Cells resident to precision templated 40-µm pore scaffolds generate small extracellular vesicles that affect CD4+ T cell phenotypes through regulatory TLR4 signaling.
Precision porous templated scaffolds (PTS) are a hydrogel construct of uniformly sized interconnected spherical pores that induce a pro-healing response (reducing the foreign body reaction, FBR) exclusively when the pores are 30-40µm in diameter. Our previous work demonstrated the necessity of Tregs in the maintenance of PTS pore size specific differences in CD4+ T cell phenotype. Work here characterizes the role of Tregs in the responses to implanted 40µm and 100µm PTS using WT and FoxP3+ cell (Treg) depleted mice. Proteomic analyses indicate that integrin signaling, monocytes/macrophages, cytoskeletal remodeling, inflammatory cues, and vesicule endocytosis may participate in Treg activation and the CD4+ T cell equilibrium modulated by PTS resident cell-derived small extracellular vesicles (sEVs). The role of MyD88-dependent and MyD88-independent TLR4 activation in PTS cell-derived sEV-to-T cell signaling is quantified by treating WT, TLR4ko, and MyD88ko splenic T cells with PTS cell-derived sEVs. STAT3 and mTOR are identified as mechanisms for further study for pore-size dependent PTS cell-derived sEV-to-T cell signaling. STATEMENT OF SIGNIFICANCE: Unique cell populations colonizing only within 40µm pore size PTS generate sEVs that resolve inflammation by modifying CD4+ T cell phenotypes through TLR4 signaling.


Substance P excitation of rat locus coeruleus neurones.
We have made extracellular recordings from locus coeruleus neurones contained in a pontine slice preparation. The in vitro technique permits application of known concentrations of drugs in the perfusion medium. Substance P excites locus coeruleus neurones in a concentration-dependent manner. The activity of substance P was found to reside in the C terminal region of the molecule. The relative potency of substance P and related peptides suggests that the substance P receptors present within the locus coeruleus are predominately of the substance P-P type. The synthetic analogue [D-Pro2,D-Trp7.9]substance P was not found to antagonise the action of substance P on locus coeruleus neurones.


Could emotional and sensitization status affect postural sway in adults with knee osteoarthritis?
The manipulation of sensory conditions and attentional demand affect the postural sway in older adults with knee osteoarthritis (KOA). However, it is not known if emotional and sensitization status affects postural sway in this population. This study aimed to test if older adults with mild and moderate knee osteoarthritis with symptoms of depression and high sensitization would change the profile of postural sway. Design: A cross-sectional study was undertaken. The center of pressure parameters of 30 older adults with mild and moderate knee osteoarthritis and 15 healthy controls were evaluated under different conditions manipulating the visual and attentional demand. We used the pressure pain threshold to measure the sensitization status. Furthermore, we applied the Beck Depression Inventory index to assess emotional status. Manipulating the visual demand affected the center of pressure parameters for both groups, without differences between them. Compared to the healthy control group, the knee osteoarthritis group presented with worse scores on the Beck Depression Inventory, lower pressure pain threshold scores, and the correlations between the symptoms of depression and sensitization status ranged from weak to moderate. Finally, in the knee osteoarthritis group, we observed few and weak significant associations between the center of pressure parameters and the Beck Depression Inventory and the pressure pain threshold scores. Emotional and sensitization status seem not to be more associated with the center of pressure of older adults with mild to moderate KOA than healthy adults. Thus, it suggests that this population can safely maintain postural sway, irrespective of depression symptoms and high sensitization.


Carney complex: Clinical and genetic 2010 update.
First described in the mid 1980s, Carney complex is a rare dominantly heritable multiple endocrine neoplasia syndrome that affects endocrine glands as the adrenal cortex, the pituitary and the thyroid. It is associated with many other nonendocrine tumors, including cardiac myxomas, testicular tumors, melanotic schwannoma, breast myxomatosis, and abnormal pigmentation or myxomas of the skin. The Carney complex gene 1 was identified 10 years ago as the regulatory subunit 1A of protein kinase A (PRKAR1A) located at 17q22-24. An inactivating heterozygous germ line mutation of PRKAR1A is observed in about two-thirds of Carney complex patients. This last decade many progresses have been done in the knowledge of this rare disease and its genetics. This review outlines the current state of this knowledge on Carney complex.


Primary non-response to antiviral therapy affects the prognosis of hepatitis B virus-related hepatocellular carcinoma.
Although antiviral treatments have been shown to affect the recurrence and long-term survival of patients with hepatocellular carcinoma (HCC) who have high viral loads, the effect of different responses to antiviral therapy on the clinical outcomes remains unclear. This study aimed to assess the effect of primary non-response (no-PR) to antiviral therapy on the survival or prognosis of patients with HCC with a high load of hepatitis B virus (HBV) DNA. A total of 493 HBV-HCC patients hospitalized at Beijing Ditan Hospital of Capital Medical University were admitted to this retrospective study. Patients were divided into two groups based on viral response (no-PR and primary response). Kaplan-Meier (KM) curves were used to compare the overall survival of the two cohorts. Serum viral load comparison and subgroup analysis were performed. Additionally, risk factors were screened and the risk score chart was created. This study consisted of 101 patients with no-PR and 392 patients with primary response. In the different categories based on hepatitis B e antigen and HBV DNA, no-PR group had a poor 1-year overall survival (OS). In addition, in the alanine aminotransferase < 50 IU/L and cirrhosis groups, primary nonresponse was related to poor overall survival and progression-free survival. Based on multivariate risk analysis, primary non-response (hazard ratio (HR) = 1.883, 95% CI 1.289-2.751, P = 0.001), tumor multiplicity (HR = 1.488, 95% CI 1.036-2.136, P = 0.031), portal vein tumor thrombus (HR = 2.732, 95% CI 1.859-4.015, P < 0.001), hemoglobin < 120 g/L (HR = 2.211, 95% CI 1.548-3.158, P < 0.001) and tumor size ≥ 5 cm (HR = 2.202, 95% CI 1.533-3.163, P < 0.001) were independent risk factors for 1-year OS. According to the scoring chart, patients were divided into three risk groups (high-, medium-, and low-risk groups) with mortality rates of 61.7%, 30.5%, and 14.1%, respectively. The level of viral decline at 3 months post-antiviral treatment may predict the OS of patients with HBV-related HCC, and primary non-response may shorten the median survival time of patients with high HBV-DNA levels.


mGlu1 potentiation enhances prelimbic somatostatin interneuron activity to rescue schizophrenia-like physiological and cognitive deficits.
Evidence for prefrontal cortical (PFC) GABAergic dysfunction is one of the most consistent findings in schizophrenia and may contribute to cognitive deficits. Recent studies suggest that the mGlu1 subtype of metabotropic glutamate receptor regulates cortical inhibition; however, understanding the mechanisms through which mGlu1 positive allosteric modulators (PAMs) regulate PFC microcircuit function and cognition is essential for advancing these potential therapeutics toward the clinic. We report a series of electrophysiology, optogenetic, pharmacological magnetic resonance imaging, and animal behavior studies demonstrating that activation of mGlu1 receptors increases inhibitory transmission in the prelimbic PFC by selective excitation of somatostatin-expressing interneurons (SST-INs). An mGlu1 PAM reverses cortical hyperactivity and concomitant cognitive deficits induced by N-methyl-d-aspartate (NMDA) receptor antagonists. Using in vivo optogenetics, we show that prelimbic SST-INs are necessary for mGlu1 PAM efficacy. Collectively, these findings suggest that mGlu1 PAMs could reverse cortical GABAergic deficits and exhibit efficacy in treating cognitive dysfunction in schizophrenia.


Audit of emergent and urgent surgery for acutely ill pediatric patients: is access timely?
There is a paucity of literature about wait times for urgent/emergent surgeries in Canada. Delays and performance of non-emergent operations overnight increase morbidity and mortality. The study aim was to determine patterns of delays and performance of less-emergent surgery overnight. A retrospective analysis (June 2011-December 2013) of emergent/urgent surgeries was conducted using the ORSOS database (prospective patient and operative data). Surgeries were classified: class 1, 2A, 2B, and 3: target times of 1, 6, 24 and 72h. In hours (IH)=7:45AM-3:30PM, M-F; others were out of hours (OOH) and overnight =2300-0700. There were 4668 operations: class 1 (5.8%), 2A (29.1%), 2B (42.1%), and 3(23%). For class 1, 2A, 2B, and 3 surgeries, mean in-room times were 2, 4.7, 15.4, and 54h respectively; 59.2% (class 1), 81.9% (class 2A), 81.2% (class 2B) and 74.4%(class 3) were performed in target. OOH occurred for 73.2% (class 1), 71.5%(class 2A), 54.7% (class 2B), and 27.7% (class 3). There were 37 class 2B and 3 surgeries overnight. There was a significant increase surgeries IH: 41.8% to 49.6%. The majority of urgent/emergent surgery occurred OOH and the most unstable patients are least likely to have their operation within target. 4.


Glycogen-rich clear cell carcinoma of the breast: a case report.
Glycogen-rich clear cell carcinoma (GRCC) of the breast is a rare malignant breast tumor. We recently encountered a case of GRCC and report our imaging findings here. The patient was a 49-year-old woman with a mass in her right breast. Mammographic study showed no definite mass shadow because the breast was dense. No calcifications were identified. Ultrasonography disclosed a hypoechoic mass that had a diameter of 1.3 cm, partially irregular borders, heterogeneous internal echoes, and posterior acoustic enhancement, suggesting an invasive carcinoma. Histologic study of core needle biopsy specimens showed a solid proliferation of large clear carcinoma cells, suggestive of a ductal carcinoma. The carcinoma cells possessed clear cytoplasm larger than that typical of ductal carcinoma cells. Breast-conserving surgery was performed with axillary sentinel lymph node biopsy. Macroscopically, the tumor was a solid, white-yellow mass with fairly well defined margins. Histologic examination of the tumor showed a characteristic feature of GRCC: the tumor cells were positive for estrogen receptor but negative for progesterone receptor and Her 2, and the sentinel lymph node was histologically negative. The patient remains well and has had no clinical recurrence of the disease after 2.5 years of follow-up without radiotherapy or adjuvant therapy. Noteworthy is the usefulness of mammography and ultrasonography, which should be used as complementary imaging tools.


Resilience in nurses in terms of perceived social support, job satisfaction and certain variables.
This study investigated the resilience of nurses, the factors that contribute to resilience, and its relationship with perceptions of social support and job satisfaction. Resilience plays an important role in how nurses cope with work-related stressors. A descriptive study was conducted with 242 nurses working at three public hospitals in Turkey. Data were collected using a descriptive data form, the Resilience Scale for Adults (RSA), the Multidimensional Scale of Perceived Social Support (MSPSS) and the Minnesota Job Satisfaction Scale (MJSS). Nurses' mean scores on the RSA, MSPSS, and MJSS were 99.80 ± 4.43, 66.66 ± 13.30, and 3.31 ± 0.72, respectively. Statistically significant relationships were detected between resilience and five factors: age, gender, mother's educational level, work experience and working hours (p < 0.05). A statistically significant positive correlation was also observed between MJSS score and both total RSA and family support subscale scores (p < 0.05). The resilience, perceived social support, and job satisfaction of participating nurses were moderate. Significant factors in their resilience were age, gender, mother's educational level, work experience, working hours, perceived social support and job satisfaction. Nurse managers can use the results to plan interventions that improve resilience among nurses.


Helical packaging of semiflexible polymers in bacteriophages.
We investigate multilayered helical packaging of double-stranded DNA, or of a general polymer chain with persistence length lb, into an ideal, inert cylindrical container, reaching densities slightly below close packaging. We calculate the free energy as a function of the packaged length, based on the energies for bending, twisting, the suffered entropy loss, and the electrostatic energy in a Debye-Hückel model. In the absence of charges on the packaged polymer, a critical packaging force can be determined, similar to the mechanism involved in DNA unzipping models. When charges are taken into consideration, in the final packaging state the charges which are chemically distant become geometrically close, and therefore a steep rise is seen in the free energy. We argue that due to the extremely ordered and almost closely packaged final state the actual packaging geometry does not influence the behaviour of the free energy, pointing towards a certain universality of this state of the polymer. Our findings are compared to a recent simulations study, showing that the model is sensitive to the screening length.


Indirect food web interactions: sea otters and kelp forest fishes in the Aleutian archipelago.
Although trophic cascades-the effect of apex predators on progressively lower trophic level species through top-down forcing-have been demonstrated in diverse ecosystems, the broader potential influences of trophic cascades on other species and ecosystem processes are not well studied. We used the overexploitation, recovery and subsequent collapse of sea otter (Enhydra lutris) populations in the Aleutian archipelago to explore if and how the abundance and diet of kelp forest fishes are influenced by a trophic cascade linking sea otters with sea urchins and fleshy macroalgae. We measured the abundance of sea urchins (biomass density), kelp (numerical density) and fish (Catch per unit effort) at four islands in the mid-1980s (when otters were abundant at two of the islands and rare at the two others) and in 2000 (after otters had become rare at all four islands). Our fish studies focused on rock greenling (Hexagrammos lagocephalus), the numerically dominant species in this region. In the mid-1980s, the two islands with high-density otter populations supported dense kelp forests, relatively few urchins, and abundant rock greenling whereas the opposite pattern (abundant urchins, sparse kelp forests, and relatively few rock greenling) occurred at islands where otters were rare. In the 2000, the abundances of urchins, kelp and greenling were grossly unchanged at islands where otters were initially rare but had shifted to the characteristic pattern of otter-free systems at islands where otters were initially abundant. Significant changes in greenling diet occurred between the mid-1980s and the 2000 although the reasons for these changes were difficult to assess because of strong island-specific effects. Whereas urchin-dominated communities supported more diverse fish assemblages than kelp-dominated communities, this was not a simple effect of the otter-induced trophic cascade because all islands supported more diverse fish assemblages in 2000 than in the mid-1980s.


Reproducibility of standardized retroillumination photography for quantification of posterior capsule opacification.
To determine the short-term reproducibility of standardized digital retroillumination images of regeneratory posterior capsule opacification (PCO) using the photographic setup at 1 institution. Department of Ophthalmology, University of Vienna, Vienna, Austria. In this prospective study, 60 retroillumination images of 30 eyes with varying degrees of PCO and different types of intraocular lenses were acquired with a standardized digital coaxial retroillumination system. Two images were taken per eye with a 1-minute interval between images. Ten other eyes were photographed in the same way but with a 5-day interval between the 2 images. All images were evaluated with a fully automated, objective PCO analysis software in which the PCO score was from 0 to 100. The 2 results (A, B) in each eye were compared, and the differences were calculated. There was a high correlation between the A and B results (r = 0.99). The mean absolute difference was 3.7%. The repeatability coefficient was 8.8%. Digital coaxial retroillumination photography provided quick acquisition of regeneratory PCO images. It provided excellent image quality and high reproducibility. The technique forms a good basis for automated quantification of PCO with new software systems.


Synthesis and biological evaluation of new ligustrazine derivatives as anti-tumor agents.
To discover new anti-cancer agents with multi-effect and low toxicity, a series of ligustrazine derivatives were synthesized using several effective anti-tumor ingredients of Shiquandabu Wan as starting materials. Our idea was enlightened by the "combination principle" in drug discovery. The ligustrazine derivatives' anti-tumor activities were evaluated on the HCT-8, Bel-7402, BGC-823, A-549 and A2780 human cancer cell lines. In addition the angiogenesis activities were valued by the chick chorioallantoic membrane (CAM) assay. 1,7-bis(4-(3,5,6-Trimethylpyrazin-2-yl)-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (4) and 3 α,12 α-dihydroxy-5β-dholanic acid-3,5,6-trimethylpyrazin-2-methyl ester (5) not only displayed antiproliferative activities on these cancer cells, but also dramatically suppressed normal angiogenesis in CAM. The LD₅₀ value of the compound 5 exceeded 3.0 g/kg by oral administration in mice.


The effects of a restorative intervention on undergraduate nursing students' capacity to direct attention.
The purpose of this study was to examine the effects of a restorative intervention on undergraduate nursing students' capacity to direct attention. Kaplan and Kaplan's attention restoration theory, which describes and links concepts of directed attention, attention fatigue, and restorative environments, formed the theoretical basis for this research. A convenience sample consisted of 33 students randomly assigned to nonintervention and intervention groups. The intervention was a 1-hr walk in natural surroundings. Both groups completed study instruments prior to and following the intervention. Intervention group students scored higher on a measure of quality of life at posttest (p < .05). Differences in a measure of perceived attention were not observed between groups over time. Both groups improved on other measures of attention; however, the results did not provide support for the hypotheses. Students were a highly functioning group participating in many activities they considered restorative, prior to the study.


Antemortem diagnosis of CDV infection by RT-PCR in distemper dogs with neurological deficits without the typical clinical presentation.
In dogs with neurological disturbances without myoclonus and extraneural signs, the clinical diagnosis of distemper is difficult perform. Considering the great infectious potential of the disease, the possibility of carrying out an antemortem diagnosis of distemper is important, particularly in hospitalized patients with neurological disease. The present study was carried out to evaluate RT-PCR for antemortem CDV detection in hospitalized dogs with neurological disturbances without the typical findings of distemper. We investigated five dogs with canine distemper virus (CDV) encephalomyelitis, in which the clinical diagnosis was not performed owing to the absence of characteristic signs of the disease, such as myoclonus and systemic signs. We observed an apparent high sensitivity of RT-PCR in urine samples for detection of CDV: four out of five urine samples were RT-PCR positive. The results of the present study suggest that urine is a good biological sample for antemortem CDV detection by RT-PCR in dogs with distemper encephalomyelitis in which the clinical diagnosis is likely to be difficult owing to the absence of suggestive distemper signs. The use of two different body fluids (urine and CSF) may increase the RT-PCR sensitivity for antemortem diagnosis of distemper in such cases.


Venous and arterial thromboembolic disease in women using oral contraceptives.
Vascular plasminogen activator was measured by means of a new chromogenic assay in 24 women who had suffered from oral contraceptive-associated thrombotic disease and was compared to that in a control group of 78 premenopausal women. Vascular plasminogen activator levels were significantly reduced in the subjects who had venous thrombosis but not in the five women who had arterial thrombosis (0.04 +/- 0.03 versus 0.38 +/- 0.31, respectively) when compared to the levels in the control group (0.19 +/- 0.20). Since vascular activator levels distribute in a non-Gaussian manner, cases and controls were also stratified into deciles. Seventeen subjects who had suffered from venous thrombosis were stratified in the lowest three deciles, and two subjects, in the fourth and fifth deciles. Subjects who had suffered from arterial thrombosis were in the fourth or higher deciles. The conclusion is that, although there is a correlation between low levels of vascular plasminogen activator and venous thrombosis, no such correlation exists for arterial thrombosis.


Identification and chemical synthesis of a tandemly repeated immunogenic region of Plasmodium knowlesi circumsporozoite protein.
Complementary DNA clones that code for the immunogenic region of the Plasmodium knowlesi circumsporozoite protein were shown to contain a tandemly repeating 36-base pair unit. A synthetic dodecapeptide corresponding to the predicted reading frame of the repeating nucleotide unit behaved, in an immunoradiometric assay, identically with the native P. knowlesi circumsporozoite protein. The repeating 36-base pair unit occurred 12 times within the gene and accounts for at least one-third of the amino acid sequence of the surface antigen protein.


Application of Alternative Nucleic Acid Extraction Protocols to ProGastro SSCS Assay for Detection of Bacterial Enteric Pathogens.
As an alternative to automated extraction, fecal specimens were processed by investigational lysis/heating (i.e., manual) and by chromatography/centrifugation (i.e., column) methods. ProGastro SSC and Shiga toxin-producing Escherichia coli (i.e., STEC) indeterminate rates for 101 specimens were 1.0% to 3.0% for automated, 11.9% for manual, and 24.8% to 37.6% for column methods. Following freeze-thaw of 247 specimens, indeterminate rates were 1.6% to 2.4% for manual and 0.8 to 5.3% for column methods. Mean processing times for manual and column methods were 30.5 and 69.2 min, respectively. Concordance of investigational methods with automated extraction was ≥98.8%.


Cyclical mastalgia: clinical and mammographic observations in a screened population.
The incidence of cyclical mastalgia in well women presenting for breast screening was 69 per cent. The incidence of cyclical mastalgia increases with age up to the menopause. There was a higher incidence of 'high risk' mammographic patterns and a lower incidence of 'low risk' patterns, according to the Wolfe classification, in women with cyclical mastalgia compared with the rest of the screened population. This finding correlated with the severity, duration and need for treatment. The differences in breast pattern did not persist after the menopause. The question of whether or not cyclical mastalgia can be regarded as a risk factor for breast cancer is uncertain and needs further evaluation.


Effects of nucleus pulposus cell-derived acellular matrix on the differentiation of mesenchymal stem cells.
Recent attempts to treat disc degeneration with mesenchymal stem cells (MSCs) showed encouraging results. Differentiating MSCs towards nucleus pulposus cell (NPC)-like lineages represents a speculative mechanism. Niche factors including hypoxia, growth factors and cell-cell interactions have been suggested but the matrix niche factor has not been studied. Our collagen microencapsulation provides a 3D model to study matrix niche as it enables the encapsulated cells to remodel the template matrix. We previously demonstrated the chondro-inductive role of of chondrocytes-derived matrix in MSCs and showed that NPCs maintained their phenotype and remodeled the template matrix of collagen microspheres into a glycosaminoglycan (GAG)-rich one. Here we aim to study the effects of NPC-derived matrix on MSC differentiation towards NPC-like lineages by firstly producing an NPC-derived matrix in collagen microspheres, secondly optimizing a decellularization protocol to discard NPCs yet retaining the matrix, thirdly repopulating the acellular NPC-derived matrix with MSCs and fourthly evaluating their phenotype. Finally, we injected these microspheres in a pilot rabbit disc degeneration model. Results showed that NPCs survived, maintained their phenotypic markers and produced GAGs. A decellularization protocol with maximal removal of the NPCs, minimal loss in major matrix components and partial retention of NPC-specific markers was identified. The resulting acellular matrix supported MSC survival and matrix production, and up-regulated the gene expression of NPC markers including type II collagen and glypican 3. Finally, injection of MSC in these microspheres in rabbit degenerative disc better maintained hydration level with more pronounced staining of GAGs and type II collagen than controls.


Laser capture microdissection and PCR for analysis of human papilloma virus infection.
Human papilloma virus (HPV) infection is considered one of the main factors involved in the pathogenesis of endocervical adenocarcinoma. However, the cellular location of HPV in this type of tumor is controversial. We have developed a method to determine the presence of HPV type 16 in endocervical cancer cells using laser capture microdissection followed by DNA extraction and qualitative polymerase chain reaction. Our results show that HPV type 16 is present in endocervical adenocarcinoma cells.


Volumetric wireless coil for wrist MRI at 1.5 T as a practical alternative to Tx/Rx extremity coil: a comparative study.
This work performs a detailed assessment of radiofrequency (RF) safety and imaging performance of a volumetric wireless coil based on periodically coupled split-loop resonators (SLRs) for 1.5 T wrist MRI versus a commercially available transceive extremity coil. In particular, we evaluated the transmit efficiency and RF safety for three setups: a whole-body birdcage coil, a transceive extremity birdcage coil, and a volumetric wireless coil inductively coupled to the whole-body birdcage coil. The imaging performance of the two latter setups was studied experimentally for nine subjects. The signal-to-noise ratio (SNR) of the images acquired with several standard pulse sequences for osteoarthritis wrist imaging was assessed. Application of the wireless coil significantly improved the specific absorption rate (SAR) efficiency of the whole-body birdcage coil, with at least 4.3-fold and 7.6-fold improvement of local and global SAR efficiencies, respectively. This setup also outperformed the transceive extremity coil in terms of SNR (up to 1.40-fold gain) with a moderate (11%) reduction of the local SAR efficiency.


Herbicidal and Cytotoxic Constituents from Aralia armata (Wall.) Seem.
Two new triterpenoids, 3β-hydroxyoleana-11,13(18)-diene-28,30-dioic acid (1) and 3-oxooleana-11,13(18)-diene-28,30-dioic acid (2), one novel triterpenoid glycoside, 3β-O-(6'-O-methyl-β-D-glucuronopyranosyl)oleana-11,13(18)-dien-28-oic acid (3) along with six known compounds (4 - 9) were isolated from the stem bark of Aralia armata (Wall.) Seem. Their structures were elucidated through extensive spectroscopic methods. The herbicidal activities of these compounds against Bidens pilosa L., an invasive weed in P. R. China, were evaluated. Compounds 3, 5, and 6 exhibited more significant herbicidal activities on B. pilosa than the positive-control pendimethalin. Their possible use as herbicidal chemicals or model compounds deserved more attention. The effects of compounds 1 - 9 on Spodoptera litura cultured cell line Sl-1 cell proliferation and its morphology were also evaluated. The results indicated that compounds 1 - 5 affected Sl-1 cell proliferation. Compound 3 showed more obvious proliferation inhibition activities on Sl-1 cell than the positive-control rotenone. With regard to the effect on morphology, compound 2 significantly changed Sl-1 cell, resulting in cell blebbing and vacuole forming. Triterpenoids aremedicinally and agriculturally important, and cytotoxicity of the three new compounds 1 - 3 deserved further studies.


Alterations in platelet count and mean platelet volume as predictors of patient outcome in the respiratory intensive care unit.
Thrombocytopenia is associated with increased mortality in intensive care unit (ICU) patients. Mean platelet volume (MPV) reflects platelet function and activation. Elevated MPV is associated with poor outcomes and increased mortality rate in diseases that are commonly encountered in the respiratory ICU. We retrospectively enrolled 95 patients who died in the ICU (dead group), 80 patients who improved and were transferred from the ICU (survived group), and 80 healthy individuals as controls. Laboratory parameters including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), albumin, and complete blood count (CBC) were recorded within 24 h on admission and transfered from the ICU or died. White blood cell (WBC) count, hemoglobin (Hb), red cell distribution width, MPV, platelet distribution width (PDW), and platelet count (PC) were obtained from the CBC. Admission PC and MPV levels were not different in the survived and dead groups. But in the survived group, admission WBC, MPV and PDW levels decreased, while PC increased when compared with admission levels. In the dead group, admission MPV and PDW levels increased, while PC decreased with respect to admission levels. The admission mean PC of the dead group was 182 103, which was above the thrombocytopenia limit. The ratio of admission thrombocytopenia was 45.3% in the dead group, which was significantly higher than that of the survived group (13.8%) (P < 0.001) CONCLUSIONS: Increasing MPV and decreasing platelet count may alert intensivists to the worse course of disease in patients who had normal platelet counts at ICU admission. The development of thrombocytopenia may also be essential to assessing the outcome of ICU patients.


Toxoplasma gondii lacks the enzymes required for de novo arginine biosynthesis and arginine starvation triggers cyst formation.
Two separate carbamoyl phosphate synthetase activities are required for the de novo synthesis of pyrimidines and arginine in most eukaryotes. Toxoplasma gondii is novel in possessing a single carbamoyl phosphate synthetase II gene that corresponds to a glutamine-dependent form required for pyrimidine biosynthesis. We therefore examined arginine acquisition in T. gondii to determine whether the single carbamoyl phosphate synthetase II activity could provide both pyrimidine and arginine biosynthesis. We found that arginine deprivation efficiently blocks the replication of intracellular T. gondii, yet has little effect on long-term parasite viability. Addition of citrulline, but not ornithine, rescues the growth defect observed in the absence of exogenous arginine. This rescue with citrulline is ablated when parasites are cultured in a human citrullinemia fibroblast cell line that is deficient in argininosuccinate synthetase activity. These results reveal the absence of genes and activities of the arginine biosynthetic pathway and demonstrate that T. gondii is an arginine auxotroph. Arginine starvation was also found to efficiently trigger differentiation of replicative tachyzoites into bradyzoites contained within stable cyst-like structures. These same parasites expressing bradyzoite antigens can be efficiently switched back to rapidly proliferating tachyzoites several weeks after arginine starvation. We hypothesise that the absence of gene activities that are essential for the biosynthesis of arginine from carbamoyl phosphate confers a selective advantage by increasing bradyzoite switching during the host response to T. gondii infection. These findings are consistent with a model of host-parasite evolution that allowed host control of bradyzoite induction by trading off virulence for increased transmission.


An analytical, mathematical annuloplasty ring curvature model for planning of valve-in-ring transcatheter mitral valve replacement.
An increasing number of high-risk patients with previous mitral valve annuloplasty require transcatheter mitral valve replacement due to recurrent regurgitation. Annulus dilation with a transcatheter balloon is often performed before valve-in-ring transcatheter mitral valve replacement, which is believed to reduce misalignment and paravalvular leakage, yet little evidence exists to support this practice. Our objective was to generate intuitive annuloplasty ring analyses for improved valve-in-ring transcatheter mitral valve replacement planning. We generated a mathematical model that calculates image-tracked differential ring curvature to build quantifications for improved planning for valve-in-ring procedures. Carpentier-Edwards Physio M24 and M30 (n = 2 each), Physio II M24 and M26 (n = 3 each), LivaNova AnnuloFlex M26 (n = 2), and Edwards Geoform M28 (n = 2) rings were tested with a 30-mm Toray Inoue balloon inflated to maximum rated pressures. Curvature variance reduces with larger ring sizes, indicating that larger rings are initially more circular than smaller ones. Evaluated semi-rigid and rigid rings showed little to no difference between pre- and post-dilation states. Annuloflex rings (flexible band) showed a postdilation variance reduction of 32.83% (P < .001) followed by an increase after 10 minutes of relaxation that was still reduced by 19.62% relative to the initial state (P < .001). We discovered that balloon dilation does not significantly deform evaluated semi-rigid or rigid rings at maximum rated balloon pressures. This may mean that dilation for these conditions before valve-in-ring transcatheter mitral valve replacement is unnecessary. Our mathematical approach creates a foundation for extended classification of this practice, providing meaningful quantification of ring geometry.


Interaction of human serum albumin with novel 3,9-disubstituted perylenes.
Human serum albumin (HSA) has been used as a model for the binding of a number of different ligands, including polyaromatic hydrocarbons, to proteins. In this case we have investigated the interaction of HSA with a novel set of perylene derivatives. Di-substituted perylene analogues have been synthesized as potentially useful organic photovoltaic materials. Their photophysical properties may make them viable for fuel cell applications too. However, these molecules are poorly soluble especially in aqueous solvents. Binding to water-soluble proteins may provide a way to solubilize them. At the same time one can study whether the photophysical processes initiated by the irradiation of a perylene ligand can cause conformational changes to the host protein. With the present study we demonstrated that of the three perylene derivatives investigated only one, the dimethoxy analogue, has a significant affinity for HSA at a binding site near the bottom of the central cleft (in proximity of the Trp214 residue). The small affinity prevents any significant photoinduced changes to occur in the protein.


T cell epitopes and post-translationally modified epitopes in type 1 diabetes.
Type 1 diabetes (T1D) is an autoimmune disease in which progressive loss of self-tolerance, evidenced by accumulation of auto-antibodies and auto-reactive T cells that recognize diverse self-proteins, leads to immune-mediated destruction of pancreatic beta cells and loss of insulin secretion. In this review, we discuss antigens and epitopes in T1D and the role that post-translational modifications play in circumventing tolerance mechanisms and increasing antigenic diversity. Emerging data suggest that, analogous to other autoimmune diseases such as rheumatoid arthritis and celiac disease, enzymatically modified epitopes are preferentially recognized in T1D. Modifying enzymes such as peptidyl deiminases and tissue transglutaminase are activated in response to beta cell stress, providing a mechanistic link between post-translational modification and interactions with the environment. Although studies of such responses in the at-risk population have been limited, current data suggests that breakdown in tolerance through post-translational modification represents an important checkpoint in the development of T1D.


NF-κB activation is a turn on for vaccinia virus phosphoprotein A49 to turn off NF-κB activation.
Vaccinia virus protein A49 inhibits NF-κB activation by molecular mimicry and has a motif near the N terminus that is conserved in IκBα, β-catenin, HIV Vpu, and some other proteins. This motif contains two serines, and for IκBα and β-catenin, phosphorylation of these serines enables recognition by the E3 ubiquitin ligase β-TrCP. Binding of IκBα and β-catenin by β-TrCP causes their ubiquitylation and thereafter proteasome-mediated degradation. In contrast, HIV Vpu and VACV A49 are not degraded. This paper shows that A49 is phosphorylated at serine 7 but not serine 12 and that this is necessary and sufficient for binding β-TrCP and antagonism of NF-κB. Phosphorylation of A49 S7 occurs when NF-κB signaling is activated by addition of IL-1β or overexpression of TRAF6 or IKKβ, the kinase needed for IκBα phosphorylation. Thus, A49 shows beautiful biological regulation, for it becomes an NF-κB antagonist upon activation of NF-κB signaling. The virulence of viruses expressing mutant A49 proteins or lacking A49 (vΔA49) was tested. vΔA49 was attenuated compared with WT, but viruses expressing A49 that cannot bind β-TrCP or bind β-TrCP constitutively had intermediate virulence. So A49 promotes virulence by inhibiting NF-κB activation and by another mechanism independent of S7 phosphorylation and NF-κB antagonism. Last, a virus lacking A49 was more immunogenic than the WT virus.


A transcriptional repressor of the ERF family confers drought tolerance to rice and regulates genes preferentially located on chromosome 11.
Plant-specific ethylene response factors (ERFs) play important roles in abiotic and biotic stress responses in plants. Using a transgenic approach, we identified two rice ERF genes, OsERF4a and OsERF10a, which conferred drought stress tolerance. In particular, OsERF4a contains a conserved ERF-associated amphiphilic repression (EAR) motif in its C-terminal region that has been shown to function as a transcriptional repression domain. Expression profiling of transgenic rice plants over-expressing OsERF4a using either a constitutively active or an ABA-inducible promoter identified 45 down-regulated and 79 up-regulated genes in common. The increased stress tolerance by over-expression of the EAR domain-containing protein OsERF4a could result from suppression of a repressor of the defense response. Expression of the putative silent information regulator 2 (Sir2) repressor protein was repressed, and expression of several stress-response genes were induced by OsERF4a over-expression. The Sir2 and 7 out of 9 genes that were down-regulated by OsERF4a over-expression were induced by high salinity and drought treatments in non-transgenic control plants. Genes that were down- and up-regulated by OsERF4a over-expression were highly biased toward chromosome 11. Rice chromosome 11 has several large clusters of disease-resistance and defense-response genes. Taken together, our results suggest that OsERF4a is a positive regulator of shoot growth and water-stress tolerance in rice during early growth stages. We propose that OsERF4a could work by suppressing a repressor of the defense responses and/or by controlling the expression of a large number of genes located on chromosome 11.


Contact dermatitis in Nigeria. (IV). Dermatitis of the feet.
Contact dermatitis of the feet is common in Nigeria. 136 patients with dermatitis of the feet were investigated; 83 had positive patch tests. 59 to chemicals in shoes; 22 reacted to rubber chemicals and 16 to chromate, 53 had negative patch tests. The causal mechanisms and treatment methods are described.


Inhibition of aflatoxin-induced liver damage in ducklings by food additives.
Inhibitory effects of food additives on toxicity induced by aflatoxin B1 was conducted in 3-day-old ducklings. Aflatoxin B1 at a dose of 5 μg/day per animal for 14 days induced severe liver damage which included necrosis, fatty changes, and biliary hyperplasia. These changes were found to be inhibited by the daily administration of turmeric (50mg), curcumin (10 mg), and ellagic acid (10 mg) in the diet. Addition of BHA-butylated hydroxy anisole (10 mg), BHT-butylated hydroxy toluene (10 mg), garlic (500 mg), and asafoetida (50 mg) inhibited necrosis and degeneration of the tissue, while biliary hyperplasia persisted. Biochemical and haematological parameters were not significantly altered under the conditions studied.


A nexus approach engaging water rights transfer for addressing water scarcity in energy and food production under uncertainty.
Water rights transfer is significantly required for alleviating the ever-intensive water crisis, particularly for arid watersheds with abundant farmland and fossil fuels. However, focusing solely on the re-allocation of water rights and disregarding agricultural water saving potential imperil the security of Water-Energy-Food (WEF) nexus. Furthermore, randomness in water availability leads to water shortage risks and subsequent impact on the whole system. In this study, a risk-based optimization model (RWEF) was proposed to promote inter-sectoral water rights transfer through encouraging energy sector to invest in agricultural water-saving works and get paid back in water rights. Chance-constrained programming is incorporated to analyze the trade-offs between system benefits and water-shortage risks. The developed model was applied to the Inner Mongolia section of the Yellow River Basin, China to verify its effectiveness, considering different development levels of food and energy industries. Results indicated that 488 million m3 of water could be transformed from agriculture to energy, without compromising agricultural production. The main recipients of transferred water rights would be traditional coal-based industries, while it would be difficult for thermal power and most modern coal chemical industries to participate. The construction of water-saving works would help safeguard agricultural production under risks. Compared against two alternative models without water rights transfer mechanism, the average benefit acquired from RWEF under varied water-shortage risks would be at least 68% higher. Particularly, when confronted with extreme water-shortage risk and increased production demands, RWEF would still be able to support agricultural and energy production, while the alternative models being incapable.


Microbiological quality and safety of minimally processed parsley (Petroselinum crispum) sold in food markets, southeastern Brazil.
This study evaluated the microbiological quality and safety of minimally processed parsley sold in southeastern Brazilian food markets. One hundred samples were submitted to the enumeration of Enterobacteriaceae by plating on MacConkey agar. Colonies of Enterobacteriaceae were randomly selected and identified by MALDI-TOF MS. Samples were also tested for Listeria monocytogenes and Salmonella sp. The mean count of Enterobacteriaceae was 6·0 ± 1·0 log CFU per gram, while 18 genera (including 30 species) of bacteria belonging to this family were identified. Salmonella and L. monocytogenes were not detected, while L. innocua was found in two samples and L. fleischmannii was found in one sample. Moreover generic Escherichia coli was found in three samples, all from different brands of minimally processed parsley. Even though microbial pathogens were not isolated, a variety of indicator micro-organisms were identified, including vegetable spoilers and species capable of causing human opportunistic infections. These results suggest hygienic failures and/or lack of temperature control during processing and storage of these ready-to-eat products. This study highlights the need for control measures during the production chain of minimally processed parsley in order to reduce microbial contamination and the risks of foodborne diseases.


Seminalplasmin, an antimicrobial protein from bull seminal plasma, inhibits growth, and synthesis of nucleic acids and proteins in S. cerevisiae.
Seminalplasmin, an antimicrobial protein present in bovine seminal plasma, is shown to inhibit the growth of, as well as nucleic acid and protein synthesis in, wild-type Saccharomyces cerevisiae SM202, when used at concentrations greater than 200 micrograms/ml, in contrast to 20 micrograms/ml that is sufficient for Escherichia coli. An osmotically labile strain of S. cerevisiae VY1160 is 1-2 orders of magnitude more sensitive to seminalplasmin than the wild-type strain. RNA synthesis in protoplasts and nuclei of S. cerevisiae SM 202 was also about as sensitive to seminalplasmin as in E. coli and S. cerevisiae VY1160. The RNA polymerases I and II from S. cerevisiae were strongly inhibited by seminalplasmin in vitro, while DNA and protein syntheses were not affected by seminalplasmin in cell-free systems, unlike in the whole cells. It is concluded that seminalplasmin acts in S. cerevisiae by entering the cells and inhibiting transcription.


Long-term increase in sensitivity to ketamine's behavioral effects in mice exposed to mild blast induced traumatic brain injury.
Neurobehavioral deficits emerge in nearly 50% of patients following a mild traumatic brain injury (TBI) and may persist for months. Ketamine is used frequently as an anesthetic/analgesic and for management of persistent psychiatric complications. Although ketamine may produce beneficial effects in patients with a history of TBI, differential sensitivity to its impairing effects could make the therapeutic use of ketamine in TBI patients unsafe. This series of studies examined male C57BL/6 J mice exposed to a mild single blast overpressure (mbTBI) for indications of altered sensitivity to ketamine at varying times after injury. Dystaxia (altered gait), diminished sensorimotor gating (reduced prepulse inhibition) and impaired working memory (step-down inhibitory avoidance) were examined in mbTBI and sham animals 15 min following intraperitoneal injections of saline or R,S-ketamine hydrochloride, from day 7-16 post injury and again from day 35-43 post injury. Behavioral performance in the forced swim test and sucrose preference test were evaluated on day 28 and day 74 post injury respectively, 24 h following drug administration. Dynamic gait stability was compromised in mbTBI mice on day 7 and 35 post injury and further exacerbated following ketamine administration. On day 14 and 42 post injury, prepulse inhibition was robustly decreased by mbTBI, which ketamine further reduced. Ketamine-associated memory impairment was apparent selectively in mbTBI animals 1 h, 24 h and day 28 post shock (tested on day 15/16/43 post injury). Ketamine selectively reduced immobility scores in the FST in mbTBI animals (day 28) and reversed mbTBI induced decreases in sucrose consumption (Day 74). These results demonstrate increased sensitivity to ketamine in mice when tested for extended periods after TBI. The results suggest that ketamine may be effective for treating neuropsychiatric complications that emerge after TBI but urge caution when used in clinical practice for enhanced sensitivity to its side effects in this patient population.


Potential impact on food safety and food security from persistent organic pollutants in top soil improvers on Mediterranean pasture.
The organic carbon of biosolids from civil wastewater treatment plants binds persistent organic pollutants (POPs), such as polychlorodibenzo -dioxins and -furans (PCDD/Fs), dioxin and non-dioxin -like polychlorobiphenyls (DL and NDL-PCBs), polybrominated diphenyl ethers (PBDEs), and perfluorooctane sulfonic acid (PFOS). The use of such biosolids, derived digestates and composts as top soil improvers (TSIs) may transfer POPs into the food chain. We evaluated the potential carry-over of main bioavailable congeners from amended soil-to-milk of extensive farmed sheep. Such estimates were compared with regulatory limits (food security) and human intakes (food safety). The prediction model was based on farming practices, flocks soil intake, POPs toxicokinetics, and dairy products intake in children, of the Mediterranean area. TSI contamination ranged between 0.20-113 ng WHO-TEQ/kg dry matter for PCDD/Fs and DL-PCBs (N = 56), 3.40-616 μg/kg for ∑6 NDL-PCBs (N = 38), 0.06-17.2 and 0.12-22.3 μg/kg for BDE no. 47 and no. 99, 0.872-89.50 μg/kg for PFOS (N = 27). For a 360 g/head/day soil intake of a sheep with an average milk yield of 2.0 kg at 6.5% of fat percentage, estimated soil quality standards supporting milk safety and security were 0.75 and 4.0 ng WHO-TEQ/kg for PCDD/Fs and DL-PCBs, and 3.75 and 29.2 μg/kg for ∑6 NDL-PCBs, respectively. The possibility to use low-contaminated TSIs to maximize agriculture benefits and if the case, to progressively mitigate highly contaminated soils is discussed.


Sexually transmitted diseases. Management and prevention strategies around the world.
Since 1982, the advance of HIV/AIDS infection has radically altered the management of STDs around the world. Prevention, especially in developing countries is paramount. A scientific basis for treatment coupled with epidemiology and case management is required. Discussion to the merits of different forms of treatment, classical clinical, etiological and syndromic management, and their evaluation, is described.


The -141C Ins/Del and Taq1A polymorphism in the dopamine D2 receptor gene may confer susceptibility to schizophrenia in Asian populations.
It has been reported that two single nucleotide polymorphisms (SNP) Taq1A and -141C Ins/Del in the DRD2 gene may be associated with susceptibility to schizophrenia. Due to inconclusive and mixed results, a meta-analysis was conducted to further clarify the relationship between the two SNP and schizophrenia susceptibility. A systematic literature search for the association of these two SNP with schizophrenia susceptibility was conducted using PubMed, ScienceDirect, Chinese Biomedical Literature Database, and Chinese National Knowledge Infrastructure. Odds ratios (OR) with 95% confidence intervals (CI) were used to assess the strength of the associations reported. A total of 5558 schizophrenic patients and 6792 healthy controls from 31 articles were included in this study. Evidence regarding the association between -141C Ins/Del polymorphism and schizophrenia was found in the allele frequency comparison (Ins versus Del: OR 1.29, 95% CI 1.06-1.57; p=0.01, Praw=0.1, PFalse Discovery Rate=0.023). In ethnic subgroup analysis, the result revealed that the 141C Ins/Del polymorphism was associated with schizophrenia in all genetic models in Asians, but not in Caucasians. For Taq1A polymorphism, a significant association was found in the allele frequency (A1 versus A2: OR 0.71, 95% CI 0.52-0.98, p=0.03). Stratification by ethnicity indicated an association between the Taq1A polymorphism and schizophrenia in Asians, but not Caucasians. The present study suggests that the -141C Ins/Del polymorphism carries a significantly increased risk of schizophrenia, while the Taq1A polymorphism carries a significantly decreased risk of schizophrenia susceptibility in Asians.


Effect of Melatonin on the Content of CD3low and CD3hi T Cells in the Thymus of Mice with Functional Pinealectomy.
Continuous lighting for 14 days (functional pinealectomy model) leads to a decrease in the relative number of CD3low and CD3hi T lymphocytes and the CD3low/CD3hi ratio in the thymus of C57BL/6 mice. Intragastric administration of melatonin in physiological doses (1 mg/kg body weight, 14 days) against the background of functional pinealectomy restores the percentage of CD3low and CD3hi thymocytes and CD3low/CD3hi ratio to the control values. Hence, prolonged continuous illumination inhibits the differentiation and maturation of young thymocytes into mature forms, while melatonin treatment helps to compensate the effects of functional pinealectomy triggering cell proliferation in the thymus from the earliest stages of proliferation and differentiation of T cells. Thus, melatonin has immunotropic properties and can be used for correction of the consequences of functional pinealectomy.


Acute intermittent porphyria causes hepatic mitochondrial energetic failure in a mouse model.
Acute intermittent porphyria (AIP), an inherited hepatic disorder, is due to a defect of hydroxymethylbilane synthase (HMBS), an enzyme involved in heme biosynthesis. AIP is characterized by recurrent, life-threatening attacks at least partly due to the increased hepatic production of 5-aminolaevulinic acid (ALA). Both the mitochondrial enzyme, ALA synthase (ALAS) 1, involved in the first step of heme biosynthesis, which is closely linked to mitochondrial bioenergetic pathways, and the promise of an ALAS1 siRNA hepatic therapy in humans, led us to investigate hepatic energetic metabolism in Hmbs KO mice treated with phenobarbital. The mitochondrial respiratory chain (RC) and the tricarboxylic acid (TCA) cycle were explored in the Hmbs(-/-) mouse model. RC and TCA cycle were significantly affected in comparison to controls in mice treated with phenobarbital with decreased activities of RC complexes I (-52%, (**)p<0.01), II (-50%, (**)p<0.01) and III (-55%, (*)p<0.05), and decreased activity of α-ketoglutarate dehydrogenase (-64%, (*)p<0.05), citrate synthase (-48%, (**)p<0.01) and succinate dehydrogenase (-53%, (*)p<0.05). Complex II-driven succinate respiration was also significantly affected. Most of these metabolic alterations were at least partially restored after the phenobarbital arrest and heme arginate administration. These results suggest a cataplerosis of the TCA cycle induced by phenobarbital, caused by the massive withdrawal of succinyl-CoA by ALAS induction, such that the TCA cycle is unable to supply the reduced cofactors to the RC. This profound and reversible impact of AIP on mitochondrial energetic metabolism offers new insights into the beneficial effect of heme, glucose and ALAS1 siRNA treatments by limiting the cataplerosis of TCA cycle.


The PNG Midwifery Leadership Buddy Program: An evaluation.
Papua New Guinea (PNG) has a high rate of preventable maternal and neonatal deaths. Developing midwifery leadership is vital to addressing the current deficits in health outcomes for women and their babies. The PNG Midwifery Leadership Buddy Program responds to this need through leadership training and partnering of midwives across PNG and Australia. Participants in the program undertake a workshop in Port Moresby and commit to a 12-month peer support relationship with a midwife 'buddy'. To evaluate participants' experiences of the Buddy Program and the impact of the program on leadership skills. All 23 midwives who had completed the program were invited to participate in the evaluation. The study used a concurrent mixed methods approach. Qualitative data were collected via interviews and then thematically analysed. Quantitative data were collected via a survey and analysed with descriptive statistics, then findings were triangulated. Participants reported increased confidence for leadership, action and advocacy. Numerous quality improvement projects were implemented in health services in PNG. Challenges to the success of the program included technological limitations, cultural differences and the COVID-19 pandemic. Participants reported the PNG Midwifery Leadership Buddy Program was successful in increasing their leadership skills and collaborative opportunities, as well as strengthening midwifery more broadly. While there were barriers, most participants valued the experience and believed it benefited them professionally and personally CONCLUSION: The Buddy Program provides a practical model for building midwifery leadership capacity that may be transferrable to other contexts.


Activation of a histone H1 kinase by tyrosine phosphorylation in v-src-transformed fibroblasts.
Using anti-phosphotyrosine immunoaffinity chromatography, we have searched for serine/threonine kinases that are directly regulated by tyrosine phosphorylation in v-src-transformed rat 3Y1 fibroblasts. Tyrosine phosphoprotein preparations from v-src-transformed cells contain a kinase activity that phosphorylates histone H1 in vitro on serine residues and this activity is present at a 20-fold greater level than that in parental cell preparations. This activity elutes from a MonoQ FPLC column as a single peak and gel filtration chromatography suggests that the kinase has a molecular mass of approximately 55 kDa. Tyrosine phosphatase treatment inactivates the histone H1 kinase and this result indicates that the specific activity of the kinase is regulated by tyrosine phosphorylation. Experiments with cells transformed with a temperature-sensitive mutant of the v-src oncogene demonstrate that the tyrosine phosphorylation of the histone H1 kinase is an early event in v-src transformation. The kinase is distinct from known cdc2 family members that contain the PSTAIR motif, because the kinase can be separated almost completely from these proteins by immunoprecipitation with an antibody against p34cdc2. The profile of antibody reactivity and sensitivity to modulators of protein kinases suggests that this activity is distinct from known second messenger-regulated kinases and from previously characterized MAP kinases.


Evaluation of diabetes care in the Otago region using a diabetes register, 1998-2003.
To assess changes in diabetes care between 1998 and 2003 using data from the Otago Diabetes Register. A regional diabetes register was established in 1998 to monitor diabetes care in the Otago region, New Zealand. Cross-sectional data relating to process and outcome measures were collected annually from participating general practices, 93% of general practitioners in the region. Generalised estimating equations with robust standard errors were used to test for trends in clinical measures across the study period. Process measures improved dramatically over the 6-year period. The proportion of patients prescribed ACE inhibitors and other antihypertensives increased markedly (32.3-52.4% and 13.2-27.1%, respectively) and both mean systolic and diastolic blood pressure decreased significantly (140.6-137.0 mmHg, p < 0.001 and 78.6-77.0 mmHg, p < 0.001, respectively). The proportion prescribed lipid lowering medication more than trebled (12.4-40.0%), while mean lipid levels improved significantly (total cholesterol: 5.94-5.21 mmol/l, p < 0.001, HDL-cholesterol: 1.23-1.28 mmol/l, p < 0.001 and triglycerides: 2.17-1.94 mmol/l, p < 0.001). Mean weight increased significantly, as did HbA1c in all treatment groups except type 2 diabetic patients treated with combined insulin and oral hypoglycaemic agents. At a population level appreciable improvements in blood pressure and lipid control were observed, but not glycaemic control, probably due to insufficient attention to necessary lifestyle changes.


Replacing actinomycin-D with Carboplatin for newly diagnosed rhabdomyosarcoma.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric age group. All patients with RMS regardless of their initial stage or group receive combination chemotherapy as 'standard therapy' consisting of vincristine, actinomycin-D and cyclophosphamide. Actinomycin-D was not readily available in Turkey at one time. Carboplatin was used instead in order to prevent delays in treatment. The aim of this report is to present the results of patients with rhabdomyosarcoma receiving carboplatin or actinomycin-D therapy. Twenty four patients with rhabdomyosarcoma treated between December 2000 and June 2011 were included in this retrospective study. The patients were treated according to International Rhabdomyosarcoma Study Group guidelines. Eleven patients were treated with actinomycin-D and 13 with carboplatin (250 mg/m2/dose for 2 days). The two groups were then compared in terms of 2- and 5-year overall survival (OS) and hematological and non-hematological toxicities. Age, sex, stage and the mean duration of follow-up were similar in both groups (p>0.05 ). Two- and five-year OS levels were 68.2% in the carboplatin group and 78.0% and 40.0%, respectively, in the actinomycin-D group. There was no statistical difference in the number of febrile episodes (p=0.86 ) and no other hematological and non-hematological adverse effects were recorded in both groups. The findings show that carboplatin can be used as an alternative drug in the primary treatment of rhabdomyosarcoma in the event that actinomycin-D is unavailable or not tolerated.


Redox activity of airborne particulate matter at different sites in the Los Angeles Basin.
Epidemiologic studies have shown associations between ambient particulate matter (PM) and adverse health outcomes including increased mortality, emergency room visits, and time lost from school and work. The mechanisms of PM-related health effects are still incompletely understood, but a hypothesis under investigation is that many of the adverse health effects may derive from oxidative stress, initiated by the formation of reactive oxygen species (ROS) within affected cells. While the adverse effects from PM have historically been associated with the airborne concentration of PM and more recently fine-particle PM, we considered it relevant to develop an assay to quantitatively measure the ability of PM to catalyze ROS generation as the initial step in the induction of oxidative stress. This ability of PM could then be related to different sources, chemical composition, and physical and spatial/temporal characteristics in the ambient environment. The measurement of ROS-forming ability in relation to sources and other factors will have potential relevance to control of redox-active PM. If oxidative stress represents a relevant mechanism of toxicity from PM, the measurement of redox activity represents a first step in the elucidation of the subsequent downstream processes. We have developed an assay for PM redox activity, utilizing the reduction of oxygen by dithiothreitol which serves as an electron source. We have found that PM will catalyze the reduction of oxygen and have examined the distribution and chemical characteristics of the redox activity of PM fractions collected in different sites in the Los Angeles Basin. Samples of concentrated coarse, fine, and ultrafine PM, obtained with aerosol concentrators, were studied with regard to their chemical properties and redox activity. Redox activity was highest in the ultrafine fraction, in agreement with results indicating ultrafines were the most potent toward inducing that heme oxygenase expression and depleting intracellular glutathione, which has relevance to induction of oxidative stress. Comparison of the redox activity with chemical composition showed a reasonable correlation of redox activity with elemental carbon (r(2)=0.79), organic carbon (r(2)=0.53), and with benzo[ghi]perylene (r(2)=0.82), consistent with species typically found in mobile emission sources.


Retroviral transduction of human peripheral blood lymphocytes with Bcl-X(L) promotes in vitro lymphocyte survival in pro-apoptotic conditions.
The prolonged in vivo survival of genetically modified effector cells is crucial to the success of any (gene-modified) adoptive cellular immunotherapy approach. In cancer clinical trials to date, however, the detection of surviving circulating gene-modified T cells has required highly sensitive techniques. In vitro studies of T cell co-stimulation have shown that up-regulation of the anti-apoptosis gene Bcl-X(L) by ligation of CD28 promotes T cell survival, but not proliferation. Here we have investigated the ability to modulate resistance to apoptosis and improve cell survival by transducing human peripheral blood lymphocytes using a retroviral vector that expresses Bcl-X(L). We show that Jurkat cells transduced with Bcl-X(L) retrovirus were partially resistant to Fas (CD95) antibody-induced apoptosis. Subsequent in vitro assays with transduced primary human lymphocytes demonstrates that over-expression of Bcl-X(L) promotes the survival of lymphocytes cultured in the absence of interleukin-2. Activation-induced apoptosis with anti-CD3(epsilon) antibody, OKT3 is also modulated. Furthermore, Bcl-X(L) over-expression in human lymphocytes delays the onset of apoptosis induced by long-term co-culture with tumour cell lines. Despite this improved in vitro survival, in a preliminary experiment to assess safety, no signs of malignancy or autoimmunity were observed in NOD/SCID mice injected with Bcl-X(L) transduced lymphocytes. These results indicate that expression of Bcl-X(L) in lymphocyte therapy either alone or in conjunction with an additional therapeutic gene could enhance persistence of cells in vivo thereby potentially improving the clinical outcome of adoptive cellular therapy.


Pathogenicity and immunity studies of Haemophilus parasuis serotypes.
After intranasal inoculation of SPF pigs with the 7 reference strains of Haemophilus parasuis only the reference strains of serotypes 1 and 5 proved to be pathogenic and were able to produce the lesions characteristic of Glässer's disease. Even though the reference strains of serotypes 2, 3, 4, 6 and 7 proved to be apathogenic, intranasal inoculation resulted in the development of circulating antibodies as demonstrated by the complement fixation test. This serological response suggests an antigenic relationship between serotypes 1 and 3 different from the relationship seen among serotypes 2, 4, 5, 6 and 7. Pigs given an aerosol with the apathogenic serotypes 2, 3, 4 and 7, respectively, resisted challenge with a virulent Danish strain of serotype 5. These results indicate that the 7 serotypes also have antigenic determinants in common and that these determinants elicit cross-protecting immunity on the respiratory mucosa.


The patterns of binding of RAR, RXR and TR homo- and heterodimers to direct repeats are dictated by the binding specificites of the DNA binding domains.
We show here that, in addition to generating an increase in DNA binding efficiency, heterodimerization of retinoid X receptor (RXR) with either retinoic acid receptor (RAR) or thyroid hormone receptor (TR) alters the binding site repertoires of RAR, RXR and TR homodimers. The binding site specificities of both homo- and heterodimers appear to be largely determined by their DNA binding domains (DBDs), and are dictated by (i) homocooperative DNA binding of the RXR DBD, (ii) heterocooperative DNA binding of RXR/RAR and RXR/TR DBDs, and (iii) steric hindrance. No homodimerization domain exists in the DBDs of TR and RAR. The dimerization function which is located in the ligand binding domain further stabilizes, but in general does not change, the repertoire dictated by the corresponding DBD(s). The binding repertoire can be further modified by the actual sequence of the binding site. We also provide evidence supporting the view that the cooperative binding of the RXR/RAR and RXR/TR DBDs to directly repeated elements is anisotropic, with interactions between the dimerization interfaces occurring only with RXR bound to the 5' located motif. This polarity, which appears to be maintained in the full-length receptor heterodimers, may constitute a novel parameter in promoter-specific transactivation.


Kinetics of permeability changes induced by electric impulses in chromaffin granules.
Electric field pulses, ranging in intensity from 20 to 50 kV/cm and in duration from 10 to 40 micronsec, caused a transient increase in the membrane permeability of chromaffin granules from the bovine adrenal medulla, that led to partial release of granule soluble constituents. This transient permeability change was long-lived, as compared to the pulse duration, and the main part of material efflux occurred after the termination of the pulse. During the latter phase the temporarily increased permeability decayed to its original value, in the absence of the electric field. This indicated that the structural perturbation induced in the membrane was transient and apparently reversible. The release event was characterized by a field-dependent permeability coefficient ranging from 2x10(-4) cm/sec at 30 kV/cm to 3x10(-3) cm/sec at 50 kV/cm. The resealing process of the membrane could be described by two relaxation times, both of which decreased with increasing field strength. Tau1 varied from about 3.0 msec at 30 kV/cm to less than 2.0 msec at 50 kV/cm, while tau2 varied from about 100 to about 40 msec in the same interval of field strength. The distribution in the degree of filling of granules that had been partially depleted by an electric field pulse indicated that the population could be considered homogeneous with respect to release.


Body Fatness and Cardiovascular Health in Newborn Infants.
Birth weight is associated with cardiovascular disease, with those at both ends of the spectrum at increased risk. However, birth weight is a crude surrogate of fetal growth. Measures of body composition may more accurately identify high risk infants. We aimed to determine whether aortic wall thickening, cardiac autonomic control, and cardiac structure/function differ in newborns with high or low body fatness compared to those with average body fatness. 189 healthy singleton term born neonates were recruited and stratified by body fat percentiles (sex and gestation-specific). Infants with low body fat had higher aortic intima-media thickness (43 µm (95% confidence interval (CI) 7, 78), p = 0.02), lower heart rate variability (log total power, -0.5 (95% CI -0.8, -0.1), p = 0.008), and thicker ventricular walls (posterior wall thickness, 3.1 mm (95% CI 1.6, 4.6), p < 0.001) compared to infants with average body fatness. Infants with high body fat showed no differences in aortic intima-media thickness (-2 µm (95% CI -37, 33), p = 0.91) or cardiac structure compared to average body fatness, although stroke volume (-0.3 mL/kg (95% CI -0.6, -0.0), p = 0.003) and heart rate variability were lower (log total power, -0.8 (95% CI -1.1, -0.5), p < 0.001). The non-linear association of body fatness with heart rate variability was independent of birth weight. Infants born with low or high body fat have altered markers of cardiovascular health. Assessment of body fatness alongside birth weight may assist in identifying high risk individuals.


Risk of diabetes mellitus in HIV-infected patients receiving highly active antiretroviral therapy: A nationwide population-based study.
Previous studies have shown that the incidence of diabetes mellitus (DM) has increased in human immunodeficiency virus (HIV)-infected patients with long-term exposure to highly active antiretroviral therapy (HAART). However, the factors associated with DM among HIV-infected patients in Asia remain unclear in the HAART era.A nationwide cohort studyData from Taiwan's National Health Insurance Research Database (NHIRD) between 2000 and 2010 were used to investigate the incidence of and factors associated with DM among HIV-infected patients. Propensity score matching was conducted to match 4797 patients receiving HAART (HAART cohort) with 4797 patients not receiving HAART (non-HAART cohort). HAART use was treated as a time-dependent variable in a Cox regression model.HAART cohort had a significantly higher 10-year incidence of DM (7.16%; 95% confidence interval [CI], 4.30%-10.03%) than non-HAART cohort (2.24%; 95% CI, 1.28%-3.20%) (P < .001). After adjusting for age, gender, and comorbidities, receiving HAART was associated with an increased incidence of DM, with a subdistribution hazard ratio (sHR) of 2.39 (95% CI, 1.65-3.45). Hypertension (sHR = 5.27; 95% CI, 3.21-8.65), gout (sHR = 2.39; 95% CI, 1.38-4.16), and hepatitis C virus (HCV) infection (sHR = 2.43; 95% CI, 1.28-4.61) were significantly associated with a higher risk of DM. Sensitivity analyses showed exposure to HAART remained significantly associated with an increased risk of DM, particularly in those without pre-existing hypertension, gout, or HCV infection.Exposure to HAART increased the risk of DM in HIV-infected Taiwanese patients, particularly in those without pre-existing hypertension, gout, or HCV infection.


Acute toxicity of ganciclovir: effect of dietary restriction and chronobiology.
The effect of diet, age and time of dose delivery on the mortality of female B6C3F1 mice from ganciclovir sodium (DHPG) was determined for both single (SD; 400 mg DHPG/kg, ip) and multiple doses (MD; same dose ip for 10 additional days) of the drug. Young (7-10 months) and middle-aged (MA; 19-22 months) mice (B6C3F1), both fed ad lib. (AL) and calorie restricted (CR), were dosed at 0, 6, 12 and 18 hr after lights on (HALO; SD study) and at 12.00 hr (MD study). The SD study mortality rate was 38% (AL) and 1.7% (CR) (P < 0.00001). Mortality was 53% (AL, young; P < 0.00001), over 20% (AL, MA), over 1.8% (CR, MA; P = 0.00004) or more than 1.7% (CR, young; P = 0.00002). Effects were independent of lean body mass differences between AL and CR mice. In the SD study, comparing AL mice only, the greatest mortality was seen in young mice at 6 HALO, (73%; P = 0.0034) and lowest mortality in MA mice at 12 HALO (8%; P = 0.026), whereas in the MD study mortality was 63% AL and 33% CR (P = 0.015). By age, MD mortality was 80% (AL, young; P = 0.0035), 50% (CR, MA), 47% (AL, MA), and 15% (CR, young; P = 0.0013). CR protected both young and MA mice in SD and young mice in MD. Lowest mortality for AL was at 12 HALO. It is suggested that dosing at 12 HALO may protect by decreasing DHPG uptake during a period of minimal DNA synthesis in the affected organ(s). CR and timing of DHPG dose may obviate the necessity to discontinue DHPG because of toxicity in humans. The most significant finding of this study is the impact of diet on mortality.


Peyronie's disease: endocavernous plaque excision without substitutive graft: critical 5-year experience.
In 2004, the Polish colleague Darewicz published his surgical experience of endocavernous plaque excision avoiding the use of any substitutive graft. Attracted by the extreme simplification in this new technique, we decided to verify such a surgical approach. The separation of the plaque from the overlying albuginea is performed with scissors or scalpel. Once the plaque is removed, the cavernous incision is sutured and the correct straightening is verified. In 5 years, we selected 24 cases of stabilized disease and preserved erection geometrically disturbed by the severe deformity. We obtained substantial straightening in all cases, even if in 3 cases we added a complementary minimally invasive surgery in the form of a plication, and 2 cases were converted into a graft technique. Case studies and current controls allow us to say that the impression is quite good, without the need of autologous tissue or heterologous matrices to be inserted, allowing a more comfortable post-operative course and a faster and easier functional recovery.


Zinc and cadmium in cell fractions of prostatic cancer tissues of different histological grading in comparison to BPH and normal prostate.
The concentrations of zinc and cadmium in cellular fractions of normal prostate gland, BPH and prostatic carcinomas of different histological grading were determined by electrothermal atomic absorption spectrometry. We found distinct differences in the content of Zn and Cd in the nuclear fractions of malignant tissues in comparison with BPH and normal prostatic tissues. The highest values of Cd were obtained in the nuclear fractions of poorly-differentiated carcinomas. In these samples we also found a low concentration of zinc. In comparison to this the highest Zn-values were found in the nuclear fraction of the BPH.


Artificial light at night impairs inhibitory control in a wild songbird.
Anthropogenic stressors, such as artificial light at night (ALAN), increasingly affect the sleep behaviour and physiology of wild birds, particularly in areas where human activity is prevalent. To understand the consequences of the resulting sleep deprivation, it is essential to investigate whether the effects of sleep deprivation on cognitive performance, observed in humans, also occur in birds. Here, we studied the impact of sleep deprivation, induced by intermittent exposure to ALAN, on inhibitory control, vigilance behaviour, and exploratory behaviour in great tits. Furthermore, we hypothesised that the effect of ALAN could depend on an individual's natural sleep duration and the timing of sleep. To achieve these goals, we measured emergence and entry times from/into the nest box in the wild, before capturing the great tits. In captivity, half of the birds were exposed to intermittent ALAN, and cognitive performance was assessed the following morning for all birds. ALAN-exposed birds were less successful on the detour reach task and when they started pecking at the test tube, they pecked more often. However, neither of the effects was related to the natural sleep duration or timing, in contrast to our hypothesis, and there were no differences between the ALAN-exposed and non-exposed group in vigilance and exploratory behaviour. Thus, even one night of exposure to ALAN can negatively affect cognitive performance in wild birds, possibly with negative effects on their performance and survival.


The organisation of health care in Nepal.
The focus of this paper is to examine the organisation of health care in Nepal from the literature available. After setting the study in context and examining health care in general, a more in-depth, look is taken at Primary Health Care (PHC) and how this recent emphasis is affecting nurse education. This leads into an analysis of whether or not nurses are the most appropriate personnel to deliver PHC. The fundamental issues of improving adult female literacy rates and providing a clean water supply are suggested as means whereby Nepal's health provision could be greatly improved.


Multiple penile horns: case report and review.
We report a case of unusually large multiple penile horns following removal of condylomata acuminata. Penile horns can grow rapidly, although malignant degeneration is uncommon. Wide excision with deep biopsy of skin at the base of the lesion probably is appropriate treatment.


Identification of a novel neuregulin 1 at-risk haplotype in Han schizophrenia Chinese patients, but no association with the Icelandic/Scottish risk haplotype.
To determine if neuregulin 1 (NRG1) is associated with schizophrenia in Asian populations, we investigated a Han Chinese population using both a family trio design and a case-control design. A total of 25 microsatellite markers and single nucleotide polymorphisms (SNPs) were genotyped spanning the 1.1 Mb NRG1 gene including markers of a seven-marker haplotype at the 5' end of the gene found to be in excess in Icelandic and Scottish schizophrenia patients. The alleles of the individual markers forming the seven marker at-risk haplotype are not likely to be causative as they are not in excess in patients in the Chinese population studied here. However using unrelated patients, we find a novel haplotype (HAP(China 1)), immediately upstream of the Icelandic haplotype, in excess in patients (11.9% in patients vs 4.2% in controls; P=0.0000065, risk ratio (rr) 3.1), which was not significant when parental controls were used. Another haplotype (HAP(China 2)) overlapping the Icelandic risk haplotype was found in excess in the Chinese (8.5% of patients vs 4.0% of unrelated controls; P=0.003, rr 2.2) and was also significant using parental controls only (P=0.0047, rr 2.1). A four-marker haplotype at the 3' end of the NRG1 gene, HAP(China 3), was found at a frequency of 23.8% in patients and 13.7% in nontransmitted parental haplotypes (P=0.000042, rr=2.0) but was not significant in the case-control comparison. We conclude that different haplotypes within the boundaries of the NRG1 gene may be associated with schizophrenia in the Han Chinese.


Long-term mortality assessment using biological measures among elderly people. Ten-year follow-up of 597 healthy elderly subjects in Taiwan.
Identifying biological measures that are predictive of mortality for elderly people aged over 65 years has not been fully elucidated in oriental studies. The associations between these biological measures and long-term mortality were therefore investigated, and classifications for risk of death were developed among Taiwanese elderly people Data used in this study were derived from a total of 597 apparently healthy subjects aged over 65 years identified from a nationwide survey that was conducted between 1989 and 1991 in Taiwan. Each participant received a physical examination and a wide range of biological measures. These 597 apparently healthy subjects were followed to 31 December 1999 to determine the cause of death. The grouping technique using factor analysis was first used to aggregate similar characteristics of biological measures into reduced components. Risk of death for each subject was classified into four groups: good (A), fair (B), modest (C) and poor (D). Hazard ratios for groups B, C, D against A were calculated. The overall 10-year survival rate was 72% [95% confidence interval (CI) 68-76%]. The adjusted hazard ratios for all-cause death in high and mid-level categories of haematological components versus the lowest group were 0.51 (95% CI 0.33-0.80) and 0.56 (95% CI 0.37-0.85), respectively. Group D had a 6-fold risk of death as compared with group A (relative risk = 6.34, 95% CI 3.85-10.52). The corresponding figures were 2.48 (95% CI 1.43-4.29) and 1.60 (95% CI 2.88-6.89) for groups B and C, respectively. The relationships of biological measures to long-term mortality were elucidated. Information on classification for risk of death may be helpful for elderly people to pay attention to their health status after receiving a health check-up.


Extragenic suppression of the requirement for diaminopimelate in diaminopimelate auxotrophs of Mycobacterium smegmatis.
Mycobacteria, like many prokaryotes, have a peptidoglycan with peptides composed of L-alanine (or glycine), D-iso-glutamine, meso-diaminopimelate, and D-alanine. We sought to study mycobacterial peptidoglycan biosynthesis by constructing diaminopimelate (DAP) auxotrophs of Mycobacterium smegmatis and then isolating spontaneous mutants of these auxotrophs that can grow in the absence of DAP. Here we report the isolation and characterization of seven classes of spontaneous M. smegmatis mutants with extragenic mutations that can suppress the DAP requirement of DAP auxotrophs.


Inhibitory effect of the leaf extract of Ginkgo biloba L. on oxidative stress-induced platelet aggregation.
The effect of the leaf extract of Ginkgo biloba L. on platelet aggregation induced by oxidative stress was studied. The extract caused a dose-dependent inhibition of platelet aggregation stimulated with tert-butyl hydroperoxide (t-BHP) and Fe2+. Similar inhibitory activity was observed when platelets were exposed to H2O2 and Fe2+. Synergistic aggregation induced by a combination of t-BHP and Fe2+ or H2O2 and Fe2+ in association with suboptimal concentration of collagen or U46619, was prevented by the extract. However, the extract failed to inhibit aggregation in response to collagen, thrombin or U46619. Ginkgolides A, B and C inhibited platelet-activating factor-induced aggregation, but not oxidant-induced aggregation. These data suggest that the suppressive effect of the extract is specific on platelet aggregation stimulated by oxidative stress, and that this effect is involved in the mechanism related to its protective effect upon cerebral or myocardial injuries.


Characteristics of exposure and health risk air pollutants in public buses in Korea.
The objective of this study was to estimate the concentrations of indoor air pollutants in unregulated public transport means in Korea and to determine the factors affecting the air quality as well as to assess the harmful effects of indoor air pollutants on the health of passengers. The correlation between particulate matter (PM10) and number of passengers on intra-city buses, express buses, town shuttle buses, or rural buses was insignificant whether it was during rush hours or non-rush hours. In regard to PM10 on express buses, there was no case where the standard limit was exceeded during the winter and summer seasons. In winter, however, the average concentration of PM10 increased by the travel distance. In regard to CO2, there was a statistically significant correlation (p < 0.05) between CO2 concentrations and the number of passengers, owing to human respiration. Unlike the case of PM10, there was a difference between rush hours and non-rush hours. Regarding volatile organic compounds (VOCs) and aldehydes, the values were high among recently manufactured vehicles regardless of bus types. The standard limit was exceeded during the summer season, which seemed to be related to the temperature and humidity in both indoor and outdoor. The results of this study indicate that the excess mortality resulting from PM10 was as high as the safety margin during both non-rush hours and rush hours among all unregulated public transportation means. The excess cancer risk and non-cancer risk of VOCs and aldehydes were as high as the safety margin during both non-rush hours and rush hours.


Dynamics of T cells subsets and lymphoproliferative responses during structured treatment interruption cycles and after definitive interruption of HAART in early chronic HIV type-1-infected patients.
Little is known about the consequences of short cycles of structured treatment interruption or definitive interruption of HAART for both T cell subset dynamics and T lymphoproliferative responses (LPR). Immunological follow-up was performed in 45 early chronical HIV-1-infected patients during short STI cycles during the first 12 weeks after the definitive interruption of HAART (DTI) and, thereafter, until VL reached a plateau. During STI cycles, CD8(+), CD8(+), CD28(+), activation markers and naive CD4(+) T cells increased significantly (p < 0.0001), while both naive CD8(+) and memory CD4(+) T cells decreased. During DTI, CD8(+) CD28(+) T cells fell and CD4(+) naive T cells stabilized and the rest of the T cell subsets presented changes similar to those during STI cycles. Despite a transient increase in LPR to recall antigens and HIV proteins during STI cycles, LPR to polyclonal stimuli and pathogens decreased over the study. Differences in T cell subset dynamics and LPR observed throughout the study suggest that multiple exposures to low levels of antigen could improve the immune system, mainly by driving T cell maturation. Conversely, higher and longer viral replication after cessation of HAART overwhelms the immune system. These data may help to guide future immune-based therapies.


Involvement of spinal noradrenergic system in the mechanism of an antinociceptive effect of delta-sleep-inducing peptide (DSIP).
We studied whether the antinociceptive effect produced by intracerebroventricular injection of delta-sleep-inducing peptide (DSIP) to mice involved the monoaminergic pathways that descended from brainstem to spinal cord (the descending inhibitory systems). In the tail-pinch test, the antinociceptive effect of DSIP was significantly reduced by the pretreatment with reserpine (3 mg/kg i.p.) which depleted endogenous monoamines. Moreover, the intrathecal injections of monoamine antagonists were performed to evaluate the roles of the spinal noradrenergic and/or serotonergic systems in the production of the DSIP antinociception. In both tail-pinch and hot plate tests, the antinociceptive effect of DSIP was significantly antagonized by the previous intrathecal administration of phentolamine (an alpha-adrenergic blocker) or yohimbine (an alpha 2-adrenergic blocker), but was unaffected by the pretreatment with methysergide (a serotonin antagonist). These results demonstrate that the activation of the descending inhibitory systems, mainly spinal noradrenergic systems, is involved in the elicitation of DSIP antinociception.


Strain-dependent effects of long-term treatment with melatonin on kainic acid-induced status epilepticus, oxidative stress and the expression of heat shock proteins.
Oxidative stress is implicated in the pathogenesis of both hypertension and epileptogenesis, therefore it could be used as a tool for studying co-morbidity of hypertension and epilepsy. Clinical data suggest that melatonin is a potent antioxidant that is effective in the adjunctive therapy of hypertension and neurodegenerative diseases. The present study aimed to explore and compare the efficacy of chronic pretreatment with melatonin infused via subcutaneous osmotic mini-pumps for 14 days (10 mg/kg per day) on kainic acid (KA)-induced status epilepticus, oxidative stress and expression of heat shock protein (HSP) 72 in spontaneously hypertensive rats (SHRs) and normotensive Wistar rats. SHRs showed higher lipid peroxidation (LP) in the frontal cortex and hippocampus and decreased cytosolic superoxide dismutase (SOD/CuZn) production in the frontal cortex compared to Wistar rats. Status epilepticus (SE) induced by KA (12 mg/kg, i.p.) was accompanied by increased LP and expression of HSP 72 in the hippocampus of the two strains and increased SOD/CuZn production in the frontal cortex of SHRs. Melatonin failed to suppress seizure incidence and intensity though the latency for seizure onset was significantly increased in SHRs. Melatonin attenuated the KA-induced increase in the level of LP in the hippocampus both in SHRs and Wistar rats. However, an increased activity in SOD/CuZn and mitochondrial SOD Mn as well as reduced expression of HSP 72 in the hippocampus was observed only in Wistar rats pretreated with melatonin. Taken together, the observed strain differences in the efficacy of chronic melatonin exposure before SE suggest a lack of a direct link between the seizure activity and the markers of oxidative stress and neurotoxicity.


Blind-ending branch of bifid ureter: report of seven cases.
Seven cases of bifid ureter with a blind-ending branch are presented: diagnosis was primarily made by excretory urogram. In 1 case the diagnosis was confirmed by retrograde pyelogram. The pelvicalyceal system showed ureteroureteral reflux into the blind-ending branch on photofluoroscopy and cineroentgenography. One rare case of blind-ending branch originating in the upper third of the ureter are described. The clinical aspects, roentgenographic findings, and treatment of these findings are reviewed.


Point-of-care testing for tetanus immunity: a systematic review and meta-analysis.
The current standard of care for tetanus prophylaxis management in patients with open wounds likely results in overtreatment and unnecessary costs. Point-of-care immunochromatographic tests, known as Tetanus Quick Sticks (TQS), have been developed to qualitatively measure tetanus immunoglobulin levels. Multiple studies advocate their use in EDs. We aim to evaluate the diagnostic accuracy and cost-effectiveness of TQS to assess their relevance in frontline emergency care. A systematic review was undertaken following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search was conducted in MEDLINE, Embase, Global Health, The Health Management Information Consortium and The Cochrane Library. Studies were eligible if sensitivity, specificity or cost-efficacy of TQS was reported. At least two authors independently assessed and extracted data from each study. A meta-analysis was conducted to evaluate summary sensitivity and specificity estimates for TQS. 12 studies were suitable for inclusion (n=1 662 865 participants): 1 modelling and 11 prospective observational cohort studies. Eight studies assessed diagnostic accuracy; the summary estimate for sensitivity was 90% (95% CI, 89% to 90%) with specificity 97% (95% CI, 95% to 100%). Six studies investigated cost-efficacy, reporting lower healthcare costs when using TQS instead of the current method of vaccination history, due to a decrease in unnecessary tetanus vaccine and immunoglobulin administration. Based on the current NHS supply chain data, TQS use could save £173.05 per tetanus-prone patient. TQS could confer the greatest cost savings if used in combination with vaccination history in patients with tetanus-prone wounds. A quality assurance process is recommended prior to implementation of TQS in EDs.


Comparing the Efficacy of Cancer Therapies between Subgroups in Basket Trials.
The need to test anticancer drugs in multiple indications has been addressed by basket trials, which are Phase I or II clinical trials involving multiple tumor subtypes and a single master protocol. Basket trials typically involve few patients per type, making it challenging to rigorously compare responses across types. We describe the use of permutation testing to test for differences among subgroups using empirical null distributions and the Benjamini-Hochberg procedure to control for false discovery. We apply the approach retrospectively to tumor-volume changes and progression-free survival in published basket trials for neratinib, larotrectinib, pembrolizumab, and imatinib and uncover examples of therapeutic benefit missed by conventional binomial testing. For example, we identify an overlooked opportunity for use of neratinib in lung cancers carrying ERBB2 Exon 20 mutations. Permutation testing can be used to design basket trials but is more conservatively introduced alongside established approaches to enrollment such as Simon's two-stage design.


The oblique popliteal ligament: an anatomic and MRI investigation.
Despite being the largest ligament on the posterior aspect of the knee, relatively little is known about the normal morphology of the oblique popliteal ligament (OPL). The aim of this study was to investigate the detailed anatomy of the OPL in cadavers and healthy volunteers. The posterior knee was investigated in 25 cadaver lower limbs (mean age 76 ± 9.5 years; 7 men) by dissection, histology, and serial plastination and in 14 healthy individuals (mean age 23 ± 3.2 years; 11 men) using magnetic resonance (MR) imaging. OPL morphology, attachments sites, ligament length and width, relationship to surrounding structures and histological composition were recorded. Intraobserver reliability was assessed using intraclass correlation coefficients. The OPL is a distinct expansion of the semimembranosus (SM) tendon and sheath, which courses superolaterally to attach to the posterolateral joint capsule or fabella (when present), at the medial margin of the lateral femoral condyle. The ligament blends with the joint capsule medially and laterally, serves as an attachment site for plantaris, and has connections with popliteus. In 70% of dissections, the OPL divided into two bands, separated by small branches of the middle genicular neurovascular bundle that pierced the posterior joint capsule. Differences in mediolateral length were noted between dissection and MR imaging (43.6 ± 6.2 vs. 57.6 ± 4.4 mm; p < 0.001). At its medial and lateral attachments, the OPL was 23.2 ± 6.9 and 17.4 ± 8.7 mm wide (proximodistal), respectively. The OPL was predominantly composed of transverse collagen layers, with little elastin. While visible on axial MR scans, delineation of its most lateral extent was difficult. Repeatability of selected measurements ranged from good to almost perfect. The OPL is a distinct ligament with identifiable anatomical limits. Based on its morphological characteristics, it appears more tendinous than ligamentous in nature. A better understanding of the OPL may help define its importance in the assessment and treatment of posterior knee injuries.


Postembolization splenic abscess in a patient with pancreatitis and splenic vein thrombosis.
We have reported a splenic abscess resulting from embolization of the splenic artery with coils. The embolization was done as treatment for portal hypertension caused by splenic vein thrombosis from pancreatitis.


Progressive quadriparesis and inflammation: A common disease, a rare presentation.
A previously healthy, 10-years-old girl presented with progressively worsening pain and weakness of the limbs for the past 2 weeks. It initially started with low-grade fever lasting for 4 days followed by severe pain over bilateral lower and upper limbs. Gradually she became bed-ridden. On examination, she had severe neck rigidity, generalized tenderness all over the body, generalized hyperalgesia, hyporeflexia, bilateral extensor plantar response and toe-walking. An initial clinical diagnosis of Landry-Guillain Barry syndrome was considered. Nerve conduction study showed generalized, demyelinating polyneuropathy. She was administered IVIG and was evaluated for other causes of arachnoiditis. MRI brain and spine showed enhancement and clumping of nerve roots in the conus and cauda equina. CECT chest showed necrotic mediastinal lymphnodes. A final diagnosis of disseminated tuberculosis with tuberculous arachnoiditis was considered and she was administered ATT, pulse methylprednisolone followed by maintenance oral corticosteroids. Currently, after 5 months of therapy, she has recovered clinically.