage modulus (G') in high concentration solutions was consistent with attractive intermolecular interactions for MAb-H and -A, and repulsive interactions for MAb-G and -E. Effect of salt addition on solution G' and k(D) indicated that the interactions were primarily electrostatic in nature. The concentration dependent viscosity data were analyzed using a modified Ross and Minton equation. The analysis explicitly differentiates between the effect of molecular shape, size, self-crowding, and electrostatic intermolecular interactions in governing high concentration viscosity behavior.


Heterotrimeric G-protein α subunit (LeGPA1) confers cold stress tolerance to processing tomato plants (Lycopersicon esculentum Mill).
Tomatoes (Lycopersicon esculentum Mill) are key foods, and their molecular biology and evolution have been well described. Tomato plants originated in the tropics and, thus, are cold sensitive. Here, we generated LeGPA1 overexpressing and RNA-interference (RNAi) transgenic tomato plants, which we then used to investigate the function of LeGPA1 in response to cold stress. Functional LeGPA1 was detected at the plasma membrane, and endogenous LeGPA1 was highly expressed in the roots and leaves. Cold treatment positively induced the expression of LeGPA1. Overexpression of LeGPA1 conferred tolerance to cold conditions and regulated the expression of genes related to the INDUCER OF CBF EXPRESSION-C-REPEAT-BINDING FACTOR (ICE-CBF) pathway in tomato plants. In the LeGPA1-overexpressing transgenic plants, the superoxide dismutase, peroxidase, and catalase activities and soluble sugar and proline contents were increased, and the production of reactive oxygen species and membrane lipid peroxidation decreased under cold stress. Our findings suggest that improvements in antioxidant systems can help plants cope with the oxidative damage caused by cold stress, thereby stabilizing cell membrane structures and increasing the rate of photosynthesis. The data presented here provide evidence for the key role of LeGPA1 in mediating cold signal transduction in plant cells. These findings extend our knowledge of the roles of G-proteins in plants and help to clarify the mechanisms through which growth and development are regulated in processing tomato plants.


Empagliflozin Ameliorates Free Fatty Acid Induced-Lipotoxicity in Renal Proximal Tubular Cells via the PPARγ/CD36 Pathway in Obese Mice.
High serum levels of free fatty acids (FFAs) could contribute to obesity-induced nephropathy. CD36, a class B scavenger receptor, is a major receptor mediating FFA uptake in renal proximal tubular cells. Empagliflozin, a new anti-diabetic agent, is a specific inhibitor of sodium-glucose co-transporter 2 channels presented on renal proximal tubular cells and inhibits glucose reabsorption. In addition, empagliflozin has shown renoprotective effects. However, the mechanism through which empagliflozin regulates CD36 expression and attenuates FFA-induced lipotoxicity remains unclear. Herein, we aimed to elucidate the crosstalk between empagliflozin and CD36 in FFA-induced renal injury. C57BL/6 mice fed a high-fat diet (HFD) and palmitic acid-treated HK-2 renal tubular cells were used for in vivo and in vitro assessments. Empagliflozin attenuated HFD-induced body weight gain, insulin resistance, and inflammation in mice. In HFD-fed mice, CD36 was upregulated in the tubular area of the kidney, whereas empagliflozin attenuated CD36 expression. Furthermore, empagliflozin downregulated the expression of peroxisome proliferator-activated receptor (PPAR)-γ. Treatment with a PPARγ inhibitor (GW9662) did not further decrease PPARγ expression, whereas a PPARγ antagonist reversed this effect; this suggested that empagliflozin may, at least partly, decrease CD36 by modulating PPARγ. In conclusion, empagliflozin can ameliorate FFA-induced renal tubular injury via the PPARγ/CD36 pathway.


Single dose peramivir for the treatment of acute seasonal influenza: integrated analysis of efficacy and safety from two placebo-controlled trials.
Current influenza treatment options include oral or inhaled antiviral agents. There is an unmet need for parenteral antiviral treatments. Peramivir, a parenteral influenza neuraminidase inhibitor (NAI), was administered by single-dose intramuscular (IM) injection in two placebo-controlled studies in adult outpatients with acute, uncomplicated influenza during two consecutive influenza seasons. In a Phase II study, peramivir treatment significantly shortened duration of fever and reduced viral load in nasopharyngeal secretions. A subsequent Phase III study was not fully enrolled; however, in both studies, the magnitude of the treatment effect favouring peramivir was consistent with that reported for other NAIs. A post-hoc analysis was conducted by integrating efficacy and safety results of 427 subjects from both studies. The median time to alleviation of symptoms (TTAS) in subjects receiving peramivir 300 mg (113.2 h) was shorter than for placebo (134.8 h; P=0.161 adjusted for smoking behaviour, influenza season and virus type; unadjusted P=0.047). The median time to resolution of fever was reduced by 24 h after treatment with peramivir 300 mg compared with placebo (P=0.004). The proportion of subjects shedding influenza virus was significantly decreased over 48 h following peramivir treatment (P=0.009). Detection of post-treatment viruses with decreased susceptibility to NAIs was uncommon. Peramivir was generally safe and well-tolerated with types and rates of adverse event similar to placebo. The results of these studies are consistent with previous reports of peramivir administered by intravenous infusion, and demonstrate a positive risk-benefit profile for peramivir in patients with acute uncomplicated influenza.


Uniportal non-intubated lung metastasectomy.
More than 15 years ago, we started a program of uniportal video-assisted thoracoscopies (VATS) lung metastasectomy in non-intubated local anesthesia. Hereby we present the short and long-term results of this combined surgical-anesthesiological technique. Between 2005 and 2015, 71 patients (37 men and 34 women) with pulmonary oligometastases, at the first episode, underwent uniportal VATS metastasectomy under non-intubated anesthesia. Four patients (5.6%) required intubation for intolerance. Mean number of lesions resected per patient was 1.51. There was no mortality. The study group demonstrated a significant reduction of operative time from the beginning of the experience (P=0.001), good level of consciousness at Richmond scale and quality of recovery after both 24 and 48 hours. Median hospital stay was 3 days and major morbidity rate was 5.5%. Both disease-free survival and overall survival were similar to those achieved with intubated surgery. VATS lung metastasectomy in non-intubated local anesthesia was safely performed in selected patients with oligometastases with significant advantages in overall operative time, hospital stay and economical costs. Long-term results were similar.


Smoking reduces surfactant protein D and phospholipids in patients with and without chronic obstructive pulmonary disease.
Pulmonary surfactant D (SP-D) has important regulatory functions for innate immunity and has been implicated as a biomarker for chronic obstructive pulmonary disease (COPD). We hypothesized that COPD patients would have reduced bronchoalveolar lavage (BAL) fluid SP-D levels compared to healthy smoking and non-smoking controls. BAL SP-D and phospholipids were quantified and corrected for dilution in 110 subjects (65 healthy never smokers, 23 smokers with normal spirometry, and 22 smokers with COPD). BAL SP-D was highest in never smokers (mean 51.9 μg/mL ± 7.1 μg/mL standard error) compared to both smokers with normal spirometry (16.0 μg/mL ± 11.8 μg/mL) and subjects with COPD (19.1 μg/mL ± 12.9 μg/mL; P < 0.0001). Among smokers with COPD, BAL SP-D correlated significantly with FEV1% predicted (R = 0.43; P < 0.05); however, the strongest predictor of BAL SP-D was smoking status. BAL SP-D levels were lowest in current smokers (12.8 μg/mL ± 11.0 μg/mL), intermediate in former smokers (25.2 μg/mL ± 14.2 μg/mL; P < 0.008), and highest in never smokers. BAL phospholipids were also lowest in current smokers (6.5 nmol ± 1.5 nmol), intermediate in former smokers (13.1 nmol ± 2.1 nmol), and highest in never smokers (14.8 nmol ± 1.1 nmol; P < 0.0001). These data suggest that smokers, and especially current smokers, exhibit significantly reduced BAL SP-D and phospholipids compared to nonsmokers. Our findings may help better explain the mechanism that leads to the rapid progression of disease and increased incidence of infection in smokers.


[Compilation of antibiotic use in farm animals via veterinary surgeries].
A feasibility study with 20 voluntarily participating veterinary surgeries was carried out in order to test, if the consumption of antibiotics in livestock can be determined systematically. Information about the statutory documents on the application of drugs of the participating surgeries were entered in a central database and analysed systematically. Surgeries that treat only livestock used significantly more antibiotics (number of treatment units per veterinarian) per veterinarian than surgeries that treat also small animals. The comparison of small and large surgeries showed that veterinarians in small surgeries treated fewer pigs and more cattle than their colleagues in large surgeries (number of treatment units per veterinarian). All in all, tetracyclines counted for more than 50% of all substances used (regarding the amount), followed by beta-lactams (25%) and sulfonamides incl. trimethoprim (11%). In poultry, polypeptides and beta-lactams were used most frequently. While cephalosporines were used only in cattle in a noteworthy frequency, fluoroquinolones were applied to poultry in almost 12% of all applications (application of one substance to one animal at one day). In total, it was shown, that harmonized documentation of consumption of antibiotics is feasible, but the relation of antibiotics to the treated population is problematic which has to be considered in the future.The number of applications is more suitable to assess the antibiotic use than the amount in kg, because the latter is dependent of the dosage. The impact of highly dosed substances like e.g. tetracyclines is overestimated by regarding the amount, while substances with low dosages are underestimated.


Characterisation of the first actinobacterial group isolated from a Mexican extremophile environment.
The "Cave of Crystals" (aka 'Naica') in Chihuahua Mexico is a natural unique subterranean ecosystem which mainly consists of crystals made of calcium sulfate. The main system of caves are found at a depth of 300 meters (m) below sea level with crystals that range in size from a few centimeters to 15 m. The crystals date from nearly 400,000 years old and are thought to be formed when the cave was fully covered by water. At present time, this place shows a nearly constant temperature of 55 °C over the year and a humidity of 100 % which makes this place incomparable and unbearable to animal and/or human life. In the present study, two actinobacterial groups were isolated from within this system of caves and subjected to a systematic study to establish their phylogenetic relationship to microorganisms belonging to this vast group of Gram positive bacteria. Phenotypic properties, chemotaxonomic and 16S rRNA gene sequencing show that the microorganisms are members of the family Pseudonocardiaceae and are most closely related to the genus Prauserella. The present study is the first to report the isolation and presence of Actinobacteria or any other microbial form of life in this exceptional place. Moreover, this unexpected biodiversity can also provide an insight of the antibiotic resistome present in the isolates reported in this study.


Evaluation of prognostic factors for vaginal delivery after cesarean section.
Although the success rate of vaginal birth after cesarean section in selected patients is > 60%, most of these women elect the option of a planned repeat cesarean section. In this study our purpose was to evaluate the predictive value and relative importance of 15 prognostic factors by using univariate and multivariate analysis in order to refine the selection of patients for a trial of labor. The analyses were based on 261 patients with one prior cesarean section who were allowed a trial of labor. The final model resulted in six significant prognostic factors. The overall predictive value of the model was 68%. However, the predictive value for a successful vaginal delivery was excellent: 94.5% (139/147) of the women predicted to deliver vaginally actually did so. This group constituted 56% (147/261) of our candidates for vaginal delivery. The predictive value of the test for failure was only 33.3% (38/114); 66.6% of the women completed a vaginal delivery despite the prediction of failure. Because the chance of a successful vaginal delivery is > 60% in women with a prediction of failure, until a selection criterion with a better prognostic value can be identified, a liberal approach to vaginal birth after cesarean section is justified even in this group. A 60% chance is perceived by many women and physicians as too low to elect this option. Since we were able to predict a successful vaginal delivery in a large proportion of the candidates, it may encourage at least this group of patients to elect a trial of labor.


Sorafenib inhibits the shedding of major histocompatibility complex class I-related chain A on hepatocellular carcinoma cells by down-regulating a disintegrin and metalloproteinase 9.
The ectodomain of major histocompatibility complex class I-related chain A (MICA) is shed from tumor cells, and may be an important means of evading antitumor immunity. This study investigated the roles of a disintegrin and metalloproteinase 9 (ADAM9) in the shedding of MICA in human hepatocellular carcinoma (HCC). Small interfering RNA-mediated knockdown (KD) of ADAM9 resulted in up-regulation of membrane-bound MICA expression on the HepG2 and PLC/PRF/5 cellular surfaces and down-regulation of soluble MICA levels in their culture supernatant. ADAM9 was cleaved at a site between Gln347 and Val348 of MICA in vitro. We constructed a plasmid of the MICA gene with mutation or deletion of the ADAM9 cleavage site to examine the detailed mechanism of MICA shedding by ADAM9 protease. The results suggested that MICA might be cleaved at the intracellular ADAM9-recognized cleavage site and was further cleaved at the extracellular ADAM9-independent cleavage site in HCC cells, resulting in the production of soluble MICA. Immunohistochemical analysis revealed that ADAM9 was overexpressed in human HCC compared to normal liver tissues. The cytolytic activity of natural killer (NK) cells against ADAM9KD-HCC cells was higher than that against control cells, and the enhancement of this cytotoxicity depended on the MICA/B and NK group 2, member D pathway. Sorafenib treatment resulted in decreased expression of ADAM9, increased expression of membrane-bound MICA expression, and decreased levels of soluble MICA in HCC cells. Adding sorafenib enhanced the NK sensitivity of HCC cells via increased expression of membrane-bound MICA. ADAM9 is involved in MICA ectodomain shedding in HCC cells, and sorafenib can modulate ADAM9 expression. Sorafenib therapy may have a previously unrecognized effect on antitumor immunity in patients with HCC.


Genetic diversity of human RNase 8.
Ribonuclease 8 is a member of the RNase A family of secretory ribonucleases; orthologs of this gene have been found only in primate genomes. RNase 8 is a divergent paralog of RNase 7, which is lysine-enriched, highly conserved, has prominent antimicrobial activity, and is expressed in both normal and diseased skin; in contrast, the physiologic function of RNase 8 remains uncertain. Here, we examine the genetic diversity of human RNase 8, a subject of significant interest given the existence of functional pseudogenes (coding sequences that are otherwise intact but with mutations in elements crucial for ribonucleolytic activity) in non-human primate genomes. RNase 8 expression was detected in adult human lung, spleen and testis tissue by quantitative reverse-transcription PCR. Only two single-nucleotide polymorphisms and four unique alleles were identified within the RNase 8 coding sequence; nucleotide sequence diversity (π = 0.00122 ± 0.00009 per site) was unremarkable for a human nuclear gene. We isolated transcripts encoding RNase 8 via rapid amplification of cDNA ends (RACE) and RT-PCR which included a distal potential translational start site followed by sequence encoding an additional 30 amino acids that are conserved in the genomes of several higher primates. The distal translational start site is functional and promotes RNase 8 synthesis in transfected COS-7 cells. These results suggest that RNase 8 may diverge considerably from typical RNase A family ribonucleases and may likewise exhibit unique function. This finding prompts a reconsideration of what we have previously termed functional pseudogenes, as RNase 8 may be responding to constraints that promote significant functional divergence from the canonical structure and enzymatic activity characteristic of the RNase A family.


Efficacy and safety of erlotinib in 1242 East/South-East Asian patients with advanced non-small cell lung cancer.
Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor that significantly increases survival for patients with previously treated advanced non-small cell lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors have been reported to be particularly effective in Asian patients and may have a distinct safety profile in this population compared with non-Asian patients. We report safety and efficacy data from a subpopulation of East/South-East (E/SE) Asian patients enrolled in a global, open-label, phase IV trial of erlotinib (Tarceva Lung Cancer Survival Treatment study). Patients who had previously failed on chemotherapy or radiotherapy, or were unsuitable for these treatments, were treated with oral erlotinib (150 mg/d) until disease progression or unacceptable toxicity. Best response data were available for 1118 E/SE Asian and 4276 non-E/SE Asian patients. The overall response rates were 27% versus 10%, respectively (p < 0.0001). The disease control rates were 78% versus 66%, respectively (p < 0.0001). Survival data were available for 1242 E/SE Asian and 5338 non-E/SE Asian patients. The median progression-free survival times were 5.78 months versus 2.92 months, respectively (hazard ratio = 0.66, p < 0.0001). The median overall survival times were 14.7 months versus 6.8 months, respectively (hazard ratio = 0.57, p < 0.0001). One-year survival rates were 58.3% and 32.7%, respectively. Safety data were available for 1242 E/SE Asian patients. Seventeen percent of these patients experienced one or more erlotinib-related adverse event (AE) (other than the most frequently occurring AEs prespecified in the protocol) and 2% experienced an erlotinib-related serious AE. Dose reductions were reported for 171 (14%) patients. Erlotinib is an effective and well-tolerated treatment for Asian patients with advanced non-small cell lung cancer.


Analysis of Mirrored Psychophysiological Change of Cardiac Surgery Team Members During Open Surgery.
Mirrored psychophysiological change in cognitive workload indices may reflect shared mental models and effective healthcare team dynamics. In this exploratory analysis, we investigated the frequency of mirrored changes, defined as concurrent peaks in heart rate variability (HRV) across team members, during cardiac surgery. Objective cognitive workload was evaluated via HRV collected from the primary surgical team during cardiac surgery cases (N = 15). Root mean square of the successive differences (RMSSD) was calculated as the primary HRV measure. Procedures were divided into consecutive nonoverlapping 5-minute segments, and RMSSD along with deviations from RMSSD were calculated for each segment. Segments with positive deflections represent above-average cognitive workload. Positive deflections and peaks across dyads within the same segment were counted. Data collection for this study took place in the cardiovascular operating room during live surgeries. Physiological data were collected and analyzed from the attending surgeon, attending anesthesiologist, and primary perfusionist involved with the recorded cases. Of the 641 five-minute segments analyzed, 325 (50.7%) were positive deflections above average, concurrently across at least 2 team members. Within the 325 positive deflections, 26 (8%) represented concurrent peaks in HRV across at least 2 active team members. Mirrored peaks across team members were observed most commonly during the coronary anastomoses or valve replacement phase (N = 12). In this pilot study, mirrored physiological responses representing peaks in cognitive workload were observed uncommonly across dyads of cardiac surgery team members (1.73 peaks/case on average). Almost half of these occurred during the most technically demanding phases of cardiac surgery, which may underpin teamwork quality. Future work should investigate interactions between technical and nontechnical performance surrounding times of mirrored peaks and expand the sample size.


Angle-ply scaffold supports annulus fibrosus matrix expression and remodeling by mesenchymal stromal and annulus fibrosus cells.
The angle-ply multilaminate structure of the annulus fibrosus is not reestablished following discectomy which leads to reherniation of the intervertebral disc (IVD). Biomimetic scaffolds developed to repair these defects should be evaluated for their ability to support tissue regeneration by endogenous and exogenous cells. Herein a collagen-based, angle-ply multilaminate patch designed to repair the outer annulus fibrosus was assessed for its ability to support mesenchymal stromal and annulus fibrosus cell viability, elongation, alignment, extracellular matrix gene expression, and scaffold remodeling. Results demonstrated that the cells remained viable, elongated, and aligned along the collagen fiber preferred direction of the scaffold, upregulated genes associated with annulus fibrosus matrix and produced collagen on the scaffold yielding biaxial mechanical properties that resembled native annulus fibrosus tissue. In conclusion, these scaffolds have demonstrated their potential to promote a living repair of defects in the annulus fibrosus and thus may be used to prevent recurrent IVD herniations.


In vitro effects of fipronil on neuronal excitability in mammalian and molluscan nervous systems.
The effect of the insecticide fipronil on non-target organisms was studied on rat brain slices and identified giant neurons of the pond snail Lymnaea stagnalis. This compound acts as an antagonist on GABA(A) receptors. Although fipronil has moderate mammalian toxicity, our experiments confirmed that it modifies neuronal excitability in the rat somatosensory cortex. The amplitudes of evoked field potentials increased significantly after 30 min fipronil treatment. Short-term plasticity was examined with paired-pulse stimulation, this phenomenon was not affected by fipronil. On the other hand, the efficacy of LTP-induction was enhanced in the treated slices. Fipronil is highly toxic to freshwater invertebrates, especially molluscs. In Lymnaea stagnalis, the firing pattern of a GABA receptor- containing neuron (RPeD1) was studied. On this neuron, GABA has an excitatory, hypopolarizing effect. Fipronil treatment decreased the action potential frequency in a concentration-dependent manner. On the membrane potential of the cell, it had a slightly hyperpolarizing effect. These experiments confirmed that fipronil toxicity is mediated by GABA receptors in the nervous system of invertebrates as well as vertebrates. These types of experiments may help in establishing tolerance levels of pesticide residues and in finding proper treatment in case of eventual poisonings.


[Cardiac arrhythmias associated with subarachnoid hemorrhage. Prospective study with dynamic electrocardiography].
Electrocardiographic abnormalities associated with intracranial diseases, especially subarachnoid hemorrhage, are well known, while there is hardly mention of cardiac arrhythmias in the neurological and cardiological literature. In order to assess the incidence of arrhythmias 52 consecutive patients with subarachnoid hemorrhage secondary to ruptured aneurysm were investigated with 24-hour Holter recordings. Bradyarrhythmias and tachyarrhythmias were found in 46 patients (88%); premature ventricular beats in 25 pts (12 of these in 3rd-5th Lown classes), ventricular tachycardia in 2, premature supraventricular beats in 14, paroxysmal atrial fibrillation in 1, sinoatrial blocks and arrests in 18, atrioventricular dissociation in 2 and idioventricular rythm in 2. Moreover in 5 pts ST segment changes were found, suggestive of transitory acute myocardial ischemia. The presence and severity of arrhythmias were correlated with the time elapsed from the episode of bleeding, with the QT interval, and with the hemorrhage extent. Our results indicate an high incidence of arrhythmias in subarachnoid hemorrhage, sometimes serious mainly in early stage. Continuous electrocardiographic monitoring is therefore extremely useful and provides data for therapeutic consideration.


Role of viral infection in porphyria cutanea tarda.
HIV infection is associated with abnormal porphyrin metabolism. While HCV infection alone is thus far not associated with significant abnormal porphyrin levels, it does contribute to further elevation of porphyrin levels in patients already infected with HIV. These infections alone are not sufficient to induce the development of clinical porphyria. However, they render patients susceptible to having symptomatic porphyria upon exposure to other porphyrinogenic agents.


Dynamic pulmonary CT: findings in healthy adult men.
The authors examined 10 healthy male subjects with dynamic computed tomography to determine normal dynamic and expiratory findings. In both the supine and prone positions, the average increase in lung attenuation during exhalation was found to be significantly greater in dependent lung regions than in nondependent lung regions. In each of the lung zones studied, there was a significant correlation between the decrease in cross-sectional lung area during exhalation and the increase in lung attenuation. At the lung bases, a greater increase in lung attenuation was noted during exhalation for a given change in cross-sectional lung area than in the upper lungs. All 10 subjects showed a distinct lobar attenuation gradient in the supine position. In general, lung attenuation increased homogeneously during exhalation, but four of the 10 subjects showed regions of inhomogeneity in lung attenuation during rapid exhalation indicative of air trapping, despite normal results on pulmonary function tests.


Antibody mediated cotton-archetypal substrate for enumeration of circulating tumor cells and chemotherapy outcome in 3D tumors.
Circulating tumor cells (CTCs) are distinct cancer biomarkers established in clinical settings for early cancer detection, metastasis progression, and minimal residual disease (MRD) monitoring. Despite numerous advances, the comprehensive molecular characterization of CTCs is extremely challenging owing to their rarity and heterogeneity. Here, we present a novel cotton microfluidic substrate (CMS) as an innovative biomedical matrix that efficiently isolates CTCs while facilitating in vitro CTC expansion to enable a further downstream analysis of these rare cells. CMS enabled static and dynamic isolation of cells from the MCF-7 cancer cell line, as well as from head and neck squamous cell carcinoma (HNSCC) patients' blood and the cell capture efficiencies were further compared with a clinically regulated OncoDiscover® Liquid Biopsy Test. Further, CMS acted as a matrix on which the captured cancer cells were grown in 3D tumor models for studying anti-cancer drug efficacy and multi-drug resistance (MDR) mechanisms. The design of the CMS employed two different surface chemistries, flattened and nanostructured surfaces, each conjugated to anti-EpCAM antibodies to evaluate the CTC capture efficiency and 3D tumor growth dynamics. The nanostructured surface was highly efficient for capturing CTCs and promoted 3D tumor spheroid formation with a 5-fold increase in size from day 03 to day 10 of culture. Moreover, when treated with an anti-cancer drug, cisplatin, an almost 1/2 reduction in tumor size was achieved within 24 hours, followed by a cytostatic threshold and eventual acquisition of drug resistance within 3 days. Conclusively, the CMS matrix exhibits potential for further development of "tissue on chip" and "point-of-care" medical devices in cancer diagnostics, and chemo-therapeutic efficacy evaluations in both drug discovery and development.


A Comparative Evaluation of the Dentoskeletal Treatment Effects Using Twin Block Appliance and Myobrace System on Class II Division I Malocclusion.
The study aimed to evaluate the dentoskeletal effects of twin block appliance and myobrace system in treating skeletal Class II Division I malocclusions in growing children taking into account the effects of normal growth in an untreated control group. Twenty subjects with Class II Division I malocclusion considered as study group were allocated randomly to two treatment groups of 10 each, consecutively treated with twin block appliances (mean age 10.850 ± 1.37 years) and myobrace system (mean age 10.40 ± 1.89 years). Ten children (mean age 10.60 ± 1.77 years) with untreated Class II Division I malocclusion were considered as a control group to eliminate possible growth effects. At the start of the treatment and end of the observation period of 18-24 months, lateral cephalograms were taken. All the angular and linear parameters measured were subjected to statistical analysis. Twin block group subjects produced more measurable and statistically significant skeletal and dentoalveolar changes at the end of the observation period, demonstrated by correction of full cuspal Class II molar relationship to Class I molar relationship and yielding mandibular growth in increments greater in magnitude than the myobrace system. Meanwhile, the myobrace system-induced favorable dentoalveolar changes by a significant reduction of overjet. The retrognathic profile, however, improved in both the intervention groups as the upper lip protrusion, mentalis strain, and the lower lip curl were eliminated in striking contrast to the untreated control group. The study demonstrates that with appropriate patient selection both myobrace system and twin block appliances can be used in conjunction with the fixed appliance therapy to achieve more stable Class II corrections. How to cite this article: Johnson JS, Satyaprasad S, Sharath Chandra H, et al. A Comparative Evaluation of the Dentoskeletal Treatment Effects Using Twin Block Appliance and Myobrace System on Class II Division I Malocclusion. Int J Clin Pediatr Dent 2021;14(S-1):S10-S17.


Community detection: Comparison among clustering algorithms and application to EEG-based brain networks.
Community structure is a feature of complex networks that can be crucial for the understanding of their internal organization. This is particularly true for brain networks, as the brain functioning is thought to be based on a modular organization. In the last decades, many clustering algorithms were developed with the aim to identify communities in networks of different nature. However, there is still no agreement about which one is the most reliable, and to test and compare these algorithms under a variety of conditions would be beneficial to potential users. In this study, we performed a comparative analysis between six different clustering algorithms, analyzing their performances on a ground-truth consisting of simulated networks with properties spanning a wide range of conditions. Results show the effect of factors like the noise level, the number of clusters, the network dimension and density on the performances of the algorithms and provide some guidelines about the use of the more appropriate algorithm according to the different conditions. The best performances under a wide range of conditions were obtained by Louvain and Leicht & Newman algorithms, while Ronhovde and Infomap proved to be more appropriate in very noisy conditions. Finally, as a proof of concept, we applied the algorithms under exam to brain functional connectivity networks obtained from EEG signals recorded during a sustained movement of the right hand, obtaining a clustering of scalp electrodes which agrees with the results of the simulation study conducted.


Early cranial ultrasound lesions predict microcephaly at age 2 years in preterm infants.
To assess how well early ultrasound lesions in preterm newborns predict reduced head circumference at 2 years, the investigators followed 923 children born before the 28th week of gestation who were not microcephalic at birth. Six percent of children who had a normal ultrasound scan were microcephalic compared with 15% to 20% who had intraventricular hemorrhage, an echolucent lesion, or ventriculomegaly. The odds ratios (95% confidence intervals) for microcephaly associated with different ultrasound images were intraventricular hemorrhage, 1.5 (0.8-3.0); ventriculomegaly, 3.3 (1.8-6.0); an echodense lesion, 1.6 (0.7-3.5); and an echolucent lesion, 3.1 (1.5-6.2). Ventriculomegaly and an echolucent lesion had very similar low positive predictive values (24% and 27%, respectively) and high negative predictive values (91% and 90%, respectively) for microcephaly. Ventriculomegaly had a higher sensitivity for microcephaly than did an echolucent lesion (24% vs 16%, respectively). Focal white-matter lesion (echolucent lesion) and diffuse white-matter damage (ventriculomegaly) predict an increased risk of microcephaly.


[Function diagnosis of small intestine absorption using the modified D-xylose absorption test].
Based on a biophysical model of the absorptive system a modified D-xylose test has been inaugurated, which is well suited to comprehensively assess the process of intestinal absorption. According to the author's experience of many years the test is a well-suited method for detecting changes in intestinal absorption. It excels by its high validity and reliability. Its practical accomplishment is easy and needs no expensive equipment. The method and the processing and evaluation of the measured values are described in detail.


Membrane-dependent interaction of factor Xa and prothrombin with factor Va in the prothrombinase complex.
Because all three protein components of prothrombinase, factors (f) Xa and Va and prothrombin, bind to negatively charged membrane phospholipids, the exact role of the membrane in the prothrombinase reaction has not been fully understood. In this study, we prepared deletion derivatives of fXa and prothrombin in which both the Gla and first EGF-like domains of the protease (E2-fXa) as well as the Gla and both kringle domains of the substrate (prethrombin-2) had been deleted. The fVa-mediated catalytic activity of E2-fXa toward prethrombin-2 was analyzed in both the absence and presence of phospholipids composed of 80% phosphatidylcholine (PC) and 20% phosphatidylserine (PS). PCPS markedly accelerated the initial rate of prethrombin-2 activation by E2-fXa, with the cofactor exhibiting saturation only in the presence of phospholipids (apparent K(d) of approximately 60 nM). Competitive kinetic studies in the presence of the two exosite-1-specific ligands Tyr(63)-sulfated hirudin(54-65) and TM456 suggested that while both peptides are highly effective inhibitors of the fVa-mediated activation of prethrombin-2 by E2-fXa in the absence of PCPS, they are ineffective competitors in the presence of phospholipids. Since neither E2-fXa nor prethrombin-2 can interact with membranes, these results suggest that interaction of fVa with PCPS improves the affinity of the activation complex for proexosite-1 of the substrate. Direct binding studies employing OG(488)-EGR-labeled fXa and E2-fXa revealed that the interaction of the Gla domain of fXa with PCPS also induces conformational changes in the protease to facilitate its high-affinity interaction with fVa.


Biotechnologies and liver diseases.
Viral hepatitis is surveyed as a European problem. The economic implications of including vaccines against hepatitis A and B in infant and adolescent immunisation programmes are discussed. The urgent need for vaccine against hepatitis C is stressed. Antiviral therapy for hepatitis B and C infections remains unsatisfactory. Costs of widespread implementation, particularly for hepatitis C, would be enormous and the selection of candidates for therapy is still under discussion. Increasing use of liver transplantation is prevented by donor shortage. Methods of artificial liver support must attract more research support.


Evaluation of contraction of the split-thickness skin graft using three dermal matrices in the treatment of burn contractures: A randomised clinical trial.
Burn injuries commonly result in serious sequelae (such as skin contractures) in surviving patients, for which no single optimal solution is known. The goal of this study was to compare the late contraction of autologous skin grafts with or without dermal matrices used in the treatment of patients with burn contractures. This parallel design prospective, randomised and controlled clinical trial included patients with burn contracture treated using autologous skin grafts and dermal matrix. Patients were randomly assigned to one of the four groups: Integra® matrix (n = 10), Pelnac® matrix (n = 10), Matriderm® matrix (n = 9) or a Control Group (n = 10, without dermal matrix, only skin graft). The boundaries of skin defect were marked and transferred to a flat sterile surface for area measurement. The current area of the skin grafts was measured during surgery and compared with those obtained at 1, 3, 6 and 12 months postoperatively. Twelve months after surgery, the Control Group presented lower rates of skin graft contraction than Integra® (p < 0.01), Matriderm® (p = 0.01) and Pelnac® (p < 0.01) groups. Pelnac® resulted in larger skin graft contraction than Matriderm® (p < 0.01) and Integra® (p = 0.02), while differences between Integra® and Matriderm® were not significant (p = 0.16). The comparison between intraoperative and 12 months after surgery showed that the worst mean rates of skin graft contraction were from the Pelnac® (51.79%) and Matriderm® (59.17%). In patients with burn contractures, the use of these three dermal matrices did not reduce or avoid the occurrence of late contraction of the skin graft, so their use for this purpose should be carefully evaluated.


Ionic liquids composed of phosphonium cations and organophosphate, carboxylate, and sulfonate anions as lubricant antiwear additives.
Oil-soluble phosphonium-based ionic liquids (ILs) have recently been reported as potential ashless lubricant additives. This study is to expand the IL chemistry envelope and to achieve fundamental correlations between the ion structures and ILs' physiochemical and tribological properties. Here we present eight ILs containing two different phosphonium cations and seven different anions from three groups: organophosphate, carboxylate, and sulfonate. The oil solubility of ILs seems largely governed by the IL molecule size and structure complexity. When used as oil additives, the ranking of effectiveness in wear protection for the anions are organophosphate > carboxylate > sulfonate. All selected ILs outperformed a commercial ashless antiwear additive. Surface characterization from the top and the cross-section revealed the nanostructures and compositions of the tribo-films formed by the ILs. Some fundamental insights were achieved: branched and long alkyls improve the IL's oil solubility, anions of a phosphonium-phosphate IL contribute most phosphorus in the tribo-film, and carboxylate anions, though free of P, S, N, or halogen, can promote the formation of an antiwear tribo-film.


Patterns of muscle activation during generalized tonic and tonic-clonic epileptic seizures.
Tonic seizures and the tonic phase of tonic-clonic epileptic seizures are defined as "sustained tonic" muscle contraction lasting a few seconds to minutes. Visual inspection of the surface electromyogram (EMG) during seizures contributed considerably to a better understanding and accurate diagnosis of several seizure types. However, quantitative analysis of the surface EMG during the epileptic seizures has received surprisingly little attention until now. The aim of our study was to elucidate the pathomechanism of the tonic muscle activation during epileptic seizures. Surface EMG was recorded from the deltoid muscles, on both sides, during 63 seizures from 20 patients with epilepsy (10 with generalized tonic and 10 with tonic-clonic seizures). Twenty age- and gender-matched normal controls simulated 100 generalized tonic seizures. To characterize the signal properties we calculated the root mean square (RMS) of the amplitudes, the median frequency (MF), and the coherence. Based on the spectrograms of both epileptic and simulated seizures, we chose to determine the relative spectral power (RP) in the higher (100-500 Hz) frequency domain. During the tonic seizures there was a significant shift toward higher frequencies, expressed by an increase in the MF and the RP (100-500 Hz). The amplitude characteristic of the signal (RMS) was significantly higher during the tonic phase of the tonic-clonic seizures as compared to the simulated ones, whereas the RMS of the tonic seizures was significantly lower than the simulated ones. The EMG-EMG coherence was significantly higher during the epileptic seizures (both types) as compared to the simulated ones. Our results indicate that the mechanism of muscle activation during epileptic seizures is different from the physiologic one. Furthermore the sustained muscle activation during the tonic phase of tonic-clonic seizures is different from that during tonic seizures: The tonic phase of tonic-clonic seizures is characterized by increased amplitude of the signal, whereas tonic seizures are produced by a significant increase in the frequency of the signal.


Extensive degeneration of catecholaminergic neurons to scrapie agent 87V in the brains of IM mice.
Scrapie is a degenerative disease of the central nervous system of sheep and goats. The causative agent has been passaged to a number of laboratory species, including mice and hamster. Amyloid plaque formation and vacuolation, the signs of senile dementia, are found in the brains of mice infected with 87V scrapie agent. Dopamine (DA) and norepinephrine (NE) concentrations in the brains of scrapie-infected mice were measured with high-performance liquid chromatography-electrochemical detector (HPLC-ECD). A significant decrease in NE level was exhibited in all regions tested, whereas the level of DA decreased significantly only in cerebral cortex. Immunohistochemistry was used to examine immunoreactive catecholamine neurons in substantia nigra and locus ceruleus using antisera against tyrosine hydroxylase (TH). The population of TH-immunoreactive neurons in the substantia nigra and locus ceruleus were significantly decreased in scrapie-infected mice compared to controls. These data suggest that both the noradrenergic and dopaminergic system are sensitive to the action of scrapie agent 87V and that changes in the catecholamine levels in the brains of scrapie-infected mice may contribute to some of the clinical symptoms of the diseases, such as ataxia and apraxia.