Effects of oxprenolol on the intra-arterial blood pressure response to dynamic exercise in hypertensive men.
The intra-arterial blood pressure of 20 male patients with essential hypertension was continuously recorded during dynamic exercise. Graded exercise testing on a bicycle ergometer and a stair-climbing test were performed prior to and during treatment with oxprenolol. Acute oxprenolol therapy was associated with a reduction in heart rate but little reduction in blood pressure. Chronic treatment for 14.3 weeks with oxprenolol (mean daily dose, 344 mg) was associated with a substantial reduction of blood pressure at rest and at each level of bicycle exercise. A similar antihypertensive effect was demonstrated during stair climbing. The normal blood pressure response to exercise as assessed by the relative (percentage) increase in pressure above the pre-exercise level and the rate of increase in blood pressure (per unit of work), as well as exercise tolerance, were unchanged by chronic beta-blockade with oxprenolol.


Charges and potentials at the nerve surface. Divalent ions and pH.
The voltage dependence of the voltage clamp responses of myelinated nerve fibers depends on the concentration of divalent cations and of hydrogen ions in the bathing medium. In general, increases of the [Ca], [Ni], or [H] increase the depolarization needed to elicit a given response of the nerve. An e-fold increase of the [Ca] produces the following shifts of the voltage dependence of the parameters in the Hodgkin-Huxley model: m(infinity), 8.7 mv; h(infinity), 6.5 mv; tau(n), 0.0 mv. The same increase of the [H], if done below pH 5.5, produces the following shifts: m(infinity), 13.5 mv; h(infinity), 13.5 mv; tau(n), 13.5 mv; and if done above pH 5.5: m(infinity), 1.3 mv; h(infinity), 1.3 mv; tau(n), 4.0 mv. The voltage shifts are proportional to the logarithm of the concentration of the divalent ions and of the hydrogen ion. The observed voltage shifts are interpreted as evidence for negative fixed charges near the sodium and potassium channels. The charged groups are assumed to comprise several types, of varying affinity for divalent and hydrogen ions. The charges near the sodium channels differ from those near the potassium channels. As the pH is lowered below pH 6, the maximum sodium conductance decreases quickly and reversibly in a manner that suggests that the protonation of an acidic group with a pK(a) of 5.2 blocks individual sodium channels.


Conversion from Calcineurin Inhibitor-Based Immunosuppression to Mycophenolate Mofetil in Monotherapy Reduces Risk of De Novo Malignancies After Liver Transplantation.
BACKGROUND Immunosuppression increases the risk of malignancy in liver transplant recipients. The potential impact of mycophenolate mofetil monotherapy on this risk has not been studied. MATERIAL AND METHODS The incidence and risk factors for de novo malignancies of 392 liver transplant recipients with a survival higher than 3 months and a mean follow-up of 8.5 years were studied. RESULTS De novo malignancies were diagnosed in 126 patients (32.1%) (64 non-melanoma skin cancer and 81 other malignancies). Sixty-nine patients (18.1%) stopped receiving calcineurin inhibitors and were maintained on mycophenolate mofetil monotherapy. The proportion of time on mycophenolate mofetil monotherapy (obtained after dividing the time on monotherapy by the time until diagnosis of neoplasia/last follow-up) was independently associated with a lower risk of de novo malignancy (HR: 0.16, 95% CI: 0.05-0.48; P=0.001), non-melanoma skin cancer (HR: 0.17, 95% CI: 0.03-0.79; P=0.024), and other malignancies (HR: 0.23, 95% CI: 0.07-0.77; P=0.017). Older age and male sex were also associated with a higher risk of malignancy, and transplantation for hepatocellular carcinoma increased the risk of non-melanoma skin cancer. CONCLUSIONS Mycophenolate mofetil monotherapy is associated with a lower risk of cancer in liver transplant recipients compared with maintenance immunosuppression with calcineurin inhibitors.


Comparative aspects of animal regeneration.
Most but not all phyla include examples of species that are able to regenerate large sections of the body plan. The mechanisms underlying regeneration on this scale are currently being studied in a variety of contexts in both vertebrates and invertebrates. Regeneration generally involves the formation of a wound epithelium after transection or injury, followed by the generation of regenerative progenitor cells and morphogenesis to give the regenerate. Common mechanisms may exist in relation to each of these aspects. For example, the initial proliferation of progenitor cells often depends on the nerve supply, whereas morphogenesis reflects the generation of positional disparity between adjacent cells-the principle of intercalation. These mechanisms are reviewed here across a range of contexts. We also consider the evolutionary origins of regeneration and how regeneration may relate to both agametic reproduction and to ontogeny.


Structure-Guided Tuning of a Selectivity Switch towards Ribonucleosides in Trypanosoma brucei Purine Nucleoside 2'-Deoxyribosyltransferase.
The use of nucleoside 2'-deoxyribosyltransferases (NDTs) as biocatalysts for the industrial synthesis of nucleoside analogues is often hindered by their strict preference for 2'-deoxyribonucleosides. It is shown herein that a highly versatile purine NDT from Trypanosoma brucei (TbPDT) can also accept ribonucleosides as substrates; this is most likely because of the distinct role played by Asn53 at a position that is usually occupied by Asp in other NDTs. Moreover, this unusual activity was improved about threefold by introducing a single amino acid replacement at position 5, following a structure-guided approach. Biophysical and biochemical characterization revealed that the TbPDTY5F variant is a homodimer that displays maximum activity at 50 °C and pH 6.5 and shows a remarkably high melting temperature of 69 °C. Substrate specificity studies demonstrate that 6-oxopurine ribonucleosides are the best donors (inosine>guanosine≫adenosine), whereas no significant preferences exist between 6-aminopurines and 6-oxopurines as base acceptors. In contrast, no transferase activity could be detected on xanthine and 7-deazapurines. TbPDTY5F was successfully employed in the synthesis of a wide range of modified ribonucleosides containing different purine analogues.


Traumatic pseudoaneurysm of axillary artery combined with brachial plexus injury.
Traumatic pseudoaneurysm of the axillary artery combined with brachial plexus injury is extremely rare. The factors that influence the symptoms and functional recovery related to this condition are unclear. Nine patients who had sustained this trauma were surgically treated at our unit between June 1999 and November 2010. The cause of trauma, symptoms, signs and examinations of neurological and vascular deficits, and the surgical findings of the involved nerves and vessels were recorded in detail. The functional recovery of vessels and nerves, as well as the extent of pain, were evaluated, respectively. The average length of patient follow-up was 4.5 years (range, 24 months to 11.3 years). After vessel repair, whether by endovascular or operative treatment, the distending, constant, and pulsating pain was relieved in all patients. Furthermore, examination of the radial artery pulse on the repaired side appeared normal at last follow-up. All patients showed satisfactory sensory recovery, with motor recovery rated as good in five patients and fair in four patients. The symptom characteristics varied with the location of the damage to the axillary artery. Ultrasound examination and computed tomography angiography are useful to evaluate vascular injury and provide valuable information for operative planning. Surgical exploration is an effective therapy with results related to the nerve injury condition of the brachial plexus.


Mutations in DNA Gyrase and Topoisomerase IV in Ciprofloxacin-Nonsusceptible Extended-Spectrum -Lactamase-Producing Escherichia coli and Klebsiella pneumoniae.
We investigated mutations in the quinolone resistance-determining region (QRDR) of ciprofloxacinnonsusceptible extended-spectrum -lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae by a statistical analysis. We collected 97 clinical isolates of ciprofloxacin-nonsusceptible ESBL-producing E. coli (55 strains) and K. pneumoniae (42 strains) from a tertiary-care university hospital in Seoul, Republic of Korea, between 2006 and 2008. The QRDR of the gyrA, gyrB, parC, and parE genes were amplified by PCR and sequenced. Most E. coli isolates (53/55; 96.4%) with a minimum inhibitory concentration of ≥ 64 mg/L against ciprofloxacin had double mutations in gyrA (Ser-83Leu and Asp-87Asn) and at least one mutation in parC (Ser-80 Ile or Glu-84Val), with or without one in parE. Fifty E. coli (90.9%) isolates had a mutation in parE, of which Ile-529Leu (70.9%) was the most frequent. However, we could not find statistically significant variables in increasing ciprofloxacin resistance in E. coli isolates. Thirty-six K. pneumoniae isolates (36/42; 85.7%) had at least one mutation in gyrA, gyrB, or parC, and the mutation in gyrA might have been associated with plasmid-mediated quinolone-resistance (PMQR). Ser-80Ile in parC and aac(6')-Ib-cr in the K. pneumoniae isolates were significantly associated with an increased MIC of ciprofloxacin by ordinal logistic regression analysis. The Ser-80Ile in parC and aac(6')-Ib-cr in K. pneumoniae are supposed to play an important role in increased ciprofloxacin resistance, but statistically significant variables could not be found in E. coli isolates in the present study.


High tibial osteotomy: our experience with hemicallotasis method.
Despite the many progresses and ever better outcomes in knee arthroplasty, surgical osteotomy in this area of the body is still commonly used. Valgus high tibial osteotomy (HTO) through external fixator progressive distraction (hemicallotasis) has given good results in the treatment of varus knee deformities. Such surgical techinque, once all controindications and favorable factors have been identified, allows to progressively correct the deformity with extreme precision without using internal fixation devices or bone grafts. The positive outcomes in all 24 subjects included in our study affected with varus knees and initial medial osteoarthritis confirm the validity of this osteotomy technique.


Comparison of INTERGROWTH-21 and Fenton growth standards to assess size at birth and extrauterine growth in very preterm infants.
This study aimed to compare the recently published prescriptive INTERGROWTH-21st standards with commonly used intrauterine based Fenton growth standards in terms of birth size classification and extrauterine growth restriction (EUGR) incidence in a sample of very preterm infants. The anthropometric measures of preterm infants born before 32 weeks of gestation at the Dokuz Eylul University Hospital during the period from January 2012 to February 2016 were obtained at birth, at the 36th gestational weeks or at the time of discharge. Birth and growth data were presented as percentiles according to the two reference standards. A total of 248 infants with mean gestational age of 29.1 ± 2.1 weeks were included. The small for gestational age (SGA) rate was significantly higher (12 versus 15%, p = .004) and the EUGR rate was significantly lower (40.2 versus 31.5%, p < .001) with the INTERGROWTH-21st charts compared with the Fentons'. Twenty-four per cent of the infants who were accepted as SGA according to the INTERGROWTH-21st standards were appropriate for gestational age (AGA) according to the Fenton preterm growth charts. However, these newly identified SGA infants according to the Intergrowth-21st standards did not have increased risks of early morbidities. Furthermore, 77% of the cases who had EUGR due to the Fenton standards were categorized as EUGR when evaluated using the INTERGROWTH-21st standards. Results indicated that almost one out of every five cases assessed as EUGR according to Fenton standards was within the normal interval according to Intergrowth standards. On the contrary, one out of every four cases assessed as SGA according to the INTERGROWTH-21st standards was within the normal interval according to Fentons'. These differences observed with INTERGROWTH-21st standards may affect in-hospital and postdischarge nutrition plan of these vulnerable infants. However, new standards are needed to be evaluated against currently used ones before they are implemented and further studies should be conducted to evaluate the functional impact of these differences on long-term outcomes including neurologic and cardio-metabolic morbidities.


Myopathy with oval inclusions in a domestic shorthair cat.
An 18-month-old castrated male domestic shorthair cat was presented with a 2-month history of collapse and severe weakness, particularly affecting the pelvic limbs. A biceps femoris muscle biopsy revealed excessive variability in myofibre size, mild necrosis, minimal centronucleation and scattered 10 μm intracytoplasmic oval inclusions. The inclusions appeared amphophilic with haematoxylin and eosin, blue with Gomori trichrome and unstained with nicotinamide adenine dinucleotide dehydrogenase tetrazolium reductase staining. ATPase staining revealed a normal mosaic pattern and atrophy of both type 1 and 2 myofibres. The pathological diagnosis was a myopathy with inclusions. In contrast to previous feline myofibre inclusions previously reported in the literature, inclusions were not identified after immunohistochemistry using anti-desmin, tubulin, spectrin, laminin, LAMP and LC3 antibodies. After supportive care and corticosteroid treatment, clinical improvement was noted and the cat was discharged 10 days after initial presentation. Clinical and neurological re-examinations were performed at 1, 3, 6 and 9 months after discharge. Owner contact at both 10 and 30 months post-discharge confirmed that persistent muscular weakness was present. This case report describes a novel and slowly progressive feline myopathy associated with oval amphophilic inclusions unreactive to immunostaining, which have not been previously reported in feline myopathies.


Does skill retention benefit from retentivity and symbolic rehearsal? - two studies with a simulated process control task.
Two experiments were designed to compare two symbolic rehearsal refresher interventions (imaginary practice, a hidden introspective process) and investigate the role of retentivity in skill retention. Retentivity is investigated as the ability to memorise and reproduce information and associations that were learned a short time ago. Both experiments comprised initial training (week 1), a symbolic rehearsal for the experimental group (week 2) and a retention assessment (week 3). In the first study, the experimental group received a symbolic rehearsal, while the control group received no rehearsal. In the second study, the experimental group received the same symbolic rehearsal used in study 1, enhanced with rehearsal tasks addressing human-computer interaction. The results showed that both symbolic rehearsal interventions were equally likely to mitigate skill decay. The retentivity showed medium to high correlations with skill retention in both studies, and the results suggest that subjects high in retentivity benefit more from a symbolic rehearsal refresher intervention. Practitioner Summary: Skill decay becomes a problem in situations in which jobs require the correct mastery of non-routine situations. Two experimental studies with simulated process control tasks showed that symbolic rehearsal and retentivity can significantly mitigate skill decay and that subjects higher in retentivity benefit more from refresher interventions.


Spindle cell sarcoma of the kidney with ganglionic elements (malignant ectomesenchymoma) associated with chromosomal abnormalities and a review of the literature.
Malignant ectomesenchymomas are tumors that exhibit both mesenchymal and neuroectodermal elements (1). We report a case thought to represent a malignant ectomesenchymoma arising in the kidney with cytogenetic abnormalities that may provide insight into the biologic basis for this unusual tumor. We discuss the clinical features, histopathologic findings, cytogenetics, treatment, and outcome of a child with a malignant ectomesenchymoma arising in the kidney. An asymptomatic 16-month-old boy had a large abdominal mass. The resected tumor contained sheets of spindled cells that expressed mesenchymal markers and cartilaginous differentiation, interspersed with clusters of ganglion cells that expressed neural markers. No blastemal or epithelial elements were demonstrated. Cytogenetic analysis of the tumor revealed a hyperdiploid count with multiple numerical and structural abnormalities, including a translocation between chromosomes 12 and 15. In addition to the surgical resection, the patient was successfully treated with adjuvant chemotherapy and local radiation therapy. This is the first report of which we are aware of an ectomesenchymoma arising within the kidney. A subset of malignant ectomesenchymomas may be related to the Ewing's family of tumors (EFTs) (2), but this case did not exhibit cytogenetic features consistent with EFT. Thus, the malignant ectomesenchymoma phenotype probably represents a heterogeneous group of tumors with different genotypes and origins. Cytogenetic analysis may be instrumental in determining the appropriate therapeutic approach when faced with such a neoplasm. The outcomes of 12 other children with ectomesenchymoma are reviewed.


The enhancing effect of interferon-beta and -gamma on the killing of Leishmania tropica major in human mononuclear phagocytes in vitro.
Both native human IFN-beta or -gamma added to human monocytes in culture increased their leishmaniacidal effect on intracellular Leishmania tropica major (L. major) amastigotes. This effect was dose-dependent, and was apparent if the IFN was added either before or after infection of the monocyte cultures with the promastigote form of the parasite. Compared on the basis of antiviral activity, IFN-gamma was shown to have a leishmaniacidal effect approximately three times greater than IFN-beta. Recombinant IFN preparations showed similar effects. In addition, IFN-gamma increased H2O2 production from human monocytes in culture in a dose-dependent manner. Monoclonal antibody to IFN-gamma abrogated both its effect on the leishmaniacidal capacity and on H2O2 production by the monocytes. These results suggest that IFN-gamma may be of therapeutic value in cutaneous leishmaniasis.


Personality Disorders in the ICD-11: Spanish Validation of the PiCD and the SASPD in a Mixed Community and Clinical Sample.
The International Classification of Diseases-11th revision (ICD-11) classification of personality disorders is the official diagnostic system that is used all over the world, and it has recently been renewed. However, as yet very few data are available on its performance. This study examines the Personality Inventory for ICD-11 (PiCD), which assesses the personality domains of the system, and the Standardized Assessment of Severity of Personality Disorder (SASPD), which determines severity. The Spanish versions of the questionnaires were administered to a community (n = 2,522) and a clinical sample (n = 797). Internal consistency was adequate in the PiCD (α = .75 to .84) but less so in the SASPD (α = .64 and .73). Factor analyses suggested a unidimensional or bidimensional structure for severity, while revealing that the personality trait qualifiers are organized into four factors: negative affectivity, detachment, dissociality, and a bipolar domain of disinhibition-anankastia. The mutual relationships between traits and severity were analyzed, as well as the ability of the whole system to identify clinical subjects. Although further improvements are required, the results generally support the use of the PiCD and the SASPD and help substantiate the new ICD-11 taxonomy that underlies them.


Acid sphingomyelinase-deficient Niemann-Pick disease: novel findings in a Greek child.
Niemann-Pick Disease (NPD) is a heterogeneous group of autosomal recessive disorders characterized by progressive accumulation of sphingomyelin and cholesterol in lysosomes. Six types of NPD have been described based on clinical presentation and involved organs. The primary defect in NPD types A and B is a deficiency of lysosomal acid sphingomyelinase (ASM). We present a case of a 5-year-old boy with type B NPD who had severe clinical manifestations, including heart involvement. He was first admitted to the hospital at 2 months because of vomiting, refusal to feed, lethargy, hepatomegaly and mild transaminasaemia. Liver biopsy at 12 months showed lipid accumulation and fibrosis. Investigations for lysosomal storage disorders revealed increased plasma chitotriosidase (549 nmol/h per ml, normal value 0-150). At 18 months, no detectable ASM activity was observed in cultured fibroblasts (normal range 23-226 nmol/h per mg protein) confirming NPD B. Pulmonary involvement was detected with high-resolution computerized tomography which revealed reticulonodular infiltrations and thickening of the interlobular septa. At 2 years growth retardation and kyphosis were noted. At 2.5 years he manifested neurodevelopment regression, indicating CNS involvement. Cardiac involvement (grade III mitral valve insufficiency) developed at 4 years and heart failure at 5 years. Genetic analysis revealed two mutations: a H421Y mutation that is common in Saudi Arabian and Turkish patients, and a W32X mutation, which has been found in other Mediterranean patients.


A method of sample-wise region-set enrichment analysis for DNA methylomics.
Aim: Gene set analysis has commonly been used to interpret DNA methylome data. However, summarizing the DNA methylation level of a gene is challenging due to variability in the number, density and methylation levels of CpG sites, and the numerous intergenic CpGs. Instead, we propose to use region sets to annotate the DNA methylome. Methods: We developed single sample region-set enrichment analysis for DNA methylome (methyl-ssRSEA) to conduct sample-wise, region-set enrichment analysis. Results: Methyl-ssRSEA can handle both microarray- and sequencing-based platforms and reproducibly recover the known biology from the methylation profiles of peripheral blood cells and breast cancers. The performance was superior to existing tools for region-set analysis in discriminating blood cell types. Conclusion: Methyl-ssRSEA offers a novel way to functionally interpret the DNA methylome in the cell.


Assessing the active living environment in three rural towns with a high proportion of Native Hawaiians and other Pacific Islanders.
Background: Existing literature on the built environment and physical activity in rural areas is very limited. Studies have shown that residents in rural areas are less likely to meet physical activity requirements than their counterparts living in urban and suburban areas. They are also less likely to have access to amenities and programs that promote physical activity. This study seeks to fill gaps in the literature by assessing the built environment in three rural towns in Hawai'i that have a high proportion of Native Hawaiians and other Pacific Islanders. Methods: The Rural Active Living Assessment (RALA) tools will be used to assess the built environment. The RALA has three components - Policy and Program Assessment (PPA), Town Wide Assessment (TWA), and Street Segment Assessment (SSA) which will be used to provide a comprehensive assessment of the active living environment. Assessments were completed in September and October 2016. Results: One assessment was completed in each town for the TWA and PPA. The SSA was completed with 60 segments (20 from each town). Conclusion: The RALA tools identified supports in these three rural towns. The assessment also identified barriers and gaps - especially with the town and school polices of each town.


Quality management for poison centers.
Poison centers are struggling with the concept of service quality and how to improve it. The business world has dealt with this concept by establishing internationally agreed-upon criteria for quality management. Poison centers deliver health care services and can benefit from the approach taken by the corporate community. This review article takes the criteria of quality management proposed by the ISO 9000 series guidelines and demonstrates their applicability to poison center operations by translating the business jargon of the ISO 9000 series into terminology more familiar to health care professionals and by providing examples and approaches to satisfy specific guidelines. This article offers poison center staff a framework to help them understand how to improve the quality of service they provide.


Synthesis and structural characterization of ruthenium carbonyl cluster complexes containing platinum with a bulky N-heterocyclic carbene ligand.
The reaction of Ru3(CO)12 with Pt(IMes)2 in benzene solvent at room temperature afforded the monoplatinum-triruthenium cluster complex Ru3Pt(IMes)2(CO)11, 1, in 21% yield and the trigonal bipyramidal cluster complex Ru3Pt2(IMes)2(CO)12, 2, in 26% yield. The reaction of Ru(CO)5 with Pt(IMes)2 in benzene solvent at 0 °C yielded two trinuclear cluster complexes, the monoplatinum-diruthenium Ru2Pt(IMes)(CO)9, 3, and the monoruthenium-diplatinum cluster complex RuPt2(IMes)2(CO)6, 4. The reaction of 2 with hydrogen at 80 °C afforded the tetrahydrido-tetraruthenium complex Ru4(IMes)(CO)11(μ-H)4, 5, and the dihydrido-diruthenium-diplatinum complex Ru2Pt2(IMes)2(CO)8(μ-H)2, 6. All six compounds were structurally characterized by single-crystal X-ray diffraction analyses.


Ligand unbinding mechanisms and kinetics for T4 lysozyme mutants from τRAMD simulations.
The protein-ligand residence time, τ, influences molecular function in biological networks and has been recognized as an important determinant of drug efficacy. To predict τ, computational methods must overcome the problem that τ often exceeds the timescales accessible to conventional molecular dynamics (MD) simulation. Here, we apply the τ-Random Acceleration Molecular Dynamics (τRAMD) method to a set of kinetically characterized complexes of T4 lysozyme mutants with small, engineered binding cavities. τRAMD yields relative ligand dissociation rates in good accordance with experiments across this diverse set of complexes that differ with regard to measurement temperature, ligand identity, protein mutation and binding cavity. τRAMD thereby allows a comprehensive characterization of the ligand egress routes and determinants of τ. Although ligand dissociation by multiple egress routes is observed, we find that egress via the predominant route determines the value of τ. We also find that the presence of a greater number of metastable states along egress pathways leads to slower protein-ligand dissociation. These physical insights could be exploited in the rational optimization of the kinetic properties of drug candidates.


Rare allelic variants determine folate status in an unsupplemented European population.
The role of folates as coenzymes in 1-carbon metabolism and the clinical consequences of disturbed folate metabolism are widely known. Folate status is a complex trait determined by both exogenous and endogenous factors. This study analyzed the association between 12 genetic variants and folate status in a Czech population with no folate fortification program. These 12 genetic variants were selected from 56 variant alleles found by resequencing the coding sequences and adjacent intronic regions of 6 candidate genes involved in folate metabolism or transport (FOLR1, FOLR2, FOLR3, MTHFR, PCFT, and RFC) from 29 individuals with low plasma and erythrocyte folate concentrations. Regression analyses of a cohort of 511 Czech controls not taking folate supplements revealed that only 2 variants in the MTHFR gene were associated with altered folate concentrations in plasma and/or erythrocytes. In our previous study, we observed that the common variant MTHFR c.665C > T (known as c.677C > T; p.A222V) was associated with decreased plasma folate concentrations. In the present study, we show in addition that the rare variant MTHFR c.1958C > T (p.T653M) is associated with significantly increased erythrocyte folate concentrations (P = 0.02). Multivariate regression analysis revealed that this uncommon variant, which is present in 2% of Czech control chromosomes, explains 0.9% of the total variability of erythrocyte folate concentrations; the magnitude of this effect size was comparable with that of the common MTHFR c.665C > T variant. This result indicates that the rare genetic variants may determine folate status to a similar extent as the common allelic variant.


[Restless legs syndrome].
Restless legs syndrome (RLS) is seen widely in clinical practice. RLS commonly occurs at night time and presents with unpleasant or uncomfortable sensations in the legs that causes an urge to move them. This article describes the epidemiology, risk factors and pathophysiology of RLS. There is a detailed description of clinical presentations, diagnostic criteria and also management of RLS.


Laboratory identification of arthropod ectoparasites.
The collection, handling, identification, and reporting of ectoparasitic arthropods in clinical and reference diagnostic laboratories are discussed in this review. Included are data on ticks, mites, lice, fleas, myiasis-causing flies, and bed bugs. The public health importance of these organisms is briefly discussed. The focus is on the morphological identification and proper handling and reporting of cases involving arthropod ectoparasites, particularly those encountered in the United States. Other arthropods and other organisms not of public health concern, but routinely submitted to laboratories for identification, are also briefly discussed.


Temporal soliton dynamics of synchronised ultrafast fibre lasers.
Synchronised ultrafast soliton lasers have attracted great research interest in recent decades. However, there is a lack of comprehensive understanding regarding the buildup mechanism of synchronised pulses. Here, we report a dynamic analysis of independent and synchronised solitons buildup mechanisms in synchronised ultrafast soliton lasers. The laser comprises an erbium-doped fibre cavity and a thulium-doped fibre cavity bridged with a common arm. Pulses operating at two different wavelengths formed in the cavities are synchronised by cross-phase modulation-induced soliton correlation in the common fibre arm. We find that the whole buildup process of the thulium-doped fibre laser successively undergoes five different stages: continuous wave, relaxation oscillation, quasi-mode-locking, continuous wave mode-locking and synchronised mode-locking. It is found that the starting time of the synchronised solitons is mainly determined by the meeting time of dual-color solitons. Our results will further deepen the understanding of dual-color synchronised lasers and enrich the study of complex nonlinear system dynamics.


Xerogel Interfaced Nanofibers Stimulate Bone Regeneration Through the Activation of Integrin and Bone Morphogenetic Protein Pathways.
A xerogel was interfaced onto biopolymer nanofibers though a core–shell electrospinning design for bone regeneration. The xerogel-interfaced biopolymer nanofibrous matrix was bioactive and highly hydrophilic, with a significant decrease in the water contact angle. The matrix showed excellent in vitro responses of primary osteoblasts in terms of adhesion, proliferation, and migration. Furthermore, the osteoblastic differentiation of cells, including alkaline phosphatase activity, mineralization, and gene expression, was significantly upregulated by the xerogel interface. In vivo animal tests in a critical-sized calvarial defect confirmed the new bone formation ability of the xerogel-surfaced nanofiber matrices. The underlying signaling mechanisms of the stimulation were implied to be integrin and bone morphogenetic protein (BMP) pathways, as demonstrated by the activation of integrin (α2β1) and downstream signaling molecules (FAK, paxillin, RhoA, MAPK, and NF-κB), as well as the BMPs and the downstream transcription factor Smad1/5/8. Taking these findings together, the xerogel-surfaced biopolymer nanofibers are proposed to be a promising scaffold candidate for bone regeneration.


Stakeholders' perceptions of a community-based advanced nurse practitioner-led integrated oncology care model for adults receiving oral anti-cancer medication-A qualitative study.
Oral anti-cancer medications (OAMs) are increasingly prescribed in oncology, and although administered at home, ongoing monitoring generally requires the patient to attend an acute hospital. With the requirement to provide safe yet convenient care and to increase hospital capacity, the potential exists to transition this cohort of patients to the community to be assessed by oncology health care professionals (HCPs). The onset of COVID-19 facilitated this planned transition. The primary objective was to understand stakeholders' perceptions of a community-based advanced nurse practitioner (ANP)-led integrated OAM care model for adults. Qualitative data from interviews and focus groups were obtained from 33 individuals; either service users who attended ANP-led OAM clinics or stakeholders involved in OAM care. Data were subsequently analysed using thematic analysis. Four themes were identified and included reflection on pre-COVID-19 system, role of ANP in current OAM care, importance of robust communication and infrastructural requirements for transition to an integrated OAM care model. This study demonstrated that patients and HCPs perceived the proposal positively. They identified the ANP as the appropriate HCP to care for this cohort and the importance of communication and strategic planning for transitioning this model of care to the community setting. ISRCTN10401455.


Nanoengineered Ultralight and Robust All-Metal Cathode for High-Capacity, Stable Lithium-Oxygen Batteries.
The successful development of Li-O2 battery technology depends on resolving the issue of cathode corrosion by the discharge product (Li2O2) and/or by the intermediates (LiO2) generated during cell cycling. As an important step toward this goal, we report for the first time the nanoporous Ni with a nanoengineered AuNi alloy surface directly attached to Ni foam as a new all-metal cathode system. Compared with other noncarbonaceous cathodes, the Li-O2 cell with an all-metal cathode is capable of operation with ultrahigh specific capacity (22,551 mAh g-1 at a current density of 1.0 A g-1) and long-term life (286 cycles). Furthermore, compared with the popularly used carbon cathode, the new all-metal cathode is advantageous because it does not show measurable reactivity toward Li2O2 and/or LiO2. As a result, extensive cyclability (40 cycles) with 87.7% Li2O2 formation and decomposition was obtained. These superior properties are explained by the enhanced solvation-mediated formation of the discharge products as well as the tailored properties of the all-metal cathode, including intrinsic chemical stability, high specific surface area, highly porous structure, high conductivity, and superior mechanical stability.


Clinical and bacteriological differences of deep neck infection in pediatric and adult patients: Review of 123 cases.
Deep neck infections (DNIs) can lead to life-threatening disease. However, the detailed pathophysiology remains unclear due to its rarity and only a few reports have directly compared DNIs in children and adults. This study aimed to reveal the clinical differences between DNIs in children and adults. We retrospectively reviewed 123 patients who suffered from DNIs at Tohoku University Hospital from August 2005 to July 2015. We extracted data on patient sex, age, antecedent illness, extension of infections, operative procedures, and bacteriology results. The patients were categorized into pediatric (≤18 years) and adult (>18 years) groups. Fisher's exact test was performed to determine significant differences between the two groups. Fifteen children (6 males and 9 females) and 108 adults (71 males and 37 females) were identified. The most common antecedent illness in pediatric patients was lymphadenitis, which was the least common in adult patients (73% vs 7%, p < 0.0001). The incidence of DNIs extending below the hyoid bone was significantly lower in pediatric patients than in adult patients (20% vs 53%, p < 0.05). Regarding bacterial culture analysis, Staphylococcus species was the most common pathogen in children (60%), whereas only 9% of adults were positive for Staphylococcus (p < 0.001). Streptococcus species were significantly less common in children than in adults (27% vs 56%, p = 0.05). Anaerobes were also significantly less common in children than in adults (13% vs 45%, p < 0.01). Concerning surgical intervention, 53% of pediatric patients underwent external incision compared with 70% of adults. Specifically, tracheostomy was significantly less frequently performed in children than in adults (7% vs 54%, p < 0.01). DNIs in children feature different characteristics from those in adults regarding severity, antecedent illness, bacteriology, and clinical management.


Four-year outcomes of aflibercept treatment for neovascular age-related macular degeneration: Results from real-life setting.
To assess long-term structural and functional outcomes of intravitreal aflibercept (Eylea®) treatment for neovascular macular degeneration (nAMD) in a real-word setting. This was a retrospective, single-centre, non-randomized interventional cohort analysis. Data from treatment-naive patients with nAMD funded for treatment with intravitreal aflibercept in the period between 1 September 2013 and 28 February 2014 and who finished 4-year follow-up entered the analysis. Epidemiological data, visual acuity (VA) measured on ETDRS charts and injection numbers were recorded. Spectral domain optical coherence tomography (SD-OCT) data including presence or absence of macular fluid and automated central subfield macular thickness (CSMT) at year 1, 2, 3 and 4 were also recorded. Ninety-four eyes of 89 patients finished 4-year follow-up. The mean number of aflibercept injections received over 4 years was 19.3. At baseline, the mean VA (SD) (Snellen) was 54.1 ± 15.5 (20/100) ETDRS letters whilst the mean CSM (SD) was 296 ± 81 µm. At 4 years, the mean VA (SD) (Snellen) was 60.4 ± 20.0 (20/63) ETDRS letters (p < 0.0001). Mean CSMT (SD) was 218 ± 79 μm (p < 0.0001). Thirty-three percent of eyes gained ⩾15 ETDRS letters at end of 4 years, and 66 (70%) eyes had no macular fluid at the end of the follow-up. The results suggest that good long-term morphological and functional treatment outcomes can be achieved using intravitreal aflibercept for nAMD in a real-life clinical setting.


Effects of chronic stress and alendronate therapy on the osseointegration of titanium implants.
The purposes of this study were to evaluate the influence of chronic stress (CS) on implant osseointegration and also to analyze whether alendronate (ALN) therapy could prevent these eventual stress-negative effects. Adult male Holtzmann rats were assigned to one of the four experimental groups: AL (ALN; 1 mg/kg/week; n = 12), ALS (ALN + CS; 1 mg/kg/week; n = 12), CTL (sterile physiological saline; n = 12), or CTLS (sterile physiological saline + CS; n = 12). After 58 days of drug therapy, the ALS and CTLS groups were exposed to CS, and 2 days later all animals underwent tibial implant installation. The animals were euthanized 28 days following the operative surgical procedure. It was observed that the CTLS group presented an impairment of bone metabolism represented by lowest levels of bone-specific alkaline phosphatase and bone area fraction occupancy values. Furthermore, these animals presented a higher proportion of empty osteocytic lacunae. In contrast, the ALN therapy showed increased osseointegration and torque value parameters, regardless of stress exposition. Analysis of the data presented suggests that CS partially impairs the osseointegration of tibial implants and that ALN therapy is able to prevent these negative effects.


Should we routinely perform blood tests in children with uncontrolled seizures?
The value of biochemical tests in treating patients with uncontrolled seizures is unclear. We present the case of an 8-year-old boy with uncontrolled seizures receiving two antiepileptic drugs. He had been diagnosed with recurrent herpes encephalitis and treated with acyclovir 1 year previously. Laboratory blood analyses, performed because of his uncontrolled seizure episodes, revealed hypocalcemia. Hypoparathyroidism was detected with elevated levels of phosphorus and low levels of parathormone. In conclusion, blood tests, especially to measure calcium, in children with uncontrolled seizures are suggested. Hypoparathyroidism causing hypocalcemia, as present here, is not a rare occurrence.


Mesenteric hyaline plasma cell lymph node hyperplasia with amyloid deposits.
Lymph node hyperplasia (mixed hyaline vascular and plasma cell type) of mesenteric localization in a young woman was accompanied by noticeable systemic manifestations--fever, highly increased sedimentation rate, anemia, and hypergammaglobulinemia--that disappeared after the tumor was removed. Perivascular deposits of amyloid material were found within the tumor and in the spleen. To our knowledge, this finding has not been previously reported. On the basis of earlier studies in the literature and other considerations, an immunologic disorder is proposed as the cause of both the general symptoms and the amyloid deposits.


Structural basis for exaggerated airway narrowing.
Airway hyperresponsiveness, particularly the ability of airways to narrow excessively in response to stimuli that normally cause little airway narrowing in nonasthmatic subjects, is a characteristic feature of asthma and the basis of its symptoms. Although airway hyperresponsiveness may be partly the result of alterations in the contractile phenotype of the airway smooth muscle, there is evidence that it may also be caused by structural changes in the airway wall, collectively termed airway remodeling. Airway remodeling is defined as changes in composition, quantity, and (or) organization of cellular and molecular constituents of the airway wall. Airway wall remodeling that occurs in asthma can result in functional alterations because of quantitative changes in airway wall compartments, and (or) because of changes in the biochemical composition or material properties of the various constituents of the airway wall. This brief review summarizes the quantitative changes in the dimensions and organization of the airway wall compartments that have been described and explains how structural alterations may lead to the exaggerated airway narrowing.


Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness.
MGA, a transcription factor and member of the MYC network, is mutated or deleted in a broad spectrum of malignancies. As a critical test of a tumor suppressive role, we inactivated Mga in two mouse models of non-small cell lung cancer using a CRISPR-based approach. MGA loss significantly accelerated tumor growth in both models and led to de-repression of non-canonical Polycomb ncPRC1.6 targets, including genes involved in metastasis and meiosis. Moreover, MGA deletion in human lung adenocarcinoma lines augmented invasive capabilities. We further show that MGA-MAX, E2F6, and L3MBTL2 co-occupy thousands of promoters and that MGA stabilizes these ncPRC1.6 subunits. Lastly, we report that MGA loss also induces a pro-growth effect in human colon organoids. Our studies establish MGA as a bona fide tumor suppressor in vivo and suggest a tumor suppressive mechanism in adenocarcinomas resulting from widespread transcriptional attenuation of MYC and E2F target genes mediated by MGA-MAX associated with a non-canonical Polycomb complex.


Prevention of Bronchopulmonary Dysplasia: A Summary of Evidence-Based Strategies.
Bronchopulmonary dysplasia (BPD) is the most common chronic complication associated with extremely preterm birth. Although BPD is now an uncommon condition in infants born with birthweights higher than 1,500 g, among infants born at or near the current limits of viability, BPD rates have not improved over the past 2 to 3 decades and may be increasing. No single therapeutic intervention is effective at preventing BPD. As such, clinicians must use multiple evidence-based strategies to help reduce BPD rates. This review examines current evidence-based approaches to BPD prevention, primarily focusing on data obtained from randomized controlled trials.


Can food matrices be considered as a potential carrier for COVID-19?
Humanity is currently facing a life-threatening challenge from the infectious and epidemic disease SARS-CoV-2. To date, the various modes of transmission of the virus have not been fully elucidated. In this regard, there is a possibility of transmission of the virus through food products. The COVID-19 pandemic disease, like those associated with SARS and MERS, is transmitted mainly through the respiratory tract and airborne aerosol particles, but the presence of fragments of the genetic virus (RNA) in the feces of numerous patients proposes that their fecal-oral pathway may be expanded. In addition, people with gastrointestinal disorders such as atrophic gastritis and metaplasia may be susceptible to COVID-19 infection. Accordingly, food may act as a potential carrier of COVID-19 due to environmental or cross-contamination. According to the available evidence, the spread and possibility of transmission of COVID-19 contamination from humans to food products are possible. Beyond that, there is some evidence that some food sources of animal origin, such as pigs and rabbits, can be contaminated by COVID-19. Therefore, the transmission of the virus through some meat products may be conceivable. Due to the rapid release rate of COVID-19 and its stability in various milieus, especially food manufacturing circumstances, it may enter the matrix during different stages of traditional or industrial food processing. Therefore, preventive measures are recommended to be utilized in the food manufacturing sector. The present study explored the risk of different food matrices, including dairy products, bread, meat and meat products, vegetables, fruits, and processed foods, as potential carriers for the transmission of COVID-19.


A Case of Acute Myocardial Infarction in a Patient Whose Initial Complaints Were Hematemesis and Epigastric Discomfort.
The patient was a 64-year-old woman with systemic lupus erythematosus, thrombophlebitis of the lower legs, cerebral infarction with left hemiparesis, and colostomy after perforation of the sigmoid colon. On the morning of her presentation, the patient felt epigastric abnormality. Thereafter, hematemesis occurred twice, leading her to call an ambulance in the afternoon. Upon arrival, electrocardiography before securing a venous route and obtaining blood samples revealed ST segment elevation in leads II, III, and aVF. As her vital signs were stable and her hemoglobin level had decreased by just 1.1 g/dl in comparison to the previous day, emergency coronary angiography (CAG) was performed. CAG revealed complete occlusion at section #4. She underwent right coronary angioplasty with stent placement. The patient's course after angioplasty was uneventful. On the 15th hospital day, esophagogastroduodenoscopy revealed esophageal erosion and superficial gastritis. She was discharged on foot the following day. When physicians treat patients with hematemesis, electrocardiography and the measurement of troponin are essential before esophagogastroduodenoscopy.


Biomarkers in fasting serum to estimate glucose tolerance, insulin sensitivity, and insulin secretion.
Biomarkers for estimating reduced glucose tolerance, insulin sensitivity, or impaired insulin secretion would be clinically useful, since these physiologic measures are important in the pathogenesis of type 2 diabetes mellitus. We conducted a cross-sectional study in which 94 individuals, of whom 84 had 1 or more risk factors and 10 had no known risk factors for diabetes, underwent oral glucose tolerance testing. We measured 34 protein biomarkers associated with diabetes risk in 250-μL fasting serum samples. We applied multiple regression selection techniques to identify the most informative biomarkers and develop multivariate models to estimate glucose tolerance, insulin sensitivity, and insulin secretion. The ability of the glucose tolerance model to discriminate between diabetic individuals and those with impaired or normal glucose tolerance was evaluated by area under the ROC curve (AUC) analysis. Of the at-risk participants, 25 (30%) were found to have impaired glucose tolerance, and 11 (13%) diabetes. Using molecular counting technology, we assessed multiple biomarkers with high accuracy in small volume samples. Multivariate biomarker models derived from fasting samples correlated strongly with 2-h postload glucose tolerance (R(2) = 0.45, P < 0.0001), composite insulin sensitivity index (R(2) = 0.91, P < 0.0001), and insulin secretion (R(2) = 0.45, P < 0.0001). Additionally, the glucose tolerance model provided strong discrimination between diabetes vs impaired or normal glucose tolerance (AUC 0.89) and between diabetes and impaired glucose tolerance vs normal tolerance (AUC 0.78). Biomarkers in fasting blood samples may be useful in estimating glucose tolerance, insulin sensitivity, and insulin secretion.


Critical evaluation of contemporary management in a new Pelvic Exenteration Unit: The first 25 consecutive cases.
To critically appraise short-term outcomes in patients treated in a new Pelvic Exenteration (PE) Unit. This retrospective observational study was conducted by analysing prospectively collected data for the first 25 patients (16 males, 9 females) who underwent PE for advanced pelvic tumours in our PE Unit between January 2012 and October 2016. Data evaluated included age, co-morbidities, American Society of Anesthesiologists (ASA) score, Eastern Cooperative Oncology Group (ECOG) status, preoperative adjuvant treatment, intra-operative blood loss, procedural duration, perioperative adverse event, lengths of intensive care unit (ICU) stay and hospital stay, and oncological outcome. Quantitative data were summarized as percentage or median and range, and statistically assessed by the χ2 test or Fisher's exact test, as applicable. All 25 patients received comprehensive preoperative assessment via our dedicated multidisciplinary team approach. Long-course neoadjuvant chemoradiotherapy was provided, if indicated. The median age of the patients was 61.9-year-old. The median ASA and ECOG scores were 2 and 0, respectively. The indications for PE were locally invasive rectal adenocarcinoma (n = 13), advanced colonic adenocarcinoma (n = 5), recurrent cervical carcinoma (n = 3) and malignant sacral chordoma (n = 3). The procedures comprised 10 total PEs, 4 anterior PEs, 7 posterior PEs and 4 isolated lateral PEs. The median follow-up period was 17.6 mo. The median operative time was 11.5 h. The median volume of blood loss was 3306 mL, and the median volume of red cell transfusion was 1475 mL. The median lengths of ICU stay and of hospital stay were 1 d and 21 d, respectively. There was no case of mortality related to surgery. There were a total of 20 surgical morbidities, which occurred in 12 patients. The majority of the complications were grade 2 Clavien-Dindo. Only 2 patients experienced grade 3 Clavien-Dindo complications, and both required procedural interventions. One patient experienced grade 4a Clavien-Dindo complication, requiring temporary renal dialysis without long-term disability. The R0 resection rate was 64%. There were 7 post-exenteration recurrences during the follow-up period. No statistically significant relationship was found among histological origin of tumour, microscopic resection margin status and postoperative recurrence (P = 0.67). Four patients died from sequelae of recurrent disease during follow-up. By utilizing modern assessment and surgical techniques, our PE Unit can manage complex pelvic cancers with acceptable morbidities, zero-rate mortality and equivalent oncologic outcomes.


Sociocultural Factors as Predictor to Exclusive Breastfeeding (EBF) Practice among Nursing Mothers in some Communities in Eastern, Nigeria.
This study examined the demographic and sociocultural influences on the level of exclusive breastfeeding (EBF) practices in Enugu state. The major instrument for data collection was a uniform set of structured questionnaire and in-depth interviews with the husbands, grandmothers/mothers-in-law, health workers, women leaders, and traditional/community leaders. Data were analyzed using frequencies, percentages and chi-squared test. Qualitative data were analyzed with ATLAS.ti. The study established that the prevalence level of EBF practice was relatively low (27%) in all the local government areas in the state. The result also showed that several sociocultural factors affected EBF practice. Some of them were: influence of TBAs (91%); poor nutrition in family menu (82%); campaign/marketing of artificial feed (78.3%), unfavorable conditions in the work place (66.8%); belief that lack of water can kill a baby (64.6%) and influence of grandmothers/mothers-in-law (64.2%). The results further revealed that age, occupation, parity, and educational qualification of the mothers influences the level of EBF practice. The findings also revealed that majority of mothers practice mixed feeding in the name of EBF practice. It is suggested that more efforts are needed in giving proper and adequate education and skilled counseling on EBF practice and sociocultural factors associated with the practice.


Effect of pooling udder skin wipes on the detection of influenza A virus in preweaning pigs.
Influenza A virus (IAV) active surveillance in pigs prior to weaning is commonly conducted by collecting individual samples, mostly nasal swabs. Recently, the use of udder skin wipes collected from lactating sows was identified as an effective sampling method to indicate IAV status of suckling piglets prior to weaning. However, there is limited information on the effect of pooling multiple udder wipes on the ability to detect IAV. We evaluated the effect of pooling 3, 5, or 10 udder wipes on the sensitivity of detecting IAV and compared the results with testing the wipes individually. The likelihood of detecting positive udder wipes decreased with pooling when the initial positive cycle threshold value was ≥31.5; pooling of up to 3 samples could be performed without affecting sensitivity significantly. Our results support pooling of udder skin wipes to conduct surveillance of IAV in pigs prior to weaning.


Societal and economic consequences of influenza.
High rates of vaccination coverage for preschool and school-aged children can reduce morbidity and mortality related to influenza outbreak. More focused and effective influenza prevention strategies are necessary to improve quality of life and to limit the burden of flu complications.


The treatment of forearm fractures with pins. By Georg Schöne, 1913.
In the case of fractures of the middle one-third of the forearm that are several weeks old, the procedure is as follows. Use a brachial block or general anesthesia. Open the radial fracture by freeing up the fracture site and clearing the medullary canals. About a 4-cm longitudinal incision is made over the dorsal aspect of the radius at the wrist distant from the fracture and between the tendons of the extensor pollicis longus and the extensor carpi radialis longus and brevis. Make a hole in the radius with a small gouge with insertion of the pin to the fracture site and then drive it into the proximal fragment. Then cut the pin off at the right length and set it into the bone with hammer blows to the driver. Remove the driver. Check the reduction of the fracture and closure of the wound. Repeat the procedure on the ulna with the difference that the trephination of the ulna is done proximally. Apply the splint. The fracture site must be protected carefully to avoid angulation. Should this occur, it can be corrected without opening the fracture site because the pins are flexible. We have operated upon four isolated fractures of the ulna, one isolated fracture of the radius, and two fractures of both radius and ulna. I believe that the procedure is simple and practical to perform. Whether and to what extent a similar procedure can be carried out satisfactorily on other bones with larger marrow canals remains to be seen.


Treatment of aplastic anemia by the kidney-tonifying and mediating method.
In this series of 65 cases of aplastic anemia, 26 cases were treated by the kidney-tonifying and mediating method, 19 cases by western drugs, and the remaining 20 cases only by tonifying the kidney as controls. The results showed that the kidney-tonifying and mediating method was significantly superior in the total effective rate to the method of western drugs and that of tonifying the kidney alone (P < 0.01), and it was also superior in the improvement of symptoms, myelogram, and peripheral blood count to the other two methods.


Compliance in epilepsy. Pharmacokinetics and medication compliance.
Pharmacokinetics is defined as the study of the time course of drug absorption, distribution and elimination. The study of pharmacokinetics involves the mathematical analysis of drug concentration-time data in blood or other tissues which yields estimates of the rate and extent that drugs enter, distribute through and leave the body. Application of pharmacokinetic principles permits prediction of plasma drug concentrations over a dosing interval, calculation of dosage regimens, management of drug interactions and assessment of non-compliance. A knowledge of pharmacokinetic principles allows one to properly interpret AED concentration data and thus more accurately assign alterations in drug concentrations to non-compliance or other causes.


Reduced representation bisulfite sequencing (RRBS) of dairy goat mammary glands reveals DNA methylation profiles of integrated genome-wide and critical milk-related genes.
DNA methylation (DNAm), a major element of epigenetics, plays critical roles in individual development. Reduced representation bisulfite sequencing (RRBS) is an effective and economical method for analyzing the DNA methylation of a single base. The aims of this study were to determine the DNAm profiles of the methylation contexts (CGs and non-CGs) of lactation and dry periods of goat mammary glands using the RRBS, and to identify potential milk-related genes. The proportion of CG was the highest among all the sequence contexts. The highest CG levels (72.44% to 75.24%) occurred in the 3' UTR region, followed by the gene body region (61.14% to 65.45%). The non-CG levels were low compared to the CG levels. Bioinformatic analysis demonstrated that the CGs were mainly enriched at high methylation levels (>90%), while non-CGs were enriched at low methylation levels. Methylation levels of 95 and 54 genes in the lactation period were up- or downregulated, respectively, relative to the dry period, such as PPARα, RXRα and NPY genes. The bisulfite sequencing PCR results showed that the methylation level of goat PPARα gene during the lactation period was significant lower than in the dry period, while the methylation level of the RXRα gene was lower in the dry period than in the lactation period. Meanwhile, the methylation levels of human PPARα and NPY genes were significantly higher in MCF-7 than in MCF-10A cells. These findings provide essential information for DNA methylation profiles of goat mammary gland and detect some potential milk-related genes in dairy goats.


Text Mining-Based Drug Discovery for Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.
Background: The current medical treatments for connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) do not show favorable efficiency for all patients, and identification of novel drugs is desired. Methods: Text mining was performed to obtain CTD- and PAH-related gene sets, and the intersection of the two gene sets was analyzed for functional enrichment through DAVID. The protein-protein interaction network of the overlapping genes and the significant gene modules were determined using STRING. The enriched candidate genes were further analyzed by Drug Gene Interaction database to identify drugs with potential therapeutic effects on CTD-PAH. Results: Based on text mining analysis, 179 genes related to CTD and PAH were identified. Through enrichment analysis of the genes, 20 genes representing six pathways were obtained. To further narrow the scope of potential existing drugs, we selected targeted drugs with a Query Score ≥5 and Interaction Score ≥1. Finally, 13 drugs targeting the six genes were selected as candidate drugs, which were divided into four drug-gene interaction types, and 12 of them had initial drug indications approved by the FDA. The potential gene targets of the drugs on this list are IL-6 (one drug) and IL-1β (two drugs), MMP9 (one drug), VEGFA (three drugs), TGFB1 (one drug), and EGFR (five drugs). These drugs might be used to treat CTD-PAH. Conclusion: We identified 13 drugs targeting six genes that may have potential therapeutic effects on CTD-PAH.


Orbital hemangiopericytoma: case report of a long-term recurrency.
Among tumors concerning the orbit, hemangiopericytoma is one of the most unusual forms. This tumor has a vascular origin and usually appears as a fleshy, well-circumscribed mass, characterized by slow growth and lack of soreness. Its biological traits include a mostly benign nature, a potential malignancy, and, most of all, a highly frequent recidivation. This study of double recidivation shows this can occur even after a long lapse of time and the new tissue can acquire malignant traits. Finally, we describe the modes of the surgical approach, which aims at intervening the most radical cases to reduce recidivation to a minimum.


Imidazole Antifungal Drugs Inhibit the Cell Proliferation and Invasion of Human Breast Cancer Cells.
Breast cancer is currently the most prevalent cancer in women, and its incidence increases every year. Azole antifungal drugs were recently found to have antitumor efficacy in several cancer types. They contain an imidazole (clotrimazole and ketoconazole) or a triazole (fluconazole and itraconazole) ring. Using human breast adenocarcinoma cells (MCF-7 and MDA-MB-231), we evaluated the effects of azole drugs on cell proliferation, apoptosis, cell cycle, migration, and invasion, and investigated the underlying mechanisms. Clotrimazole and ketoconazole inhibited the proliferation of both cell lines while fluconazole and itraconazole did not. In addition, clotrimazole and ketoconazole inhibited the motility of MDA-MB-231 cells and induced G1-phase arrest in MCF-7 and MDA-MB-231 cells, as determined by cell cycle analysis and immunoblot data. Moreover, Transwell invasion and gelatin zymography assays revealed that clotrimazole and ketoconazole suppressed invasiveness through the inhibition of matrix metalloproteinase 9 in MDA-MB-231 cells, although no significant changes in invasiveness were observed in MCF-7 cells. There were no significant changes in any of the observed parameters with fluconazole or itraconazole treatment in either breast cancer cell line. Taken together, imidazole antifungal drugs showed strong antitumor activity in breast cancer cells through induction of apoptosis and G1 arrest in both MCF-7 and MDA-MB-231 cells and suppression of invasiveness via matrix metalloproteinase 9 inhibition in MDA-MB-231 cells. Imidazole drugs have well-established pharmacokinetic profiles and known toxicity, which can make these generic drugs strong candidates for repositioning as antitumor therapies.


[Significance of mineral substances in interstitial lung diseases].
Authors studied on 19 patients with interstitial pulmonary diseases bioptic material from the lungs gained with Hausser -needle especially for mineral components. With energy dispersive X-ray analysis (EDAX) in connection with electron microscopy exogen pigments were identified in every case. The pigment deposition proved to be the result of professional dust exposition. The inhaled dusts can be considered as etiologic factors if their source can be demonstrated unanimously, if other pathogens can be excluded and the characteristic tissue reactions can be demonstrated.


Mechanisms underlying sex bias in oral immune-mediated conditions, an insight.
The predilection for women in systemic autoimmune diseases is well established. However, this sex bias in oral autoimmune diseases has been classically reported from an epidemiological perspective without any elaborate attempts to unveil the underlying mechanisms. The unique nature of the oral environment is likely to impose a combination of systemic and local factors that ultimately result in the sex bias in autoimmune diseases of the oral cavity. Variations of immune responses, target organ vulnerability, endocrine and genetic factors, sex chromosomes and modes of parental inheritance are potential systemic factors, while the oral microbiome, oral tolerance, saliva, and oral epithelial stem cells may account for local contributing factors. This review will discuss the preponderance of women in oral immune-mediated diseases, the potential systemic and local mechanisms underlying this predominance and highlight the crucial need for further research in this area.


Comparison of three different PCR methods for quantifying human papillomavirus type 16 DNA in cervical scrape specimens.
We compared real-time LightCycler and TaqMan assays and the GP5+/6+ PCR/enzyme immunoassay (EIA) to assess the human papillomavirus type 16 (HPV16) load in cervical scrape specimens. Both real-time PCR assays determined the HPV16 load in scrape specimens similarly. The level of agreement between these assays and the GP5+/6+ PCR/EIA was low (P = 0.004), suggesting that the latter method is not suited for quantifying HPV16 DNA.


Disruptions in self-regulatory processes predict depression and sleep disturbance in bereaved young adults.
Losing a loved one is both common and profoundly stressful for young adults. Little research has examined the longitudinal course of post-loss cognitive processing, depression, and sleep difficulties. Further, little is known about the context of other stressors or the role of individual regulatory resources, such as attentional regulation, that might determine whether loss-related cognitive processing reduces distress. This prospective study examined changes in depression and sleep disturbance over 9 weeks as a function of within- and between-person variation in stress exposure, loss-related cognitive processing, and attention regulation. Participants were 108 recently bereaved college students completing a lab-based assessment of attention regulation and four self-report surveys, spaced three weeks apart. Results revealed that most participants gradually reduced loss-related processing over the study period, with corresponding improvements in depression and sleep. Stress exposure was associated with increased processing, depression, and sleep disturbance. In exploratory analyses, high attentional alertness and slow re-orienting strengthened the association of within-person loss processing with sleep disturbance. Both within- and between-person variation in stress appear to engender risk for a prolonged course of bereavement. Future research should integrate objective attention measures with self-reported adjustment to stress to illuminate reciprocal links between depression, sleep, and loss-related cognitive processing.


Thermal dilution cardiac output units.
We evaluated five units (four modules and one stand-alone) from five manufacturers. All units were rated Acceptable. Most of the test results met our accuracy and precision criteria; other units that demonstrated a small margin of error were still clinically useful. The utility of the thermal dilution (TD) method depends largely on proper technique, as well as the volume and temperature of the injection, number of injections, and the type of probe used.


c-met is amplified but not mutated in a cell line with an activated met tyrosine kinase.
The putative tyrosine kinase receptor encoded by the oncogene c-met is activated (tyrosine-phosphorylated in vivo) in the human gastric carcinoma cell line GTL-16. The corresponding gene is amplified and over-expressed. In this study we show that c-met is part of an amplification unit measuring more than 3000 kb. The multiple copies of the amplicon are located on a novel chromosome different from chromosome 7. We have previously shown that the c-met protein present in GTL-16 cells is indistinguishable from that found in other cells. Kinase activation could be due to over-expression of the normal c-met protein or to the presence of activating mutation(s). To verify the primary structure of the c-met protein in GTL-16 cells we sequenced a series of overlapping cDNAs obtained from GTL-16 cell RNA by reverse transcription and polymerase chain reaction. Two differences were found in the c-met coding region with respect to the published human c-met cDNA: (1) the lack of 54 nucleotides corresponding to a stretch of 18 amino acids located in the extracellular domain of the receptor, and (2) the substitution of the codon specifying alanine 1209 (located in the tyrosine kinase domain) with one coding for glycine. However, we also obtained cDNAs identical to that just described from a number of control cell lines. These results suggest: (1) that the present c-met cDNA presumably reflects the sequence of the most abundant transcript in several cell types, and (2) that over-expression of the normal c-met protein, alone or in combination with an autocrine loop, is most probably responsible for the activation of the c-met kinase in GTL-16 cells.


Evaluation of clinical efficacy of fasudil for the treatment of pulmonary arterial hypertension.
Multiple cell types in the vascular wall rely upon the rho-kinase (ROCK) signaling pathway for homeostatic function and response to injury. These cell types include endothelial and vascular smooth muscle cells, inflammatory cells, and fibroblasts. Rho is a guanosine triphosphate binding protein that activates its downstream target rho-kinase, in response to activation of a variety of G-protein coupled receptors. When activated, ROCK inhibits myosin phosphatase and conversely upregulates the ezrin-radixin-moesin family of kinases. In vitro activation of these signaling cascades results in modulation of multiple cellular processes, including enhanced vasoconstriction, proliferation, impaired endothelial response to vasodilators, chronic pulmonary remodeling, and upregulation of vasoactive cytokines via the NF-κB transcription pathway. ROCK activity has also been linked specifically to a number of known effectors of pulmonary arterial hypertension (PAH), including endothelin-1, serotonin, and endothelial nitric oxide synthase, among others. Recently, elevated ROCK activity has been demonstrated in various animal models of PAH with ROCK inhibitors associated with pulmonary vasodilatation and regression of PAH. ROCK inhibitors are a new class of agents which may be beneficial in the treatment of PAH. Fasudil (Daiichi Chemical and Pharmacological Company, Ibaragi, Japan), a first generation ROCK inhibitor, has been widely studied. Emerging evidence from both animal and human studies suggests that fasudil can promote vasodilation independent of the mechanism that induces vasoconstriction and will be useful in conditions in which endothelial function is impaired including PAH. Several recent patents have described fasudil as a potential therapeutic option in PAH. This article provides an overview of the role of ROCK in the pathogenesis of PAH and discusses the clinical efficacy of fasudil as a therapeutic option for treating PAH.


Blood protein adsorption onto chitosan.
Chitosan was recently indicated to enhance osteogenesis, improve wound healing but to activate the coagulation and the complement systems. In the present study approximately 10 nm thick chitosan film were prepared on aminopropyltriethoxysilane (APTES) coated silicon. The surfaces were incubated in serum or plasma and subsequently in antibodies towards key complement and contact activation of coagulation proteins. The deposited amounts were compared with those on hydrophilic and hydrophobic silicon, APTES and IgG coated reference samples. Although large amounts of serum deposited to chitosan only a weak transient activation of the complement system and no activation of the intrinsic pathway was observed. Upon acetylation the chitosan layer became a strong activator of the alternative pathway of the complement. After incubation in human plasma anti-fibrinogen deposited onto chitosan but not onto the acetylated chitosan, a finding that may explain previous observations of procoagulant activity by chitosan.


[High-dose gamma globulin in autoimmune diseases].
The short-term benefit of high-dose intravenous gammaglobulin (IvIgG) in autoimmune diseases is widely accepted in patients with chronic immune thrombocytopenic purpura (ITP). Recent studies reported remission or stabilization of the disease in some patients receiving long-term IvIgG therapy. It has been suggested that this long-term effect may be due to antiidiotypic antibodies in IvIgG down-regulating the immune response in chronic ITP. Because of the high costs and the transient effect in most instances, this treatment should not be used routinely. IvIgG may be considered in severely thrombocytopenic patients with chronic ITP who develop serious bleeding.


Congenital cardiac disease in dogs.
Nonselective angiocardiography is used to delineate certain congenital cardiac defects. It is useful in demonstrating lesions causing a right-to-left shunt, as in tetralogy of Fallot and a reverse right-to-left patent ductus arteriosus, but not for lesions causing a left-to-right shunt, as in ventricular septal defect. Positive-contrast medium, injected IV as a bolus at 0.5 ml/lb, opacifies the heart chambers and great vessels. Using a rapid film-changing device, 3 films are made in 6 seconds. A rapid film changer can be constructed from plywood, wooden slats and plexiglass. Three cassettes are loaded into the device, the first beneath the x-ray beam and overlying plexiglass window and patient. The first film is exposed just after injection of the contrast medium, and the second and third 2 and 4 seconds later, respectively.


Seroprevalence of IgA and IgM antibodies to Bordetella pertussis in healthy Japanese donors: Assessment for the serological diagnosis of pertussis.
Pertussis is a human respiratory infection caused by the gram-negative bacterium, Bordetella pertussis. To evaluate the pertussis burden and vaccine efficacy, diagnosis and epidemiological surveillance should be based on accurate and valid diagnostic methods. Recently, the serodiagnostic tests Novagnost Bordetella pertussis IgA and IgM were approved in Japan for pertussis diagnostics. Although the anti-pertussis toxin (PT) IgG assay has been used for pertussis diagnosis worldwide, little is known about the anti-B. pertussis IgA and IgM assays. In this study, serum samples from 460 healthy donors were examined to determine the seroprevalence of anti-B. pertussis IgA and IgM in a Japanese population, and its correlation with donor age. Our data demonstrated that anti-B. pertussis IgA and IgM are positively and negatively correlated with age (r = 0.27, r = -0.37; P < 0.001, respectively). Age-specific analysis revealed high titers of anti-B. pertussis IgA in adults (46-50 years), while anti-B. pertussis IgM titers were high in schoolchildren (6-10, 11-15 years). When applying the arbitrary cut-off values for these ages, 17.6% and 39.5% of healthy donors were interpreted as pertussis-positive or indeterminate with anti-B. pertussis IgA (46-50 years) and IgM (11-15 years) titers, respectively. Overall, our findings indicated that the Novagnost Bordetella pertussis IgA and IgM testing could be greatly affected by subject age, limiting its value for pertussis diagnosis.


Effect of ginsenoside Rh1 on myocardial injury and heart function in isoproterenol-induced cardiotoxicity in rats.
The present study was designed to investigate the effect of ginsenoside Rh1 on myocardial injury and heart function in isoproterenol-induced cardiotoxicity in rats. Sprague-Dawley rats were subcutaneously injected with isoproterenol (20 mg/kg). Cardiac marker enzymes in serum, antioxidative parameters and inflammatory cytokines in left ventricles were measured. Hemodynamic parameters were monitored and recorded as well. Histopathological examination of left ventricles was performed. It was found that creatine kinase-MB (CK-MB) activity and troponin T level in isoproterenol-treated rats were significantly increased. Isoproterenol caused declines of left ventricular systolic pressure, positive and negative maximal values of the first derivative of left ventricular pressure, and an elevation of left ventricular end diastolic pressure. Isoproterenol enhanced the content of malondialdehyde (MDA), tumor necrosis-α (TNF-α), interleukin-1β (IL-1β) and decreased the activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px) in left ventricles. Ginsenoside Rh1 significantly ameliorated myocardial injury and heart function impairment induced by isoproterenol. The cardioprotective effect of ginsenoside Rh1 was further confirmed by histopathological examination. Ginsenoside Rh1 also partially inhibited the increase of MDA, TNF-α, IL-1β contents and the decrease of SOD, catalase, and GSH-Px activities in left ventricles. The results indicated that ginsenoside Rh1 possessed the effect against isoproterenol-induced cardiotoxicity, and that the mechanism of pharmacological action was related to regulating the activities of SOD, catalase, and GSH-Px and decreasing the contents of TNF-α and IL-1β.


The Comparison of the Effect of Flour Particle Size and Content of Damaged Starch on Rice and Buckwheat Slurry, Dough, and Bread Characteristics.
The effect of botanical origin, the flour particle size, and the content of damaged starch on flour pasting properties, dough behavior during a uniaxial deformation test, and bread characteristics were evaluated on rice and buckwheat flours. The rice flour with a median particle size D(0.5) of 60.2, 70.6, 106.8, and 189.4 μm, and buckwheat flour with a D(0.5) of 56.4, 68.4, and 95.8 μm were prepared using the same milling technology. The botanical origin of the flours was the strongest factor influencing the flour pasting properties, stress accumulated in dough during the uniaxial deformation test, loaf characteristics, texture, and sensory characteristics of breads. The flour particle size significantly influenced mainly the flour pasting properties. The effect of the content of damaged starch was the weakest among the studied factors. The flour particle size and the content of damaged starch were closely related. The flour botanical origin was the strongest factor; therefore, it seems not to be possible to predict the bread-baking potential of gluten-free flours based on the results obtained for flour of a different botanical origin. More research on flours from different plants prepared by the same milling process is required to support this hypothesis.


Molecular underpinnings of systemic treatment resistance in metastatic castration-resistant prostate cancer
In the last few years, several new drugs with various mechanisms of action have been approved for the treatment of castration-resistant prostate cancer. Due to this development, therapeutic decision-making has become increasingly complex. Therefore, therapy selection as well as timing and sequence of treatments need to be optimized in an individual manner. In addition, also for these novel therapies, baseline and acquired as well as cross-resistance have been observed. Underlying mechanisms become increasingly clear, resulting in a shift from empiric-based towards rational-based therapeutic decision-making. In the present review, we provide an overview on the resistance mechanisms against the most frequently applied systemic treatments of metastatic castration-resistant prostate cancer such as docetaxel, abiraterone and enzalutamide. We summarize - among others - the mechanisms by MDR (multidrug-resistant) protein expression, alterations of androgen receptor, Wnt, p53 and DNA-repair pathways (BRCA/ATM) as well as resistance through therapy-induced neuroendocrine differentiation of the tumour. Orv Hetil. 2020; 161(20): 813-820.


Hydrophobic Cellulose Acetate Aerogels for Thermal Insulation.
As naturally derived material, cellulose aerogels have excellent thermal insulation properties due to their unique high porosity and three-dimensional mesoporous structure. However, its hydrophilic properties limit its application in the field of building insulation. Here, we propose a method to prepare high hydrophobicity by adopting the sol-gel method and chemical vapor reaction strategy using cellulose acetate type II as raw material and 2,4-toluene diisocyanate as the cross-linking agent. Thermal properties of cellulose acetate aerogels (CAAs) were measured, where pyridine was the catalyst, acetone was the solvent, and perfluorodecyltriethoxysilane (PFDS), hexamethyldisilazane (HMDS), and methyltriethoxysilane (MTES) were used as hydrophobic agents (by process hydrophobic test). Compared with MTES-modified cellulose acetate aerogels (M-CAAs) and HMDS (H-CAAs)-modified cellulose acetate aerogels, PFDS-modified (P-CAAs) cellulose acetate aerogels are the most hydrophobic. By implementing hydrophobic modification of PFDS both inside and outside the structure of cellulose acetate aerogels, the water contact angle can reach up to 136°, strongly demonstrating the potential of PFDS as a hydrophobic agent. The results show that the thermal conductivity and compressive strength of cellulose acetate aerogel with the best hydrophobic properties are 0.035 W m-1 K-1 at normal pressure and 0.39 MPa at 3% strain, respectively. This work shows that the highly hydrophobic cellulose acetate aerogel has potential as a waterproof material in the field of building thermal-insulation materials.


Case Report on Sleeve Avulsion of Patella in Young Adult.
Sleeve avulsion of patella is extremely rare, limited almost to children. However, few cases have been reported in adults. Rarity of this fracture makes the diagnosis and choice of treatment difficult. Inability to raise leg remains important clinical sign for quadriceps mechanism insufficiency. In the absence of standard treatment guidelines pullout sutures through patella provides a secure and stable fixation option. Our case remains the first to be reported ever in English literature in a 23-year-old male with a superior pole avulsion patella being treated with Krakow pullout suture. A 23-year-old Indian male was admitted with left knee pain and swelling following fall from bike. He had knee pain, swelling, and inability to bear weight. Active straight leg raising was not possible. On X-ray he had small bony sleeve visible near proximal pole of patella. Magnetic resonance imaging (MRI) was done which showed sleeve avulsion of patella at proximal pole. Under spinal anesthesia fracture was exposed through midline approach. Pullout Krakow sutures were taken through quadriceps tendon and fracture fragments using 3 no Polyester suture. Transosseous tunnels were drilled in patella and tied distally. At 4 months patient had no extension lag with full range of movements. At 14 months follow-up patient is asymptomatic and able to run, squat, sit cross legged, and do his day-to-day activities. Sleeve avulsion of patella in adults is extremely rare with only few cases reported in literature. MRI is not only useful for diagnosis but also for deciding treatment modality. Krackow technique with Polyester suture through quadriceps tendon incorporating fracture fragment passed through patellar transosseous tunnel provides secure fixation with excellent results. Also avoids any future hardware problems in this subcutaneous bone.


Image fusion of thallium-201 SPECT and MR imaging for the assessment of recurrent head and neck tumors following flap reconstructive surgery.
The aim of this study was to assess the value of fused MR and Tl-201 single photon emission computed tomography (SPECT) images in the diagnosis of recurrent head and neck tumors in patients after flap reconstruction surgery. Twenty-four patients after resection of primary head and neck tumors with flap reconstruction were suspected of having recurrent tumor by follow-up MR examination. Both MR examination and Tl-201 SPECT were prospectively performed to produce fused images. For qualitative analysis, two independent readers separately evaluated the existence of tumor recurrence in the fused images. The Tl-201 uptake of the lesion (Tl index) was also quantitatively compared with that of the normal nuchal muscles. Eighteen patients were histologically proved as having recurrence. The remaining 6 patients, false positive on MRI alone, had non-recurrence. Using the fused images, false positive was found in 1 case for one reader and 2 cases for the other reader. The Tl index of recurrent tumors was significantly higher (p < 0.001) than that of non-recurrent mass lesions. In the assessment of recurrent tumors following flap reconstruction surgery in the head and neck, the use of fused MRI and Tl-201 SPECT images can reduce the number of false positives.


Failure to demonstrate any interaction between polyclonal rheumatoid factors and IgG antinuclear antibodies or other IgG autoantibodies.
The autoantibody profile results from 750 randomly selected patients with rheumatoid factor (RF) and/or antinuclear antibody (ANA) positive tests were retrospectively analysed in order to discover if there was any evidence to show that the presence of polyclonal rheumatoid factors affects the incidence and titre of IgG-ANA in these patients. The incidence of IgG-ANA in the RF-positive group (34.4%) was significantly greater than that found in the RF-negative groups (19.6%) (P < 0.001), and there was no significant difference between the mean IgG-ANA titres of the two groups (P = 0.987). The possibility that the presence of IgM-RF in serum might be responsible for the inhibition of IgG-ANA was examined by treating the sera of selected patients who were RF-positive but IgG-ANA-negative with the dissociating agent D-penicillamine (DP). After treatment, IgG-ANA could not be detected in any of the sera. Similar studies were carried out to ascertain if there was a masking effect by RF on two other IgG autoantibodies, anti-keratin antibody (AKA) and gastric parietal cell antibody (GPCA). There was no evidence from these studies that the presence of RF affects the incidence of either AKA or GPCA. We conclude from these results that the presence of RF is not a significant factor controlling the incidence of either IgG-ANA or other IgG autoantibodies and that the routine treatment of RF-containing serum with a dissociating agent before testing for autoantibodies would be unnecessary.


Oral administration of BCG as a local immunotherapy of gastrointestinal cancer.
Antitumor effect of oral bacille Calmette Guérin (BCG) administration was investigated by both animal experimentation and clinical trials. In animal experiments, orally administered BCG inhibited metastasis of syngeneic tumor from the initial site in caecum to mesenteric lymph nodes. Measurement of chemiluminescent intensity of adherent cells obtained from mesenteric lymph nodes of treated hosts revealed elevated activities of these cells. In the clinical trials it was found that marked histiocytosis occurred in mesenteric lymph nodes of stomach and colorectal cancer patients treated by the oral BCG. The 2-year survival rate of treated patients with stage IV stomach cancer (44.4%) was significantly higher than that of the untreated patients (6.3%). The results of the present study indicate that the oral BCG administration would be an effective local adjuvant therapy following radical surgery to treat patients with gastrointestinal cancer.


Association of interferon-alpha-induced depression and improved treatment response in patients with hepatitis C.
Thirty-nine patients with hepatitis C viral infection on interferon-alpha (IFN-alpha) therapy were monitored weekly using the Beck Depression Inventory (BDI). Thirteen of thirty-nine patients (33%) developed IFN-alpha-induced major depressive disorder (MDD). During the course of IFN-alpha therapy, patients who became depressed were treated with citalopram, a selective serotonin reuptake inhibitor (SSRI) antidepressant. Results indicated that: (1) IFN-alpha response rates were significantly higher in those patients who developed IFN-alpha-induced MDD than in those who did not (end-of-treatment response (ETR) rates: 61.5% versus 26.9% and sustained viral response (SVR) rates: 38.5% versus 11.5%), (2) male patients with ETR to IFN-alpha therapy were, on average, approximately 33 pounds lighter in body weight than male patients who did not respond, and (3) gender, race, past history of MDD, and past history of substance abuse were not significantly associated with ETR. In conclusion, our findings suggest that IFN-alpha-induced MDD may be a predictor of a positive response to IFN-alpha therapy, or an indication of optimal dosing.


Cyclosporin-induced hypertension is associated with the up-regulation of Na+-K+-2Cl- cotransporter (NKCC2).
The use of Cyclosporin A (CsA) is hampered by the development of nephrotoxicity including hypertension, which is partially dependent on renal sodium retention. To address this issue, we have investigated in vivo sodium reabsorption in different nephron segments of CsA-treated rats through micropuncture study coupled to expression analyses of sodium transporters. To translate the findings in rats to human, kidney transplanted patients with CsA treatment were enrolled in the study. Adult male Sprague-Dawley rats were treated with CsA (15 mg/kg/day) for 21 days, followed by micropuncture study and expression analyses of sodium transporters. CsA-treated kidney transplanted patients with resistant hypertension have been challenged with 50 mg furosemide. CsA-treated rats developed hypertension associated with reduced glomerular filtration rate (GFR). In vivo microperfusion study demonstrated a significant decrease in rate of absolute fluid reabsorption (Jv) in the proximal tubule (PT) but enhanced sodium reabsorption (JNa) in thick ascending limb of Henle's loop (TAL). Expression analyses of sodium transporters at the same nephron segments further revealed a reduction in Na+-H+ exchanger isoform 3 (NHE3) in the renal cortex, while TAL-specific, furosemide-sensitive Na+-K+-2Cl- cotransporter (NKCC2) and NHE3 were significantly upregulated in ISOM. CsA-treated patients had a larger excretion of urinary NKCC2 protein at basal condition, and higher diuretic response to furosemide, showing increased FeNa+, FeCl- and FeCa2+ compared to both healthy controls and FK506-treated transplanted patients. All together, these findings suggest that up-regulation of NKCC2 along the TAL facilitates sodium retention and contributes to the development of CsA-induced hypertension.


Pediatric isolated bilateral iliac aneurysm.
Aneurysms are rare in children. Isolated iliac artery aneurysms are very rare, especially bilateral aneurysms. Pediatric aneurysms are usually secondary to connective tissue disorders, arteritis, or mycotic causes. We present a case of a 3-year-old child with bilateral idiopathic common iliac aneurysms that were successfully repaired with autogenous vein grafts.


Human disturbances, habitat characteristics and social environment generate sex-specific responses in vigilance of Mediterranean mouflon.
In prey species, vigilance is an important part of the decision making process related to predation risk effects. Therefore, understanding the mechanisms shaping vigilance behavior provides relevant insights on factors influencing individual fitness. We investigated the role of extrinsic and intrinsic factors on vigilance behavior in Mediterranean mouflon (Ovis gmelini musimon×Ovis sp.) in a study site spatially and temporally contrasted in human pressures. Both sexes were less vigilant in the wildlife reserve compared to surrounding unprotected areas, except for males during the hunting period. During this period, males tended to be less strictly restricted to the reserve than females what might lead to a pervasive effect of hunting within the protected area, resulting in an increase in male vigilance. It might also be a rutting effect that did not occur in unprotected areas because males vigilance was already maximal in response to human disturbances. In both sexes, yearlings were less vigilant than adults, probably because they traded off vigilance for learning and energy acquisition and/or because they relied on adult experience present in the group. Similarly, non-reproductive females benefited of the vigilance effort provided by reproductive females when belonging to the same group. However, in the absence of reproductive females, non-reproductive females were as vigilant as reproductive females. Increasing group size was only found to reduce vigilance in females (up to 17.5%), not in males. We also showed sex-specific responses to habitat characteristics. Females increased their vigilance when habitat visibility decreased (up to 13.8%) whereas males increased their vigilance when feeding on low quality sites, i.e., when concomitant increase in chewing time can be devoted to vigilance with limited costs. Our global approach was able to disentangle the sex-specific sources of variation in mouflon vigilance and stressed the importance of reserves in managing and conserving wild sheep populations.


Combinatorial structure of a body muscle-specific transcriptional enhancer in Caenorhabditis elegans.
We describe the dissection of a body muscle-specific enhancer sequence contained within the Caenorhabditis elegans myosin heavy chain gene unc-54. A 90-base pair segment that was sufficient for both enhancer function and tissue specificity was subjected to mutational analysis. Several separated sites within this region were required for activity; mutations in these sites led to dramatic decreases in enhancer activity, while substitutions in the intervening regions had minimal effects on activity. The individual sites appear to function as semi-independent and partially interchangeable enhancer subelements, as seen by our ability to create functional enhancers by constructing novel multimers and combinations. Four different enhancer subelements (designated O, I, II, and III) were identified in this way. Although partially interchangeable, some differences between these subelements were evident. In particular, concatamers of site III exhibited the highest levels of activity but had a broader tissue specificity than the intact enhancer, including both hypodermal and muscle tissue. The specificity of the intact enhancer thus reflects a combinatorial function of the specificities of the constituent subelements.


When is diabetes mellitus a relative or absolute contraindication to liver transplantation?
1. Diabetes mellitus is common in patients with cirrhosis; patients with DM undergoing liver transplantation often have many other co-morbid illnesses including obesity, coronary artery disease (CAD), autonomic neuropathy, gastroparesis, and nephropathy. 2. Long-term survival of patients with diabetes mellitus (DM) is significantly lower and morbidity higher when compared to non-diabetics mainly because of cardiovascular complications, infections, and renal failure. 3. Obesity, CAD, and renal failure are confounding factors that result in poor patient survival. 4. Patients with DM should undergo careful cardiovascular diagnostic work up, including routine coronary arteriogram, and necessary interventions before liver transplantation. This is especially important in those over 50 years old, and in those with retinopathy, nephropathy, and neuropathy. 5. Patients with coronary artery disease that is not amenable to surgery or stents, and those with impaired left ventricular function, should not be considered for liver transplantation. Other relative or absolute contraindications are those with proteinura and renal failure who are not candidates for combined liver/kidney transplantation, those with severe gastroparesis, especially when it is associated with diabetic autonomic neuropathy, and those with two or more risk factors such as CAD, morbid obesity, and renal failure. 6. Future studies should focus on risk stratification of patients with DM undergoing liver transplantation and better interventions to reduce the risk of diabetic complications before and after liver transplantation.


Meningioma associated with acute subdural hematoma: A review of the literature.
Classically meningiomas present with a gradual onset of symptoms and their acute presentation with hemorrhagic events seems to be a rare event. A review of the literature shows only 18 cases of meningioma associated with acute subdural hematoma. The possible mechanisms of hemorrhage are not yet fully understood. We report a case of sphenoid wing meningioma associated with acute subdural hematoma, without history of trauma. The presence of meningioma was discovered during the surgery. The tumor and hematoma were removed without postoperative complications. The authors have discussed the etiology of an acute subdural hemorrhage and reviewed the pertinent literature.