Sleep problems in anxious and depressive older adults.
The objective of this study was to identify the sleep problems most often encountered by the elderly according to the presence or absence of anxiety and mood disorders. The aim was also to determine whether groups of anxious, depressive, and asymptomatic individuals differ in relation to sleep onset latency; awakenings at night or early in the morning; subjective quality of sleep; taking of sleep medication; and daytime sleepiness. Structured interviews based on the DSM-IV-TR were administered to a sample of 2,759 seniors aged 65 years and older at the participants' home by health professionals. Awakening was found to be the most common disturbance. Increased sleep onset latency was the second most frequent sleep difficulty. Taking more than 30 minutes to fall asleep was associated with the likelihood of meeting the diagnostic criteria for an anxiety disorder, and even reduced the risk of meeting the diagnostic criteria for a mood disorder rather than an anxiety disorder. Awakenings were associated with the probability of suffering from an anxiety disorder or a mood disorder. Quality of sleep, as perceived by the elderly, was not found to be associated with the probability of suffering from a mental disorder. These findings should help to facilitate the practitioner's diagnosis and add further nuances to be considered when encountering symptoms of an anxious or depressive appearance. All of these data also add fuel to the ongoing debate about whether anxiety and depression are one or two distinct categories of disorders.


Investigation of the correlation between mood disorder symptoms and disease activity and functional status in rheumatoid arthritis patients
To investigate the correlation between depressive-anxiety symptoms, mixed features, disease activity, and functional status in patients with rheumatoid arthritis (RA) in the light of the shared underlying etiology in both disorders. The study included 556 patients with RA. RA disease activity was measured using the Disease Activity Score 28-joint count C reactive protein (DAS28-CRP), and the patients were evaluated by a Health Assessment Questionnaire (HAQ). The Hospital Anxiety and Depression Scale (HADS), Mood Disorder Questionnaire (MDQ), and Modified Hypomania Checklist (mHCL) were used to evaluate the mixed depression and bipolarity status of the patients. Of the patients, 430 (77.3%) were female and 126 (22.7%) were male. The median age was 57 years, the median HAQ score was 0.55 points, and the median DAS28-CRP score was 4.1 points. The evaluation of the patients by DAS28-CRP revealed that 58.5% of the patients had moderate and severe disease activity, while only 23.4% of them were in remission. The group using the combination of synthetic disease-modifying anti-rheumatic drugs (sDMARD) and steroid therapy had significantly higher HAD-depression, HAD-anxiety, mHCL, DAS28-CRP, HAQ, and MDQ scores than the group using sDMARD alone. The grouping of the patients based on the DAS28-CRP cut-off scores showed that the patients with moderate and severe disease activity had significantly higher HADS, mHCL, MDQ scores than those in remission and those with mild disease activity (p < 0.001). Disease severity and functional status in RA can be affected by comorbid anxiety-depressive and mixed symptoms. Therefore, clinicians should consider screening the depressive-anxiety and mixed mood symptoms of RA patients. Moreover, patients who use steroid therapy are more susceptible to mood symptoms (anxiety, depression, bipolarity), which should also be considered during the follow-up of patients.


Biochemical evidence for the coexistence of monomorphic and polymorphic N-acetyltransferase activities on a common protein in rabbit liver.
New Zealand White rabbits were classified as rapid or slow acetylators by measuring the N-acetylation half-life of i.v. administered sulfadiazine, by pedigree analysis and by determination of liver N-acetyltransferase (NAT) activity in vitro. Slow acetylator rabbits were found to have significantly lower levels of p-aminobenzoic acid NAT activity in vitro than did rapid acetylator rabbits, demonstrating genetic covariation of p-aminobenzoic acid (monomorphic) and isoniazid (polymorphic) NAT activity. Monomorphic and polymorphic NAT activities could not be separated by two extensive purification procedures involving sequential centrifugation, fractional precipitation with ammonium sulfate, ion-exchange chromatography on DEAE-cellulose, gel filtration on Sephadex or Sephacryl and isoelectric focusing or electrophoresis on polyacrylamide gels. In addition, indistinguishable heat inactivation patterns were demonstrated for the two NAT activities utilizing highly purified NAT preparations at two different temperatures. Each of these findings support the coexistence of monomorphic and polymorphic NAT activities on a common protein.


High-resolution CT investigation of nonchromaffin paragangliomas of the temporal bone.
Twenty-six cases of surgically verified nonchromaffin paragangliomas (NCPs) of the temporal bone were investigated by contrast-enhanced, thin-section, multiplanar high-resolution computed tomography (CT). Based on the high-resolution CT findings the tumors were classified according to a recently introduced surgical classification of NCP into four main types (A, B, C1-C3, and D1-D3). With high-resolution CT tumors were correctly classified in all cases, as was shown with intraoperative correlation. On the basis of these findings, high-resolution CT should replace conventional tomography and should be regarded as complementary to selective angiography in the preoperative evaluation of NCP.


Dural arteriovenous fistula of the spinal cord: an uncommon cause of myelopathy.
Dural arteriovenous fistula is an uncommon cause of myelopathy. The nidus of the malformation is on or within the dura and results in a mass of serpentine vessels on the dorsal surface of the spinal cord, usually at low thoracic or lumbar levels. Onset is usually between ages 40 and 70 years. Male to female ratio is 4:1. Symptoms include pain, progressive proximal weakness of lower limbs, saddle area numbness, claudication, and difficulty with urination. Course may be fluctuating or slowly progressive. Signs include upper and lower motor neuron abnormalities and nondermatomal sensory loss. Spinal bruit is rare. Magnetic resonance imaging may show an enlarged cord or abnormalities on its dorsal surface. Myelography (patient prone and supine) is the procedure of choice. Motor neuron disease, disc disease, spinal cord tumor, and multiple sclerosis are differential considerations. Untreated patients have a poor prognosis. Excision of the nidus, ligation of the draining vein, and endovascular embolization may be helpful even in patients with severe deficits.


Cardiac implantable electrical devices: bioethics and management issues near the end of life.
Cardiac implantable electrical devices (CIEDs) are extremely sophisticated modern devices that provide patients with many beneficial effects, including increased survival and enhanced quality of life. CIEDs, however, may complicate and unnecessarily prolong the process of dying from terminal illnesses. A rational plan for CIED deactivation near the end of life should therefore be carefully drawn up well in advance by the patient in concert with loved ones and treating physicians.


Inhibition of cellular proteasome activities enhances hepadnavirus replication in an HBX-dependent manner.
The X protein (HBX) of the hepatitis B virus (HBV) is not essential for the HBV life cycle in vitro but is important for productive infection in vivo. Our previous study suggests that interaction of HBX with the proteasome complex may underlie the pleiotropic functions of HBX. With the woodchuck model, we demonstrated that the X-deficient mutants of woodchuck hepatitis virus (WHV) are not completely replication defective, possibly behaving like attenuated viruses. In the present study, we analyzed the effects of the proteasome inhibitors on the replication of wild-type and X-negative HBV and WHV. Recombinant adenoviruses or baculoviruses expressing replicating HBV or WHV genomes have been developed as a robust and convenient system to study viral replication in tissue culture. In cells infected with either the recombinant adenovirus-HBV or baculovirus-WHV, the replication level of the X-negative construct was about 10% of that of the wild-type virus. In the presence of proteasome inhibitors, the replication of the wild-type virus was not affected, while the replication of the X-negative virus of either HBV or WHV was enhanced and restored to the wild-type level. Our data suggest that HBX affects hepadnavirus replication through a proteasome-dependent pathway.


A phase I pharmacodynamic trial of sequential sunitinib with bevacizumab in patients with renal cell carcinoma and other advanced solid malignancies.
Sunitinib treatment results in a compensatory increase in plasma VEGF levels. Acute withdrawal of sunitinib results in a proliferative withdrawal flare, primarily due to elevated VEGF levels. Concurrent sunitinib plus bevacizumab is poorly tolerated with high (37 %) incidence of microangiopathic hemolytic anemia (MAHA). We evaluated a sequential design administering bevacizumab during the sunitinib treatment break to suppress the sunitinib withdrawal flare. Patients with no prior VEGF treatment were enrolled in this study. All patients had target lesions amenable to serial FLT PET/CT imaging. Sunitinib 37.5 mg was given on days 1-28 every 6 weeks with bevacizumab 5 mg/kg on day 29. If safe and tolerable, sunitinib increased to 50 mg. FLT PET/CT scans would be obtained at baseline (D1), week 4, and week 6 to evaluate pharmacodynamics of the sequential combination. Sunitinib pharmacokinetics and total, free, and bound VEGF levels were obtained on each cycle at D1, pre-bevacizumab (D29), 4 h post-bevacizumab (D29H4), and day 42 (D42). Six patients enrolled in the safety cohort of sunitinib 37.5 mg plus bevacizumab (see Table). One patient experienced grade 1 MAHA, and after discussion with the Cancer Therapy Evaluation Program (CTEP), the trial was closed to further accrual. No imaging scans were obtained due to early closure. Total and free VEGF levels during cycle 1 Cycle 1 Total VEGF (pg/mL) Mean ± SD Free VEGF (pg/mL) Mean ± SD D1 80 ± 70 51 ± 47 D29 150 ± 62 103 ± 35 D29H4 10 ± 12 2 ± 5 D42 177 ± 34 97 ± 18 CONCLUSIONS: Subclinical MAHA was seen despite using sequential sunitinib with low-dose bevacizumab, and this combination was not feasible for further development. As predicted, VEGF levels increased during sunitinib exposure followed by a rapid decline after bevacizumab. Due to the long half-life of bevacizumab, we expected VEGF ligand suppression through D42, but instead observed a complete rebound in total/free VEGF levels by D42. The increase in VEGF at D42 was unexpected based on sunitinib alone and contrary to the hypothesis that we would block VEGF flare with low-dose bevacizumab. VEGF ligand production may increase as a result of bevacizumab, implying a robust host compensatory mechanism to VEGF signaling pathway inhibition. A greater understanding of the compensatory mechanism would aid future sequencing strategies of new agents.


Treatment Difficulties in Hypomagnesemia Secondary to the Transient Receptor Potential Melastatin 6 Gene: A Case Report with Novel Mutation
Hypomagnesemia is a rare cause of seizures in childhood but should be kept in mind in recurrent and intractable seizures and hypocalcemia in communities where consanguineous marriages are common. Familial hypomagnesemia with secondary hypocalcemia is a rare genetic cause of hypomagnesemia, due to variants in the transient receptor potential melastatin 6 (TRPM6) genes. Here, a three year-old boy with a novel variant in this gene and had difficulties with enteral hypomagnesemia treatment is presented. He had recurrent seizures since two years of age and was diagnosed with epilepsy and treated with multiple antiepileptic drugs. Subsequently, he was diagnosed with rickets due to severe hypocalcemia at another center. The patient was hypotonic and neurodevelopmentally poor. The most prominent laboratory finding was of hypomagnesemia with secondary hypocalcemia. The genetic analysis revealed a novel variant in the TRPM6 gene. After parental treatment of intravenous magnesium (Mg2+) sulfate and calcium, the treatment was switched to enteral Mg2+ medications, due to persistent hypomagnesemia and the gastrointestinal side-effects, different oral preparations were used. The patient was stable on an oral maintenance dose of Mg2+ oxide with borderline blood Mg2+ levels and resolution of hypocalcemia. Hypomagnesemia is one of the causes of hypocalcemia. Enteral replacement is the key treatment but the treatment should be individualized for each patient. Normalization of hypomagnesemia is not always easy and should not be the aim of the treatment.


The proteolysis of membrane-associated protein kinase C as a possible component of the signalling pathway leading to c-myc induction in B lymphocytes.
Occupancy of surface immunoglobulin (sIg) receptor for antigen expressed on resting B cells initiates increased turnover of membrane-associated phosphatidylinositol (PI), which ultimately leads to the enhanced expression of c-myc mRNA. The mechanism which links these initial membrane biochemical changes to subsequent alterations in c-myc transcription is unclear. The present study examines the possible involvement of PKC and its calpain-generated proteolytic fragment, protein kinase M (PKM), in conveying the membrane-associated signal to the nucleus. Utilizing an in vitro phosphorylation assay, we have shown that a calcium-dependent protease, similar to calpain, is involved in the downregulation of membrane-associated PKC induced by anti-immunoglobulin or phorbol 12-myristate 13-acetate (PMA) and ionomycin stimulation of resting B cells. In addition, we have confirmed previous studies showing that PMA and ionomycin are both required for optimal expression of c-myc mRNA. The enhanced expression of c-myc mRNA is sensitive to inhibitors of PKC, such as H-7 and sangavimycin, providing evidence for a prominent role of PKC and/or PKM in the receptor-mediated up-regulation of c-myc message expression. Finally, a calpain inhibitor interferes with the transmission of the membrane-associated signal which induces the increased expression of c-myc mRNA. Our results are consistent with the hypothesis that the calpain-mediated proteolysis of membrane-associated PKC is involved in the sIg-mediated signal transduction pathway.


Addressing urinary incontinence by gender: a nationwide population-based study in Turkiye.
Urinary incontinence (UI), which usually occurs in women but affects both sexes, is a significant public health challenge. This study aims to comprehensively investigate the prevalence and determinants of UI in men and women, considering gender-specific factors. The study performed a secondary analysis on data obtained from 13,383 individuals surveyed in the 2019 Turkish Health Survey, providing a representation of the Turkish population. The dataset included sociodemographic and health-related variables like UI, body mass index (BMI), physical activity, smoking, and chronic diseases-statistical analysis employed chi-square tests and gender-stratified logistic regression models to identify UI-associated factors. Our results showed that UI affected 8.8% of the population, with a striking gender disparity. Women had a notably higher prevalence at 11.2%, while men had a lower rate of 5.5%. Importantly, this gender gap narrowed with age. For example, in the 34-44 age group, the female/male ratio was 6.9, but it decreased to 1.4 in the 65-74 age group. Marital status and employment status played significant roles. Separated, divorced, or widowed individuals, particularly women, had the highest prevalence at 19.3%. Employment status influenced UI prevalence, with employed men having the lowest rate (2.1%), while retired women faced the highest rate (15.0%). Higher BMI, especially in obese individuals, significantly raised UI prevalence, reaching 7.9% for men and 15.8% for women. Physical inactivity, notably in women (17.0%), and prolonged sedentary hours (13.9%) were associated with higher UI rates. Former smokers, especially women (15.9%), had a notable impact on UI. Poor perceived health and chronic conditions like Chronic Obstructive Pulmonary Disease (COPD), hypertension, and diabetes were significantly associated with higher UI prevalence. Logistic regression analysis revealed that age, education, perceived health status, COPD, and diabetes were significant factors associated with UI in both sexes, while in women, BMI, physical activity, and smoking also played notable roles. This extensive UI study has unveiled notable gender disparities and determinants. Notably, these disparities decrease with age, underlining UI's changing nature over time. Modifiable factors impact women more, while non-modifiable factors are linked to men. The study underscores the importance of tailoring healthcare strategies to address UI based on gender.


Aflatoxicosis in feedlot cattle.
Aflatoxicosis was diagnosed in lightweight feedlot cattle fed aflatoxin-contaminated cottonseed or gin trash. Clinical signs of hepatic damage and death were recorded for more than 200 of the 14,000 animals in a feedlot. Aflatoxin concentration in feedlot products fed to these cattle ranged from 96 to 1,700 ng/g. Diagnosis was based on the correlation of characteristic microscopic liver lesions, high concentration of aflatoxin in cottonseed feed products, and isolation and detection of aflatoxin B1 and aflatoxin M1 in urine and liver from affected calves. This report describes a large-scale outbreak of aflatoxicosis and demonstrates the need for careful quality control of feed products susceptible to aflatoxin contamination.


Endothelin XIII.
Twenty-five years ago, a groundbreaking paper from Tsukuba University in Japan was published, identifying the sequence of the endothelin gene and peptide (Nature 332, 411-415, 1988). This work opened the way for the discovery of the endothelin receptors and the development of orally active endothelin receptor antagonists (ERAs). Today, ERAs are part of medical therapy of patients around the world for the treatment of pulmonary arterial hypertension. Since the discovery of endothelin, about 1000 papers per year have been published, with more than 27,000 articles available today. Many important and break-through findings presented in the endothelin conferences have been published in the conferences' proceedings. Endothelin XIII is the proceedings of the Thirteenth International Conference on Endothelin, held at Tokyo Campus of Tsukuba University, Japan, in September 2013. At the conference, the 25th anniversary of endothelin's discovery was celebrated and articles produced from data presented at the conference are compiled in this Special Issue of Life Sciences. Endothelin XIII includes more than fifty articles, including review articles by experts in the field and numerous original research articles. As the Editors of this special issue, we are proud to present Endothelin XIII and wish the field continued growth for the benefit of patients and for the advancement of biomedical science.


Genetic relatedness and virulence properties of enteropathogenic Escherichia coli strains of serotype O119:H6 expressing localized adherence or localized and aggregative adherence-like patterns on HeLa cells.
Enteropathogenic Escherichia coli (EPEC) induce attaching and effacing (A/E) lesions in enterocytes and produce the bundle-forming pilus (BFP) contributing to the localized adherence (LA) pattern formation on HeLa cells. Enteroaggregative E. coli (EAEC) produce aggregative adherence (AA) on HeLa cells and form prominent biofilms. The ability to produce LA or AA is an important hallmark to classify fecal E. coli isolates as EPEC or EAEC, respectively. E. coli strains of serotype O119:H6 exhibit an LA+ phenotype and have been considered as comprising a clonal group of EPEC strains. However, we have recently identified O119:H6 EPEC strains that produce LA and an AA-like pattern concurrently (LA/AA-like+). In this study, we evaluated the relatedness of three LA/AA-like+ and three LA+ O119:H6 strains by comparing their virulence and genotypic properties. We first found that the LA/AA-like+ strains induced actin accumulation in HeLa cells (indicative of A/E lesions formation) and formed biofilms on abiotic surfaces more efficiently than the LA+ strains. MLST analysis showed that the six strains all belong to the ST28 complex. All strains carried multiple plasmids, but as plasmid profiles were highly variable, this cannot be used to differentiate LA/AA-like+ and LA+ strains. We further obtained their draft genome sequences and the complete sequences of four plasmids harbored by one LA/AA-like+ strain. Analysis of these sequences and comparison with 37 fully sequenced E. coli genomes revealed that both O119:H6 groups belong to the E. coli phylogroup B2 and are very closely related with only 58-67 SNPs found between LA/AA-like+ and LA+ strains. Search of the draft sequences of the six strains for adhesion-related genes known in EAEC and other E. coli pathotypes detected no genes specifically present in LA/AA-like+ strains. Unexpectedly however, we found that a large plasmid distinct from pEAF is responsible for the AA-like phenotype of the LA/AA-like+ strains. Although we have not identified any plasmid genes specifically present in all LA/AA-like+ strains and absent in the LA+ strains, these results suggest the presence of an unknown mechanism to promote the AA-like pattern production and biofilm formation by the LA/AA-like+ strains. Because their ability to produce A/E lesions and biofilm concomitantly could exacerbate the clinical condition of the patient and lead to persistent diarrhea, the mechanism underlying the enhanced biofilm formation by the LA/AA-like+ O119:H6 strains and their spread and involvement in severe diarrheal diseases should be more intensively investigated.


Factors hampering the use of patient complaints to improve quality: an exploratory study.
This study aims to explore factors that might hamper the use of patient complaints to improve quality. A teaching hospital in Taiwan was purposefully chosen for a case study based on data triangulation. The study included in-depth interviews with hospital senior managers, senior social workers, government officials and non-government organizations staff; as well as analysis of documents. In the Case Hospital, the organizational responses to complaints appear to be influenced by the interaction between managerial factors, operational factors and technical factors. Externally, there were no national guidelines to regulate how the hospital handled complaints. This was bound to have a major influence on the response of the hospital to complaints. Internally, the hospital itself did not place great importance on complaints. The mindset of the hospital was that patient complaints are not welcome. If the hospital attempts to use patient complaints to improve its quality of care, senior hospital management needs to recognize the values of complaints handling and respond to these in a more constructive manner. Moreover, the government has to set up the protocols of using complaints to improve quality at the policy level. This legal incentive would encourage the hospital to handling complaints effectively.


Morphological observation of tumor infiltrating immunocytes in human rectal cancer.
To investigate the morphological characterization of tumor infiltrating dendritic cells (TIDCs) and tumor infiltrating lymphocytes (TILs) in human rectal cancer. Light and electron microscopy as well as immunohistochemistry were used to observe the distributive and morphological changes of TIDCs and TILs. TIDCs were mainly located in tumor-surrounding tissue. The number of TIDCs in the earlier stage was higher than that in the later stage (P<0.01). TILs were mainly seen in adjacent tissue of cancers and tumor-surrounding tissue. There were more TILs in the earlier stage than that in the later stage (P<0.01). Under electron microscope, TIDCs were irregular in shape and exhibited many dendritic protrusions. It is not obvious that cancer cells perforated the basement membrane and TILs were arranged along the basement membrane in the earlier stage. In the later stage, it is explicit that cancer cells perforated the basement membrane and surrounded by TILs. There were contacts among TIDCs, TILs and tumor cell. One TIDCs contacted one or several TILs which clustered around TIDCs. Glycogen granules were seen between TIDCs and TILs. The number of TIDCs and TILs is related with tumor progression There exist close relationships among TIDCs, TILs and tumor cell.


The epidemiology of failure in total knee arthroplasty: avoiding your next revision.
Total knee arthroplasty (TKA) is a cost effective and extremely successful operation. As longevity increases, the demand for primary TKA will continue to rise. The success and survivorship of TKAs are dependent on the demographics of the patient, surgical technique and implant-related factors. Currently the risk of failure of a TKA requiring revision surgery ten years post-operatively is 5%. The most common indications for revision include aseptic loosening (29.8%), infection (14.8%), and pain (9.5%). Revision surgery poses considerable clinical burdens on patients and financial burdens on healthcare systems. We present a current concepts review on the epidemiology of failed TKAs using data from worldwide National Joint Registries.


Near-field probing the magnetic field vector of visible light with a silicon nanoparticle probe and nanopolarimetry.
Magnetic light-matter interaction plays a crucial role in nanophysics, such as in photonic topological insulators and metamaterials. Recent advances in all-dielectric nanophotonics especially demand vectorial mapping of magnetic light at visible wavelengths. Here, we report that a novel functional nanoprobe decorated with a silicon nanoparticle predominantly senses both the vertical and lateral magnetic field, that is, the magnetic field vector, complementary to a metal nanoparticle probe detecting the local electric field vector. As a proof-of-principle experiment, we demonstrate the mapping of magnetic field vectors in a transverse electric (TE) evanescent standing wave by this probe in a scanning near-field optical microscope (SNOM) with nanopolarimetry. It is for the first time that the full magnetic field vector of visible light, whose frequency exceeds 550 THz, can be directly detected with deep subwavelength resolution. Such functional probe and nanopolarimetry may pave the way toward complete vectorial near-field characterization over the whole visible band for nano-optics and subwavelength optics.


Hyporesponsivity to mu-opioid receptor agonism in the Wistar-Kyoto rat model of altered nociceptive responding associated with negative affective state.
Chronic pain is often comorbid with anxiety and depression, altering the level of perceived pain, which negatively affects therapeutic outcomes. The role of the endogenous mu-opioid receptor (MOP) system in pain-negative affect interactions and the influence of genetic background thereon are poorly understood. The inbred Wistar-Kyoto (WKY) rat, which mimics aspects of anxiety and depression, displays increased sensitivity (hyperalgesia) to noxious stimuli, compared with Sprague-Dawley (SD) rats. Here, we report that WKY rats are hyporesponsive to the antinociceptive effects of systemically administered MOP agonist morphine in the hot plate and formalin tests, compared with SD counterparts. Equivalent plasma morphine levels in the 2 rat strains suggested that these differences in morphine sensitivity were unlikely to be due to strain-related differences in morphine pharmacokinetics. Although MOP expression in the ventrolateral periaqueductal gray (vlPAG) did not differ between WKY and SD rats, the vlPAG was identified as a key locus for the hyporesponsivity to MOP agonism in WKY rats in the formalin test. Moreover, morphine-induced effects on c-Fos (a marker of neuronal activity) in regions downstream of the vlPAG, namely, the rostral ventromedial medulla and lumbar spinal dorsal horn, were blunted in the WKY rats. Together, these findings suggest that a deficit in the MOP-induced recruitment of the descending inhibitory pain pathway may underlie hyperalgesia to noxious inflammatory pain in the WKY rat strain genetically predisposed to negative affect.


Metabolomic analysis characterizes tissue specific indomethacin-induced metabolic perturbations of rats.
In this study, the promising metabolomic approach integrating with ingenuity pathway analysis (IPA) was applied to characterize the tissue specific metabolic perturbation of rats that was induced by indomethacin. The selective pattern recognition analyses were applied to analyze global metabolic profiling of urine of rats treated by indomethacin at an acute dosage of reference that has been proven to induce tissue disorders in rats, evaluated throughout the time-course of -24-72 h. The results preliminarily revealed that modifications of amino acid metabolism, fatty acid metabolism and energetically associated metabolic pathways accounted for metabolic perturbation of the rats that was induced by indomethacin. Furthermore, IPA was applied to deeply analyze the biomarkers and their relations with the metabolic perturbations evidenced by pattern recognition analyses. Specific biochemical functions affected by indomethacin suggested that there is an important correlation of its effects in kidney and liver metabolism, based on the determined metabolites and their pathway-based analysis. The IPA correlation of the three major biomarkers, identified as creatinine, prostaglandin E2 and guanosine, suggested that the administration of indomethacin induced certain levels of toxicity in the kidneys and liver. The changes in the levels of biomarker metabolites allowed the phenotypical determination of the metabolic perturbations induced by indomethacin in a time-dependent manner.


Comparison of linear array and line blot assay for detection of human papillomavirus and diagnosis of cervical precancer and cancer in the atypical squamous cell of undetermined significance and low-grade squamous intraepithelial lesion triage study.
We evaluated Linear Array (LA), a newly commercialized PGMY09/11 L1 consensus primer PCR test that detects 37 human papillomavirus (HPV) genotypes by reverse line blot hybridization, for the detection of individual HPV genotypes and carcinogenic HPV and its clinical performance for detecting 2-year cumulative cervical precancer and cancer using archived specimens from the Atypical Squamous Cell of Undetermined Significance (ASCUS) and Low-Grade Squamous Intraepithelial Lesion Triage Study. LA testing was conducted on enrollment specimens from women referred because of an ASCUS Pap test. To gauge the performance of the new test, the results were compared to those of its prototype predecessor assay, Line Blot Assay (LBA), restricted to paired results (n = 3,335). LA testing was done masked to LBA results and clinical outcomes. The results of LA and LBA testing were compared for detection of carcinogenic HPV and clinical outcomes of cervical precancer and cancer. Overall, 50% and 55% of the women tested positive for carcinogenic HPV by LBA and LA, respectively (P < 0.0001). The percent agreement for carcinogenic HPV detection was 88%, percent positive agreement was 80%, and kappa was 0.76 for detection of carcinogenic HPV by the two assays. There was a significant increase in detection by LA for most of the 37 HPV genotypes targeted by both assays, including for 13 of 14 carcinogenic HPV genotypes. LA detected more multiple-genotype infections for all HPV genotypes among HPV-positive women (P < 0.0001) and for carcinogenic HPV genotypes among carcinogenic-HPV-positive women (P < 0.0001). LA was more sensitive (92.3% versus 87.1%; P = 0.003) and less specific (48.2% versus 54.0%; P < 0.0001) than LBA for 2-year cumulative cervical precancer and cancer as diagnosed by the Pathology Quality Control Group. In conclusion, we found LA to be a promising assay for the detection of HPV genotypes and carcinogenic HPV, and it may be clinically useful for the detection of cervical precancer and cancer in women with equivocal cytology.


[A comparative study of the mechanisms of the immunosuppressive action of morphine and adrenaline in leukocytes in vitro].
The effect of morphine (10(-6) M) and adrenaline (0.2 microgram/10(6) cells) on the oxidant and antioxidant activity in cells of the immunophagocytic system was compared in vitro. Morphine and adrenaline caused different changes in production of active forms of oxygen (AFA) and antioxidant activity of the enzymes superoxide dismutase and glutathione reductase in neutrophils, monocytes, and lymphocytes in human peripheral blood. The effect of these drugs, however, was unidirectional in character in each type of cells. Eleutherococcus (obtained in the drug-store and diluted 10- to 11-fold) or indomethacin (10(-7) M) injected together with morphine removed the morphine-induced increase of APA production in the neutrophils, they also prevented the effect of morphine on enzyme activation in the neutrophils and monocytes, but had no influence on the effect of morphine on the antioxidant enzymes in the neutrophils. The results of the study point to the existence of common mediators in direct action of adrenaline and morphine on the cells of the immunophagocytic system.


Complex coacervates of oppositely charged co-polypeptides inspired by the sandcastle worm glue.
Sandcastle worms secrete a water-resistant proteinaceous glue that is used to bind mineral particulates into their protective tubing. Previous proteomics studies have shown that the constitutive proteins of the glue are oppositely charged co-polypeptides that form a complex coacervate precursor phase, which is critical for stable underwater delivery of the adhesive. Using ring-opening polymerization (ROP) from N-carboxyanhydride (NCA) monomers, we synthesized oppositely charged co-polypeptides that mimic the amino acid composition and molecular weight of the native glue-forming proteins. The synthesis strategy enabled the incorporation of non-standard phosphoserine (pSer) and 3,4-Dihydroxyphenylalanine (Dopa) amino acids in the co-polypeptides, thereby duplicating chemical functionalities of the native glue that are key for electrostatic complexation and adhesion. Complex coacervates were obtained from these oppositely charged co-polypeptides, thus mimicking the self-assembly process of the native adhesive secreted by the sandcastle worm. Varying the relative ratio of the co-polypeptides enabled the fine-tuning of coacervation conditions such as pH and ionic strength. Wetting and rheological characterization demonstrated that our oppositely charged co-polypeptide complexes exhibited the key features associated with coacervates, namely, low surface tension, shear thinning behaviour, and viscoelastic response, making these sandcastle worm glue-inspired polypeptide coacervates a suitable modality for water-resistant bioadhesives.


Microarray compound screening (microARCS) to identify inhibitors of HIV integrase.
A novel high-throughput strand transfer assay has been developed, using Microarray Compound Screening (microARCS) technology, to identify inhibitors of human immunodeficiency virus (HIV) integrase. This technology utilizes agarose matrices to introduce a majority of the reagents throughout the assay. Integration of biotinylated donor DNA with fluorescein isothiocyanate (FITC)-labeled target DNA occurs on a SAM membrane in the presence of integrase. An anti-FITC antibody conjugated to alkaline phosphatase (AP) was used to do an enzyme-linked immunosorbent assay with the SAM. An agarose gel containing AttoPhos, a substrate of AP, was used for detection of the integrase reactions on the SAM. For detection, the AttoPhos gel was separated from the SAM after incubation and then the gel was imaged using an Eagle Eye II closed-circuit device camera system. Potential integrase inhibitors appear as dark spots on the gel image. A library of approximately 250,000 compounds was screened using this HIV integrase strand transfer assay in microARCS format. Compounds from different structural classes were identified in this assay as novel integrase inhibitors.


Comprehensive numerical modelling of the performance of a second harmonic generation stage coupled with a low-gain optical parametric amplifier.
We present a comprehensive model for predicting the full performance of a second harmonic generation-optical parametric amplification system that aims at enhancing the temporal contrast of laser pulses. The model simultaneously takes into account all the main parameters at play in the system such as the group velocity mismatch, the beam divergence, the spectral content, the pump depletion, and the length of the nonlinear crystals. We monitor the influence of the initial parameters of the input pulse and the interdependence of the two related non-linear processes on the performance of the system and show its optimum configuration. The influence of the initial beam divergence on the spectral and the temporal characteristics of the generated pulse is discussed. In addition, we show that using a crystal slightly longer than the optimum length and introducing small delay between the seed and the pump ensures maximum efficiency and compensates for the spectral shift in the optical parametric amplification stage in case of chirped input pulse. As an example, calculations for bandwidth transform limited and chirped pulses of sub-picosecond duration in beta barium borate crystal are presented.


[Importance of the tumor-associated antigen CA 19-9 in the differential diagnosis of pancreatic diseases].
Tumour-associated antigen CA 19-9 was determined in serum from 166 patients (30 without gastro-intestinal disease, 32 with liver cirrhosis, 9 with choledocholithiasis, 65 with acute or chronic pancreatitis and 30 with malignant tumors in the region of pancreas and bile passages). The specificity of CA-19-9 as tumour marker was 97% in patients without gastro-intestinal disease, but in those with liver cirrhosis or choledocholithiasis it was only 56% and 44%, respectively. In particular, cholestasis reduced specificity. Acute pancreatitis in its initial attack gave false-positive CA 19-9 values in 27% of cases, repeated bouts in chronic recurrent pancreatitis in as many as 50%. In chronic pancreatitis the specificity was 90%. Malignant tumours of pancreas and bile ducts were diagnosed with a sensitivity of 80%. Determination of CA 19-9 in pure pancreatic secretion failed to differentiate between the control group (30), chronic pancreatitis (21) and carcinoma of the pancreas (22).


Influence of oxygen concentration on the neuroprotective effect of hydrogen inhalation in a rat model of cardiac arrest.
Post-cardiac arrest (CA) brain injury is the main cause of death in patients resuscitated from CA. Previous studies demonstrated that hydrogen inhalation mitigates post-CA brain injury. However, factors affecting the efficacy of hydrogen remain unknown. In the present study, we investigated the influence of oxygen concentration and targeted temperature on neuroprotective effect in a CA rat model of ventricular fibrillation (VF). Cardiopulmonary resuscitation (CPR) was initiated after 7 min of untreated VF in adult male Sprague-Dawley rats. Immediately following successful resuscitation, animals were randomized to be ventilated with 21% oxygen and 79% nitrogen (21%O2); 2% hydrogen, 21% oxygen, and 77% nitrogen (2%H2 + 21%O2); 2% hydrogen, 50% oxygen, and 48% nitrogen (2%H2 + 50%O2); or 2% hydrogen and 98% oxygen (2%H2 + 98%O2) for 3 h. For each group, the target temperature was 37.5°C for half of the animals and 35.0°C for the other half. No statistical differences in baseline measurements and CPR characteristics were observed among groups. For animals with normothermia, 2%H2 + 50%O2 (123 [369] vs. 500 [393], p = 0.041) and 2%H2 + 98%O2 (73 [66] vs. 500 [393], p = 0.002) groups had significantly lower neurological deficit scores (NDSs) at 96 h and significantly higher survival (75.0 vs. 37.5%, p = 0.033 and 81.3 vs. 37.5%, p = 0.012) than 21%O2 group. For animals with hypothermia, no statistical difference in NDS among groups but 2%H2 + 98%O2 has significantly higher survival than the 21%O2 group (93.8 vs. 56.3%, p = 0.014). In this CA rat model, inhaling 2% hydrogen combined with a high concentration of oxygen improved 96-h survival, either under normothermia or under hypothermia.


Intracellular Osteopontin Induced by CagA-positive Helicobacter pylori Promotes Beta-catenin Accumulation and Interleukin-8 Secretion in Gastric Epithelial cells.
Osteopontin, an important immune modulator and oncogenic promoter, is upregulated in H. pylori-infected gastric mucosa. However, the underlying mechanisms and biological significance are poorly understood. We investigated whether osteopontin was upregulated in gastric epithelial cells by H. pylori and the virulence factors involved. Moreover, cellular component changes caused by osteopontin were also investigated. The gastric epithelial cell line MKN45 was cocultured with wild-type and mutant H. pylori to analyze osteopontin expression. Beta-catenin levels in cell lysate and interleukin-8 levels in supernatant were analyzed. The difference in osteopontin expression levels in both gastric epithelium and plasma was compared between H. pylori-infected patients and uninfected controls. H. pylori induced intracellular, but not secretory, osteopontin expression in MKN45 cells. Accordingly, osteopontin expression intensity in gastric epithelium was higher in H. pylori-infected patients than in controls, but osteopontin levels in plasma were similar between both patient groups. H. pylori virulence factor CagA delivered via the type IV secretion system was essential for intracellular osteopontin upregulation. H. pylori induced β-catenin accumulation and interleukin-8 secretion, whereas osteopontin knockdown completely abrogated these effects, in MKN45 cells. TLR2 antagonist abolished iOPN expression induced by H. pylori gastritis strain, but not by H. pylori cancer strain. H. pylori is dependent on CagA translocation via the type IV secretion system to induce intracellular osteopontin expression in gastric epithelial cells. Upregulated intracellular osteopontin may promote gastric carcinogenesis via increased β-catenin accumulation and interleukin-8 secretion.


[The long-term toxicity of polychemotherapy in successfully treated testicular carcinoma].
Of 55 patients with testicular cancer, treated by combination chemotherapy including cisplatin, 21 (mean age 35 [21-51] years) were reexamined for late sequelae of the chemotherapy 1-9 years later. No patient had a recurrence or second malignancy. They all had normal renal function (renal sequence scintigraphy; creatinine clearance). Seven of 20 patients had a polyneuropathy, nine of 18 had high-tone hearing loss. Two patients became fathers after treatment. In nine of 20 patients the serum concentration of follicle-stimulating hormone was raised to above 20 mU/ml, evidence of germ-cell damage. Six of 13 patients had an abnormal ejaculation following retroperitoneal lymphadenectomy or excision of a residual tumour. There was no evidence of any life-limiting toxicity of the chemotherapy.


Tumor stroma as a target in cancer.
Solid tumors are composed of the malignant cell itself (most commonly a carcinoma) and supporting cells that comprise the stroma. Significant stromal components include the extracellular matrix, supporting fibroblasts, vessels comprised of endothelium, pericytes and in some cases vascular smooth muscle, lymphatics and usually a major leukocyte infiltration. Indeed, macrophages may constitute up to 50% of the viable cells within the tumor. For many years, researchers have concentrated almost exclusively on the malignant carcinoma and looked for ways to either selectively kill or restrict its growth. In recent years the frustrating lack of advances in cytotoxic cancer therapy provoked a search for more novel strategies and foremost amongst these were anti-angiogenesis and vascular targeting. The purpose of this article is to illustrate how the stroma is now being pursued as an anti-cancer target. The article will briefly touch on anti-angiogenics that are now entering the clinic but concentrate on recent studies looking at vascular disrupting agents, stromal tumor fibroblasts and macrophages. Target identification is illustrated by the search for tumor endothelial markers. Finally, we draw attention to efforts to develop a cancer vaccine. The genetic instability and variation found in carcinoma cells made vaccination in the past a near impossibility. In contrast, genetically stable tumor endothelium with its unique accessibility to blood borne agents, together with recent advances in immunotherapy means that the possibility of a cancer vaccine now takes on a reality not previously recognised.


Diethylpyrocarbonate inactivation of NAD-malic enzyme from Ascaris suum.
Treatment with diethylpyrocarbonate results in a first-order loss of the malate oxidative decarboxylase activity of NAD-malic enzyme. First-order plots are biphasic, with about 40-50% activity loss in the first phase. The inactivation process is not saturable, and the second-order rate constant is 4.7 M-1 S-1. Malate (250 mM) provides complete protection against inactivation (as measured by a decrease in the inactivation rate), and less malate is required with Mg2+ present. Partial protection (50%) is afforded by either NAD+ (1 mM) or Mg2+ (50 mM). Treatment of modified (inactive) enzyme with hydroxylamine restores activity to 100% of the control when corrected for the effect of hydroxylamine on unmodified enzyme. A total of 10-13 histidine residues/subunit are acylated concomitant with loss of activity while 1-2 tyrosines are modified prior to any activity loss. The presence of Mg2+ and malate at saturating concentrations protect 1-2 histidine residues/subunit. The intrinsic fluorescence of the enzyme decreases with time after addition of diethylpyrocarbonate, but the rate constant for this process is at least 10-fold too low to account for the biphasicity observed in the first order plots. The histidine modified which is responsible for loss of activity has a pK of 8.3 as determined from the pH dependence of the rate of inactivation. The histidine titrated is still modified under conditions where the residue is completely protonated but at a rate 1/100 the rate of the unprotonated histidine. The results suggest that 1-2 histidines are in or near the malate binding site and are required for malate oxidative decarboxylation.


Labor, Health, and Marginalization: A Culture-Centered Analysis of the Challenges of Male Bangladeshi Migrant Workers in the Middle East.
Based on the culture-centered approach, we examine the meanings of health and negotiations of health care structures among low socioeconomic status (SES) Bangladeshi male migrant workers in the United Arab Emirates (UAE). We engage in coconstructive problem definition and strategizing through 44 semistructured in-depth interviews/focus groups about health, migration, and well-being. Our analysis of the participants' narratives elucidates the intersectionality of health as a lived experience of migrant labor within neoliberal structures focused on labor extraction, highlighting health not as a static or purely epidemiological construct, but as a combination of the physical, mental, spiritual, and socioeconomic material realities within which they are located. These include a recognition of the importance of interconnectedness of physical and mental well-being, drawing upon one's cultural and familial roles and responsibilities, as well as locating health within structurally exploitative practices. Specifically, the participants articulate the absence of substantive health and labor protections that result in poor health outcomes for them.


Enhancement of broadband optical absorption in photovoltaic devices by band-edge effect of photonic crystals.
We numerically investigate broadband optical absorption enhancement in thin, 400-nm thick microcrystalline silicon (µc-Si) photovoltaic devices by photonic crystals (PCs). We realize absorption enhancement by coupling the light from the free space to the large area resonant modes at the photonic band-edge induced by the photonic crystals. We show that multiple photonic band-edge modes can be produced by higher order modes in the vertical direction of the Si photovoltaic layer, which can enhance the absorption on multiple wavelengths. Moreover, we reveal that the photonic superlattice structure can produce more photonic band-edge modes that lead to further optical absorption. The absorption average in wavelengths of 500-1000 nm weighted to the solar spectrum (AM 1.5) increases almost twice: from 33% without photonic crystal to 58% with a 4 × 4 period superlattice photonic crystal; our result outperforms the Lambertian textured structure.


In healthy habitual smokers acetylsalicylic acid abolishes the effects of tobacco smoke on the platelet aggregate ratio.
After abstinence for at least 8 hours, 20 healthy habitual smokers smoked two unfiltered cigarettes during each of two 20-minute periods separated by 48 hours. They had taken one 0.32-g tablet of acetylsalicylic acid (ASA) the night before the second period. The mean platelet aggregate ratios in venous blood taken immediately before and after each period of smoking were 0.79 and 0.70 respectively when ASA had not been taken beforehand and 0.89 and 0.91 when it had. The mean after smoking was significantly higher when ASA had been taken beforehand. In conjunction with the previous finding that in nonsmokers ASA prevented a lowering of the platelet aggregate ratio by experimental smoking without affecting the ratio before smoking, the data from the present study suggest that ASA abolishes both acute and longer-lasting effects of tobacco smoke on the platelet aggregate ratio in healthy habitual smokers.


Impact of age on improvement in health-related quality of life 5 years after coronary artery bypass grafting.
The aim of this study was to describe the relief of symptoms and improvement in other aspects of health-related quality of life 5 years after coronary artery by-pass grafting in relation to age. Patients in western Sweden were approached with an inquiry prior to surgery and 5 years after the operation. Health-related quality of life was estimated with 3 different instruments: Physical Activity Score (PAS), Nottingham Health Profile (NHP), Psychological General Well-Being Index (PGWB). Prior to surgery patients were approached either in the ward or by post and 5 years after surgery they were approached by post. A total of 1719 patients were available for the survey, of whom 876 (51%) responded to the survey both prior to and after 5 years. Among the 876 respondents 287 were <60 years, 331 were 60-67 years and 258 were >67 years. In terms of physical activity, chest pain and dyspnoea, a similar improvement was observed regardless of age. In terms of health-related quality of life questionnaires, there was an inverse association between age and improvement when using PAS and a similar trend was observed with NHP and PGWB. In conclusion, 5 years after coronary artery bypass grafting relief of symptoms and improvement in physical activity was not associated with age, whereas improvement in other aspects of health-related quality of life tended to be less marked in elderly people. Overall age seemed to have a small impact on the improved well-being 5 years after coronary surgery. However, due to the limited response rate the results may not be applicable to a non-selected coronary artery bypass grafting population.


Desmozoon lepeophtherii n. gen., n. sp., (Microsporidia: Enterocytozoonidae) infecting the salmon louse Lepeophtheirus salmonis (Copepoda: Caligidae).
A microsporidian was previously reported to infect the crustacean parasite, Lepeophtheirus salmonis (Krøyer, 1837) (Copepoda, Caligidae), on farmed Atlantic salmon (Salmo salar L.) in Scotland. The microsporidian was shown to be a novel species with a molecular phylogenetic relationship to Nucleospora (Enterocytozoonidae), but the original report did not assign it to a genus or species. Further studies examined the development of the microsporidian in L. salmonis using electron microscopy and re-evaluated the molecular findings using new sequence data available for the group. Here we report a full description for the microsporidian and assign it to a new genus and species. The microsporidian infects subcuticular cells that lie on the innermost region of the epidermal tissue layer beneath the cuticle and along the internal haemocoelic divisions. The mature spores are sub-spherical with a single nucleus and an isofilar polar filament with 5-8 turns in a double coil. The entire development is in direct contact with the host cell cytoplasm and is polysporous. During early merogony, a diplokaryotic nuclear arrangement exists which is absent throughout the rest of the developmental cycle. Large merogonial plasmodia form which divide to form single uninucleate sporonts. Sporogonial plasmodia were not observed; instead, binucleate sporonts divide to form two sporoblasts. Prior to final division, there is a precocious development of the polar filament extrusion apparatus which is associated with large electron lucent inclusions (ELIs). Analyses of DNA sequences reveal that the microsporidian is robustly supported in a clade with other members of the Enterocytozoonidae and confirms a close phylogenetic relationship with Nucleospora. The ultrastructural findings of the precocious development of the polar filament and the presence of ELIs are consistent with those of the Enterocytozoonidae. However, the confirmed presence of an early diplokaryotic stage and a merogonial plasmodium that divides to yield uninucleate sporonts instead of transforming into a sporogonial syncitium, are features not currently associated with the family. Yet, analyses of DNA sequence data clearly place the microsporidian within the Enterocytozoonidae. Therefore, due to the novelty of the copepod host, the ultrastructural findings and the robust nature of the phylogenetic analyses, a new genus should be created within the Enterocytozoonide; Desmozoon lepeophtherii n. gen. n. sp. is proposed.


A two-part energy burden imposed by growth of Enterobacter cloacae and Escherichia coli in sodium dodecyl sulfate.
Enterobacter cloacae, like most enteric bacteria, can grow in the presence of 10% sodium dodecyl sulfate (SDS). The bacteria tolerate the detergent and do not metabolize it. In a defined glucose-salts medium the growth rate remained unchanged (G = 55 min) as the detergent concentration was increased from 0 to 10% SDS. However, growth in SDS exhibited a two-part energy dependence. In part 1, the SDS-grown cells underwent rapid lysis when they ran out of energy. Cells that had entered stationary phase owing to carbon limitation lysed, while those that had entered owing to nitrogen or phosphorus limitation did not. We attribute part 1 of the energy dependence to SDS as a detergent. In part 2, the cells grown in 5 or 10% SDS exhibited longer lag periods, potassium accumulation, decreased cell yields, and higher oxygen consumption. The higher oxygen consumption occurred during both exponential phase and nitrogen-limited stationary phase. However, the decreased cell yield and higher oxygen consumption of SDS-grown cells were mimicked by cells grown in equivalent concentrations of sucrose or polyethylene glycol. We attribute part 2 of the energy dependence to SDS as a solute. Finally, with regard to the as yet unidentified bacterial osmotic stress detector, we used the micelle-forming nature of SDS to conclude that the detector was responding to turgor pressure-water activity rather than to osmolarity itself.


Transluminally placed endovascular grafts to exclude undesirable intracardiac vascular communications.
In this report, we summarize our early experience using transluminally placed endovascular grafts (TPEG) to close intracardiac communications within surgically created conduits. Three patients with surgically corrected congenital heart disease were treated in this study. All three patients had intracardiac conduits [Modified Fontan (n = 2) or Mustard procedure (n = 1)]. All three patients had intracardiac shunts causing hypoxemia. The shunts were caused by a surgically created fenestration (n =1), a leak at a surgical anastomosis (n = 1) and perforations of a pericardial baffle (n = 1). All three patients were treated percutaneously from venous side approaches. The TPEG devices were constructed of pre-expanded polytetrafluoroethylene (PTFE) sutured to a Palmaz stent. In the two patients with the modified Fontan procedures, the leaks were completely excluded; in the patient with the Mustard procedure, the perforations in the baffle were not completely excluded. All patients experienced immediate improvements in oxygen saturation ranging from 17Eth 26% (mean, 20.3%). The improvements in oxygen saturation were sustained with values ranging from 12Eth 22% (mean, 17.3%) at the time of clinical follow-up. Clinical follow-up has ranged from 13Eth 19 months (mean, 15 months) and has demonstrated improved exercise tolerance and weight gain. Echocardiographic follow-up has shown no complications of TPEG stenoses, occlusions or migrations. There were no immediate or delayed complications associated with the TPEG devices. We report our experience using TPEG devices to exclude intracardiac communications in 3 patients with surgically corrected congenital heart disease. The preliminary results are encouraging and suggest that further investigation in this area should be done.


Low-grade inflammation and the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy.
To investigate the role of inflammation in the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy (HCM). Clinical study. Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland. Twenty-four patients with a single HCM-causing mutation D175N in the α-tropomyosin gene and 17 control subjects. Endomyocardial biopsy samples taken from the patients with HCM were compared with matched myocardial autopsy specimens. Levels of high-sensitivity C-reactive protein (hsCRP) and proinflammatory cytokines were measured in patients and controls. Myocardial late gadolinium enhancement (LGE) in cardiac MRI (CMRI) was detected. Endomyocardial samples in patients with HCM showed variable myocyte hypertrophy and size heterogeneity, myofibre disarray, fibrosis, inflammatory cell infiltration and nuclear factor kappa B (NF-κB) activation. Levels of hsCRP and interleukins (IL-1β, IL-1RA, IL-6, IL-10) were significantly higher in patients with HCM than in control subjects. In patients with HCM, there was a significant association between the degree of myocardial inflammatory cell infiltration, fibrosis in histopathological samples and myocardial LGE in CMRI. Levels of hsCRP were significantly associated with histopathological myocardial fibrosis. hsCRP, tumour necrosis factor α and IL-1RA levels had significant correlations with LGE in CMRI. A variable myocardial and systemic inflammatory response was demonstrated in patients with HCM attributable to an identified sarcometric mutation. Inflammatory response was associated with myocardial fibrosis, suggesting that myocardial fibrosis in HCM is an active process modified by an inflammatory response.


Characterization technique of optical whispering gallery mode resonators in the microwave frequency domain for optoelectronic oscillators.
Optical Q factor measurements are performed on a whispering gallery mode (WGM) disk resonator using a microwave frequency domain approach instead of using an optical domain approach. An absence of hysteretic behavior and a better linearity are obtained when performing linewidth measurements by using a microwave modulation for scanning the resonances instead of the piezoelectric-based frequency tuning capability of the laser. The WGM resonator is then used to stabilize a microwave optoelectronic oscillator. The microwave output of this system generates a 12.48 GHz signal with -94 dBc/Hz phase noise at 10 kHz offset.


Airway exposure to TiO2 nanoparticles and quartz and effects on sperm counts and testosterone levels in male mice.
Several types of engineered nanoparticles (ENP) have been shown to adversely affect male reproduction in rodent studies, but the airway route of exposure has been little investigated. This precludes adequate risk assessment of ENP exposure in occupational settings. Titanium dioxide nanoparticles (TiO2 NP) have been shown to affect total sperm count in adult male mice after intravenous and oral administration. This study aimed to investigate whether also airway exposure would affect sperm counts in male mice. Mature C57BL/6J mice were intratracheally instilled with 63 μg of rutile nanosized TiO2, once weekly for seven weeks. Respirable α-quartz (SRM1878a) was included at a similar dose level as a positive control for pulmonary inflammation. BALF cell composition showed neutrophil granulocyte influx as indication of pulmonary inflammation in animals exposed to TiO2 NP and α-quartz, but none of the particle exposures affected weight of testes or the epididymis, sperm counts or plasma testosterone when assessed at termination of the study.


The Tahoe Study: bias in the interpretation of Papanicolaou test results when human papillomavirus status is known.
Knowledge of human papillomavirus (HPV) status is expected to bias the morphologic evaluation of Papanicolaou (Pap) test results. To characterize Pap test result interpretive bias when the HPV status is known at the microscopic evaluation. Forty HPV-positive liquid-based Pap test results initially interpreted as negative for squamous intraepithelial lesion or malignancy were selected from a quality assurance program, separated into 2 groups of 20 slides each, and circulated in 2 groups to 22 members of the College of American Pathologists Cytopathology Committee. Each member reviewed each case and indicated whether the result was negative for squamous intraepithelial lesion or malignancy or was an epithelial cell abnormality (ECA). The participants assessed the severity of ECAs using the Bethesda System. The participants were not informed of the HPV status in the initial review round. Each group of 20 slides was then distributed to the opposite group (to avoid slide recall), and the participants were informed that all slides were from patients who were high-risk HPV positive. Differences in the responses between groups were analyzed by χ(2) test and Cochran-Mantel-Haenszel test at the .05 significance level. Without knowledge of the HPV status, slides were more often categorized as negative for squamous intraepithelial lesion or malignancy and less likely identified as an ECA (P < .001). There was an increase across all categories of ECAs in the biased responses compared with the unbiased responses (P = .002). Knowledge of positive HPV status biases morphologic Pap test result interpretation. If the HPV status is positive, observers are more likely to report a Pap test result as abnormal across all categories of ECAs.


Differential Roles of Plasma Protein Corona on Immune Cell Association and Cytokine Secretion of Oligomeric and Fibrillar Beta-Amyloid.
Alzheimer's disease (AD) is a primary neurological disease with no effective cure. A hallmark of AD is the presence of intracellular tangles and extracellular plaques derived from the aberrant aggregation of tau- and beta-amyloid (Aβ). Aβ presents in the brain as well as in cerebrospinal fluid and the circulation, and Aβ toxicity has been attributed to amyloidosis and inflammation, among other causes. In this study, the effects of the plasma protein corona have been investigated with regard to the blood cell association and cytokine secretion of oligomeric (Aβo) and fibrillar Aβ1-42(Aβf), two major forms of the peptide aggregates. Aβo displayed little change in membrane association in whole blood or washed blood (i.e., cells in the absence of plasma proteins) at 37 °C, while Aβf showed a clear preference for binding with all cell types sans plasma proteins. Immune cells exposed to Aβo, but not to Aβf, resulted in significant expression of cytokines IL-6 and TNF measured in real-time by a localized surface plasmon resonance sensor. These observations indicate greater immune cell association and cytokine stimulation of Aβo than Aβf and shed new light on the contrasting toxicities of Aβo and Aβf resulting from their differential capacities in acquiring a plasma protein corona. These results further implicate a close connection between Aβ amyloidosis and immunopathology in AD.


[The effect of a long-term administration of fluorine with food on the carcinogenesis and biochemical changes in the liver of rats].
The effect of different amounts of fluorine in the ingested food (1.5 and 5 mg per 1 kg of body weight) on the development of tumours and biochemical changes in the liver of rats with carcinogenesis caused by their feeding on DAB was studied. With a long-term administration of fluorine in a dose of 1.5 mg/kg the appearance of macroscopically visible tumours in the liver proved less notable than with a lower dose or complete absence of fluorine. With carcinogenesis the rate of glycolysis in the liver of rats increases. A relationship between the inhibiting action of sodium fluoride on the glycolysis and changed activity of phosphofructokinase has been ascertained.


Associations of vitamin C, calcium and protein with bone mass in postmenopausal Mexican American women.
We investigated the associations of vitamin C, calcium and protein intakes with bone mass at the femoral neck and lumbar spine in postmenopausal Mexican American women. Bone mass was measured by dual-energy X-ray absorptiometry (DXA) and expressed as areal (BMD, g/cm2) and volumetric (bone mineral apparent density or BMAD, g/cm3) bone mineral density. Diet was assessed using a modified version of the National Cancer Institute Food Questionnaire, which was administered by trained bilingual interviewers familiar with Mexican dietary practices. Data gathered from 125 subjects were analyzed using multiple linear regression analysis with age, body mass index (BMI), acculturation, years of estrogen use, physical activity, total energy intake, and the nutrient of interest as independent variables. Neither calcium nor calcium/protein ratio was associated with bone mineral density. There was evidence of a positive association between dietary vitamin C intake and femoral neck BMD (beta = 0.0002 g/cm2 per mg/day, SE = 0.00006, p < 0.05), but vitamin C was not associated with lumbar spine bone mass. Further investigation of the role of vitamin C in skeletal health is warranted.


Genomically Driven Tumors and Actionability across Histologies: BRAF-Mutant Cancers as a Paradigm.
The diagnosis, classification, and management of cancer are traditionally dictated by the site of tumor origin, for example, breast or lung, and by specific histologic subtypes of site-of-origin cancers (e.g., non-small cell versus small cell lung cancer). However, with the advent of sequencing technologies allowing for rapid, low cost, and accurate sequencing of clinical samples, new observations suggest an expanded or different approach to the diagnosis and treatment of cancer-one driven by the unique molecular features of the tumor. We discuss a genomically driven strategy for cancer treatment using BRAF as an example. Several key points are highlighted: (i) molecular aberrations can be shared across cancers; (ii) approximately 15% of all cancers harbor BRAF mutations; and (iii) BRAF inhibitors, while approved only for melanoma, have reported activity across numerous cancers and related disease types bearing BRAF aberrations. However, BRAF-mutated colorectal cancer has shown poor response rate to BRAF inhibitor monotherapy, striking a cautionary note. Yet, even in this case, emerging data suggest BRAF-mutated colorectal cancers can respond well to BRAF inhibitors, albeit when administered in combination with other agents that impact resistance pathways. Taken together, these data suggest that molecular aberrations may be the basis for a new nosology for cancer. Mol Cancer Ther; 15(4); 533-47. ©2016 AACR.


Combined orthodontic and restorative management of oligodontia.
A 14-year-old patient suffering from congenital absence of almost her entire permanent dentition was referred by her GDP. Management of the case required an integrated orthodontic and restorative approach. The authors describe how the imaginative use of a combination of relatively simple techniques achieved a greatly improved dental appearance for the patient.


Occurrence of gastrointestinal parasites in dogs in a rural area of Santa Catarina, Brazil.
We investigated the occurrence of gastrointestinal parasites in dogs in rural areas of the municipality of Painel, Santa Catarina, Brazil. For this, 91 canine feces samples were collected from 82 farms between August, 2017 and January, 2018. These fecal materials were processed using the techniques of spontaneous sedimentation, centrifugation-floatation in zinc sulfate and Ziehl-Neelsen staining. A questionnaire in the form of an interview was administered to the dogs' owner and information about the farm and the main care provided for the dogs was obtained. Among 91 sampled dogs, 27 (29.7%) were positive for at least one parasite species. Ancylostoma was the most prevalent genus (16.5%), followed by Giardia duodenalis (14.3%), Trichuris vulpis (6.6%), Toxocara canis (5.5%), Entamoeba spp. (4.8%), Cryptosporidium spp. (3.3%) and Taeniidae (1.1%). Most dogs do not receive veterinarian care and rarely received antiparasitic treatment. They were free to roam and had free access to animal remains and garbage, which was reflected in the significant associations with the occurrence of parasites that were found. We conclude that rural dogs harbor gastrointestinal parasites, but that their owners are unaware of the risks that these parasites can bring to human health.


Small molecules unravel complex interplay between auxin biology and endomembrane trafficking.
The establishment and maintenance of controlled auxin gradients within plant tissues are essential for a multitude of developmental processes. Auxin gradient formation is co-ordinated via local biosynthesis and transport. Cell to cell auxin transport is facilitated and precisely regulated by complex endomembrane trafficking mechanisms that target auxin carrier proteins to their final destinations. In turn, auxin and cross-talk with other phytohormones regulate the endomembrane trafficking of auxin carriers. Dissecting such rapid and complicated processes is challenging for classical genetic experiments due to trafficking pathway diversity, gene functional redundancy, and lethality in loss-of-function mutants. Many of these difficulties can be bypassed via the use of small molecules to modify or disrupt the function or localization of proteins. Here, we will review examples of the knowledge acquired by the use of such chemical tools in this field, outlining the advantages afforded by chemical biology approaches.


The case for the radar radius of venus.
The Venus radius of 6085 +/- 10 kilometers, deduced from combining observations made with the Venera 4 and Mariner V space probes is incompatible with the value of 6050 +/- kilometers determined from Earth-based radar mesurements.


[Influence of lithium hydroxybutyrate on the electroencephalographic effects of fenamin].
Lithium hydroxybutyrate (10 mg/kg) prevents the amphetamine-induced EEG arousal and amplitude frequency alterations in the motor and visual cortex, posterior hypothalamus, midbrain reticular formation, and caudate nucleus but potentiates the action of the psychostimulant on the EEG of the hippocamp and amygdala. The response to the light flickering rhythm in the visual cortex remains within initial upon concurrent administration of both the drugs.


In situ temperature measurement in the pressure chamber of diamond anvil cell.
The measurements of temperature directly influence the reasonability of experiments at high pressure and high temperature. In this article, we proposed a new integration design, the built-in thermocouple, for in situ temperature measurements in high-pressure-high-temperature experiments by fusing the characteristics of thermocouples and diamond anvil cells together. By integrating an S-type thermocouple inside the gasket of a diamond anvil cell, we successfully measured the temperature of the sample straight inside the pressure chamber at high pressure and high temperature. The setup underwent multiple experimental tests using internal and external heating techniques, the results of which revealed its capability to directly characterize the temperature of the sample with comparable accuracy and reliability to that of the typical external thermocouple setup. The proposed setup has also resolved the issue of the discrepancy of temperatures inside and outside the sample chamber and enormously expedited the temperature measurements by significantly reducing the response time of the thermocouple. In conclusion, the built-in thermocouple is a promising approach toward high-efficiency, in situ temperature measurements under extreme conditions.


Efficacy of psychostimulant drugs for cocaine dependence.
Cocaine dependence is an increasingly prevalent disorder for which no medication is approved yet. Likewise opioid for heroin dependence, replacement therapy with psychostimulant could be efficacious for cocaine dependence. To ascertain the efficacy of psychostimulants for cocaine dependence on cocaine use, sustained cocaine abstinence and retention in treatment. The influence of type of drug, comorbid disorders and clinical trial reporting quality over psychostimulants efficacy has also been studied. MEDLINE, EMBASE, PsycINFO, CENTRAL, references of obtained articles and experts in the field. Randomized parallel group controlled clinical trials comparing the efficacy of a psychostimulant against placebo have been included. Two authors evaluated and extracted data. The Relative Risk (RR) was used to assess dichotomous outcomes except for adverse event (AE) induced dropouts for which the risk difference (RD) was preferred. The Standardized Mean Difference (SMD) was used to assess continuous outcomes. To determine the influence of moderating variables, a stratified analysis was conducted. Funnel plots were drawn to investigate the possibility of publication bias. Sixteen studies have been included, which have enrolled 1,345 patients. Seven drugs with psychostimulant effect or metabolized to a psychostimulant have been investigated: bupropion, dexamphetamine, methylphenidate, modafinil, mazindol, methamphetamine and selegiline. Psychostimulants did not reduce cocaine use (SMD 0.11, 95%CI: -0.07 to 0.29), showed a statistical trend over improving sustained cocaine abstinence (RR 1.41, 95%CI: 0.98 to 2.02, p=0.07) and did not improve retention in treatment (RR 0.97, 95%CI: 0.89 to 1.05). The proportion of AE induced dropouts was similar for psychostimulants and placebo (RD 0.01, 95%CI: -0.02 to 0.03). When the type of drug was included as a moderating variable, it was shown that the proportion of patients achieving sustained cocaine abstinence was higher with bupropion and dextroamphetamine, and also with modafinil, at a statistical trend of significance, than with placebo. Nevertheless, no studied drug was efficacious on any of the remaining outcomes. Besides, psychostimulants appeared to increase the proportion of patients achieving sustained cocaine and heroin abstinence amongst methadone maintained dual heroin-cocaine addicts. The main findings did not seem to be influenced by clinical trial reporting quality. No evidence of publication bias was found. This review found mixed results, therefore evidence of the efficacy of psychostimulants for cocaine dependence is inconclusive. Nevertheless promising results exist for methadone maintained dual heroin-cocaine addicts and for some specific drugs such as dexamphetamine and bupropion.


Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF-VEGF receptor 2 binding in diabetic retinopathy.
It has been shown that the balance between vascular endothelial growth factor (VEGF), a major angiogenic stimulator, and pigment epithelium-derived factor (PEDF), a potent angiogenic inhibitor, is critical for the regulation of vascular permeability and angiogenesis. However, the regulation of the balance is largely unclear. The present study demonstrated that there is a reciprocal interaction between VEGF and PEDF in the retina. PEDF significantly decreased VEGF expression in both retinal capillary endothelial cells (RCEC) and Müller cells. This PEDF effect was confirmed in the retina of rats with oxygen-induced retinopathy. Silencing of the PEDF gene by siRNA in Müller cells resulted in a significant upregulation of VEGF expression at both the RNA and protein levels, suggesting that PEDF is an endogenous negative regulator of VEGF. The further study of the mechanism showed that PEDF inhibited hypoxia-induced increases in VEGF promoter activity, HIF-1 nuclear translocation and mitogen activated protein kinase phosphorylation. These results suggest that PEDF inhibits VEGF expression at the transcriptional level. In addition, PEDF effectively inhibited VEGF binding to RCEC. Moreover, in vitro receptor-binding assay demonstrated that PEDF competed with VEGF for binding to VEGF receptor 2, which may represent a new mechanism for PEDF activity. On the other hand, VEGF significantly downregulated PEDF expression in RCEC, but not in retinal Müller cells, suggesting a VEGF receptor-mediated process. These results suggest that the reciprocal regulation between VEGF and PEDF may play a role in angiogenic control. The decrease in PEDF levels in the retina is at least partially responsible for the increase in VEGF expression and subsequent vascular leakage and neovascularization in diabetes.


Acetylsalicylic acid protects erectile function in diabetic rats.
We aimed to evaluate the effect of acetylsalicylic acid (ASA) treatment on diabetes-induced erectile dysfunction. Adult male Sprague-Dawley rats were divided into four groups as follows: (i) control (C), (ii) diabetic (D), (iii) ASA-treated control (C+ASA) and (iv) ASA-treated diabetic (D+ASA) groups. In groups 2 and 4, diabetes was induced by injection of 35 mg kg(-1) streptozotocin. ASA (100 mg kg(-1) day(-1) , orally) was administrated to rats in groups 3 and 4 for 8 weeks. Both intracavernosal pressure (ICP) and mean arterial blood pressure (MAP) were measured in in vivo studies. In organ bath, the relaxation responses to acetylcholine (ACh), electrical field stimulation (EFS) and sodium nitroprusside were tested in corpus cavernosum (CC) strips. The mRNA expression for neuronal nitric oxide synthase (nNOS) was calculated using reverse transcription polymerase chain reaction technique. In in vivo experiments, diabetic rats displayed reduced ICP/MAP values, which were normalised with ASA treatment. The relaxant response to high-dose ACh and EFS at low frequencies (1-8 Hz) in CC strips from the D+ASA group were significantly higher when compared to the D group. Treatment with ASA normalised the raised mRNA expressions of nNOS in diabetic penile tissues. ASA may be involved in mRNA of protein synthesis of NO released from nonadrenergic and noncholinergic cavernosal nerve in diabetes.


Detection of peonidin and pelargonidin glycosides in black carrots (Daucus carota ssp. sativus var. atrorubens Alef.) by high-performance liquid chromatography/electrospray ionization mass spectrometry.
Anthocyanins of black carrots (Daucus carota ssp. sativus var. atrorubens Alef.) were investigated by high-performance liquid chromatography/electrospray ionization mass spectrometry. Besides the main compounds which have already been characterized in detail as cyanidin glycosides, six anthocyanins with m/z 757, 565, 595, 903, 933 and 903 were detected and unambiguously characterized as peonidin and pelargonidin glycosides, based on their fragmentation patterns. Peonidin and pelargonidin were identified after acid hydrolysis by comparison of the fragmentation patterns and retention times of the released aglycones with those of standard compounds. To the best of our knowledge this is the first report on anthocyanins in black carrots consisting of aglycones other than cyanidin.


Prevention of Tetanus Outbreak Following Natural Disaster in Indonesia: Lessons Learned from Previous Disasters.
In Indonesia, the Aceh earthquake and tsunami in 2004 killed 127,000 people and caused half a million injuries, while the Yogyakarta earthquake in 2006 caused 5,700 deaths and 37,000 injuries. Because disaster-affected areas are vulnerable to epidemic-prone diseases and tetanus is one such disease that is preventable, we systematically reviewed the literature related to tetanus outbreaks following previous two natural disasters in Indonesia. Based on our findings, recommendations for proper vaccination and education can be made for future countermeasures. Using specified keywords related to tetanus and disasters, relevant documents were screened from PubMed, the WHO website, and books. Reports offering limited data and those released before 2004 were excluded. In all, 16 publications were reviewed systematically. Results show that 106 cases of tetanus occurred in Aceh, with a case fatality ratio (CFR) of 18.9%; 71 cases occurred in Yogyakarta, with CFR of 36.6%. For both outbreaks, most patients had been wounded during scavenging or evacuation after the disaster occurred. Poor access to health care because of limited transportation or hospital facilities, and low vaccination coverage and lack of awareness of tetanus risk contributed to delayed treatment and case severity. Tetanus outbreaks after disasters are preventable by increasing vaccination coverage, improving wound care treatment, and establishing a regular surveillance system, in addition to good practices of disaster management and supportive care following national guidelines. Furthermore, health education for communities should be provided to raise awareness of tetanus risk reduction.


The ability of prostate-specific antigen (PSA) density to predict an upgrade in Gleason score between initial prostate biopsy and prostatectomy diminishes with increasing tumour grade due to reduced PSA secretion per unit tumour volume.
Study Type - Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Due to sampling error, the Gleason score of clinically localized prostate cancer is frequently underestimated at the time of initial biopsy. Given that this may lead to inappropriate surveillance of patients with high-risk disease, there is considerable interest in identifying predictors of significant undergrading. Recently PSAD has been proposed to be an accurate predictor of subsequent upgrading in patients diagnosed with Gleason 6 disease on biopsy. We examined the predictive characteristics of PSAD in patients with low- and intermediate-risk disease on biopsy subsequently treated with radical prostatectomy. We found that although PSAD was a significant predictor of upgrade of biopsy Gleason 6 and 3 + 4 = 7 tumours, it failed to predict upgrading in patients with Gleason 7 tumours taken as a whole. When we explored reasons for this discrepancy, we found that the amount of PSA produced per unit tumour volume decreased with increasing Gleason score, thereby diminishing the predictive value of PSAD. To analyse the performance of PSA density (PSAD) as a predictor of Gleason score upgrade in a large cohort stratified by Gleason score. We and others have shown that an upgrade in Gleason score between initial prostate biopsy and final radical prostatectomy (RP) pathology is a significant risk factor for recurrence after local therapy. Patients undergoing RP with matching biopsy information were identified from two prospective databases. Patients were analysed according to the concordance between biopsy and final pathology Gleason score in three paired groups: 6/>6, 3 + 4/>3 + 4, 7/>7. Receiver-operating characteristic (ROC) curves were generated stratified by Gleason score, and the area under the curve (AUC) calculated. Logistic regression models were fitted to identify significant predictors of tumour upgrade. From 1516 patients, 435 (29%) had an upgrade in Gleason score. ROC analysis showed a decline in AUC with increasing biopsy Gleason score, from 0.64 for biopsy Gleason score 6, to 0.57 for Gleason score 7. In logistic regression models containing pretreatment variables, e.g. clinical stage and number of positive cores, for Gleason score 6 and 3 + 4, PSAD was the strongest predictor of subsequent tumour upgrade (odds ratio [OR] 1.46, 95% confidence interval [95% CI] 1.18-1.83, P= 0.001 and OR 1.37, 95% CI 1.14-1.67, P= 0.002, respectively). Surprisingly, in tumours upgraded from Gleason score 7 to >7, PSAD was not predictive even on univariable analysis, whereas clinical stage and number of positive cores were significant independent predictors. To explore the relationship between serum PSA and Gleason score, tumour volume was calculated in 669 patients. There was a strong association between Gleason score and tumour volume, with the median volume of Gleason score 7 and Gleason score >7 tumours being approximately twice and four-times that of Gleason score 6 tumours, respectively (P < 0.001). In contrast, the median serum PSA level per millilitre tumour volume decreased significantly with increasing grade, from 5.4 ng/mL for Gleason score 6 to 2.1 ng/mL for >7 (P < 0.001). There is a strong correlation between Gleason score and tumour volume in well/intermediate differentiated tumours, and as they produce relatively high amounts of PSA per unit volume of cancer, high PSAD is the strongest single predictor of tumour undergrading. However, as higher grade tumours produce less PSA per unit volume, PSAD loses its predictive ability, and other clinical markers of tumour volume such as palpable disease and numbers of positive cores become more predictive.


Study design and rationale for ELPIS: A phase I/IIb randomized pilot study of allogeneic human mesenchymal stem cell injection in patients with hypoplastic left heart syndrome.
Despite advances in surgical technique and postoperative care, long-term survival of children born with hypoplastic left heart syndrome (HLHS) remains limited, with cardiac transplantation as the only alternative for patients with failing single ventricle circulations. Maintenance of systemic right ventricular function is crucial for long-term survival, and interventions that improve ventricular function and avoid or defer transplantation in patients with HLHS are urgently needed. We hypothesize that the young myocardium of the HLHS patient is responsive to the biological cues delivered by bone marrow-derived mesenchymal stem cells (MSCs) to improve and preserve right ventricle function. The ELPIS trial (Allogeneic Human MEsenchymal Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome: An Open Label Pilot Study) is a phase I/IIb trial designed to test whether MSC injection will be both safe and feasible by monitoring the first 10 HLHS patients for new major adverse cardiac events. If our toxicity stopping rule is not activated, we will proceed to the phase IIb component of our study where we will test our efficacy hypothesis that MSC injection improves cardiac function compared with surgery alone. Twenty patients will be enrolled in a randomized phase II trial with a uniform allocation to MSC injection versus standard surgical care (no injection). The 2 trial arms will be compared with respect to improvement of right ventricular function, tricuspid valve annulus size, and regurgitation determined by cardiac magnetic resonance and reduced mortality, morbidity, and need for transplantation. This study will establish the safety and feasibility of allogeneic mesenchymal stem cell injection in HLHS patients and provide important insights in the emerging field of stem cell-based therapy for congenital heart disease patients.


Enrichment of Lignin-Derived Carbon in Mineral-Associated Soil Organic Matter.
A modern paradigm of soil organic matter proposes that persistent carbon (C) derives primarily from microbial residues interacting with minerals, challenging older ideas that lignin moieties contribute to soil C because of inherent recalcitrance. We proposed that aspects of these old and new paradigms can be partially reconciled by considering interactions between lignin decomposition products and redox-sensitive iron (Fe) minerals. An Fe-rich tropical soil (with C4 litter and either 13C-labeled or unlabeled lignin) was pretreated with different durations of anaerobiosis (0-12 days) and incubated aerobically for 317 days. Only 5.7 ± 0.2% of lignin 13C was mineralized to CO2 versus 51.2 ± 0.4% of litter C. More added lignin-derived C (48.2 ± 0.9%) than bulk litter-derived C (30.6 ± 0.7%) was retained in mineral-associated organic matter (MAOM; density >1.8 g cm-3), and 12.2 ± 0.3% of lignin-derived C vs 6.4 ± 0.1% of litter C accrued in clay-sized (<2 μm) MAOM. Longer anaerobic pretreatments increased added lignin-derived C associated with Fe, according to extractions and nanoscale secondary ion mass spectrometry (NanoSIMS). Microbial residues are important, but lignin-derived C may also contribute disproportionately to MAOM relative to bulk litter-derived C, especially following redox-sensitive biogeochemical interactions.


Placental transfer of naloxone.
Maternal and umbilical venous serum naloxone concentrations were measured after the i.v. (30 mothers) or i.m. (seven mothers) injection of naloxone 400 micrograms. Following i.v. naloxone there was rapid transfer to the fetus and therapeutic plasma concentrations could be expected in 1 or 2 min. However, following i.m. administration, neonatal concentrations were variable. In five non-pregnant volunteers naloxone 400 micrograms i.v. resulted in concentrations greater than 2.5 micrograms ml-1 for up to 30 min. After naloxone 2 mg i.m., a peak was reached at 10 min, followed by slow clearance over several hours.


Evaluation of a DLA-79 allele associated with multiple immune-mediated diseases in dogs.
Immune-mediated diseases are common and life-threatening disorders in dogs. Many canine immune-mediated diseases have strong breed predispositions and are believed to be inherited. However, the genetic mutations that cause these diseases are mostly unknown. As many immune-mediated diseases in humans share polymorphisms among a common set of genes, we conducted a candidate gene study of 15 of these genes across four immune-mediated diseases (immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, immune-mediated polyarthritis (IMPA), and atopic dermatitis) in 195 affected and 206 unaffected dogs to assess whether causative or predictive polymorphisms might exist in similar genes in dogs. We demonstrate a strong association (Fisher's exact p = 0.0004 for allelic association, p = 0.0035 for genotypic association) between two polymorphic positions (10 bp apart) in exon 2 of one allele in DLA-79, DLA-79*001:02, and multiple immune-mediated diseases. The frequency of this allele was significantly higher in dogs with immune-mediated disease than in control dogs (0.21 vs. 0.12) and ranged from 0.28 in dogs with IMPA to 0.15 in dogs with atopic dermatitis. This allele has two non-synonymous substitutions (compared with the reference allele, DLA-79*001:01), resulting in F33L and N37D amino acid changes. These mutations occur in the peptide-binding pocket of the protein, and based upon our computational modeling studies, are likely to affect critical interactions with the peptide N-terminus. Further studies are warranted to confirm these findings more broadly and to determine the specific mechanism by which the identified variants alter canine immune system function.


Health-Promoting Leadership: Concept, Measurement, and Research Framework.
Employee health is not only positively related to the employee well-being and family happiness, but also impacts organizations, and society as a whole. We searched the health-promoting leadership literature in the following databases: Web of Science, ProQuest, EBSCO, and a Chinese local database. Based on this research, we clarify the concept of health-promoting leadership, propose a definition of health-promoting leadership, and examine measurement scales for this type of leadership. We also suggest a research framework for health-promoting leadership, demonstrating its potential outcomes at both the individual level (e.g., health, well-being, job attitudes) and the organizational level (e.g., health management culture and practices); the mechanisms for its development based on conservation of resources theory, the job demands-resources model, social learning theory, and social exchange theory; and antecedents (e.g., health values, health awareness, organizational health culture, organizational health climate, and organizational health promotion behavior control). Finally, we identify six potential research areas: Research level, performance, the impacts of health-promoting leaders on themselves, moderators, research methods, and intervention effects on health-promoting leadership.


Underuse of indicated medications among physically frail older US veterans at the time of hospital discharge: results of a cross-sectional analysis of data from the Geriatric Evaluation and Management Drug Study.
Medication underutilization, or the omission of a potentially beneficial medication indicated for disease management, is common among older adults but poorly understood. The aims of this work were to assess the prevalence of medication underuse and to determine whether polypharmacy or comorbidity was associated with medication underuse among physically frail older veterans transitioning from the hospital to the community. This was a cross-sectional analysis of patients who were discharged from 11 US veterans' hospitals to outpatient care, based on data from the Geriatric Evaluation and Management Drug Study, a substudy of the Veterans Affairs Cooperative Study of geriatric evaluation and management. Patients were enrolled between August 31, 1995, and January 31, 1999. To qualify for the study, patients had to be aged > or =65 years, hospitalized in a medical or surgical ward for >48 hours, and meet > or =2 of the following criteria: moderate functional disability; recent cerebrovascular accident with residual neurological deficit; history of > or =1 fall in the previous 3 months; documented difficulty with walking (ie, requiring personal assistance or equipment), not including preadmission use of a wheelchair with ability to transfer to and from chair independently; malnutrition (admission serum albumin of 3.5 g/dL, <80% of ideal body weight, or recent > or =15-lb weight loss reported in admission history); dementia; depression; documented diagnosis of new fracture or revision needed of older fracture; unplanned admission within 3 months of previous admission; and prolonged bed rest. Clinical pharmacist/physician pairs reviewed medical records and medication lists and independently applied the Assessment of Underutilization (AOU) index to determine omissions of indicated medications. Discordances in index ratings were resolved during clinical consensus conferences. The primary outcome measure was the percentage of patients with > or =1 medication omission detected by the AOU. Multivariable logistic regression analyses identified factors associated with underuse. A total of 384 patients were included in the study. The majority (53.6%) were between the ages of 65 and 74 years, and the mean (SD) Charlson comorbidity index was 2.44 (1.93). Overall, 374 patients (97.4%) were men and 274 (71.4%) were white. Medication undertreatment occurred in 238 participants (62.0%). Diseases of the Accepted for publication October 26, 2009. circulatory, endocrine/nutritional, musculoskeletal, and respiratory systems were the most commonly undertreated conditions. The indicated medications most likely to be omitted were nitrates for those with a history of myocardial infarction, multivitamins in those with malnutrition, and inhaled anticholinergics for chronic obstructive airways disease. Statistically significant factors associated with medication underuse included limitations in activities of daily living (adjusted odds ratio [AOR], 2.17 [95% CI, 1.27-3.71]; P = 0.01), being white (AOR, 1.70 [95% CI, 1.06-2.71]; P = 0.03), and Charlson comorbidity index (AOR, 1.13 for each 1-point increase [95% CI, 1.00-1.27]; P = 0.04). Discharge from a general medicine service as opposed to a surgical service was associated with lower risk of medication underuse (AOR, 0.61 [95% CI, 0.38-0.98]; P = 0.04). Medication underuse was relatively common in this study. Patients with greater comorbidity, but not polypharmacy, had increased odds of undertreatment.


Exponential or polynomial learning Curves? - case-based studies
Learning curves exhibit a diversity of behaviors such as phase transition. However, the understanding of learning curves is still extremely limited, and existing theories can give the impression that without empirical studies (e.g., cross validation), one can probably do nothing more than qualitative interpretations. In this note, we propose a theory of learning curves based on the idea of reducing learning problems to hypothesis-testing ones. This theory provides a simple approach that is potentially useful for predicting and interpreting (a diversity of) learning curve behaviors qualitatively and quantitatively, and it applies to finite training sample size and finite learning machine and for learning situations not necessarily within the Bayesian framework. We illustrate the results by examining some exponential learning curve behaviors observed in Cohn and Tesauro (1992)'s experiment.