Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology.
Emerging evidence indicates that reactive oxygen species, especially superoxide and hydrogen peroxide, are important signaling molecules in cardiovascular cells. Their production is regulated by hormone-sensitive enzymes such as the vascular NAD(P)H oxidases, and their metabolism is coordinated by antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. Both of these reactive oxygen species serve as second messengers to activate multiple intracellular proteins and enzymes, including the epidermal growth factor receptor, c-Src, p38 mitogen-activated protein kinase, Ras, and Akt/protein kinase B. Activation of these signaling cascades and redox-sensitive transcription factors leads to induction of many genes with important functional roles in the physiology and pathophysiology of vascular cells. Thus, reactive oxygen species participate in vascular smooth muscle cell growth and migration; modulation of endothelial function, including endothelium-dependent relaxation and expression of a proinflammatory phenotype; and modification of the extracellular matrix. All of these events play important roles in vascular diseases such as hypertension and atherosclerosis, suggesting that the sources of reactive oxygen species and the signaling pathways that they modify may represent important therapeutic targets.


Angioblast differentiation and morphogenesis of the vascular endothelium in the mouse embryo.
Bandeiraea simplicifolia B4 isolectin (BSLB4) and polyclonal antisera against von Willebrand factor (VWF) were used to study the origin of endothelial cells and their organization into blood vessels in the postimplantation mouse embryo. Examination of BSLB4-stained whole mounted and sectioned embryos revealed intense staining of the endothelium, highlighting large vessels, capillaries, and many individual cells. Dorsal aorta formation was first obvious at E7 when many lectin-positive cells appeared in paraxial and lateral plate mesoderm. As development proceeded to E8, BSLB4-positive cells became organized into craniocaudal lines destined to become the aorta proper. At E9, BSLB4 stained all vessels of the embryo including the dorsal aorta, the intersomitic arteries, and the endocardium. VWF expression was not detected until E8 when BSLB4/VWF double-stained sections revealed the dorsal aortae as the first VWF-positive vessels, while other endothelium visible with BSLB4 remained negative for VWF immunostaining. By E12 many other vessels became VWF-positive, including the aortic arches, the intersomitic arteries, and the cardinal veins. However, many angioblasts and capillaries remained VWF-negative, reflecting the heterogeneous expression of VWF among endothelium that has been reported in adults of other species. The histochemical data reported here support the conclusions of earlier avian studies by showing distinct vascular patterns in the initial formation of vessels from isolated angioblasts (vasculogenesis), followed by the extension and organization of the initial vascular structures (angiogenesis). Moreover, our data suggest that the endothelium arises from distinct VWF-positive sources associated with the dorsal aorta, as well as VWF-negative sources associated with other vessels in the embryo.


Directional collisions during a route-following task.
Neurologically normal people tend to collide with objects on the right side more frequently than with objects located on the left side of space. This phenomenon could be attributable to pseudoneglect wherein individuals selectively attend to the left field. The current study investigated this effect using a virtual route-following task that was presented centrally, in the lower field, and in the upper field. Handedness was also examined. Fifty-two participants (four left handed) completed this task, and when presented in the lower field, more left-side collisions emerged. In the upper condition, this bias reversed direction to the expected rightward bias. In the central condition, there was no significant directional bias in collision behavior. An interaction between handedness and presentation condition indicated that left-handed participants experienced more right-side collisions in the central condition. Collectively, these results suggest that directional biases (i.e., left vs. right) in collision behavior are modulated by both location in the visual field (central, upper, or lower) and handedness.


Escalating low-dose Δ9 -tetrahydrocannabinol exposure during adolescence induces differential behavioral and neurochemical effects in male and female adult rats.
Cannabinoid administration during adolescence affects various physiological processes, such as motor and affective response, cognitive-related functions and modulates neurotransmitter activity. Literature remains scant concerning the parallel examination of the effects of adolescent escalating low-dose Δ9 -tetrahydrocannabinol (Δ9 -THC) on the behavioral and plasticity profile of adult rats in both sexes. Herein, we investigated the long-term behavioral, neurochemical and neurobiological effects of adolescent escalating low Δ9 -THC doses in adult male and female rats. In adult males, adolescent low-dose Δ9 -THC exposure led to increased spontaneous locomotor activity, impaired behavioral motor habituation and defective short-term spatial memory, paralleled with decreased BDNF protein levels in the prefrontal cortex. In this brain area, serotonergic activity was increased, as depicted by the increased serotonin turnover rate, while the opposite effect was observed in the hippocampus, a region where SERT levels were enhanced by Δ9 -THC, compared with vehicle. In adult females, adolescent Δ9 -THC treatment led to decreased spontaneous vertical activity and impaired short-term spatial memory, accompanied by increased BDNF protein levels in the prefrontal cortex. Present findings emphasize the key role of adolescent escalating low Δ9 -THC exposure in the long-term regulation of motor response, spatial-related cognitive functions and neuroplasticity indices in adulthood. In this framework, these changes could, at a translational level, contribute to clinical issues suggesting the development of psychopathology in a sex-differentiated manner following Δ9 -THC exposure during adolescence.


Determinants of the nuclear localization of the heterodimeric DNA fragmentation factor (ICAD/CAD).
Programmed cell death or apoptosis leads to the activation of the caspase-activated DNase (CAD), which degrades chromosomal DNA into nucleosomal fragments. Biochemical studies revealed that CAD forms an inactive heterodimer with the inhibitor of caspase-activated DNase (ICAD), or its alternatively spliced variant, ICAD-S, in the cytoplasm. It was initially proposed that proteolytic cleavage of ICAD by activated caspases causes the dissociation of the ICAD/CAD heterodimer and the translocation of active CAD into the nucleus in apoptotic cells. Here, we show that endogenous and heterologously expressed ICAD and CAD reside predominantly in the nucleus in nonapoptotic cells. Deletional mutagenesis and GFP fusion proteins identified a bipartite nuclear localization signal (NLS) in ICAD and verified the function of the NLS in CAD. The two NLSs have an additive effect on the nuclear targeting of the CAD-ICAD complex, whereas ICAD-S, lacking its NLS, appears to have a modulatory role in the nuclear localization of CAD. Staurosporine-induced apoptosis evoked the proteolysis and disappearance of endogenous and exogenous ICAD from the nuclei of HeLa cells, as monitored by immunoblotting and immunofluorescence microscopy. Similar phenomenon was observed in the caspase-3-deficient MCF7 cells upon expressing procaspase-3 transiently. We conclude that a complex mechanism, involving the recognition of the NLSs of both ICAD and CAD, accounts for the constitutive accumulation of CAD/ICAD in the nucleus, where caspase-3-dependent regulation of CAD activity takes place.


Read length and repeat resolution: exploring prokaryote genomes using next-generation sequencing technologies.
There are a growing number of next-generation sequencing technologies. At present, the most cost-effective options also produce the shortest reads. However, even for prokaryotes, there is uncertainty concerning the utility of these technologies for the de novo assembly of complete genomes. This reflects an expectation that short reads will be unable to resolve small, but presumably abundant, repeats. Using a simple model of repeat assembly, we develop and test a technique that, for any read length, can estimate the occurrence of unresolvable repeats in a genome, and thus predict the number of gaps that would need to be closed to produce a complete sequence. We apply this technique to 818 prokaryote genome sequences. This provides a quantitative assessment of the relative performance of various lengths. Notably, unpaired reads of only 150nt can reconstruct approximately 50% of the analysed genomes with fewer than 96 repeat-induced gaps. Nonetheless, there is considerable variation amongst prokaryotes. Some genomes can be assembled to near contiguity using very short reads while others require much longer reads. Given the diversity of prokaryote genomes, a sequencing strategy should be tailored to the organism under study. Our results will provide researchers with a practical resource to guide the selection of the appropriate read length.


A Light-Controlled Allosteric Modulator Unveils a Role for mGlu4 Receptors During Early Stages of Ischemia in the Rodent Cerebellar Cortex.
Metabotropic glutamate receptors (mGlus) are G Protein coupled-receptors that modulate synaptic transmission and plasticity in the central nervous system. Some act as autoreceptors to control neurotransmitter release at excitatory synapses and have become attractive targets for drug therapy to treat certain neurological disorders. However, the high degree of sequence conservation around the glutamate binding site makes the development of subtype-specific orthosteric ligands difficult to achieve. This problem can be circumvented by designing molecules that target specific less well conserved allosteric sites. One such allosteric drug, the photo-switchable compound OptoGluNAM4.1, has been recently employed to reversibly inhibit the activity of metabotropic glutamate 4 (mGlu4) receptors in cell cultures and in vivo. We studied OptoGluNAM4.1 as a negative modulator of neurotransmission in rodent cerebellar slices at the parallel fiber - Purkinje cell synapse. Our data show that OptoGluNAM4.1 antagonizes pharmacological activation of mGlu4 receptors in a fully reversible and photo-controllable manner. In addition, for the first time, this new allosteric modulator allowed us to demonstrate that, in brain slices from the rodent cerebellar cortex, mGlu4 receptors are endogenously activated in excitotoxic conditions, such as the early phases of simulated cerebellar ischemia, which is associated with elevated levels of extracellular glutamate. These findings support OptoGluNAM4.1 as a promising new tool for unraveling the role of mGlu4 receptors in the central nervous system in physio-pathological conditions.


A National Survey of Outpatient Parenteral Antibiotic Therapy Practices.
We conducted a national survey of pediatric infectious diseases (ID) clinicians on outpatient parenteral antibiotic therapy (OPAT) practices and post-discharge ID follow-up. Only 15% of sites required ID consultation for all OPAT. ID division resources for post-discharge care varied. Opportunities exist to increase ID involvement in post-discharge management of serious infections.


Interferons in the management of viral hepatitis.
Since their discovery in 1957, interferons (IFNs) have been noted to have protective effects against human viral infections. The use and safety of IFNs in patients with acute or chronic hepatitis B or C infections have evolved over the last 20 years. The most studied IFN for the management of viral hepatitis is IFN-alpha, but others have recently been evaluated through controlled clinical trials. IFN treatment is not currently indicated for patients with acute hepatitis B, but has proven beneficial in chronic hepatitis B. The success of treatment in this group of patients has been measured by the normalization of liver enzymes, loss of hepatitis B e antigen and loss of detectable serum DNA of hepatitis B. It has been estimated in several clinical trials that as many as 40% of treated patients will respond to therapy, as defined above. Although only a few and limited studies have evaluated the use of IFNs in acute hepatitis C, treatment appears to decrease the likelihood of chronicity, and should be considered. In chronic hepatitis C, treatment has been effective in achieving sustained viral eradication in up to 20% of patients taking the FDA-approved dosage of three million units, three times weekly for 6-12 months. However, higher doses, longer duration of treatment or combining IFN with other antiviral agents may improve the rate of response. It has become clear during the last two decades that IFNs have beneficial effects for patients with viral hepatitis B or C. Much more effort is needed to establish the optimal dose and duration of therapy. Studies addressing the pharmacokinetics of IFNs in patients with viral hepatitis are needed, and methods to improve the bioavailability of these products to affected tissues such as the liver may improve efficacy and minimize side-effects.


Familial clustering of tic disorders and obsessive-compulsive disorder.
Tourette syndrome/chronic tic disorder (TS/CT) and obsessive-compulsive disorder (OCD) overlap in their phenomenological features and often co-occur in affected individuals and families. Understanding how these disorders cluster in families provides important clinical information and is an important step in understanding the causes of these disorders. To determine familial recurrence for TS/CT and OCD using a national epidemiologic sample. We performed a population-based study of national health registries in Denmark, including all individuals (n = 1 741 271) born in Denmark from January 1, 1980, through December 31, 2007, and followed up through December 31, 2013. We identified those with TS/CT and/or OCD. The prevalence of TS/CT and OCD and relative recurrence risk (RRR) for TS/CT or OCD among individuals with an oldest sibling or a parent diagnosed as having TS/CT or OCD compared with individuals without an affected oldest sibling or an affected parent. In this sample, 5596 individuals were diagnosed as having TS/CT; 6191, OCD; and 412, both disorders. The overall cohort prevalence of TS/CT was 0.42% (95% CI, 0.41%-0.43%) and of OCD, 0.84% (95% CI, 0.81%-0.87%). The mean sibling recurrence risk for TS/CT across all birth years was 9.88% (95% CI, 8.02%-12.16%) and for OCD, 4.01% (95% CI, 2.78%-5.76%). The sibling RRR for TS/CT was 18.63 (95% CI, 15.34-22.63). In contrast, the sibling RRR for OCD was 4.89 (95% CI, 3.45-6.93). The parent-offspring RRR for TS/CT was 61.02 (95% CI, 44.43-83.82), whereas the parent-offspring RRR for OCD was 6.25 (95% CI, 4.82-8.11). The sibling and parent-offspring cross-disorder risks were also significant, ranging from 3.20 (95% CI, 2.22-4.62) to 10.27 (95% CI, 5.17-20.39). Tourette syndrome/CT and OCD cluster in families. The familial aggregation of TS/CT is profound and substantially higher than the familial aggregation for OCD. The recurrence risk estimates provide an important clinical framework for identifying individuals at risk and provide insights into the causes of these disorders.


Interplay of brain structure and function in neonatal congenital heart disease.
To evaluate whether structural and microstructural brain abnormalities in neonates with congenital heart disease (CHD) correlate with neuronal network dysfunction measured by analysis of EEG connectivity. We studied a prospective cohort of 20 neonates with CHD who underwent continuous EEG monitoring before surgery to assess functional brain maturation and network connectivity, structural magnetic resonance imaging (MRI) to determine the presence of brain injury and structural brain development, and diffusion tensor MRI to assess brain microstructural development. Neonates with MRI brain injury and delayed structural and microstructural brain development demonstrated significantly stronger high-frequency (beta and gamma frequency band) connectivity. Furthermore, neonates with delayed microstructural brain development demonstrated significantly weaker low-frequency (delta, theta, alpha frequency band) connectivity. Neonates with brain injury also displayed delayed functional maturation of EEG background activity, characterized by greater background discontinuity. These data provide new evidence that early structural and microstructural developmental brain abnormalities can have immediate functional consequences that manifest as characteristic alterations of neuronal network connectivity. Such early perturbations of developing neuronal networks, if sustained, may be responsible for the persistent neurocognitive impairment prevalent in adolescent survivors of CHD. These foundational insights into the complex interplay between evolving brain structure and function may have relevance for a wide spectrum of neurological disorders manifesting early developmental brain injury.


The cardiolipin transacylase, tafazzin, associates with two distinct respiratory components providing insight into Barth syndrome.
Mutations in the mitochondrial cardiolipin (CL) transacylase, tafazzin (Taz1p), result in the X-linked cardioskeletal myopathy, Barth syndrome (BTHS). The mitochondria of BTHS patients exhibit variable respiratory defects and abnormal cristae ultrastructure. The biochemical basis for these observations is unknown. In the absence of its target phospholipid, CL, a very large Taz1p complex is missing, whereas several discrete smaller complexes are still observed. None of the identified Taz1p complexes represents Taz1p homodimers. Instead, yeast Taz1p physically assembles in several protein complexes of distinct size and composition. The ATP synthase and AAC2, both required for oxidative phosphorylation, are identified in separate stable Taz1p complexes. In the absence of CL, each interaction is still detected albeit in reduced abundance compared with when CL is present. Taz1p is not necessary for the normal expression of AAC2 or ATP synthase subunits or assembly of their respective complexes. In contrast, the largest Taz1p complex requires assembled ATP synthase and CL. Mitochondria in Delta taz1 yeast, similar to ATP synthase oligomer mutants, exhibit altered cristae morphology even though ATP synthase oligomer formation is unaffected. Thus, the Taz1p interactome defined here provides novel insight into the variable respiratory defects and morphological abnormalities observed in mitochondria of BTHS patients.


Longitudinal patterns of behavioral, emotional, and social difficulties and self-concepts in adolescents with a history of specific language impairment.
This study explored the prevalence and stability of behavioral difficulties and self-concepts between the ages of 8 and 17 years in a sample of children with a history of specific language impairment (SLI). We investigated whether earlier behavioral, emotional, and social difficulties (BESD); self-concepts; and language and literacy abilities predicted behavioral difficulties and self-concepts at 16/17 years. In this prospective longitudinal study, 65 students were followed up with teacher behavior ratings and individual assessments of language, literacy, and self-concepts at 8, 10, 12, 16, and 17 years. The students had consistently higher levels than norms of 5 domains of BESD, which had different trajectories over time, and poorer scholastic competence, whose trajectory also varied over time. Earlier language ability did not predict later behavioral difficulties or self-concepts, but the prediction of academic self-concept at 16 by literacy at 10 years approached significance. The importance of distinguishing domains of behavioral difficulties and self-concept is demonstrated. Language, when measured at 8 or 10 years of age, was not a predictor of behavior or self-concepts at 16 years, or of self-concepts at 17 years. The study stresses the importance of practitioners addressing academic abilities and different social-behavioral domains in delivering support for adolescents with SLI.


New directions in alcohol and drug treatment under managed care.
To examine the potential effects of the introduction and expansion of managed care on the financing and organization of public and private alcohol and drug abuse treatment systems by reviewing studies on managed care and substance abuse. Spending on treatment for alcohol and drug abuse, the organization of treatment, treatment workforce composition, provision of services, and their implications for access and treatment outcome were examined by review of the treatment literature. Managed care has had major effects on the organization of service delivery, the workforce, and the provision of services. Most of the changes have occurred without the benefit of clinical or policy research. Although managed care has the potential ability to address longstanding problems associated with alcohol and drug treatment, it also presents additional barriers to access and improving treatment outcome. The review suggests that organizational approaches, particularly the settings in which treatment is placed, will differ in their impact on ties between treatment agencies and the medical community, and ties with other health and social service agencies. Also of importance is a new emphasis on accountability of treatment through the mechanisms of outcomes monitoring and performance indicators. It remains to be seen whether these innovations will be meaningfully linked with outcomes research. It is incumbent on researchers and clinicians to explore these issues.


Electroconductive Polymers.
Polymers of a new type with an unusual combination of properties have been synthesized. They are of high molecular weight, they are soluble in organic solvents, and they can be cast as films. Their electrical conduction is electronic in the solid state and can be controlled up to a conductivity of 10(-2) ohm(-1) cm(-1).


OCT-guided laser hyperthermia with passively tumor-targeted gold nanoparticles.
The goal of this study is the development of a method of local laser hyperthermia with gold nanoparticles under noninvasive optical monitoring of nanoparticle accumulation in tumor tissue in vivo. Bifunctional plasmon resonant nanoparticles that are optimal for OCT diagnostics and laser heating at the wavelength of 810 nm were used in the study. The OCT examination showed that the accumulation of gold nanoparticles in the tumor invading into skin was maximal 4-5 h after intravenous injection. It was demonstrated that nanoparticle accumulation in tumor allowed more local heating and enhanced thermal sensitivity of tumor tissue. Laser hyperthermia that heated tumor up to 44-45 °C at maximum nanoparticle accumulation induced apoptotic death of tumor cells and inhibited tumor growth by 104% on the 5th day after treatment.


Heck coupling of olefins to mixed methyl/thienyl monolayers on Si(111) surfaces.
The Heck reaction has been used to couple olefins to a Si(111) surface that was functionalized with a mixed monolayer comprised of methyl and thienyl groups. The coupling method maintained a conjugated linkage between the surface and the olefinic surface functionality, to allow for facile charge transfer from the silicon surface. While a Si(111) surface terminated only with thienyl groups displayed a surface recombination velocity, S, of 670 ± 190 cm s(-1), the mixed CH3/SC4H3-Si(111) surfaces with a coverage of θSC4H3 = 0.15 ± 0.02 displayed a substantially lower value of S = 27 ± 9 cm s(-1). Accordingly, CH3/SC4H3-Si(111) surfaces were brominated with N-bromosuccinimide, to produce mixed CH3/SC4H2Br-Si(111) surfaces with coverages of θBr-Si < 0.05. The resulting aryl halide surfaces were activated using [Pd(PPh3)4] as a catalyst. After activation, Pd(II) was selectively coordinated by oxidative addition to the surface-bound aryl halide. The olefinic substrates 4-fluorostyrene, vinylferrocene, and protoporphyrin IX dimethyl ester were then coupled (in dimethylformamide at 100 °C) to the Pd-containing functionalized Si surfaces. The porphyrin-modified surface was then metalated with Co, Cu, or Zn. The vinylferrocene-modified Si(111) surface showed a linear dependence of the peak current on scan rate in cyclic voltammetry, indicating that facile electron transfer had been maintained and providing evidence of a robust linkage between the Si surface and the tethered ferrocene. The final Heck-coupled surface exhibited S = 70 cm s(-1), indicating that high-quality surfaces could be produced by this multistep synthetic approach for tethering small molecules to silicon photoelectrodes.


Tracking the motion of the KV1.2 voltage sensor reveals the molecular perturbations caused by a de novo mutation in a case of epilepsy.
KV1.2 channels, encoded by the KCNA2 gene, regulate neuronal excitability by conducting K+ upon depolarization. A new KCNA2 missense variant was discovered in a patient with epilepsy, causing amino acid substitution F302L at helix S4, in the KV1.2 voltage-sensing domain. Immunocytochemistry and flow cytometry showed that F302L does not impair KCNA2 subunit surface trafficking. Molecular dynamics simulations indicated that F302L alters the exposure of S4 residues to membrane lipids. Voltage clamp fluorometry revealed that the voltage-sensing domain of KV1.2-F302L channels is more sensitive to depolarization. Accordingly, KV1.2-F302L channels opened faster and at more negative potentials; however, they also exhibited enhanced inactivation: that is, F302L causes both gain- and loss-of-function effects. Coexpression of KCNA2-WT and -F302L did not fully rescue these effects. The proband's symptoms are more characteristic of patients with loss of KCNA2 function. Enhanced KV1.2 inactivation could lead to increased synaptic release in excitatory neurons, steering neuronal circuits towards epilepsy. An exome-based diagnostic panel in an infant with epilepsy revealed a previously unreported de novo missense variant in KCNA2, which encodes voltage-gated K+ channel KV1.2. This variant causes substitution F302L, in helix S4 of the KV1.2 voltage-sensing domain (VSD). F302L does not affect KCNA2 subunit membrane trafficking. However, it does alter channel functional properties, accelerating channel opening at more hyperpolarized membrane potentials, indicating gain of function. F302L also caused loss of KV1.2 function via accelerated inactivation onset, decelerated recovery and shifted inactivation voltage dependence to more negative potentials. These effects, which are not fully rescued by coexpression of wild-type and mutant KCNA2 subunits, probably result from the enhancement of VSD function, as demonstrated by optically tracking VSD depolarization-evoked conformational rearrangements. In turn, molecular dynamics simulations suggest altered VSD exposure to membrane lipids. Compared to other encephalopathy patients with KCNA2 mutations, the proband exhibits mild neurological impairment, more characteristic of patients with KCNA2 loss of function. Based on this information, we propose a mechanism of epileptogenesis based on enhanced KV1.2 inactivation leading to increased synaptic release preferentially in excitatory neurons, and hence the perturbation of the excitatory/inhibitory balance of neuronal circuits.


Microorganisms inhabiting follicular contents of facial acne are not only Propionibacterium but also Malassezia spp.
To clarify the relationship between major cutaneous microorganisms (Propionibacterium, Staphylococcus and Malassezia spp.) and acne vulgaris (acne), we examined the microbiota quantitatively in the follicular contents of inflammatory acne and on the facial skin of patients with acne. Fifteen Japanese untreated acne outpatients were studied. The follicular contents from inflammatory acne lesions of the face were collected using a comedo extractor. The skin surface samples were obtained by the swab method from 10 cm(2) of facial skin. The microbiota was analyzed using polymerase chain reaction. The microbiota in follicular contents was similar to that on the skin surface, namely, there were large populations of Propionibacterium spp., Staphylococcus spp. and Malassezia spp. Moreover, the number of Malassezia spp. on the skin surface was correlated with that of inflammatory acne and that in follicular contents. This study clarified that there are large populations of Propionibacterium spp., Staphylococcus spp. and Malassezia spp. in follicular contents. These results suggest the possibility that not only Propionibacterium acnes but also other cutaneous resident microorganisms are related to acne. Particularly, we considered that Malassezia spp. is closely related.


Risk factors of venous thromboembolism for liver tumors: a systematic review and meta-analysis.
Venous thromboembolism (VTE) is a significant complication in liver tumors patients, and understanding the associated risk factors is essential for effective risk assessment, prevention, and management strategies. This systematic review and meta-analysis aimed to identify key risk factors and their clinical implications for VTE in liver tumors patients. A comprehensive search of multiple databases was conducted to identify relevant studies. Eligible studies were selected, and odds ratios (ORs) and 95% confidence intervals (CIs) were extracted and synthesized for meta-analysis. A total of 11 studies involving 73,652 liver tumors patients and 2049 VTE cases were included. The analysis identified several significant risk factors for VTE in liver tumors patients. Age (≥65 years), male gender, high BMI, diabetes, hepatitis B and C infections, elevated D-dimer and AST levels, reduced albumin levels, and MELD score were all associated with increased VTE risk. This systematic review and meta-analysis revealed several key risk factors for VTE in liver tumors patients, these findings highlight the importance of risk assessment, prevention, and management strategies in this high-risk population. Further research with larger sample sizes and standardized methods is needed to strengthen the existing evidence and validate these findings.


Psychotropic medications and HIV.
Patients with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome have high rates of psychiatric illness. The effective management of these psychiatric conditions can improve a patient's quality of life and may improve antiretroviral adherence. Care providers for patients with HIV infection frequently encounter clinical situations in which psychotropic medications are needed or are being used. Those clinical situations require familiarity with the broad category of medications termed "psychotropic." That familiarity should include a basic understanding of indications, adverse effects, and drug interactions. In particular, it is very important to recognize the many potential interactions based on cytochrome P450 metabolism, which is common to many psychotropics, the protease inhibitors, and the nonnucleoside reverse-transcriptase inhibitors. In a brief review of the use of psychotropic medications in patients with HIV infection, we discuss indications, adverse effects, and drug interactions for commonly used antidepressants, mood stabilizers, anxiolytics, antipsychotics, psychostimulants, and drugs of abuse.


Several GABAA receptor subunits are expressed in LHRH neurons of juvenile female rats.
Gamma aminobutyric acid (GABA), the dominant inhibitory neurotransmitter in brain, is involved in the developmental regulation of LHRH secretion. Morphological studies in rodents have demonstrated that LHRH neurons are innervated by GABA-containing processes, suggesting that LHRH secretion is under direct transsynaptic GABAergic control. While GABA acts through two different receptors, GABAA and GABAB, to exert its effects, it appears that GABAA receptors are able to mediate both inhibitory and stimulatory effects of GABA on LHRH neurons. GABAA receptors are heterooligomeric ligand-gated anion channels that exhibit a diverse array of functional and pharmacological properties. This diversity is determined by the structural heterogeneity of the receptors, which are assembled from the combination of different classes of subunits with multiple isoforms. Although several studies have described the effect of GABAA receptor stimulation on LHRH and/or gonadotropin release in prepubertal animals, nothing is known about the receptor subunits that may be expressed in LHRH neurons at this phase in development. Double immunohistofluorescence followed by confocal laser microscopy revealed that subsets of prepubertal LHRH neurons are endowed with alpha 1, alpha 2, beta 2/3, and gamma 2 GABAA receptor subunits. Combined immunohistochemistry for LHRH neurons and in situ hybridization for GABAA subunit mRNAs confirmed that the genes encoding the alpha 1, alpha 2, beta 3 and gamma 2 subunits, but not the gamma 1 subunit, are expressed in LHRH neurons. Notwithstanding the relative insensitivity of these methods, both the immunohistochemical and hybridization histochemical approaches employed indicate that only a fraction of LHRH neurons are endowed with GABAA receptors. This arrangement suggests that those LHRH neurons bearing the appropriate GABAA receptors are responsible for either the entire secretory response to direct GABAergic inputs or for its initiation.


If bone is the answer, then what is the question?
In the 19th century, several scientists attempted to relate bone trabecular morphology to its mechanical, load-bearing function. It was suggested that bone architecture was an answer to requirements of optimal stress transfer, pairing maximal strength to minimal weight, according to particular mathematical design rules. Using contemporary methods of analysis, stress transfer in bones was studied and compared with anatomical specimens, from which it was hypothesised that trabecular architecture is associated with stress trajectories. Others focused on the biological processes by which trabecular architectures are formed and on the question of how bone could maintain the relationship between external load and architecture in a variable functional environment. Wilhelm Roux introduced the principle of functional adaptation as a self-organising process based in the tissues. Julius Wolff, anatomist and orthopaedic surgeon, entwined these 3 issues in his book The Law of Bone Remodeling (translation), which set the stage for biomechanical research goals in our day. 'Wolff's Law' is a question rather than a law, asking for the requirements of structural optimisation. In this article, based on finite element analysis (FEA) results of stress transfer in bones, it is argued that it was the wrong question, putting us on the wrong foot. The maximal strength/minimal weight principle does not provide a rationale for architectural formation or adaptation; the similarity between trabecular orientation and stress trajectories is circumstantial, not causal. Based on computer simulations of bone remodelling as a regulatory process, governed by mechanical usage and orchestrated by osteocyte mechanosensitivity, it is shown that Roux's paradigm, conversely, is a realistic proposition. Put in a quantitative regulatory context, it can predict both trabecular formation and adaptation. Hence, trabecular architecture is not an answer to Wolff's question, in the sense of this article's title. There are no mathematical optimisation rules for bone architecture; there is just a biological regulatory process, producing a structure adapted to mechanical demands by the nature of its characteristics, adequate for evolutionary endurance. It is predicted that computer simulation of this process can help us to unravel its secrets.


Shadows of complexity: what biological networks reveal about epistasis and pleiotropy.
Pleiotropy, in which one mutation causes multiple phenotypes, has traditionally been seen as a deviation from the conventional observation in which one gene affects one phenotype. Epistasis, or gene-gene interaction, has also been treated as an exception to the Mendelian one gene-one phenotype paradigm. This simplified perspective belies the pervasive complexity of biology and hinders progress toward a deeper understanding of biological systems. We assert that epistasis and pleiotropy are not isolated occurrences, but ubiquitous and inherent properties of biomolecular networks. These phenomena should not be treated as exceptions, but rather as fundamental components of genetic analyses. A systems level understanding of epistasis and pleiotropy is, therefore, critical to furthering our understanding of human genetics and its contribution to common human disease. Finally, graph theory offers an intuitive and powerful set of tools with which to study the network bases of these important genetic phenomena.


Accurate, sensitive, and precise determination of cobalt in soil matrices by the combination of batch type gas-liquid separator-assisted photochemical vapor generation and atomic absorption spectrophotometry.
Determination of cobalt at low concentrations is an important issue because of its potential harmful effects on human health. Although flame atomic absorbance spectrometry (FAAS) is a fast and cheap method, it has high detection limits compared to other methods due to low nebulizer efficiency. In this study, the sensitivity, accuracy, and precision of the conventional FAAS were tried to be improved for cobalt determination using a photochemical vapor generation (PVG) system equipped with a batch type gas-liquid separator (BTGLS). The system parameters including organic acid type and concentration, UV irradiation period, mixing type, atomizer temperature, carrier gas flow rate, and sample volume were optimized to improve the detection power. The limits of detection and quantification were found to be 8.7 and 28.9 μg L-1, respectively. The low relative standard deviation results indicated high precision. Applicability and accuracy of the method to soil samples was determined by recovery studies and percent recoveries were obtained between 98.9-107.0%. Graphical abstract Please provide caption for the graphical abstract.PVG-BT-GLS-AAS system .


Preventive therapy in pediatric migraine.
Preventive therapy for migraine headache includes identification of migraine precipitants, possible adjustments in lifestyle, appropriate management of acute headache, and, when necessary, the use of pharmacologic agents. There are no well-controlled clinical trials with sufficient patient numbers to support the use of any agent in the prevention of migraine headache in children. Data on the use of amitriptyline and divalproex sodium in open-label studies suggest that these agents may be efficacious. The mechanism of action for these agents is unknown but may be related to the 5-hydroxytyptamine-2 (5-HT2) receptor antagonism or regulation of ion channels. A review of the pertinent literature on migraine prophylaxis in children is presented. Dosing guidelines are presented based on the limited data available and clinical experience.


Nonmedical use of d-Amphetamines and Methylphenidate in Medical Students.
The purpose of this study was to determine the prevalence of medical and nonmedical use of prescription attention deficit hyperactive disorder (ADHD) stimulant medication among medical students. An IRB approved 19-question web survey was sent out to all students from a Puerto Rico (PR) medical school to assess use of ADHD medication. Out of the 250 stu-dents consulted there was a response of 152 surveys. Data was cross-referenced and compared with data from other studies. From the results gathered, the study's sample had a higher prevalence of use than the 15% reported in previous studies, reaching 47.4%. Among students who had used these drugs, 89.4% indicated using it without a prescription. 86.8% of all respondents used some form of stimulant or substance in order to cope with the academic workload of medical school, includ-ing coffee, energy drinks, cigarettes, and alcohol. The majority of students (60.5%) considered study techniques workshops and exercise programs to succeed academically. This study suggests a higher prevalence of ADHD medication use amongst the PR medical student sample compared to findings reported of US medical students, as well as a high prevalence related to nonmedical use as a means for medical students to cope with their training. The nonmedical use of stimulants in the medical school setting remains of utmost public health and clinical concern. The results of this study could help develop proper workshops and non-pharmacological techniques to help medical students cope with their workload.


[The humoral immunity changes in experimental cranio-cerebral trauma, concurrent with diabetes mellitus].
The results of studying in dynamics of the humoral immunity indices were adduced in experimental cranio-cerebral truma (CCT) in conjunction with diabetes mellitus (DM). Peculiarities of the immune answer while the period of an acute reaction on trauma and early signs of posttraumatic period have been characterized by reduction of content in the main classes of immunoglobulins IgA, IgM, IgG and enhancement of the circulating immune complexes (CIC) concentration. Experimental DM was accompanied by raising of functional activity of humoral immunity in accordance with immunoglobulins level and CIC. The specificity of changes in humoral immunity in conditions of CCT on the DM background consisted of more profound lowering of the immunoglobulins level and rapid enhancement of the CIC content.


Examining Rural and Racial Disparities in the Relationship Between Loneliness and Social Technology Use Among Older Adults.
Loneliness, the subjective negative experience derived from a lack of meaningful companionship, is associated with heightened vulnerability to adverse health outcomes among older adults. Social technology affords an opportunity to cultivate social connectedness and mitigate loneliness. However, research examining potential inequalities in loneliness is limited. This study investigates racial and rural-urban differences in the relationship between social technology use and loneliness in adults aged 50 and older using data from the 2016 wave of the Health and Retirement Study (N = 4,315). Social technology use was operationalized as the self-reported frequency of communication through Skype, Facebook, or other social media with family and friends. Loneliness was assessed using the UCLA Loneliness scale, and rural-urban differences were based on Beale rural-urban continuum codes. Examinations of race focused on differences between Black/African-American and White/Caucasian groups. A path model analysis was performed to assess whether race and rurality moderated the relationship between social technology use and loneliness, adjusting for living arrangements, age, general computer usage. Social engagement and frequency of social contact with family and friends were included as mediators. The primary study results demonstrated that the association between social technology use and loneliness differed by rurality, but not race. Rural older adults who use social technology less frequently experience greater loneliness than urban older adults. This relationship between social technology and loneliness was mediated by social engagement and frequency of social contact. Furthermore, racial and rural-urban differences in social technology use demonstrated that social technology use is less prevalent among rural older adults than urban and suburban-dwelling older adults; no such racial differences were observed. However, Black older adults report greater levels of perceived social negativity in their relationships compared to White older adults. Interventions seeking to address loneliness using social technology should consider rural and racial disparities.


Delayed versus immediate reconstruction of mandibular segmental defects using recombinant human bone morphogenetic protein 2/absorbable collagen sponge.
To compare the efficiency of recombinant human bone morphogenetic protein 2 (rhBMP2)/absorbable collagen sponge (ACS) in the delayed versus immediate reconstruction of mandibular segmental defects in a canine model. We randomized 11 dogs into 2 groups: immediate reconstruction (group 1, n = 6) and delayed reconstruction (group 2, n = 5). A 35-mm osteoperiosteal segmental defect was created on the left side of the mandible. Reconstruction with rhBMP2/ACS was carried out in the same setting in group 1 or at 4 weeks postoperatively in group 2. The contralateral side acted as an internal control. Animals were monitored both clinically and radiographically throughout the experiment. Twelve weeks after the application of rhBMP2/ACS, the quantity of bone formation was evaluated using regenerate mapping and histomorphometric analysis. Qualitative evaluation was performed based on bone mineral density and Vickers microhardness (μHV) testing. Postoperative seromas were observed in 83.3% of group 1 dogs only. Group 1 showed significantly larger physical dimensions than group 2 in most regenerate zones. Successful regeneration was achieved in 83.3% of group 1 dogs (discontinuity defect was seen in 1 of 6 dogs in group 1). Meanwhile, none of the 5 dogs in group 2 could be considered to have undergone successful regeneration (3 dogs had discontinuity defects, bony union occurred only in the basal third in the fourth dog, and the last dog showed union with only a shell of bone). The percent bone area and percent defect filling were significantly higher in group 1 than in group 2 (percent bone area, 52.4% ± 5.6% in group 1 and 36.6% ± 11.2% in group 2 [P = .02]; percent defect filling, 56.3% ± 5.5% in group 1 and 38.5% ± 10.8% in group 2 [P = .01]). Group 1 showed higher bone mineral density (0.7 ± 0.3 mg/cm(3) in group 1 and 0.4 ± 0.1 mg/cm(3) in group 2, P = .1). Finally, μHV was significantly higher in group 1 (20.3 ± 2.6 μHV) than in group 2 (13.2 ± 2.4 μHV) (P = .01). Delaying the application of rhBMP2/ACS for 4 weeks attenuated the quantity and quality of regenerated bone in mandibular segmental defects.


Balance and gait in children with dyslexia.
Tests of postural stability have provided some evidence of a link between deficits in gross motor skills and developmental dyslexia. The ordinal-level scales used previously, however, have limited measurement sensitivity, and no studies have investigated motor performance during walking in participants with dyslexia. The purpose of this study was to investigate if continuous-scaled measures of standing balance and gait could discriminate between groups of impaired and normal readers when investigators were blind to group membership during testing. Children with dyslexia ( n=22) and controls ( n=18), aged 10-12 years, performed walking tests at four different speeds (slow-preferred-fast-very fast) on an even and an uneven surface, and tests of unperturbed and perturbed body sway during standing. Body movements were registered by a triaxial accelerometer over the lower trunk, and measures of reaction time, body sway, walking speed, step length and cadence were calculated. Results were controlled for gender differences. Tests of standing balance with eyes closed did not discriminate between groups. All unperturbed standing tests with eyes open showed significant group differences ( P<0.05) and classified correctly 70-77.5% of the subjects into their respective groups. Mean walking speed during very fast walking on both flat and uneven surface was > or =0.2 m/s ( P< or =0.01) faster for controls than for the group with dyslexia. This test classified 77.5% and 85% of the subjects correctly on flat and uneven surface, respectively. Cadence at preferred or very fast speed did not differ statistically between groups, but revealed significant group differences when all subjects were compared at a normalised walking speed ( P< or =0.04). Very fast walking speed as well as cadence at a normalised speed discriminated better between groups when subjects were walking on an uneven surface compared to a flat floor. Continuous-scaled walking tests performed in field settings may be suitable for motor skill assessment as a component of a screening tool for developmental dyslexia.


Treatment of extension contracture of the hip in cerebral palsy.
Twenty patients with cerebral palsy had a total of 35 extension contractures of the hip, resulting from tightness of the gluteus maximus or hamstring muscles, with associated quadricepts muscle spasticity. Associated deformities included anteriorly dislocated hips, patella alta, lumbar lordosis, thoracic kyphosis and calcaneus feet. Active and passive exercises, surgical release of contractures and reduction of anteriorly dislocated hips improved function. Hip flexor or adductor tenotomies must be considered cautiously for patients with spastic hip extensor muscles, because severe extension constricture may develop after either procedure.


Expression and characterization of a heme oxygenase (Hmu O) from Corynebacterium diphtheriae. Iron acquisition requires oxidative cleavage of the heme macrocycle.
A full-length heme oxygenase gene from the pathogenic bacterium Corynebacterium diphtheriae has been subcloned and expressed in Escherichia coli. The enzyme is expressed at high levels as a soluble catalytically active protein that results in the accumulation of biliverdin within the E. coli cells. The purified heme oxygenase forms a 1:1 complex with heme (Kd = 2.5 +/- 1 microM) and has hemeprotein spectra similar to those previously reported for the purified eukaryotic heme oxygenases. In the presence of an E. coli NADPH-dependent reductase isolated during the purification of Hmu O, the heme-Hmu O complex is catalytically turned over to yield biliverdin IXalpha and carbon monoxide. A number of redox partners were investigated for their ability to reconstitute Hmu O activity in vitro. Of these the most efficient appeared to be the recombinant NADH-dependent putidaredoxin/putidaredoxin reductase from Pseudomonas putida. As with the E. coli NADPH-dependent reductase the final products of the reaction were biliverdin IXalpha and carbon monoxide. This is the first bacterial heme oxygenase to be described to date. The close relationship between iron acquisition and pathogenesis suggests that the release of iron from heme by heme oxygenase may play a crucial role in the pathogenicity of C. diphtheriae.


Molecular and Cellular Mechanisms Responsible for Beneficial Effects of Mesenchymal Stem Cell-Derived Product "Exo-d-MAPPS" in Attenuation of Chronic Airway Inflammation.
Mesenchymal stem cells (MSCs), due to their potential for differentiation into alveolar epithelial cells and their immunosuppressive characteristics, are considered a new therapeutic agent in cell-based therapy of inflammatory lung disorders, including chronic obstructive pulmonary disease (COPD). Since most of the MSC-mediated beneficent effects were the consequence of their paracrine action, herewith, we investigated the effects of a newly designed MSC-derived product "Exosome-derived Multiple Allogeneic Protein Paracrine Signaling (Exo-d-MAPPS)" in the attenuation of chronic airway inflammation by using an animal model of COPD (induced by chronic exposure to cigarette smoke (CS)) and clinical data obtained from Exo-d-MAPPS-treated COPD patients. Exo-d-MAPPS contains a high concentration of immunomodulatory factors which are capable of attenuating chronic airway inflammation, including soluble TNF receptors I and II, IL-1 receptor antagonist, and soluble receptor for advanced glycation end products. Accordingly, Exo-d-MAPPS significantly improved respiratory function, downregulated serum levels of inflammatory cytokines (TNF-α, IL-1β, IL-12, and IFN-γ), increased serum concentration of immunosuppressive IL-10, and attenuated chronic airway inflammation in CS-exposed mice. The cellular makeup of the lungs revealed that Exo-d-MAPPS treatment attenuated the production of inflammatory cytokines in lung-infiltrated macrophages, neutrophils, and natural killer and natural killer T cells and alleviated the antigen-presenting properties of lung-infiltrated macrophages and dendritic cells (DCs). Additionally, Exo-d-MAPPS promoted the expansion of immunosuppressive IL-10-producing alternatively activated macrophages, regulatory DCs, and CD4+FoxP3+T regulatory cells in inflamed lungs which resulted in the attenuation of chronic airway inflammation. In a similar manner, as it was observed in an animal model, Exo-d-MAPPS treatment significantly improved the pulmonary status and quality of life of COPD patients. Importantly, Exo-d-MAPPS was well tolerated since none of the 30 COPD patients reported any adverse effects after Exo-d-MAPPS administration. In summing up, we believe that Exo-d-MAPPS could be considered a potentially new therapeutic agent in the treatment of chronic inflammatory lung diseases whose efficacy should be further explored in large clinical trials.


Radical hysterectomy with bilateral pelvic node dissection. Our experience at the Philippine General Hospital.
From June 1961 to Jan. 1989 (28 & 1/2 years) a total of 627 patients were subjected to radical hysterectomy with bilateral pelvic node dissection (Meigs Operation). The main indication was cancer of the uterine cervix, which comprised 96%. There were 6 surgical deaths, with a mortality rate of 0.9%. The causes of death were hemorrhage, sepsis, atelectasis, and blood transfusion reaction. In the unirradiated group, the most common postoperative complication was infection, which was encountered in 23.8%. The most common site of infection was the urinary tract, 13.6%, followed by the incision (5.5%), and the pelvis (4.7%). One of the most distressing complications of the operation, ureterovaginal fistula, occurred in 7 patients, a rate of 1.3%, which is quite low. All except one were repaired successfully. There were 3 vesicovaginal fistulas (0.5%), and two of these healed spontaneously. In the irradiated group, the complication rate was much higher and more serious. The incidence of serious infection was 48.4%, which was more than double the unirradiated group. In addition, there were six cases of rectovaginal fistula (9.7%), two cases of vesicovaginal fistula, and 1 case of ureterovaginal fistula. The 3 year survival rate for stage I cancer of the cervix was 68.5%, stage IIa, 52.8%, recurrent cervical cancer, 25.8% and for stage II endometrial cancer, 89%.


Current developments in the genetics of autism: from phenome to genome.
Despite compelling evidence from twin and family studies indicating a strong genetic involvement in the etiology of autism, the unequivocal detection of autism susceptibility genes remains an elusive goal. The purpose of this review is to evaluate the current state of autism genetics research, with attention focused on new techniques and analytic approaches. We first present a brief overview of evidence for the genetic basis of autism, followed by an appraisal of linkage and candidate gene study findings and consideration of new analytic approaches to the study of complex psychiatric conditions, namely, genome-wide association studies, assessment of structural variation within the genome, and the incorporation of endophenotypes in genetic analysis.


Total synthesis of a stereoisomer of bistramide C and assignment of configuration of the natural product.
After the isolation of the bioactive polyether bistramide C from the marine ascidian Lissoclinum bistratum in 1988, NMR spectroscopic investigations over the next 12 years reduced the total number of possible stereoisomers of this compound from 1024 to 32. Based on the preparation of segments of the natural product as well as the total synthesis of a randomly selected stereoisomer of bistramide C, the stereochemical puzzle could be further simplified to eight possible stereoisomers. A convergent three-segment coupling strategy, the use of a common, D-glucose-derived intermediate for the preparation of pyran rings in two segments, a stereoselective photo-spiroketalization, and the use of azides to minimize protective group manipulations before segment couplings are highlights of the synthetic approach. The total synthesis also provided the key segments for a chiroptical analysis according to van't Hoff's principle of optical superposition, which was crucial for the assignment of a sole relative and absolute configuration of the natural product. Bistramide C represents therefore the first member of this class of structurally unusual marine polyethers whose configuration is known as a result of the combined use of synthetic and chiroptical tools.


Pineal N-acetyltransferase, pineal and serum melatonin response to isoproterenol stimulation in underfed male rats.
Adult male rats were subjected to 4 weeks of 50% food restriction under lighting regimen of 14 h light and 10 h dark. The pineal response to isoproterenol (ISO) was determined. In the time-course study, animals were injected with 0.5 mg/Kg ISO subcutaneously (SC) and killed at different times up to 180 min post injection. In the dose-response study, various doses of ISO (0.2 mg/Kg to 5.0 mg/Kg) were injected intraperitoneally (IP) and animals were killed 120 min post injection. Body weight, pineal N-acetyltransferase (NATase), pineal and serum melatonin (MT) were determined. After 4 weeks of restricted feeding, body weight was reduced by 40%. In the time-course study, peak pineal NATase occurred 120 min post injection in the ad libitum fed animals. By contrast, the food restricted animals showed a gradual increase of pineal NATase up to 180 min post injection. In the dose-response study, the ad libitum fed animals demonstrated a dose dependent increase of pineal NATase up to 5 mg/kg dose. The food restricted animals, however, achieved their maximal pineal NATase at 1 mg/Kg dose with no further increment at 5 mg/Kg dose. These differences in responsiveness were also reflected in pineal and serum MT levels. These results indicate that underfed animals have abnormal pineal NATase, pineal and serum MT responses to ISO stimulation.


[Multiple organ failure syndrome in critically ill patients].
A new approach to defining the notion of multiple organ failure is proposed. It is based on division of the organ humoral injuries at the stages of dysfunction, insufficiency, and failure. Criteria of these stages are defined for the central nervous and cardiovascular systems, lungs, liver, kidneys, and gastrointestinal tract.


Lamb wave scattering analysis for reflector characterization.
The potential use of guided waves for defect characterization is studied. The influence of defect shape and size on transmitted and reflected fields is considered. Using the hybrid boundary element technique, the reflection and transmission coefficients for selected guided wave modes are numerically calculated and compared to experimental data. Selecting the aspect ratio as a shape parameter for various defects, the transmission and reflection coefficients are measured for certain guided wave modes input to the defect. The influence of defect size is then studied by monitoring the transmission and reflection coefficients for defects of various shapes and depths. The studies presented indicate that defect characterization is possible if a proper mode selection criteria can be established. The suitable features related to transmission and reflection coefficient data can also be used for algorithm development and implementation purposes of defect characterization.


[Value of the "regression-to-mean" effect in the evaluation of arterial blood pressure in adolescents in epidemiological studies].
Patterns of systolic and diastolic blood pressure were assessed in adolescents who were 12-13 at the time of first examination. Three-year follow-up consisted of 5 check-ups. Upon the first examination, all adolescents were divided into three groups: those with low (below the 10th percentile), normal (between the 10th and 90th percentiles) and high (above the 90th percentile) arterial BP values. Repeated checkups covered all adolescents with low and high arterial BP as well as a 20% sample of normotensive subjects. Over the three years of follow-up; the greatest increment in systolic and diastolic arterial BP was noted in the hypotensive group, and the smallest, in the hypertensive group. Various hypotheses are discussed that might explain the demonstrated regularity; the "regression-to-mean" effect is proposed as a possible explanation.


Udenafil for the treatment of erectile dysfunction.
Erectile dysfunction (ED) is often perceived by both patients and sexual partners as a serious problem that can jeopardize quality of life, psychosocial or emotional well-being, and the partnership in the long term. Since their introduction, oral phosphodiesterase type 5 inhibitors (PDE5Is) have been found to be highly effective and well tolerated, and are available as the first-line therapy for the treatment of ED. Udenafil is one of the selective PDE5Is made available in recent years for the treatment of ED. Udenafil has clinical properties of both relatively rapid onset and long duration of action due to its pharmacokinetic profile, thereby providing an additional treatment option for ED men to better suit individual needs. There is positive evidence that udenafil is effective and well tolerated in the treatment of ED of a broad spectrum of etiologies or severity. Udenafil is as effective in the treatment of diabetes mellitus-associated ED as other PDE5Is. Due to the clinical property of relatively long duration of action, udenafil may be another option in daily dosing treatment for ED, as suggested by its favorable efficacy and safety profile. Most adverse effects reported from clinical trials are mild or moderate in severity, without any serious adverse event, with headache and flushing being the most common. Also, the concomitant use of anti-hypertensive drugs or alpha-1-blockers does not significantly affect the efficacy and safety profile of udenafil. However, additional studies with larger cohorts including prospective, multicenter, comparative studies with patients of different ethnicities are needed to further validate the favorable findings of udenafil in the treatment of ED.


[Population frequency of neural tube defects in the population of the city of Moscow].
A sample investigation was carried out in 14 maternity homes of Moscow during 1970--1976 in order to determine the population incidence of defects of the neural tibe. Among 282336 newborns 220 probands with these anomalies were found including 11 with syndromes of non-multifactorial etiology. The total incidence of multifactorial forms was 0.74 +/- 0.10 per 1000 newborns, the incidence of the anencephaly was 0.33 +/- 0.07% and the frequency of the spina bifida was 0.41 +/- 0.07% respectively. The sex ratio 0.61 among probands was statistically significantly different from that normal among newborns. An insignificant increase of the incidence of the defects was observed during the autumn and winter seasons. No correlation was observed between the mother's age, the birth order and the incidence of the neural tube defects.


Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa.
Phylostratigraphy is a method used to correlate the evolutionary origin of founder genes (that is, functional founder protein domains) of gene families with particular macroevolutionary transitions. It is based on a model of genome evolution that suggests that the origin of complex phenotypic innovations will be accompanied by the emergence of such founder genes, the descendants of which can still be traced in extant organisms. The origin of multicellularity can be considered to be a macroevolutionary transition, for which new gene functions would have been required. Cancer should be tightly connected to multicellular life since it can be viewed as a malfunction of interaction between cells in a multicellular organism. A phylostratigraphic tracking of the origin of cancer genes should, therefore, also provide insights into the origin of multicellularity. We find two strong peaks of the emergence of cancer related protein domains, one at the time of the origin of the first cell and the other around the time of the evolution of the multicellular metazoan organisms. These peaks correlate with two major classes of cancer genes, the 'caretakers', which are involved in general functions that support genome stability and the 'gatekeepers', which are involved in cellular signalling and growth processes. Interestingly, this phylogenetic succession mirrors the ontogenetic succession of tumour progression, where mutations in caretakers are thought to precede mutations in gatekeepers. A link between multicellularity and formation of cancer has often been predicted. However, this has not so far been explicitly tested. Although we find that a significant number of protein domains involved in cancer predate the origin of multicellularity, the second peak of cancer protein domain emergence is, indeed, connected to a phylogenetic level where multicellular animals have emerged. The fact that we can find a strong and consistent signal for this second peak in the phylostratigraphic map implies that a complex multi-level selection process has driven the transition to multicellularity.


Treatment of acute myocardial infarction by invasive cardiology techniques.
The role of coronary angioplasty as a means of reperfusion therapy in the patient who suffered an acute myocardial infarction has continued to evolve. Adjunctive angioplasty immediately after thrombolytic therapy has been discarded as a routine therapeutic approach. Rescue angioplasty after failed thrombolysis has limited applicability due to the inability to readily diagnose a failure of thrombolysis. Primary angioplasty is the appropriate reperfusion approach in those patients ineligible for thrombolysis and perhaps offers advantages over thrombolysis in the elderly patients, in the patients with a large anterior infarction, and in patients in cardiogenic shock secondary to the acute infarction.


Effects of adenosine on the functions of circulating polymorphonuclear leukocytes during hyperdynamic endotoxemia.
Endotoxin-activated polymorphonuclear leukocytes (PMNL) adhere to the vascular endothelium and cause damage by the release of toxic superoxide anions (O2-). Because adenosine is a potent inhibitor of PMNL in vitro, the present study investigates the effects of this nucleoside on the functions of circulating PMNL in a standardized porcine model of hyperdynamic endotoxemia. Ten anesthesized pigs received an intravenous (i.v.) 330-min infusion of endotoxin (5 microg/kg of body weight per h). Another 10 pigs were also infused with endotoxin plus adenosine (150 microg/kg/min [i.v.]); this treatment was begun 30 min prior to the beginning of endotoxin treatment. Control groups (five animals per group) received either adenosine or physiological saline. Infusion of endotoxin caused severe neutropenia, shedding of L-selectin, upregulation of beta2-integrins, increased binding of C3-coated zymosan particles, and subsequent phagocytosis by PMNL. While phagocytosis-induced production of oxygen radicals appeared to decrease, extracellular release of superoxide anions was strongly enhanced. Infusion of adenosine during endotoxemia had no effect on neutropenia, expression of adhesion molecules, C3-induced adhesion, phagocytosis, or intracellular production of oxygen radicals, whereas extracellular release of O2- was strongly inhibited. Thus, i.v. infusion of adenosine during endotoxemia could be useful in protecting from O2(-)-mediated tissue injury without compromising the bactericidal mechanisms of PMNL.


Factors associated with the number of drugs in darunavir/cobicistat regimens.
Darunavir/cobicistat can be used as mono, dual, triple or more than triple therapy. To assess factors associated with the number of drugs in darunavir/cobicistat regimens. A nationwide retrospective cohort study of consecutive HIV-infected patients initiating darunavir/cobicistat in Spain from July 2015 to May 2017. Baseline characteristics, efficacy and safety at 48 weeks were compared according to the number of drugs used. There were 761 patients (75% men, 98% were antiretroviral-experienced, 32% had prior AIDS, 84% had HIV RNA <50 copies/mL and 88% had ≥200 CD4 cells/mm3) who initiated darunavir/cobicistat as mono (n=308, 40%), dual (n=173, 23%), triple (n=253, 33%) or four-drug (n=27, 4%) therapy. Relative to monotherapy, triple therapy was more common in men aged <50 years, with prior AIDS and darunavir plus ritonavir use, and with CD4 cells <200/mm3 and with detectable viral load at initiation of darunavir/cobicistat; dual therapy was more common with previous intravenous drug use, detectable viral load at initiation of darunavir/cobicistat and no prior darunavir plus ritonavir; and four-drug therapy was more common with prior AIDS and detectable viral load at initiation of darunavir/cobicistat. Monotherapy and dual therapy showed a trend to better virological responses than triple therapy. CD4 responses and adverse effects did not differ among regimens. Darunavir/cobicistat use in Spain has been tailored according to clinical characteristics of HIV-infected patients. Monotherapy and dual therapy have been common and preferentially addressed to older patients with a better HIV status, suggesting that health issues other than HIV infection may have been strong determinants of its prescription.


Dipeptidyl peptidase IV (CD26) activity in human alloreactive T cell subsets varies with the stage of differentiation and activation status.
Dipeptidyl peptidase IV (DPP IV), also known as CD26, is a transmembrane serine aminopeptidase which has an ontogenically related expression on T cells and participates on several immunological functions. CD26 appears to play an important role in alloimmunity during host T cell activation subsequent to alloantigen encounter and is a way by which effector T cells traverse graft endothelial barriers. In order to help to elucidate the role of the CD26 molecule in alloimmune responses, DPP IV activity and CD26 antigenic expression were assessed during the initial phases of completely MHC-disparate human mixed lymphocyte reactions (MLRs) and in several long-term alloreactive T cell clones. Our methods involved the use of a rhodamine-110-conjugated dipeptide substrate specific for DPP IV in two-colour cytofluorographic analysis that allowed stimultaneous lineage marker evaluation. Polyclonal populations of alloreactive CD4 and CD8 T cells contained DPP IV activity at 1 and 10 min of incubation that was variably elevated from resting T cells with the enzyme activity confined to CD26+ cells. T cell clones derived from MLRs were established with IL-2 supplementation and alloantigen restimulation and had reduced CD62L expression with functional specificity to the stimulating MHC. While CD26 expression remained stable, DPP IV activity was variable in the alloreactive T cell clones, with enzyme function in the latter appearing to coincide with the timing of alloantigen restimulation. These studies demonstrate that DPP IV activity varies among phenotypically distinct alloreactive T cell subsets and appears to be altered with the activation status of the effector cells. These findings raise the potential of a role for CD26/DPP IV in the generation of specific alloimmunity. With this methodology, it may be possible to reveal whether specific alterations in the activity of this molecule in T cell populations promote graft acceptance and to determine the molecular requirements for these changes.


The digitus quintus, rigid stoma, 4-5 position gastroplasty.
In 55 patients a rigid stoma gastroplasty was performed. The operative technique is described. It includes the construction of a rigid stoma and a double line of staples across the stomach to give a pouch volume of 40 to 60 ml. The diameter of the stoma is established by a nasogastric tube and the digitus quintus of the assistant's hand at the level of the cuticle. A 1- to 2-year follow-up indicates that these stomas do not dilate but tend to decrease in diameter. Stomal stenosis occurred in 2 of the 55 patients studied. Weight loss was satisfactory, although incomplete in most patients. It is likely that the weight loss will not be as great as with intestinal bypass. There were no serious late postoperative complications. However, an appreciable number of patients had emesis early in the postoperative period, intolerance of red meat and constipation. It is apparent that a rigid stoma of constant diameter is at least as important as a small gastric pouch in achieving adequate and lasting weight loss. A longer follow-up is necessary to assess this procedure completely.


Bleeding in patients with sickle cell disease: a population-based study.
Bleeding is a known complication of sickle cell disease (SCD) and includes hemorrhagic stroke, hematuria, and vitreous hemorrhage. However, the incidence of bleeding events in patients with SCD has not been well described. We present a retrospective, population-based study examining the cumulative incidence of bleeding in 6423 patients with SCD from 1991 to 2014. We also studied risk factors associated with bleeding and the effects of bleeding on mortality, using Cox proportional hazards regression models. We used California emergency department and hospitalization databases to identify patients with SCD with intracranial hemorrhage, gastrointestinal (GI) bleeding, hemophthalmos, gross hematuria, epistaxis, menorrhagia, and other bleeding events. The cumulative incidence of any first bleeding event at age 40 years was 21% (95% confidence interval [CI], 19.8%-22.3%), increasing with age to 41% by age 60 years (95% CI, 38.8%-43.1%). The majority of bleeding events were GI (41.6%), particularly from the upper GI tract. A higher bleeding risk was associated with increased frequency of hospitalization (hazard ratio [HR], 2.16; 95% CI, 1.93-2.42), venous thromboembolism 180 days before bleeding event (HR, 4.24; 95% CI, 2.86-6.28), osteonecrosis of the femoral head (HR, 1.25; 95% CI, 1.08-1.46), and ischemic stroke (HR, 1.65; 95% CI, 1.20-2.26). Bleeding was also associated with a twofold increased risk for death (HR, 2.09; 95% CI, 1.82-2.41) adjusted for other SCD-related complications. Our novel finding of a high incidence of bleeding in patients with SCD, particularly from the upper GI tract, suggests that patients with SCD may be predisposed to bleeding, with possible etiologies including increased use of nonsteroidal anti-inflammatory drugs, mucosal infarction from vascular occlusion by sickled red blood cells, and increased stress ulceration from frequent hospitalization.


Community-based treatment of cutaneous leishmaniasis using cryotherapy and miltefosine in Southwest Ethiopia: the way forward?
Cutaneous leishmaniasis (CL) is a common, yet massively underreported skin morbidity in Ethiopia. Most patients never seek treatment, as this is offered only in specialized treatment centers. Early diagnosis and treatment through decentralization is crucial to decrease transmission and to reach the NTD roadmap goals. However, little information is available on outcomes and challenges of community-based treatment initiatives. A community-based prospective cohort study was conducted in Ochollo. Patients with clinically or microscopy confirmed CL were included. Cryotherapy was (to be) given weekly with at least four sessions for uncomplicated lesions, and miltefosine was given for 4 weeks for complicated lesions. Miltefosine adherence was assessed by counting pill strips. Clinical and patient-reported outcomes (dermatological life quality index and patient-global assessment) were assessed at month 6 (M6). A total of 107 patients were included, with a median age of 6 years. Two patients refused, and 15 could not be treated as they were too young (<4 years) for miltefosine. Giving cryotherapy to patients weekly was not feasible due to long wound healing times and required use of topical antibiotics. Only 52.4% of miltefosine patients finished >90% of their tablets by M1. Among 46 patients treated with cryotherapy, 24 (52.2%) were cured at M6, and 9 (19.6%) had substantial improvement. The cure rate was 16/39 (41.0%) for miltefosine with 28.2% (11/39) substantial improvement. Before treatment, more than half (57.8%) of patients reported that CL did not negatively impact their life, which significantly increased to 95.2% at M6. At this time, 61.7% of patients said their lesion was clear, which was 1% before treatment. Our study is the first to identify the challenges and opportunities of miltefosine and cryotherapy for community treatment of CL. Although overall cure rates were lower than expected, patient-reported outcomes were generally positive and quite some patients had good improvement.


Chicoric acid binds to two sites and decreases the activity of the YopH bacterial virulence factor.
Chicoric acid (CA) is a phenolic compound present in dietary supplements with a large spectrum of biological properties reported ranging from antioxidant, to antiviral, to immunostimulatory properties. Due to the fact that chicoric acid promotes phagocytic activity and was reported as an allosteric inhibitor of the PTP1B phosphatase, we examined the effect of CA on YopH phosphatase from pathogenic bacteria, which block phagocytic processes of a host cell. We performed computational studies of chicoric acid binding to YopH as well as validation experiments with recombinant enzymes. In addition, we performed similar studies for caffeic and chlorogenic acids to compare the results. Docking experiments demonstrated that, from the tested compounds, only CA binds to both catalytic and secondary binding sites of YopH. Our experimental results showed that CA reduces activity of recombinant YopH phosphatase from Yersinia enterocolitica and human CD45 phosphatase. The inhibition caused by CA was irreversible and did not induce oxidation of catalytic cysteine. We proposed that inactivation of YopH induced by CA is involved with allosteric inhibition by interacting with essential regions responsible for ligand binding.


Genetic and environmental links between cognitive and physical functions in old age.
In old age, cognitive and physical functions are correlated. Knowing the correlations between genetic and environmental influences underlying this correlation can help to clarify the reasons for the observable (phenotypic) correlation. We estimated these correlations in a sample of 1,053 pairs of twins from the Longitudinal Study of Aging Danish Twins. Cognitive function was measured using forward and backward digit span, immediate and delayed memory, and fluency tasks. Physical function was measured using self-report of ability to carry out physical activities including walking, running, and climbing stairs. The phenotypic correlation between latent variable representations was .46 (95% confidence interval 0.27-0.65). The genetic correlation was .56 (95% confidence interval 0.15-1.00) and the nonshared environmental correlation .48 (95% confidence interval 0.35-0.61). We discuss several ways of interpreting these correlations.


Spatiotemporal analysis of spontaneous myogenic contractions in the urinary bladder of the rabbit: timing and patterns reflect reported electrophysiology.
The dynamics of propagating myogenic contractions in the wall of the resting ex vivo urinary bladder of the rabbit were characterized by spatiotemporal maps and related to cyclic variation in intravesical pressure (Pves). Patches of propagating contractions (PPCs) enlarged and involuted in near synchrony with peaks in Pves [mean 3.85 ± 0.3 cycles per minute (cpm)] and were preceded by regions of stretch. The maximum area of the bladder undergoing contraction (55.28 ± 2.65%) and the sizes of individual PPCs (42.61 ± 1.65 mm2) coincided with the peak in Pves PPCs originated and propagated within temporary patch domains (TPDs) and comprised groups of nearly synchronous cyclic propagating individual contractions (PICs). The TPDs were located principally along the vertical axis of the anterior surface of the bladder. The sites of origin of PICs within PPCs were inconsistent, consecutive contractions often propagating in opposite directions along linear maps of strain rate. Similar patterns of movement occurred in areas of the anterior bladder wall that had been stripped of mucosa. Pves varied cyclically with area of contraction and with the indices of aggregation of PPCs, indicating that they grew by peripheral enlargement and collision without annihilation. The synchronization of PICs within PPCs was sometimes lost, uncoordinated PICs then occurring irregularly (between 4 and 20 cpm) having little effect on Pves We postulate that the formation and involution of PPCs within a TPD resulted from cyclic variation in excitation that increased the incidence and distance over which component PICs propagated.


Paenibacillus piri sp. nov., isolated from urban soil.
A rod-shaped, Gram-stain-positive bacterial strain, MS74T, was isolated from soil beside Itaewon road, Seoul, Republic of Korea. The strain could grow well on R2A, nutrient agar and tryptone soya agar, but not in LB agar. MS74T tolerated 3.0 % NaCl (w/v), pH 9.0 and a temperature range from 10 to 35 °C (optimal temperature, 28 °C). From the comparison of 16S rRNA gene sequence, the strain is most closely related to Paenibacillus vulneris CCUG 53270T , Paenibacillus esterisolvens CFH S0170T, Paenibacillus rigui JCM 16352T and Paenibacillus yunnanensis YN2T with similarity percentages of 96.6 %, 96.4 %, 95.9 % and 95.8 % respectively. Major polar lipids were diphosphatidylglycerol (DPG), phosphatidylglycerol (PG), and phosphatidylethanolamine (PE). The major menaquinone was MK-7. The fatty acids profile mainly consisted of C15 : 0 anteiso, C15 : 0 iso, C16 : 0 iso, and C16 : 0. The DNA G+C content of the isolated strain determined from the whole-genome sequence was 51 mol%. MS74T had an average nucleotide identity (ANI) value of 73.9 % and a digital DNA-DNA hybridization (dDDH) value of 20.6 % with most closely related strain, Paenibacillus vulneris CCUG 53270T. On the basis of phenotypic, chemotypic and genotypic evidence, the isolate was identified as representing a novel species of the genus Paenibacillus, for which the name Paenibacillus piri sp. nov. is proposed. The type strain is MS74T (=KACC 19385T =DSM 105496T).


The effect of type of physical activity measure on the relationship between body fatness and habitual physical activity in children: a meta-analysis.
The relationship between activity levels and body fat in children is unclear, despite a large number of studies. The issue is clouded by the wide variety of methods used to assess children's activity levels. It is important to assess whether the type of activity measure influences the fatness-activity relationship. This is a first step to uncovering the role of modifying variables such as gender, age, maturity, etc. This study uses meta-analytic procedures to synthesize the results of such studies and to assess whether the type of activity measure used has an effect on the strength of the relationship observed. Fifty studies were located that satisfied the inclusion criteria. Seventy-eight per cent of the studies showed a negative relationship, 18% no relationship and 4% a positive relationship between physical activity and body fatness. Data were analysed using the meta-analytic procedures described by Rosenthal (Meta-analytic Procedures for Social Research, Sage, 1991). The mean effect size indicated a small to moderate, inverse relationship (r = -0.16). Mean effect sizes differed significantly (F(3,52) = 8.04, p < 0.001) according to the activity measure used: questionnaire, r = -0.14; motion counters, r = -0.18; observation, r = -0.39; heart rate (HR), r = 0.00. Observation measures elicited a significantly stronger relationship with body fat than did questionnaire or heart rate measures (p < 0.05). However, there was no significant difference between the effect sizes elicited by observation and motion counters. Correlational analyses revealed no effect of age group or gender on the strength of the relationship between fatness and activity. This meta-analysis suggests there is a small to moderate relationship between body fat and activity in children. It is important to note, however, that the size of the relationship depends on the activity measure used. It is therefore recommended that direct measures of movement, such as observation or motion counter methods, are used to assess the relationship of activity levels with health.


Neighborhood decline and mixed land uses: mitigating housing abandonment in shrinking cities.
Neighborhood decline is a critical issue in shrinking cities. Components of sustainable urbanism such as mixed land uses have risen as possible urban planning-based approaches to help mitigate urban and neighborhood decline. This research identifies examines if mixed land uses can help mitigate urban decline by using the tax delinquent status of single family houses as a proxy for decline in Dayton, Ohio, USA. Logistic regression models are utilized to estimate the probability of tax delinquency. The results suggest that the proximity to mixed land uses is associated with increasing or decreasing the probability of tax delinquent for single family lots. The number of commercial and industrial lots in a neighborhood also has effects on the probability of a lot becoming tax delinquent, but the specific types of commercial and industrial lots dictate the direction of effects. The existence of commercial apartment lots, retail lots, and industrial food and drink plant lots were shown to help decrease the probability of tax delinquent lots. Also, decreasing the amount of property tax applied to parcels can help to limit distress in neighborhoods. This research contributes to the ongoing efforts to stymie the amount of residential abandonment in depopulating and declining cities.


An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children.
The multidrug-resistance transporter gene (MDR1) encoding for P-glycoprotein (P-gp) and genes encoding for isoenzymes of cytochrome P450 (CYP) have an important role in transport and metabolism of antiretroviral agents. This research examined the impact of single nucleotide polymorphisms (SNP) of MDR1 and CYP genes on nelfinavir and efavirenz pharmacokinetics and the response to highly active antiretroviral therapy (HAART) in HIV-1 infected children. Seventy-one HIV-1-infected children from PACTG 382 receiving nelfinavir, efavirenz and one or two nucleoside reverse transcriptase inhibitors had genomic DNA from PBMC evaluated for MDR1 and CYP SNP by real-time PCR. Plasma drug concentrations, CD4 lymphocyte counts and HIV-1 RNA were measured during HAART. The frequencies of C/C, C/T and T/T genotypes in the MDR1-3435-C-->T polymorphisms were 44% (n = 31), 46% (n = 33) and 10% (n = 7), respectively. Ninety-one percent of children with the C/T genotype reached plasma HIV-1 RNA < 400 copies/ml by week 8 compared to 59% of children with the C/C genotype (P = 0.01). Children with the C/T genotypes had higher 8 h postdose concentration (P = 0.02) and lower clearance rate (P = 0.04) for nelfinavir compared to those with the C/C genotype. The seven children with the T/T genotype had nelfinavir pharmacokinetics and virologic response similar to those with the C/C genotype. No compensatory polymorphisms were observed between MDR1 and CYP genotypes. HIV-1 infected children with the MDR1-3435-C/T genotype had more rapid virologic responses to HAART at week 8 with higher plasma nelfinavir concentrations compared to those with the C/C genotype. These findings suggest that P-gp may play an important role in the pharmacokinetics and virologic response to HAART containing nelfinavir.


Neural network analysis of quasistationary magnetic fields in microcoils driven by short laser pulses.
Optical generation of kilo-tesla scale magnetic fields enables prospective technologies and fundamental studies with unprecedentedly high magnetic field energy density. A question is the optimal configuration of proposed setups, where plenty of physical phenomena accompany the generation and complicate both theoretical studies and experimental realizations. Short laser drivers seem more suitable in many applications, though the process is tangled by an intrinsic transient nature. In this work, an artificial neural network is engaged for unravelling main features of the magnetic field excited with a picosecond laser pulse. The trained neural network acquires an ability to read the magnetic field values from experimental data, extremely facilitating interpretation of the experimental results. The conclusion is that the short sub-picosecond laser pulse may generate a quasi-stationary magnetic field structure living on a hundred picosecond time scale, when the induced current forms a closed circuit.


Effect of specific proteolytic cleavages on tubulin polymer formation.
The capacity for self-polymerization and shape of the tubulin polymers assembled after digestion with trypsin, Pronase, chymotrypsin, subtilisin, Staphylococcus aureus proteinase V8 and proteinase K were investigated. Digestion with trypsin, Pronase or chymotrypsin resulted in a decrease in the ability of tubulin for self-assembly, whereas limited proteolysis with subtilisin, S. aureus proteinase V8 or proteinase K resulted in an increase in such ability. The shape of the assembled polymers varied from typical microtubules (after the treatment with trypsin or Pronase) to sheets (after the treatment with chymotrypsin) and from hooked microtubules with a constant polarity (after the treatment with subtilisin) to the disappearance of a defined polarity of such polymers (after the treatment with S. aureus V8 proteinase or proteinase K). These results indicate that the tubulin C-terminal regions are involved in the regulation of microtubule polymerization, shape, directional growth and lateral interactions between tubulin protofilaments.


Strain-specific differences in the proline-rich proteins and glycoproteins induced in rat salivary glands by chronic isoprenaline treatment.
Parotid and submandibular glands were isolated from five strains of rat after chronic injection of the beta-adrenergic receptor agonist isoprenaline (isoproterenol). The glands were observed to have undergone a marked increase in wet weight, owing to hypertrophy and hyperplasia. The 100 000 g soluble fraction of gland cell lysates were extracted with 10% (w/v) trichloroacetic acid, and the soluble material subsequently analysed by SDS (sodium dodecyl sulphate)/polyacrylamide-gel electrophoresis. By this procedure, evidence was obtained for the induction, in isoprenaline-treated parotid and submandibular glands, of proline-rich proteins with apparent Mr values ranging from 20 000 to 40 000. Heterogeneity was evident in the proteins produced for a specific gland between the rat strains, although the amino acid compositions were the same. Products from induced mRNAs translated in vitro had similar mobilities in SDS/polyacrylamide gels, despite the apparent difference in mobility of trichloracetic acid-extracted proline-rich proteins from the various strains. Strain-specific differences were noted for the proline-rich glycoproteins from control salivary glands as well as those induced as a consequence of isoprenaline treatment. Although the glycoproteins had similar amino acid compositions, there was considerable heterogeneity in the carbohydrate compositions for these proteins, suggesting that the differences were the result of post-translational modifications during glycosylation. Induction of the increased activity of the Golgi membrane marker enzyme UDP-galactose:2-acetamido-2-deoxy-D-glucosamine 4 beta-galactosyltransferase (EC 18.104.22.168) occurred to the same extent in the parotid glands of all strains examined. There was no change in the specific activity of a second enzyme, UDP-galactose:N-acetylgalactosaminyl-protein 3 beta-galactosyltransferase (no EC designation).


Diabetic neuropathy and restless legs syndrome: can a known chronic condition slow down our diagnostic way of thinking? A case report and a short literature overview.
Restless legs syndrome is a common lifelong neurological disorder with a negative impact on the patients' sleep and quality of life. Despite its common occurrence in the general population, the condition usually remains undiagnosed. Patients with diabetes run at a higher risk to suffer from restless legs syndrome. Diabetic neuropathy, in particular, shares similar clinical characteristics with restless legs syndrome and reduces significantly the patients' quality of life. Our aim was to report on an interesting case of restless legs syndrome in a patient with diabetes seeking medical advice for a ten-year long insomnia. Sleep deprivation was falsely attributed to diabetic neuropathy. A literature overview of the up-to-date knowledge was performed in order to summarize available information and provide primary care physicians with a comprehensive way of clinical thinking to differentiate peripheral neuropathy and restless legs syndrome manifestations.


Generalized Low-Rank Update: Model Parameter Bounds for Low-Rank Training Data Modifications.
In this study, we have developed an incremental machine learning (ML) method that efficiently obtains the optimal model when a small number of instances or features are added or removed. This problem holds practical importance in model selection, such as cross-validation (CV) and feature selection. Among the class of ML methods known as linear estimators, there exists an efficient model update framework, the low-rank update, that can effectively handle changes in a small number of rows and columns within the data matrix. However, for ML methods beyond linear estimators, there is currently no comprehensive framework available to obtain knowledge about the updated solution within a specific computational complexity. In light of this, our study introduces a the generalized low-rank update (GLRU) method, which extends the low-rank update framework of linear estimators to ML methods formulated as a certain class of regularized empirical risk minimization, including commonly used methods such as support vector machines and logistic regression. The proposed GLRU method not only expands the range of its applicability but also provides information about the updated solutions with a computational complexity proportional to the number of data set changes. To demonstrate the effectiveness of the GLRU method, we conduct experiments showcasing its efficiency in performing cross-validation and feature selection compared to other baseline methods.


Prolonged exposure to M. faeni in strain II guinea-pigs: pulmonary interstitial inflammation.
Models of hypersensitivity pneumonitis (HP) should exhibit progression of pulmonary histological abnormalities during continuing challenges. Strain II guinea-pigs were sensitized with Micropolyspora faeni and received 2, 4, or 8 weekly intratracheal (i.t.) particulate M. faeni challenges. Control animals received normal saline (NS). Four days after the last exposure, randomly selected microscopic fields of lung (200/animal) were judged to be normal or abnormal. If abnormal, the location and nature of the abnormalities were determined. Compared with NS treated guinea-pigs, those exposed to 2, 4 and 8 weekly M. faeni challenges exhibited more extensive (P less than 0.001) pulmonary histological abnormalities which involved both the intraalveolar and interstitial compartments. More extensive abnormalities in the 8 week group compared with the 4 week group were caused by increased extent of interstitial mononuclear cell infiltration. The extent of pulmonary interstitial histological abnormalities transiently (four challenges) decreases, but then increases, so that progressive pulmonary inflammation occurs during continuing challenges.


Fluoride uptake and release by composites and glass ionomers in a high caries challenge situation.
To evaluate the behavior of composite resins and glass ionomer cements with regard to the uptake and release of fluoride, in a high caries challenge situation. Standard test specimens of glass ionomer cement (Chelon Fil), a resin-modified glass ionomer (Vitremer), two polyacid-modified composite resins (VariGlass and Dyract) and a composite resin (Heliomolar), were submitted for 14 days to demineralization and remineralization cycles in order to simulate a high caries challenge, while from the eighth day onward, a fluoridated dentifrice solution was applied for 5 minutes twice a day and the daily fluoride release of those materials to the mediums was quantified and compared. Fifteen test specimens were prepared for each material, making up a total of 75. All materials studied, except for Heliomolar from day 4 to day 7 in the demineralizing solution, were capable of releasing fluoride in measurable quantities during the whole experiment. The fluoride amounts released by Chelon Fil, Vitremer, VariGlass and Dyract were significantly higher in the demineralizing solution (ANOVA, P < 0.05) than in the remineralizing solution, during almost the entire experiment. The fluoride amounts released by Heliomolar were significantly higher in the remineralizing solution (ANOVA, P < 0.05) than in the demineralizing solution, during almost the entire experiment. All materials studied were capable of uptaking fluoride from the dentifrice solution and of later releasing it to the solution, maintaining the release relatively constant and at a higher level than that seen between days 5 and 7.