Quantitative Proteomic Profiling Reveals That Diverse Metabolic Pathways Are Influenced by Melatonin in an in Vivo Model of Ovarian Carcinoma.
To obtain more information into the molecular mechanisms underlying ovarian cancer (OC), we proposed a comparative proteomic analysis in animals receiving long-term melatonin as therapy or only vehicle using multidimensional protein identification combined with mass spectrometry. To induce tumor, a single dose of 100 μg 7,12-dimethylbenz(a)anthracene (DMBA) dissolved in 10 μL of sesame oil was injected under the left ovarian bursa of 20 Fischer 344 rats. The right ovaries were injected with sesame oil only. After tumors were developed, half of the animals received intraperitoneal administration of melatonin (200 μg/100g body weight/day) for 60 days. Melatonin therapy promoted down-regulation in numerous proteins involved in OC signaling pathways. The most significant portion of these proteins are involved in several metabolic processes, mainly those associated with mitochondrial systems, generation of metabolites and energy, hypoxia-inducible factor-1 signaling, antigen processing and presentation, endoplasmic reticulum stress-associated pathways, and cancer-related proteoglycans. A small number of proteins that were overexpressed by melatonin therapy included ATP synthase subunit β, fatty acid-binding protein, and 10-kDa heat shock protein. Taken together, our findings suggest that melatonin therapy efficiently modulated important signaling pathways involved in OC, and these proteins might be further targets that should be explored in new therapeutic opportunities for OC.


Differential targeting of androgen and glucocorticoid receptors induces ER stress and apoptosis in prostate cancer cells: a novel therapeutic modality.
Androgen (AR) and glucocorticoid (GR) receptor signaling play opposing roles in prostate tumorigenesis: in prostate, AR acts as an oncogene, and GR is a tumor suppressor. Recently, we found that non-steroidal phyto-chemical Compound A (CpdA) is AR/GR modulator acting as anti-inflammatory anti-androgen. CpdA inhibits AR and prevents GR transactivation while enhancing GR transrepression. GR and AR are controlled by proteasomal degradation. We found that prolonged exposure of LNCaP, LNCaP-GR, DU145 and PC3 prostate carcinoma (PCa) cells to proteasome inhibitor Bortezomib (BZ) caused AR degradation and GR accumulation. BZ enhanced CpdA ability to inhibit AR and to augment GR transrepression. We also found that CpdA+BZ differentially regulated GR/AR to cooperatively suppress PCa cell growth and survival and to induce endoplasmic reticulum stress (ERS). Importantly, CpdA+BZ differentially regulated GR-responsive genes. CpdA+BZ blocked activation of glucocorticoid-responsive pro-survival genes, including SGK1, but activated BZ-induced ERS-related genes BIP/HSPA5 and CHOP /GADD153. Using ChIP, we showed that SGK1, BIP/HSPA5 and CHOP regulation was due to effects of CpdA and CpdA+BZ on GR loading on their promoters. We also found that AR and GR are abundant in advanced PCa from patients treated by androgen ablation and/or chemotherapy: 56% of carcinomas from treated patients expressed both receptors, and the other 27% expressed either GR or AR. Overall, our data validate the concept of dual AR/GR targeting in prostate cancer (PC) and suggest that BZ combination with dual-target steroid receptor modulator CpdA has high potential for PC therapy.


Frequency response of pig intervertebral disc cells subjected to dynamic hydrostatic pressure.
The pathogenesis of vibration-induced disorders of intervertebral disc at the cellular level is largely unknown. Dynamic loads with frequencies close to that of the in vivo human spine resonant frequency (4-6 Hz) have a destructive effect, which may induce extracellular disc matrix (ECM) degradation. To investigate this issue, three-dimensional (3D) alginate cultures of normal pig intervertebral disc nucleus and inner annulus cells were tested under dynamic hydrostatic loading. Alginate cultures of each region were divided into six groups; five groups were exposed to cyclic hydrostatic pressures of frequencies 1, 3, 5, 8, and 10 Hz with the same amplitude (1 MPa), and group 6 was the control group (no loading). Cultures of different groups were loaded for 3 days (30 min daily) in a hydraulic chamber. Effects of loading frequency on disc collagen and protein metabolism were investigated by measuring 3H-proline-labeled proteins associated with the cells in the extracellular matrix and release of 3H-proline-labeled molecules into culture medium. The results indicated a poor synthesis rate and more degradation near the 5 Hz frequency. The repeatability of experiments was verified by performing two experiments with the same protocol. Both experiments indicated that a threshold frequency of around 5 Hz disrupted protein metabolism.


All-solid-state spatial light modulator with independent phase and amplitude control for three-dimensional LiDAR applications.
Spatial light modulators are essential optical elements in applications that require the ability to regulate the amplitude, phase and polarization of light, such as digital holography, optical communications and biomedical imaging. With the push towards miniaturization of optical components, static metasurfaces are used as competent alternatives. These evolved to active metasurfaces in which light-wavefront manipulation can be done in a time-dependent fashion. The active metasurfaces reported so far, however, still show incomplete phase modulation (below 360°). Here we present an all-solid-state, electrically tunable and reflective metasurface array that can generate a specific phase or a continuous sweep between 0 and 360° at an estimated rate of 5.4 MHz while independently adjusting the amplitude. The metasurface features 550 individually addressable nanoresonators in a 250 × 250 μm2 area with no micromechanical elements or liquid crystals. A key feature of our design is the presence of two independent control parameters (top and bottom gate voltages) in each nanoresonator, which are used to adjust the real and imaginary parts of the reflection coefficient independently. To demonstrate this array's use in light detection and ranging, we performed a three-dimensional depth scan of an emulated street scene that consisted of a model car and a human figure up to a distance of 4.7 m.


Expression and signaling specificity of the IFNAR chain of the type I interferon receptor complex.
The IFNAR chain of the type I interferon (IFN) receptor (IFNIR) undergoes rapid ligand-dependent tyrosine phosphorylation and acts as a species-specific transducer for type I IFN action. Using the vaccinia/T7 expression system to amplify IFNAR expression, we found that human HeLa-S3 cells transiently express high levels of cell surface IFNAR chains (approximately 250,000 chains per cell). Metabolic labeling and immunoblot analysis of transfected HeLa cells show that the IFNAR chain is initially detected as 65-kDa and 98-kDa precursors, and then as the 130-kDa mature protein. Due to variation in N-glycosylation, the apparent molecular mass of the mature IFNAR chain varies from 105 to 135 kDa in different cells. IFNIR structure was characterized in various human cell lines by analyzing 125I-labeled IFN cross-linked complexes recognized by various antibodies against IFNIR subunits and JAK protein-tyrosine kinases. Precipitation of cross-linked material from Daudi cells with anti-IFNAR antibodies showed that IFNAR was present in a 240-kDa complex. Precipitation of cross-linked material from U937 cells with anti-TYK2 sera revealed a 240-kDa complex, which apparently did not contain IFNAR and was not present in IFN-resistant HEC1B cells. The tyrosine phosphorylation and down-regulation of the IFNAR chain were induced by type I IFN in several human cell lines of diverse origins but not in HEC1B cells. However, of type I IFNs, IFN-beta uniquely induced the tyrosine phosphorylation of a 105-kDa protein associated with the IFNAR chain in two lymphoblastoid cell lines (Daudi and U266), demonstrating the specificity of transmembrane signaling for IFN-beta and IFN-alpha through the IFNAR chain.


Fas enhances fibrogenesis in the bile duct ligated mouse: a link between apoptosis and fibrosis.
Hepatocyte apoptosis and fibrosis are both features of liver injury. However, the potential mechanistic link between these 2 processes remains obscure. Our aim was to ascertain if Fas-mediated hepatocyte apoptosis promotes liver fibrogenesis during extrahepatic cholestasis. Wild-type and Fas-deficient lymphoproliferation (lpr) mice underwent bile duct ligation. Liver injury was assessed by quantitating hepatocyte apoptosis with the terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay and determining serum ALT values. mRNA expression was quantitated using real-time polymerase chain reaction technology. Liver fibrosis was assessed by digital image analysis of Sirius red-stained sections. In 3-day bile duct ligated (BDL) animals, TUNEL-positive hepatocytes and serum ALT values were reduced in lpr versus wild-type animals. Likewise, hepatic mRNA transcripts for alpha-smooth muscle actin and platelet-derived growth factor receptor-beta (initiation phase of stellate cell activation) and transforming growth factor beta1 mRNA, collagen 1alpha, and tissue inhibitor of matrix metalloproteinases (perpetuation phase of stellate cell activation) were also reduced in 3-day BDL wild-type mice compared with lpr mice. Finally, in 3-week BDL mice, immunoreactivity for alpha-smooth muscle actin and Sirius red staining for collagen were significantly less in lpr compared with wild-type animals. Fas-mediated hepatocyte injury is mechanistically linked to liver fibrogenesis. These observations suggest that inhibition of Fas-mediated apoptosis may be a therapeutic antifibrogenic strategy in cholestatic liver diseases.


[Role of IL-12P40 and IL-10 in progression of colorectal cancer].
The aim of study was to investigate the association between serum levels of IL-12p40 and IL-10 and progression of the colorectal cancer (CRC). Be observed an association between severity of CRC and serum levels of investigated cytokines. IL-12p40 was in the highest level in stage-I (423.6 +/- 224.7 pg/ml) compared to more severe stages. In the opposite direction were the data for immunosuppressive cytokine, IL-10. Patients with stage-IV had the highest level of IL-10 (36.02 +/- 9.5 pg/ml). On the basis of our results we could conclude that IL-12p40 and IL-10 serum levels were associated with tumour progression. More severe stages of CRC are characterized by low IL-12p40 and high IL-10 serum levels.


Feedback circuitry via let-7c between lncRNA CCAT1 and c-Myc is involved in cigarette smoke extract-induced malignant transformation of HBE cells.
Cigarette smoking is a primary risk factor for the development of lung cancer, which is regarded as the leading cause of cancer-related deaths. The process of malignant transformation of cells, however, is complex and elusive. The present study investigated the roles of an lncRNA, CCAT1, and a transcriptional factor, c-Myc, in human bronchial epithelial (HBE) cell transformation induced by cigarette smoke extract. With acute and chronic treatment of HBE cells, cigarette smoke extract induced increases of CCAT1 and c-Myc levels and decreases of levels of let-7c, a microRNA. Down-regulation of c-Myc reduced the degree of malignancy and the invasion/migration capacity of HBE cells transformed by cigarette smoke extract. ChIP assays established that c-Myc, increased by cigarette smoke extract, binds to the promoter of CCAT1, activating its transcription. Further, let-7c suppressed the expression of c-Myc through binding to its 3'-UTR. In turn, CCAT1 promoted the accumulation of c-Myc through binding to let-7c and decreasing free let-7c, which influenced the neoplastic capacity of HBE cells transformed by cigarette smoke extract. These results indicate that a positive feedback loop ensures expression of cigarette smoke extract-induced CCAT1 and c-Myc via let-7c, which is involved in cigarette smoke extract-induced malignant transformation of HBE cells. Thus, the present research establishes a new mechanism for the reciprocal regulation between CCAT1 and c-Myc and provides an understanding of cigarette smoke extract-induced lung carcinogenesis.


IgA-deficient humans exhibit gut microbiota dysbiosis despite secretion of compensatory IgM.
Immunoglobulin A is the dominant antibody isotype found in mucosal secretions and enforces host-microbiota symbiosis in mice, yet selective IgA-deficiency (sIgAd) in humans is often described as asymptomatic. Here, we determined the effects of IgA deficiency on human gut microbiota composition and evaluated the possibility that mucosal secretion of IgM can compensate for a lack of secretory IgA. We used 16S rRNA gene sequencing and bacterial cell sorting to evaluate gut microbiota composition and taxa-specific antibody coating of the gut microbiota in 15 sIgAd subjects and matched controls. Despite the secretion of compensatory IgM into the gut lumen, sIgAd subjects displayed an altered gut microbiota composition as compared to healthy controls. These alterations were characterized by a trend towards decreased overall microbial diversity as well as significant shifts in the relative abundances of specific microbial taxa. While secretory IgA in healthy controls targeted a defined subset of the microbiota via high-level coating, compensatory IgM in sIgAd subjects showed less specificity than IgA and bound a broader subset of the microbiota. We conclude that IgA plays a critical and non-redundant role in controlling gut microbiota composition in humans and that secretory IgA has evolved to maintain a diverse and stable gut microbial community.


Spontaneous Multiloculated Lumbar Abscess in a Middle-Aged Male With Unexplained Progressive Back Pain and Muscle Weakness.
A 54-year-old man with a past medical history significant for sciatica, as well as multiple orthopedic surgeries with hardware, was transferred from an outside rural facility for further workup of a two-month history of progressive back pain and muscle weakness. Investigations ultimately revealed abnormal enhancement from T11 to sacrum, with a large epidural abscess from L5 to the sacrum, best visualized on an MRI. Following the MRI confirmation of loculated complex thoracolumbar abscess, neurosurgery performed a left L3-S1 unilateral laminotomy and evacuation of compressive multiloculated epidural abscesses. The patient was then treated with empirical antimicrobial coverage for epidural abscess with vancomycin and ceftriaxone, which was narrowed to cefazolin based on positive methicillin-susceptible Staphylococcus aureus (MSSA) wound cultures obtained in the operating room. The patient completed a total six-week course of antibiotic therapy. Apart from some superficial wound dehiscence postoperative, the patient ultimately recovered well and had a resolution of most presenting symptoms.


Pharmacokinetic Interaction of Rifampicin with Oral Versus Intravenous Anticancer Drugs: Challenges, Dilemmas and Paradoxical Effects Due to Multiple Mechanisms.
Since many drugs are cytochrome P450 (CYP)-3A4 substrates, it has become common practice to assess drug-drug interaction (DDI) potential with a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) in early drug development. Such an evaluation is relevant to anticancer drugs with metabolism governed by CYP3A4. DDIs with rifampicin are complex, involving other physiological mechanisms that may impact overall pharmacokinetics. Our objective was to study and delineate such mechanisms for oral versus intravenous anticancer drugs. We hypothesized that DDIs between anticancer drugs and rifampicin were primarily driven by CYP3A4 induction. This hypothesis was proven for the oral anticancer drugs; however, in some cases, other intrinsic mechanisms such as P-glycoprotein (Pgp)/UDP glucuronosyl transferase (UGT) induction and transporter inhibition may have played an important role alongside the induced CYP3A4 enzymes. The hypothesis that CYP3A4 induction would decrease drug exposure appeared paradoxical for intravenous romidepsin and-to a somewhat lesser extent-for cabazitaxel. In light of this dilemma in the interpretation of the pharmacokinetic data with rifampicin, several questions require further consideration. Given the complexity and paradoxical effects arising with DDIs with rifampicin, the continued preference for rifampicin as CYP3A4 inducer needs immediate re-appraisal.


Systematic review and narrative synthesis of computerized audit and feedback systems in healthcare.
(1) Systematically review the literature on computerized audit and feedback (e-A&F) systems in healthcare. (2) Compare features of current systems against e-A&F best practices. (3) Generate hypotheses on how e-A&F systems may impact patient care and outcomes. We searched MEDLINE (Ovid), EMBASE (Ovid), and CINAHL (Ebsco) databases to December 31, 2020. Two reviewers independently performed selection, extraction, and quality appraisal (Mixed Methods Appraisal Tool). System features were compared with 18 best practices derived from Clinical Performance Feedback Intervention Theory. We then used realist concepts to generate hypotheses on mechanisms of e-A&F impact. Results are reported in accordance with the PRISMA statement. Our search yielded 4301 unique articles. We included 88 studies evaluating 65 e-A&F systems, spanning a diverse range of clinical areas, including medical, surgical, general practice, etc. Systems adopted a median of 8 best practices (interquartile range 6-10), with 32 systems providing near real-time feedback data and 20 systems incorporating action planning. High-confidence hypotheses suggested that favorable e-A&F systems prompted specific actions, particularly enabled by timely and role-specific feedback (including patient lists and individual performance data) and embedded action plans, in order to improve system usage, care quality, and patient outcomes. e-A&F systems continue to be developed for many clinical applications. Yet, several systems still lack basic features recommended by best practice, such as timely feedback and action planning. Systems should focus on actionability, by providing real-time data for feedback that is specific to user roles, with embedded action plans. PROSPERO CRD42016048695.


Relationship between major depression and heart rate variability. Clinical consequences and implications for antidepressive treatment.
A high sympathetic and/or a low cardiovagal activity in patients with major depression (MD) may contribute to the higher cardiac morbidity and mortality of MD patients. Standardized tests of heart rate variability (HRV) allow a quantitative estimation of autonomic nervous system function. However, previous studies on the relationship between HRV and MD have revealed conflicting results. Our study compared time and frequency domain HRV indices (5-min resting study, deep breathing test, Valsalva test) between 32 patients with MD (DSM-III-R) and 64 non-depressed controls. The severity of depressive symptoms was assessed by the Hamilton Depression Scale (HAM-D); patients were divided into subgroups with moderate (M-HAM-D<25) or severe depressive symptoms (S-HAM-D>or=25). After controlling for age, gender and smoking, S-HAM-D patients showed a higher heart rate and a significantly lower modulation of cardiovagal activity compared to controls. Although some of the HRV indices of the M-HAM-D group did not differ significantly from controls, they were in the expected direction. There was a significantly negative correlation between the HAM-D scores and the vagal HRV indices, suggesting a direct association between the severity of depressive symptoms and the modulation of cardiovagal activity. Clinical consequences arising from these findings and possible implications for treatment are discussed.


Stability of [123I]IBZM SPECT measurement of amphetamine-induced striatal dopamine release in humans.
Binding competition between endogenous dopamine (DA) and the D2 receptor radiotracer [123I]IBZM allows measurement of the change in synaptic DA following amphetamine challenge with SPECT in the living human brain. Previous investigations using this technique in healthy subjects have shown that the magnitude of amphetamine effect on [123I]IBZM binding potential (BP) is small (range between 5 to 15% decrease), and that a large between-subject variability in this effect is observed. Therefore, it was unclear how much of the apparent between-subject variability was due to a low signal-to-noise ratio in the measurement, vs. true between-subject differences in the magnitude of the response. The goals of this investigation were to test the within-subject reproducibility and reliability of amphetamine-induced decrease in [123I]IBZM BP with a test/retest paradigm, and to establish the presence or absence of tolerance or sensitization to single administration ofi.v. amphetamine. Six healthy male subjects, never previously exposed to psychostimulants, twice underwent measurement of striatal amphetamine-induced DA release (between-measurement interval 16 +/- 10 days) using SPECT and the [123I]IBZM constant infusion technique. Results demonstrated an excellent within-subject reproducibility of amphetamine-induced DA release: amphetamine-induced decreases in [123I]IBZM BP were significant on each day, and had an intraclass correlation coefficient (ICC) of 0.89. Moreover, values from the second experiment were not significantly different from first experiment, suggesting the absence of either sensitization or tolerance to the effect of amphetamine on DA release in these experimental conditions. The subjective activation, as rated by the subjects on analog scales, was also highly reproducible. In conclusion, this scanning technique provides a reliable measurement of amphetamine-induced reduction of [123I]IBZM BP and enables detection of between-subject differences that appear stable over time.


A multiple drug interaction study of stavudine with agents for opportunistic infections in human immunodeficiency virus-infected patients.
The effects of multiple opportunistic infection medications on stavudine pharmacokinetics were evaluated. Ten patients with CD4 counts of less than 200 cells/mm3 received stavudine (40 mg twice daily) in combination with one to three other drugs used to treat opportunistic infections. Serial blood samples for stavudine concentrations were collected after 1 week of therapy on each regimen and assayed for stavudine by using a validated high-pressure liquid chromatography method. Although the maximum concentration of drug in serum was significantly decreased when the drug was given in combination with three opportunistic infection medications, the area under the concentration-time curve did not significantly differ across various treatment regimens. Stavudine exposure was not significantly altered by multiple concomitant medications. Side effects were minor throughout the 3-month study period. The tolerability of stavudine, combined with its lack of drug interactions, makes it an attractive agent for use as part of a combination regimen.


Role of the Trichoderma harzianum endochitinase gene, ech42, in mycoparasitism.
The role of the Trichoderma harzianum endochitinase (Ech42) in mycoparasitism was studied by genetically manipulating the gene that encodes Ech42, ech42. We constructed several transgenic T. harzianum strains carrying multiple copies of ech42 and the corresponding gene disruptants. The level of extracellular endochitinase activity when T. harzianum was grown under inducing conditions increased up to 42-fold in multicopy strains as compared with the wild type, whereas gene disruptants exhibited practically no activity. The densities of chitin labeling of Rhizoctonia solani cell walls, after interactions with gene disruptants were not statistically significantly different than the density of chitin labeling after interactions with the wild type. Finally, no major differences in the efficacies of the strains generated as biocontrol agents against R. solani or Sclerotium rolfsii were observed in greenhouse experiments.


Identification of catalase negative/weak Campylobacter jejuni from human blood and faecal cultures by numerical analysis of electrophoretic protein patterns.
Twenty-eight isolates of catalase-negative/weak (CNW) thermophilic campylobacters from human blood and faecal cultures were characterized by one-dimensional (1-D) high-resolution SDS-PAGE of cellular proteins. A further 11 Campylobacter strains were included for reference purposes. Partial protein patterns were used as the basis for numerical analysis, which showed that all of the hippurate-positive strains had a high similarity to C. jejuni. Two subclusters were formed within C. jejuni corresponding to C. jejuni subsp. doylei (15 strains) and C. jejuni subsp. jejuni (4 strains). Most of the paediatric strains from South Africa were members of C. jejuni subsp. doylei. Hippurate-negative CNW thermophilic strains were identified as "C. upsaliensis". The analysis demonstrated that the catalase-negative C. jejuni strains were quite distinct from "C. upsaliensis" and that electrophoretic protein patterns provide an excellent criterion for the identification of subspecies within C. jejuni.


Healthcare professionals' perceptions of dignity-preserving care for older home-dwelling women with incurable cancer in Norway.
Municipal end-of-life care for older home-dwelling patients with cancer is a complex matter requiring healthcare professionals (HCPs) to recognize gender differences in a social, historical and organizational context. A qualitative approach was chosen to explore and identify HCPs value-based principles and organizational conditions promoting dignity-preserving care practice for these women. HCPs recognized the importance of sheltering the women's identity, their sense of being home and acknowledged their personal preferences as value-based principles, whereas creating a flexible culture of care, establishing a functional professional collaboration and developing individualized plans of care, were crucial organizational conditions influencing the practice of dignity-preserving care.


Substitution effects of rice for corn grain in total mixed ration on rumen fermentation characteristics and microbial community in vitro.
This study determined the substitution effects of rice for corn as the main grain source in a total mixed ration (TMR). In vitro rumen fermentation characteristics and microbes were assessed using two experimental diets. Diets included 33% dry matter (DM) of either corn (Corn TMR) or rice grains (Rice TMR). In a 48-h in vitro incubation, DM digestibility (IVDMD), neutral detergent fiber degradability (IVNDFD), crude protein digestibility (IVCPD), volatile fatty acids (VFAs), pH and ammonia nitrogen (NH3-N) were estimated. Gas production has been calculated at 3, 6, 12, 24 and 48 h. Our results indicate that the gas production, VFAs, IVDMD, and IVNDFD of Rice TMR were higher than those of Corn TMR (p < 0.05). Ruminal pH and total fungi were significantly higher in Corn TMR (p < 0.05) than in Rice TMR; however, NH3-N and IVCPD were not affected by treatment type. In conclusion, substituting rice for corn at 33% DM in TMR appears to have no negative effects on in vitro rumen fermentation characteristics. Therefore, rice grains are an appropriate alternative energy source in early fattening stage diets of beef cattle.


Endocardial/endothelial angiocrines regulate cardiomyocyte development and maturation and induce features of ventricular non-compaction.
Non-compaction cardiomyopathy is a devastating genetic disease caused by insufficient consolidation of ventricular wall muscle that can result in inadequate cardiac performance. Despite being the third most common cardiomyopathy, the mechanisms underlying the disease, including the cell types involved, are poorly understood. We have previously shown that endothelial cell-specific deletion of the chromatin remodeller gene Ino80 results in defective coronary vessel development that leads to ventricular non-compaction in embryonic mouse hearts. We aimed to identify candidate angiocrines expressed by endocardial and endothelial cells (ECs) in wildtype and LVNC conditions in Tie2Cre;Ino80fl/fltransgenic embryonic mouse hearts, and test the effect of these candidates on cardiomyocyte proliferation and maturation. We used single-cell RNA-sequencing to characterize endothelial and endocardial defects in Ino80-deficient hearts. We observed a pathological endocardial cell population in the non-compacted hearts and identified multiple dysregulated angiocrine factors that dramatically affected cardiomyocyte behaviour. We identified Col15a1 as a coronary vessel-secreted angiocrine factor, downregulated by Ino80-deficiency, that functioned to promote cardiomyocyte proliferation. Furthermore, mutant endocardial and endothelial cells up-regulated expression of secreted factors, such as Tgfbi, Igfbp3, Isg15, and Adm, which decreased cardiomyocyte proliferation and increased maturation. These findings support a model where coronary endothelial cells normally promote myocardial compaction through secreted factors, but that endocardial and endothelial cells can secrete factors that contribute to non-compaction under pathological conditions.


Corrosion and weight loss from copper wire in the Fincoid IUD in utero.
A total of 190 Fincoid IUDs were removed after varying periods of use in utero. Of 84 wires removed after 4 years of use, the 1st 12 wires were SEM photographed. In 1 of these wires, which was fragmented, a SEM photograph revealed deep corrosion pits. In the 11 unbroken wires, SEM photographs disclosed no clear pitting corrosion. Among 84 copper wires removed after 4 years of use, there were 4 fragmented ones. The risk of fragmentation after 4 years was thus 4.8%. Among the 106 copper wires removed for different reasons before the lapse of 4 years, there was not a single fragmented one. Annually, the mean daily release of copper ranged from 40.2 mcg to 43.3 mcg without any markedly higher initial release, 80% of the original weight still existing in the copper wires after 4 years in utero. The low incidence of pitting corrosion and fragmentation is most probably attributable to the higher positioning of the copper wire on the IUD. It is concluded that the effective life of the Fincoid IUD is more than 4 years.


Enterobacter cloacae bloodstream infections traced to contaminated human albumin.
In August 1996, a patient in Kansas developed an Enterobacter cloacae bloodstream infection (BSI) shortly after receiving Albuminar, a brand of human albumin. Albuminar contamination was suspected. A case-control study of patients with primary gram-negative bacterial BSIs showed that patients with E. cloacae BSIs were significantly more likely than patients with non-E. cloacae gram-negative BSIs to have received Albuminar within 3 days of developing their BSIs (3 of 5 vs. 0 of 9; OR, undefined; P=.03). The E. cloacae isolate from the Kansas patient was found by pulsed-field gel electrophoresis to be identical to the isolate from the patient's Albuminar vial, to isolates from 2 previously unopened Albuminar vials, and to an isolate from a Wisconsin patient who had received Albuminar. A worldwide recall of approximately 116,000 Albuminar vials took place. This multistate outbreak was detected because of clinical astuteness and prompt reporting. Combined epidemiological and laboratory approaches are valuable when investigating potentially contaminated blood components and plasma derivatives.


Loss of the Y chromosome: an age-related or clonal phenomenon in acute myelogenous leukemia/myelodysplastic syndrome?
The clinical association between loss of the Y chromosome and acute myelogenous leukemia and myelodysplastic syndrome (AML/MDS) has been debated because both phenomena are related to aging. A prior publication suggests that loss of the Y chromosome in more than 75% of cells may indicate a clonal phenomenon that could be a marker for hematologic disease. To evaluate the relationship between loss of the Y chromosome and AML/MDS. A retrospective review of cytogenetic reports of 2896 male patients ascertained from 1996 to 2007 was performed. Results were stratified based on the percentage of cells missing the Y chromosome and were correlated with patients' ages and bone marrow biopsy reports through logistic regression analysis with adjustment for age. Loss of the Y chromosome was found in 142 patients. Of these, 16 patients demonstrated myeloid disease, with 2 cases of AML and 14 cases of MDS. An increased incidence (P < .05) of AML/MDS was seen only in the group composed of 8 patients with complete loss of the Y chromosome in all karyotyped cells (1 case of AML and 7 cases of MDS). Loss of the Y chromosome appears to be primarily an age-related phenomenon. However, in individuals in which all cells on cytogenetic analysis showed loss of the Y chromosome, there was a statistically significant increase in AML/MDS, suggesting that the absence of any normal-dividing cells in a bone marrow analysis may be indicative of AML/MDS.


Measurement of metabolic tumor volume: static versus dynamic FDG scans.
Metabolic tumor volume assessment using positron-emission tomography [PET] may be of interest for both target volume definition in radiotherapy and monitoring response to therapy. It has been reported, however, that metabolic volumes derived from images of metabolic rate of glucose (generated using Patlak analysis) are smaller than those derived from standardized uptake value [SUV] images. The purpose of this study was to systematically compare metabolic tumor volume assessments derived from SUV and Patlak images using a variety of (semi-)automatic tumor delineation methods in order to identify methods that can be used reliably on (whole body) SUV images. Dynamic [18F]-fluoro-2-deoxy-D-glucose [FDG] PET data from 10 lung and 8 gastrointestinal cancer patients were analyzed retrospectively. Metabolic tumor volumes were derived from both Patlak and SUV images using five different types of tumor delineation methods, based on various thresholds or on a gradient. In general, most tumor delineation methods provided more outliers when metabolic volumes were derived from SUV images rather than Patlak images. Only gradient-based methods showed more outliers for Patlak-based tumor delineation. Median measured metabolic volumes derived from SUV images were larger than those derived from Patlak images (up to 59% difference) when using a fixed percentage threshold method. Tumor volumes agreed reasonably well (< 26% difference) when applying methods that take local signal-to-background ratio [SBR] into account. Large differences may exist in metabolic volumes derived from static and dynamic FDG image data. These differences depend strongly on the delineation method used. Delineation methods that correct for local SBR provide the most consistent results between SUV and Patlak images.


Introduction.
Homogeneous, periodic, quasiperiodic, irregular and disordered spatial structures have been at the heart of scientific interest and research for a long time and in many disciplines as diverse as chemistry, physics, biology and morphology. Some recent, spectacular achievements in experimental quantum optics have, however, made it possible to study quantum effects in a variety of spatial structures. The main aim of this Focus Issue is to present some of the most recent theoretical, numerical and experimental progresses in the area of Quantum Structures, i.e. spatial structures that display quantum features. A short background overview of Quantum Structures is provided at the beginning of this Focus Issue, in which individual authors' works are specifically commented. In brief, we can say that the articles can be catalogued into two main areas of research interest in Quantum Structures: quantum effects in spatial structures in nonlinear optics, and in atomic physics.


A multi-frequency method for ultrasonic ranging.
This paper presents a method for ultrasonic ranging based on the cross-correlation of two multi-frequency signals. The stimulus signal is composed by multiple sine-wave bursts/segments, each containing a different frequency and an integer number of periods. The frequency of each sine-wave burst is different from that of the adjacent bursts, but it is very close to the transducer resonant frequency. The time-of-flight (TOF) is estimated by finding the maximum of the cross-correlation. Interpolation is used to increase the measurement resolution. The experimental error corresponding to two standard deviations, for a range up to 1 m, is less than 0.3 mm.


Growing tumors induce a local STING dependent Type I IFN response in dendritic cells.
The importance of endogenous Type I IFNs in cancer immune surveillance is well established by now. Their role in polarization of tumor-associated neutrophilic granulocytes into anti-tumor effector cells has been recently demonstrated. Yet, the cellular source of Type I IFNs as well as the mode of induction is not clearly defined. Here, we demonstrate that IFN-β is induced by growing murine tumors. Induction is mainly mediated via STING-dependent signaling pathways, suggesting tumor derived DNA as trigger. Transcription factors IRF3 and IRF5 were activated under these conditions which is consistent with tumor infiltrating dendritic cells (DCs) being the major cellular source of IFN-β at the tumor site. Besides DCs, tumor cells themselves are induced to contribute to the production of IFN-β. Taken together, our data provide further information on immune surveillance by Type I IFNs and suggest novel potent cellular targets for future cancer therapy.


Therapeutic Strategies and Enhanced Production of Stem Cell-Derived Exosomes for Tissue Regeneration.
Exosomes are nanovesicles surrounded by a plasma membrane and carry bioactive molecules (e.g., proteins, lipids, and nucleic acids) of the origin cell type. The bioactive molecules delivered by exosomes to the recipient cells have attracted considerable attention, as they play an important role in intercellular communication. Moreover, exosomes have unique properties, including the ability to penetrate the biological barrier with minimal immunogenicity and side effects, which can influence various physiological and pathological processes. Thus, exosomes are a promising therapeutic platform for various diseases (e.g., malignancies and allergies), as well as for the regeneration of damaged tissues. However, challenges of obtaining exosomes, such as complex extraction procedures, low yield, and difficulty in quantification are yet to be overcome, which limits the use of exosomes in clinical settings. In this review, we describe the state-of-the-art engineering techniques and strategies for highly efficient mass production of exosomes. Moreover, we discuss the functional aspects and potential therapeutic applications of stem cell-derived exosomes, and deliberate upon various engineering techniques and platform combinations for improved tissue regeneration by exosomes.


Identifying preseizure state in intracranial EEG data using diffusion kernels.
The goal of this study is to identify preseizure changes in intracranial EEG (icEEG). A novel approach based on the recently developed diffusion map framework, which is considered to be one of the leading manifold learning methods, is proposed. Diffusion mapping provides dimensionality reduction of the data as well as pattern recognition that can be used to distinguish different states of the patient, for example, interictal and preseizure. A new algorithm, which is an extension of diffusion maps, is developed to construct coordinates that generate efficient geometric representations of the complex structures in the icEEG data. In addition, this method is adapted to the icEEG data and enables the extraction of the underlying brain activity. The algorithm is tested on icEEG data recorded from several electrode contacts from a patient being evaluated for possible epilepsy surgery at the Yale-New Haven Hospital. Numerical results show that the proposed approach provides a distinction between interictal and preseizure states.


Ecology and evolution of pathogens in natural populations of Lepidoptera.
Pathogens are ubiquitous in insect populations and yet few studies examine their dynamics and impacts on host populations. We discuss four lepidopteran systems and explore their contributions to disease ecology and evolution. More specifically, we elucidate the role of pathogens in insect population dynamics. For three species, western tent caterpillars, African armyworm and introduced populations of gypsy moth, infection by nucleopolyhedrovirus (NPV) clearly regulates host populations or reduces their outbreaks. Transmission of NPV is largely horizontal although low levels of vertical transmission occur, and high levels of covert infection in some cases suggest that the virus can persist in a nonsymptomatic form. The prevalence of a mostly vertically transmitted protozoan parasite, Ophryocystis elektroscirrha, in monarch butterflies is intimately related to their migratory behaviour that culls highly infected individuals. Virulence and transmission are positively related among genotypes of this parasite. These systems clearly demonstrate that the interactions between insects and pathogens are highly context dependent. Not only is the outcome a consequence of changes in density and genetic diversity: environmental factors, particularly diet, can have strong impacts on virulence, transmission and host resistance or tolerance. What maintains the high level of host and pathogen diversity in these systems, however, remains a question.


Hemodialysis arteriovenous fistula maturity: US evaluation.
To compare various objective ultrasonographic (US) criteria for native arteriovenous fistula (AVF) maturation with subsequent fistula outcomes and clinical evaluation by experienced dialysis nurses. US fistula evaluation results were analyzed retrospectively in 69 patients within 4 months after AVF placement; adequacy for dialysis was known in 54. Measurements included minimum venous diameter and blood flow rate. Experienced dialysis nurses examined 30 fistulas clinically. Predictors of fistula adequacy were analyzed with univariate and multivariate logistic regression. Mean fistula diameters and blood flow rates were compared by using analysis of variance or unpaired Student t tests. Fistula adequacy for dialysis doubled if the minimum venous diameter was 0.4 cm or greater (89% [24 of 27]) versus less than 0.4 cm (44% [12 of 27]; P <.001). Fistula adequacy for dialysis was nearly doubled if flow volume was 500 mL/min or greater (84% [26 of 31]) versus less than 500 mL/min (43% [nine of 21]; P =.002). Combining venous diameter and flow volume increased fistula adequacy predictive value: minimum venous diameter of 0.4 cm or greater and flow volume of 500 mL/min or greater (95% [19 of 20]) versus neither criterion met (33% [five of 15]; P =.002). Women were less likely to have an adequate fistula diameter of 0.4 cm or greater: 40% (12 of 30) of women versus 69% (27 of 39; P =.015) of men. No significant differences in blood flow or minimum venous diameter were found during 2-4 postoperative months. Experienced dialysis nurses' accuracy in predicting eventual fistula maturity was 80% (24 of 30). US measurements of AVF at 2-4 months in patients undergoing hemodialysis are highly predictive of fistula maturation and adequacy for dialysis.


(2R,3R)-1-(4-Chloro-phen-yl)-2-[(S)-2-nitro-1-phenyl-eth-yl]-3-phenyl-pentan-1-one.
The title compound, C(25)H(24)ClNO(3), has three contiguous chiral centres. The absolute structure was determined by anomalous dispersion. The chloro-benzene ring is inclined to the two phenyl rings by 14.98 (9) and 59.05 (9)°. The two phenyl rings are inclined to one another by 49.51 (10)°. In the crystal, neighbouring mol-ecules are linked via C-H⋯O hydrogen bonds, forming chains propagating along [010]. There is also a C-H⋯π inter-action present that leads to the formation of a three-dimensional network.


Attachment and Executive Functions in ADHD Symptomatology-Independent Inputs or an Interaction?
Despite a multitude of research on executive functions and attachment in Attention Deficit Hyperactivity Disorder (ADHD), a synthetic approach to the matter seems to have been lacking. In this review, we attempt to check the available data against two hypotheses: (1) executive functions and attachment influence ADHD symptoms independently; (2) executive functions and attachment interact to produce ADHD symptoms. We found no evidence falsifying the former hypothesis and some evidence to refute the latter. Limitations of current study approaches and suggestions for further research are discussed. Specifically, we propose an attachment representation, rather than attachment style, approach to measuring the mediation thereof between executive dysfunctions and ADHD.


Symptomatic Medial Bone Excrescence in the Distal Phalanx of the Hallux after the First Metatarsophalangeal Joint Arthrodesis: A Case Report and Radiographic Reviews.
Medial bone excrescence at the base of the distal phalanx of the hallux is a common manifestation which is rarely painful. In this case report, we described the first case of the excrescence becoming symptomatic one year after a metatarsophalangeal (MTP) joint arthrodesis of the great toe in a 74-year-old female. The medial bony excrescence which was obscure preoperatively became obvious postoperatively in the anteroposterior foot radiographs. The patient was successfully treated by an excision of the excrescence. In order to clarify the pathology of the excrescence, we reviewed the radiographs with respect to the excrescence before and after hallux surgeries including 97 metatarsal osteotomies and 33 MTP joint arthrodesis. The width of the excrescence measured in the anteroposterior foot radiographs displayed substantial increment one month after the hallux surgeries (osteotomy group: 0.9 ± 0.7 vs. 1.5 ± 0.7 mm, p < 0.01; arthrodesis group: 1.3 ± 0.8 vs. 1.8 ± 1.0 mm, p < 0.01). However, there was no significant difference in the width of the excrescence between one month after surgery and at the most recent follow-up of around 20 months in average after the surgery (osteotomy group: 1.5 ± 0.7 vs. 1.4 ± 0.7 mm, p = 0.62; arthrodesis group: 1.8 ± 1.0 vs. 1.8 ± 0.7 mm, p = 0.37). The present case and our radiographic review suggested that the postoperative medial bony excrescence was not the result of change of position of the preexisting excrescence. The correction of pronation deformity through hallux surgeries could emphasize the medial bony excrescence and cause symptomatic irritation upon shoe contact.


Green tea (Camellia sinensis) protects against selenite-induced oxidative stress in experimental cataractogenesis.
Cataract is the leading cause of blindness worldwide. It is a multifactorial disease primarily associated with oxidative stress produced by free radicals. The protection offered by various antioxidants in cataract development is well established. Polyphenolic compounds present in green tea (Camellia sinensis) are reported to possess antioxidant property in various pathological conditions. The present study was undertaken to evaluate the anticataract potential of green tea leaf (GTL) extract in the development of lens opacification. Enucleated rat lenses were randomly divided into normal, control and treated groups and incubated for 24 h at 37 degrees C. Oxidative stress was induced by sodium selenite in the culture medium of the two groups (except the normal group). The medium of the treated group was additionally supplemented with GTL extract. After incubation, lenses were subjected to glutathione and malondialdehyde estimation. Enzyme activity of superoxide dismutase, catalase and glutathione peroxidase was also measured in different sets of the experiment. In vivo cataract was induced in 9-day-old rat pups of both control and treated groups by a single subcutaneous injection of sodium selenite. The treated pups were injected GTL extract intraperitoneally prior to selenite challenge and continued for 2 consecutive days thereafter. Cataract incidence was evaluated on 16th postnatal day by slit lamp examination. There was positive modulation of biochemical parameters in the organ culture study. Green tea was also found to reduce the incidence of selenite cataract in vivo. The results suggest that green tea possesses significant anticataract potential and acts primarily by preserving the antioxidant defense system.


Loss of Tryptophan Fluorescence Correlates With Mechanical Stiffness Following Photo-Crosslinking Treatment of Rabbit Cornea.
A clinical treatment option for keratoconus involves the use of UV-initiated photo-crosslinking with riboflavin to increase corneal stiffness. Our study investigates whether endogenous fluorescence changes following treatment for keratoconus can be correlated to alterations in the stiffness of the cornea, thereby guiding treatment of keratoconus. A total of 78 ex vivo rabbit eyes were treated with either riboflavin-dextran solution plus UV light, dextran solution plus UV light, or riboflavin-dextran solution only for half treatment (2.84 J/cm2), standard treatment (5.28 J/cm2), or prolonged treatment (15.84 J/cm2) times. Fluorescent spectroscopy was performed on all samples before and after treatment. The stress-strain relationship was measured for all samples using a uniaxial tensiometer following treatment. We found a dose-dependent decrease in the 290/340 nm excitation/emission fluorescence pair with increase in corneal stiffening following treatment that was significant (P < 0.01) for both standard (5.28 J/cm2 total fluence) and prolonged treatment (15.84 J/cm2) times. We did not observe a significant change in this excitation/emission pair for the dextran-plus-UV or riboflavin-only treatment groups. Loss of fluorescence intensity at the 290/340 nm excitation/emission pair could offer a noninvasive, in situ measurement for guiding the photo-crosslinking treatment of keratoconus. Larger relative decreases in this pair are significantly correlated with longer treatment times and with increases in stiffness and Young's modulus.


Interaction of Gibberellic Acid and Indole-3-acetic Acid in the Growth of Excised Cuscuta Shoot Tips in Vitro.
Gibberellic acid (GA(3)) induced a marked elongation of 2.5-centimeter shoot tips of Cuscuta chinensis Lamk. cultured in vitro. In terms of the absolute amount of elongation, this growth may be the largest reported for an isolated plant system. The response to hormone was dependent on an exogenous carbohydrate supply. The hormone-stimulated growth was due to both cell division and cell elongation. The growth response progressively decreased if GA(3) was given at increasingly later times after culturing, but the decreased growth response could be restored by the application of indole-3-acetic acid (IAA) to the apex. Explants deprived of GA(3) gradually lost their ability to transport IAA basipetally, but this ability was also restored by auxin application. The observations are explained on the basis that: (a) the growth of Cuscuta shoot tip in vitro requires, at least, both an auxin and a gibberellin; and (b) in the absence of gibberellin the cultured shoot tip explants lose the ability to produce and/or transport auxin.


Electronic Health Record-Related Stress Among Nurses: Determinants and Solutions.
Background: Documentation and navigation through electronic health records (EHRs) is an essential, but stressful, task. We present the magnitude, determinants of such events, and solutions proposed by nurses to address EHR-related stress (EHR-S) at a tertiary eye hospital in Saudi Arabia. Methods: Nurses of an eye hospital were surveyed in 2019 about EHR-S. A Likert scale was used to assess the responses of 10 components of EHR-related work. The total score was graded as follows: minimum (<-10), mild (<0 to -10), moderate (1-10), and severe (>11). The score was correlated with determinants. Solutions suggested by nurses to reduce stress were reviewed. Results: This survey covered 212 nurses. Of them, 106 (50%; 95% confidence interval: 43.3-56.7) reported EHR-S. The median EHR-S score was -3.0 (interquartile range: -9.0; +8.0). Thirty-five (16%) nurses reported severe EHR-S. Senior nurses (M-W, p < 0.02) and those working in emergency and recovery units (M-W, p < 0.01) had statistically higher EHR-S. The main stressors were incomplete EHR work by other departments affecting nursing care (70.8%), difficulty in correction after entering the data (60.4%), and difficulty in data retrieval (60.4%). The main solutions to reduce EHR-S were to reduce the frequency of changes to configuration of the EHR (58%), more training (54.2%), and appreciation of good work (52.8%). Conclusions: EHR-S is experienced by half of the nurses working at an eye care hospital. Implementation of solutions such as better training and fewer changes to the EHR system could reduce stress levels of nurses.


Maternal life event stress and congenital anomalies.
We used data from a population-based case-control study to explore the relation between certain life events during the periconceptional period and several types of congenital anomalies. We ascertained cases from pregnancies ending in 1987-1989 and randomly selected controls from eligible liveborn infants. In telephone interviews, women reported deaths of anyone close to them. They also reported job losses or separations/divorces, for themselves or anyone close to them. Experiencing at least one stressful event during the periconceptional period was associated with a prevalence odds ratio of 1.4-1.5 for the delivery of infants with conotruncal heart defects, neural tube defects, and isolated cleft lip with or without palate. These associations tended to be restricted to women who were not obese and women with less than or equal to a high school education. This study suggests that women who experience stressful life events around the time of conception or early gestation may be at increased risk of delivering infants with certain congenital anomalies.


[The systems of neurochemical regulation at brain pathologies].
The paper summarises the comprehensive concept on main groups of chemical substances and on their diverse regulatory function in the brain. Neurotransmitters, neuropeptides, neurotrophic and growth factors, and cytokines are considered as many-storied, integral structure. The proper analysis of ischemic and neurodegenerative brain disturbances evidently demonstrates the active participation of basic families of these chemical regulators at all stages of the pathogenesis. The main theoretical positions involving these regulatory substances in the control of normal and pathological situations include: (a) dogma on the imbalance of chemical regulators, as the initial pathogenetic principle; (b) genetically heterogeneity of brain structures, which demonstrate selective vulnerability or, to the contrary, steadiness for damaging exposure. As a general principle for increasing number of clinical and experimental pathologies, the induction of apoptic cascade processes is postulated; their "normal" biological function in nervous tissues is a key factor for development of majority of brain diseases.


Anterior Cruciate Ligament Length in Pediatric Populations: An MRI Study.
As regards anterior cruciate ligament (ACL) reconstruction (ACLR), graft diameter has been identified as a major predictor of failure in skeletally mature patients; however, this topic has not been well-studied in the higher risk pediatric population. Hamstring tendon autograft configuration can be adjusted to increase graft diameter, but tendon length must be adequate for ACLR. Historical parameters of expected tendon length have been variable, and no study has quantified pediatric ACL morphology with other osseous parameters. To develop magnetic resonance imaging (MRI)-derived predictors of native ACL graft length in pediatric patients so as to enhance preoperative planning for graft preparation in this skeletally immature patient population. Cross-sectional study; Level of evidence, 3. MRI scans of 110 patients were included (64 girls, 46 boys; median age, 10 years; range, 1-13 years). Patients with musculoskeletal diseases or prior knee injuries were excluded. The following measurements were taken on MRI: ACL length; sagittal and coronal ACL inclination; intercondylar notch width and inclination; and femoral condyle depth and width. Associations between these measurements and patient sex and age were investigated. Univariate linear regression and multivariable regression models were created for each radiographic ACL measure to compare R 2. Female ACL length was most strongly associated with the depth of the lateral femoral condyle as viewed in the sagittal plane (R 2 = 0.65; P < .001). Other statistically significant covariates of interest included distal femoral condylar width, age, and coronal notch width (P < .05). For males, the ACL length was most strongly associated with the distal femoral condyle width as viewed in the coronal plane (R 2 = 0.70; P < .001). Other statistically significant covariates of interest for male ACL lengths were lateral femoral condyle depth, age, and coronal notch width (P < .05). In pediatric populations, femoral condylar depth/width and patient age may be valuable in assessing ACL size and determining appropriate graft dimensions and configuration for ACLRs. The use of this information to optimize graft diameter may lower the rates of ACL graft failure in this high-risk group.


Inhibitory effects of baicalein on the influenza virus in vivo is determined by baicalin in the serum.
Baicalein, an extract from Scutellaria baicalensis, was evaluated for its ability to inhibit the influenza virus in vivo. Oral administration of baicalein to BALB/c mice infected with the influenza A/FM1/1/47(H1N1) virus showed significant effects in preventing death, increasing the mean time to death, inhibiting lung consolidation, and reducing the lung virus titer in a dose-dependent manner. These effects are believed to be due to baicalin, the metabolite of baicalein in the serum. At a concentration of baicalin 2 microg/ml in overlay medium, it showed significant inhibition in the plaque assay, and the mean IC(50) value of baicalin was calculated as 1.2 microg/ml in the cytopathic effect assay. Our results showed that baicalein warrants further research as a potential antiinfluenza viral agent.


Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP.
We have introduced a targeted mutation in SH2D1A/DSHP/SAP, the gene responsible for the human genetic disorder X-linked lymphoproliferative disease (XLP). SLAM-associated protein (SAP)-deficient mice had normal lymphocyte development, but on challenge with infectious agents, recapitulated features of XLP. Infection of SAP- mice with lymphocyte choriomeningitis virus (LCMV) or Toxoplasma gondii was associated with increased T cell activation and IFN-gamma production, as well as a reduction of Ig-secreting cells. Anti-CD3-stimulated splenocytes from uninfected SAP- mice produced increased IFN-gamma and decreased IL-4, findings supported by decreased serum IgE levels in vivo. The Th1 skewing of these animals suggests that cytokine misregulation may contribute to phenotypes associated with mutation of SH2D1A/SAP.


Use of Protein Content, Amylose Content, and RVA Parameters to Evaluate the Taste Quality of Rice.
Taste quality of rice is the key to its value. However, it is greatly affected by rice types and the environment. It is a complex but necessary factor to accurately evaluate the taste quality of various types of rice in different environments. In this study, 7 different types of rice with different taste values were used as materials, and 12 nitrogen fertilizer treatments were applied to obtain 84 different rice taste values. We used protein content, amylose content, and RVA to evaluate changes in the taste value of rice. Rice with high taste value tended to have higher amylose content, peak viscosity, hold viscosity, final viscosity, and breakdown, as well as lower protein content, pasting temperature, and peak time. Protein and amylose contents affected the taste value of rice by affecting the RVA profiles except for setback. For high and low taste-value rice types, protein content could explain 66.8 and 42.9% of the variation in taste value, respectively. In the case of medium taste-value type, protein content was not enough to evaluate the taste quality of rice. Stickiness could explain 59.6% of the variation in taste value. When the protein content of rice was less than 6.61% or greater than 9.34%, it could be used to reflect the taste quality of rice. When the protein content was in between the two, protein content was not enough to reflect the taste quality of rice. Our results suggested that protein content could better reflect the taste quality change for rice, which provided a theoretical and technical basis for the accurate evaluation of the taste value of various types of rice.


Effect of varying solids concentration and organic loading on the performance of temperature phased anaerobic digestion process.
The effect of varying total solids (TS) and volatile solids (VS) concentrations and organic loading on the performance of a temperature phased anaerobic digestion (TPAD) system treating a mixture of primary and waste activated sludges was evaluated. An optimum volatile solids destruction of 61.5% occurred at a feed concentration of 4.9% (corresponding to 3.8% VS concentration) in the system operated at a total detention time of 20 days. At a total solids concentration of 7.9% (5.8% VS concentration), the volatile solids destruction efficiency dropped to 52.5%. At all conditions (4.4 to 7.9% TS) the TPAD system was able to meet the requirements for Class A biosolids, including those for fecal coliform and volatile solids destruction. The effluent fecal coliform concentration never exceeded 628 most probable number (MPN)/g TS. Thermophilic biomass activity tests were run on both the thermophilic (55 degrees C) and the mesophilic (35 degrees C) sludge. Biomass from the thermophilic reactor showed much greater activity at 55 degrees C than at 35 degrees C. However, significant activity was still present when the test was run at 35 degrees C. Activity tests completed on samples from the mesophilic reactor also had high activities at 55 degrees C, sometimes equal to the activity of the thermophilic biomass. These results suggest that the bacterial consortia in the TPAD system may be temperature-tolerant and not necessarily two distinct communities with two distinct temperature regimes as had been previously assumed.


FLN-1/filamin is required for maintenance of actin and exit of fertilized oocytes from the spermatheca in C. elegans.
Filamin, known primarily for its actin cross-linking function, is a stretch-sensitive structural and signaling scaffold that binds transmembrane receptors and a wide variety of intracellular signaling proteins. The Caenorhabditis elegans filamin ortholog, FLN-1, has a well conserved overall structure, including an N-terminal actin-binding domain, and a series of 20 immunoglobulin (Ig)-like repeats. FLN-1 partially colocalizes with actin filaments in spermathecal and uterine cells. Analysis of phenotypes resulting from a deletion allele and RNAi depletion indicates FLN-1 is required to maintain the actin cytoskeleton in the spermatheca and uterus, and to allow the exit of embryos from the spermatheca. FLN-1 deficient animals accumulate embryos in the spermatheca, lay damaged and unfertilized eggs, and consequently exhibit dramatically reduced brood sizes. The phospholipase PLC-1 is also required for the exit of embryos from the spermatheca, and analysis of doubly mutant animals suggests that PLC-1 and FLN-1 act in the same pathway to promote proper transit of embryos from the spermatheca to the uterus. Given the modular protein structure, subcellular localization, genetic interaction with PLC-1, and known mechanosensory functions of filamin, we postulate that FLN-1 may be required to convert mechanical information about the presence of the oocyte into a biochemical signal, thereby allowing timely exit of the embryo from the spermatheca.


Composition of the bacterial population of refrigerated beef, identified with direct 16S rRNA gene analysis and pure culture technique.
The composition of the dominating population of freshly cut beef, and beef stored at 4 degrees C for 8 d, was studied by direct analysis of the 16S rRNA gene (PCR amplification, cloning and sequencing) and compared with pure culture technique where the isolates picked from the viable plate count were identified by sequencing of the 16S rRNA gene. The composition of the bacterial population was recorded at two different time points, at the start when the viable plate count of the meat was 4 x 10(2) colony forming unit (cfu) per cm(2) and when it was 5 x 10(7) cfu per cm(2). Direct gene analysis by PCR amplification generated 30 clones, and 79 isolates were picked from the plate count, and identified by 16S rRNA gene sequencing. At the low initial bacterial load of the beef, the two sampling strategies showed variations in the composition of species. Direct 16S rRNA gene analysis revealed a domination of Bacillus-like sequences while no such sequences were found in isolates from the viable plate count. Instead the population of the plate count was dominated by Chryseobacterium spp. In contrast, the two sampling strategies matched on the multiplying beef population, where both methods indicated Pseudomonas spp. as the dominating group (99% of the population-sequences), irrespectively of sampling strategy. Pseudomonas panacis/Pseudomons brennerii was the dominating taxon (99% similarity to type strain), but sequences with highest similarity to Pseudomonas lundensis (99%), Pseudomonas beteli (99%) and Pseudomonas koreensis (100%) were also found.


Distribution of acidic fibroblast growth factor mRNA-expressing neurons in the adult mouse central nervous system.
The distribution of acidic fibroblast growth factor (aFGF) mRNA-expressing neurons was studied throughout the adult mouse central nervous system (CNS) with in situ hybridization histochemistry using a radiolabelled synthetic oligodeoxynucleotide probe complementary to the mRNA of human aFGF. We report here a widespread distribution of aFGF mRNA in several defined functional systems of the adult mouse brain, whereby the highest levels of aFGF mRNA were found in large somatomotor neurons in the nuclei of the oculomotor, trochlear, abducens, and hypoglossal nerves; in the motoneurons of the ventral spinal cord and the special visceromotor neurons in the motor nucleus of the trigeminal nerve; and in the facial and ambiguus nuclei. Labelled perikarya were also detected in all central structures of the auditory pathway including the level of the inferior colliculus, i.e., the lateral and medial superior nuclei; the trapezoid, cochlear, and lateral lemniscal nuclei; and parts of the anterior colliculus. Furthermore, many aFGF-positive cell bodies were found in the vestibular system and other structures projecting to the cerebellum, in the deep cerebellar nuclei, in somatosensory structures of the medulla (i.e., in the gracile, cuneate, and external cuneate nuclei), as well as in the spinal nucleus of the trigeminal nerve. The findings that aFGF mRNA is expressed in all components of several well-defined systems (i.e., in sensory structures) as well as in central neurons that process sensory information and, finally, in some efferent projections point towards a concept of aFGF expression primarily within certain neuronal circuitries.


[Preventive examinations of hollow glassware cutters].
In a group of 429 glass cutters complaints in the region of the ulnar nerve were reported in 44.7%, the local findings in 36.8%. Most complaints in men were reported between the eleventh and twentieth year of glass cutting, in women during the first five years of occupation. Electromyographic studies showed in 24.0% the limit of the normal, in 14.0% discrete pathological findings. The fewest subjective complaints were reported in workers, who had leaned on their forearms instead of their elbows and had been using a rubber rest. In a group of 40 glass cutters a lot of clinical examinations and epidemiological parameters was evaluated. It was found that the upper limits of vibrations transferred to the arms were exceeded. X-ray-examinations of the cervical spine showed pathological findings in 39 of 40 glass cutters. Electromyographic studies revealed disturbances of the ulnar nerve and the median nerve, too. Clinical findings in a group of 422 apprentice glass grinders were discrete but increased year by year. Most clinical findings were seen either during the fourth or during the seventh respectively eighth year of glass cutting.


Presynaptic muscarinic M(2)-receptor-mediated inhibition of N-type Ca(2+) channels in cultured sphenopalatine ganglion: direct evidence for acetylcholine inhibition of cerebral nitrergic neurogenic vasodilation.
Results of previous pharmacological studies suggested that presynaptic muscarinic M(2) receptors on cerebral perivascular nitric oxidergic (nitrergic) nerves mediated inhibition of nitric oxide release from these nerves. The inhibition was thought to be primarily attributable to a decreased Ca(2+) influx through N-type Ca(2+) channels on nitrergic nerves, but direct evidence supporting this hypothesis was not presented. In the present study, we used cultured rat sphenopalatine ganglion (SPG), a major source of nitrergic nerves to cerebral blood vessels, to investigate the role of muscarinic M(2) receptors in modulating voltage-dependent Ca(2+) channels. SPG neuronal soma and dendrites were immunoreactive for both N-type Ca(2+) channels and muscarinic M(2) receptors, indicating that muscarinic M(2) receptors were colocalized with N-type Ca(2+) channels. Using the whole-cell voltage-clamp technique, we found that voltage-dependent Ca(2+) currents in cultured SPG were largely blocked by omega-conotoxin, an N-type calcium channel antagonist, but were not affected by nifedipine, an L-type calcium antagonist. The Ca(2+) current was inhibited by acetylcholine (ACh) and arecaidine but-2-ynyl ester tosylate (ABET), a preferential muscarinic M(2)-receptor agonist, in a concentration-dependent manner. The inhibition was reversed by atropine and methoctramine (a muscarinic M(2)-receptor antagonist), but was not affected by muscarinic M(1)-, M(3)-, or M(4)-receptor antagonists. Consistent with this, preferential muscarinic M(1)-receptor agonists McN-A-343 and oxotremorine did not affect the Ca(2+) current. Furthermore, pretreatment with pertussis toxin and guanosine 5'-O-(3-thio)triphosphate prevented ACh and ABET inhibition of Ca(2+) currents. These results are consistent with pharmacological findings in the pig basilar arteries and provide direct evidence supporting our hypothesis that M(2)-receptor-mediated inhibition of cerebral nitrergic neurogenic vasodilation is due to a G(i)-protein-mediated suppression of Ca(2+) influx via voltage-dependent N-type Ca(2+) channels on perivascular nerves.


A radiographic and anthropometric study of the effect of a contoured sandal and foot orthosis on supporting the medial longitudinal arch.
In-shoe foot orthoses improve conditions such as plantar heel pain (fasciitis), probably due to their ability to raise the medial longitudinal arch of the foot and lower the stress on the plantar tissues. Increasingly the arch-profile form of the in-shoe foot orthosis is being incorporated into sandal footwear, providing an alternative footwear option for those who require an orthosis. The purpose of this study was to evaluate if a sandal that incorporates the arch-profile of an in-shoe foot orthosis does indeed raise the medial longitudinal arch. Three commercially available non-medical devices (contoured and flat sandal, prefabricated in-shoe orthosis) worn by healthy individuals were studied in two independent experiments, one using radiographic measurements in Australia (n = 11, 6 female, age 26.1 ± 4.3 yrs, BMI 22.0 ± 2.4 kg/m(2)) and the other utilising anthropometric measures in the USA (n = 10, 6 female, age 26.3 ± 3.8 yrs, BMI 23.5 ± 3.7 kg/m(2)). A barefoot condition was also measured. Dorsal arch height was measured in both experiments, as well as in subtalar neutral in the anthropometric experiment. One way repeated measures ANOVA with follow up Bonferroni-corrected pairwise comparisons were used to test differences between the conditions (contoured and flat sandal, orthosis, barefoot). Mean difference and 95% confidence intervals (CI) and standardised mean differences (SMD) were also calculated. The contoured sandal significantly increased dorsal arch height compared to barefoot and flat sandal in both the anthropometric and radiographic experiments with SMD ranging from 0.95 (mean difference 5.1 mm (CI: 0.3, 1.6)) to 1.8 (4.3 mm (1.9, 6.6)). There were small differences between the contoured sandal and orthosis of 1.9 mm (0.6, 3.3) in the radiographic experiment and 1.2 mm (-0.4, 0.9) in the anthropometric experiment. The contoured sandal approximated the subtalar neutral position (0.4 mm (-0.5, 0.7)). Medial longitudinal arch height is elevated by contoured sandals and approximates subtalar joint neutral position of the foot and that achieved by an orthosis. Practitioners wanting to increase the medial longitudinal arch can do so with either an orthosis or a contoured sandal that includes the raised arch profile form of an orthosis.


A comparison between tau and amyloid-β cerebrospinal fluid biomarkers in chronic traumatic encephalopathy and Alzheimer disease.
Cerebrospinal fluid (CSF) tau and beta-amyloid levels in chronic traumatic encephalopathy (CTE), a disease which can be clinically indistinguishable from Alzheimer's disease (AD), are largely unknown. We examined postmortem CSF analytes among participants with autopsy confirmed CTE and AD. In this cross-sectional study 192 participants from the Boston University AD Research Center, VA-BU-CLF Center, and Framingham Heart Study (FHS) had post-mortem CSF collected at autopsy. Participants were divided into pathological groups based on AD and CTE criteria, with 61 CTE participants (18 low, 43 high stage), 79 AD participants (23 low, 56 intermediate to high), 11 participants with CTE combined with AD, and 41 participants lacking both CTE and AD neuropathology. The Meso Scale Discovery immunoassay system was utilized to measure amyloid-beta (Aβ1-40, Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau181 and p-tau231). CSF analytes were then compared across the pathological groups: no CTE/no AD (control), Low CTE, Low AD, High CTE, Intermediate/High AD, and AD+CTE. Among the Low disease state groups, the Low CTE group had significantly higher levels of p-tau231 versus the control group and compared to the Low AD group. The Low CTE group was also found to have significantly lower levels of Aβ1-42 compared to the control group. The high CTE group had higher levels of p-tau231 and lower levels of Aβ1-42 compared to Intermediate/High AD group. Importantly, p-tau231 and Aβ1-42 were predictors of diagnosis of CTE vs. control and CTE vs. AD. Increased CSF p-tau231 is a promising potentially sensitive biomarker of CTE, and CSF Aβ1-42 needs further investigation in CTE.


[Twin-twin transfusion syndrome and cardiovascular complications].
Twin-twin transfusion syndrome carries high morbidity and mortality, related in part to the cardiovascular alterations that it produces. Patient 1 underwent a cesarian section at week 28 due to myocardial dysfunction and severe tricuspid regurgitation in the recipient twin. Twelve hours after birth the recipient twin developed refractory shock. Severe biventricular hypertrophy was observed and the twin died 60 hours after birth from multisystemic failure. Patient 2 underwent a cesarian section at week 29 due to cardiomegaly and cardiac insufficiency in the recipient twin. At birth, he showed hypertension and poor peripheral perfusion. Biventricular hypertrophy was observed, which increased until it produced a mild right midventricular stenosis at 72 hours, decreasing after the 8th day. Mild hypertrophy persisted at 6 months of life. Cardiovascular alterations appear only in recipient fetuses affected by twin-twin transfusion syndrome. The most frequent findings are cardiac dilation, hypertrophy, myocardial dysfunction, tricuspid regurgitation and pulmonary stenosis. These alterations usually disappear during the first few months of life, but may also worsen.


Efficacy and safety of transcatheter coil embolization in congenital coronary artery fistulas guided by preinterventional cardiac computed tomography.
Transcatheter coil embolization of coronary artery fistulas (CAFs) has emerged as an alternative to surgical closure despite limited data in the current literature. The aim of this study was to show the efficacy of CAF closure and the benefit of the combined preinterventional use of cardiac computed tomography and coronary angiography to evaluate the feasibility and enhance the safety of this procedure by obtaining precise information about the CAF anatomy. Five consecutive patients (three men, two women, age 51-68 years) with symptomatic angiographically proven CAFs were screened for transcatheter treatment and underwent preinterventional cardiac multidetector computed tomography (MDCT). On the basis of CAF-associated clinical symptoms, exercise-induced ischemia, coronary angiography, and cardiac MDCT, four of five patients with a CAF draining into the pulmonary artery system were considered eligible for transcatheter coil embolization, whereas in MDCT the fifth patient had multiple draining sites of the CAF and a relevant drainage into the right ventricular myocardium and was thus excluded from the procedure. Coil embolization was successfully performed in the remaining four cases without any complications. There was no residual flow through the CAF after the procedure. Clinical symptoms resolved almost completely in all four patients during a median 15.6-month follow-up. Transcatheter coil embolization is a feasible and effective method for the treatment of symptomatic CAFs in selected cases. The adjunctive preinterventional use of cardiac MDCT with conventional angiography can identify vessels that are anatomically applicable for transcatheter closure, defer therapy in morphologically unsuitable complex cases, and thus optimize the safety of the procedure.


A rare case of primary mantle cell lymphoma of the prostate: clinical aspects and open problems.
A case of primary prostate involvement by mantle-cell lymphoma diagnosed at the time of transvesical adenomectomy is reported. Diagnostic difficulties and clinical outcome are also presented. The possibility of prostate involvement by malignant lymphomas, albeit rare, should be considered in any case of histological evidence of dense prostate lymphoid infiltrate in patients with lower urinary tract obstruction, and should be highly suspected in patients with prior history of systemic lymphoma. Immunohistochemical analysis is essential for a correct diagnosis. Both urologists and pathologists should be aware of the existence of such a rare clinical condition.


Congenital tracheal stenosis in Pfeiffer syndrome.
We report an infant with Pfeiffer syndrome (acrocephalosyndactyly type V) and a solid cartilaginous trachea lacking rings. This airway abnormality has been reported in a child with Crouzon syndrome but has not been described in Pfeiffer syndrome.


Pulmonary disease due to Mycobacterium arosiense, an easily misidentified pathogenic novel mycobacterium.
Mycobacterium arosiense is a newly described species. After noticing it was misidentified as Mycobacterium intracellulare by the commercial identification system GenoType CM (Hein, Nehren, Germany), we detected 4 such strains among 33 that were previously misidentified as M. intracellulare. Three more strains were found among unidentified mycobacteria not tested previously with GenoType. The first case of pulmonary disease due to M. arosiense is reported here, and the novel species, of which so far only one strain had been investigated, is further characterized.


Inhibition of degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vivo by cysteine protease inhibitors.
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is a key regulatory enzyme of cholesterol biosynthesis and is located in the endoplasmic reticulum (ER). A fusion protein, HMGal, consisting of the membrane domain of HMG-CoA reductase fused to Escherichia coli beta-galactosidase and expressed in Chinese hamster ovary (CHO) cells from the SV40 promoter, was previously constructed and was found to respond to regulatory signals for degradation in a similar fashion to the intact HMG-CoA reductase. Degradation of both HMG-CoA reductase and HMGal in CHO cells was enhanced by addition of mevalonate or low density lipoprotein (LDL). In this report we show that 2 cysteine protease inhibitors, N-acetyl-leucyl-leucyl-norleucinal (ALLN) and N-acetyl-leucyl-leucyl-methioninal (ALLM), completely inhibit the mevalonate- or LDL-accelerated degradation of HMG-CoA reductase and HMGal and also block the basal degradation of these enzymes. It has been shown that in vitro these protease inhibitors inhibit the activities of Ca(2+)-dependent neutral proteases as well as lysosomal proteases, including cathepsin L, cathepsin b, and cathepsin D. However, the mevalonate-accelerated degradation of HMG-CoA reductase and HMGal is not affected by lysosomotropic agents, suggesting that the site of action of these inhibitor peptides in preventing the degradation is not the cathepsins. In brefeldin A-treated cells, where protein export from the ER is blocked, ALLN is still effective in inhibiting the degradation of HMG-CoA reductase and HMGal. These results indicate the involvement of non-lysosomal Ca(2+)-dependent proteases in the basal and the accelerated degradation of HMG-CoA reductase and HMGal. Enzymatic assays in vitro and immunoblot analyses have revealed calpain- and calpastatin-like proteins in CHO cells. The activities and the amount of these proteins do not change under conditions of enhanced degradation, indicating that the levels of these proteins are not subject to mevalonate regulation.


Kinetic determination of serum adenosine deaminase.
A new kinetic method for the determination of serum adenosine deaminase (EC 22.214.171.124) is described, with adenosine as the substrate and nucleoside phosphorylase and xanthine oxidase as the reaction enzymes. Inosine is produced, which is converted to hypoxanthine. The hypoxanthine is oxidized to xanthine, which is further oxidized to uric acid. In these two reactions, blue 2,6-dichlorophenolindophenol is reduced to a colorless compound and the decrease in color is measured spectrophotometrically at 606 nm. The assay was automated by using a Cobas Mira analyzer. The automated assay had a CV of < 7%, and the calibration curve was linear from 10 to 120 U/L. The assay correlates well with an established method, based on detection of liberated NH3 with Berthelot's reaction. The reference interval (mean +/- 2 SD) was 14-34 U/L (mean 24 U/L, n = 84). The enzymatic method described is easily automated and seems to be suitable for the routine determination of adenosine deaminase in serum.


Complications and survival after surgical treatment of 214 metastatic lesions of the humerus.
The humerus is the second most common long-bone site of metastatic bone disease. We report complications, risk factors for failure, and survival of a large series of patients operated on for skeletal metastases of the humerus. This study was based on 208 patients treated surgically for 214 metastatic lesions of the humerus. Reconstructions were achieved by intramedullary nails in 148, endoprostheses in 35, plate fixation in 21, and by other methods in 10. The median age at surgery was 67 years (range, 29-87 years). Breast cancer was the primary tumor in 31%. The overall failure rate of the surgical reconstructions was 9%. The reoperation rate was 7% in the proximal humerus, 8% in the diaphysis, and 33% in the distal part of the bone. Among 36 operations involving an endoprosthesis, 2 were failures (6%) compared with 18 of 178 osteosynthetic devices (10%). In the osteosynthesis group, intramedullary nails failed in 7% and plate fixation failed in 22%. Multivariate Cox regression analysis showed that prostate cancer was associated with an increased risk of failure after surgery (hazard ratio, 7; P < 0.033). The cumulative survival after surgery was 40% (95% confidence interval [CI] 34-47) at 1 year, 21% (95% CI, 15-26) at 2 years, and 16% (95% CI, 12-19) at 3 years. Our method of choice is the cemented hemiprosthesis for pathologic proximal humeral fractures and interlocked intramedullary nail for lesions in the diaphysis. Pathologic fractures in the distal humerus are uncommon and associated with a very high reoperation rate.


WaterLOGSY NMR experiments in conjunction with molecular-dynamics simulations identify immobilized water molecules that bridge peptide mimic MDWNMHAA to anticarbohydrate antibody SYA/J6.
X-ray crystallographic data of the carbohydrate mimic MDWNMHAA when bound to an anti-Shigella flexneri Y mAb SYA/J6 indicate the immobilization of water molecules, that is, the presence of "bound" waters, in the active site. Water Ligand Observed via Gradient Spectroscopy (WaterLOGSY) was used in conjunction with saturation transfer difference (STD)-NMR spectroscopy to probe the existence of immobilized water molecules in the complex of MDWNMHAA 1 bound to mAb SYA/J6. Molecular dynamics simulations using the ZymeCAD Molecular Dynamics platform were then used to specify the likely locations of these water molecules. Of note, those waters involved in providing complementarity between the peptide and mAb SYA/J6 remained throughout the course of the simulation. Together, the experimental and computational protocols have been used to identify the bound water molecules present in the antibody-peptide complex.


CYP2E1 expression in human lymphocytes from various ethnic populations.
Monitoring CYP2E1 levels in alcoholic individuals holds inherent appeal because such determinations might indicate individuals at increased risk for alcoholic liver disease. We previously demonstrated that lymphocyte CYP2E1 expression reflects in vivo activity of the hepatic enzyme. To further validate this approach, the current investigation compared lymphocyte CYP2E1 content and chlorzoxazone pharmacokinetics in 51 alcoholic and nonalcoholic White, Navajo, and Mexican American subjects. After an oral dose of chlorzoxazone, blood samples were collected and lymphocytes isolated. Alcoholics exhibited a 2-fold elevation in lymphocyte CYP2E1 messenger ribonucleic acid (mRNA) and protein compared to nonalcoholics. Chlorzoxazone clearance rates were 1.9-fold higher and area under the concentration curve (AUC) values 1.8-fold lower in alcoholic individuals compared to nonalcoholics. Furthermore, chlorzoxazone clearance rates correlated (r = 0.55, p < 0.01, n = 38) with lymphocyte CYP2E1 mRNA content, and transcript levels further correlated (r = 0.52, p < 0.001, n = 38) with CYP2E1 protein content. To compare phenotype with genotype, restriction fragment length polymorphism analyses on deoxyribonucleic acid samples were performed to identify polymorphisms in the CYP2E1 gene. No subjects were homozygous for rare alleles c2 or C. Nonetheless, 27% of the Navajos and 15% of the Mexican Americans were heterozygous for the c2 allele. Two White subjects appeared heterozygous (c1/c2) when RsaI was used to characterize CYP2E1 genotype but homozygous (c1/c1) at the PstI locus. Fifteen percent of Mexican American subjects, 20% of Navajo subjects, and 6% of White subjects were heterozygous for the C allele. Neither CD nor cl/c2 genotypes were associated with alcoholism. Human lymphocyte CYP2E1 mRNA levels may be useful predictors of alcohol-mediated alterations in hepatic CYP2E1 activity. Moreover, ethnicity does not appear to play a major role in the levels of expression of lymphocyte CYP2E1.


Immediate maternal and fetal outcome following percutaneous mitral valve balloon commissurotomy: a 6-year single-center experience from sub-Saharan Africa.
Mitral stenosis is the most common valvular heart disease during pregnancy. When severe, it leads to significant maternal and fetal morbidity and mortality. Percutaneous mitral valve balloon commissurotomy can be performed during pregnancy, and the present study aimed to describe the immediate maternal and fetal outcomes after percutaneous mitral valve balloon commissurotomy was done in a cohort of 23 pregnant patients with severe mitral stenosis in Addis Ababa, Ethiopia. Included in the current study were all pregnant mothers who had severe rheumatic mitral valve stenosis and who underwent percutaneous mitral valve balloon commissurotomy at the Cardiac Center of Ethiopia over 6-year period. Data were collected through chart abstraction using a structured proforma and then analysed using STATA version 13.0. Median gestational age was 22 weeks and percutaneous mitral valve balloon commissurotomy was successful resulting in a significant increase in the mean mitral valve area of the group from 0.78 ± 0.20 cm2 to 1.89 ± 0.31 cm2 (p < 0.001). The mean mitral valve inflow gradient of the group was 23.95 ± 6.27 mmHg and 6.80 ± 2.44 mmHg, respectively, before and after the percutaneous mitral valve balloon commissurotomy procedure (p < 0.001). Post-procedure, there was no significant increment in mitral valve incompetence. The mean pulmonary artery pressure of the group decreased from 77.68 ± 23.19 mmHg to 42.31 ± 9.95 mmHg (p < 0.001). There was no fetal or maternal death following the procedure. Pregnancy ended at term gestation for 19/23 (82.6%) of the mothers and the mean birth weight of the neonates was 2800 g. Percutaneous mitral valve balloon commissurotomy procedure can safely be done for severe symptomatic rheumatic mitral stenosis in pregnancy in our setting.


INSIG2 G-102A promoter variant exhibits context-dependent effect on HDL-cholesterol levels but not on BMI in Caucasians.
The INSIG2 (INSIG2 is primarily involved in the regulation of fatty acid and cholesterol synthesis) gene is suggested to be obesity related. An INSIG2 promoter variant, G-102A, has been detected and was demonstrated to be of potential functional significance. In two cohorts of middle-aged men, the association between this variant and BMI was suggested. We sought to replicate the association between the INSIG2 G-102A variant and BMI in three large Slavonic Caucasian populations. Further, we analysed the possible effect of this variant on BMI changes in a short-time intervention study. One thousand ninety-nine males and 1368 females (population- based Czech MONICA three-year cohort), 908 females from the 3PMFs study, together with 94 overweight (BMI > 27 kg/m2) females who underwent nine weeks of dietary/exercise intervention were genotyped for the INSIG2 G-102A variant using PCR-RFLP analysis. We could not detect any association between the INSIG2 G-102A variant and BMI or WHR with or without adjusting for age and gender in any population. Neither the BMI change nor anthropometric and lipid parameter changes were affected by the INSIG2 G-102A gene variant in intervened overweight females. However, MONICA females (but not males) carrying the common GG genotype had higher plasma levels of HDL cholesterol (GG homozygotes 1.51 ± 0.36 mmol/l vs. A allele carriers 1.45 ± 0.33; P < 0.05) in both surveys. Our results indicated that the G-102A INSIG2 polymorphism has no consistent effect on BMI in general populations, but could influence HDL cholesterol in females.


[Glaucoma as etiopathogenic hypothesis of amaurosis after blepharoplasty. Apropos of a clinical case].
Amaurosis after blepharoplasty is a complication which is considered to be rare, but which nevertheless deserves extreme attention. Although various hypotheses have been proposed (and sometimes proved) its etiopathogenesis is still uncertain. The observation of a case of temporary loss of vision after blepharoplasty, which promptly regressed after medical therapy, led us to a revision of the most common causes of amaurosis, and to formulate, for this case, the etiopathogenetic hypothesis of acute glaucoma, which has already been reported in scientific literature, but without any case report.


An Inborn Error of Potassium Metabolism in the Tomato, Lycopersicon esculentum.
A mutant of the tomato (Lycopersicon esculentum Mill.) was obtained through treatment of the seed with ethyl methane sulfonate. Its chief distinguishing characteristic is the requirement for an extraordinarily high K concentration in the medium (20 mm) if it is to develop without pronounced K deficiency symptoms, while the wild type grows without any such symptoms at 0.1 to 0.2 mm K. The lesion of the K-inefficient mutant does not lie in its inability to absorb and translocate K.


Cellular and humoral immune responses induced in cattle by vaccination with Babesia divergens culture-derived exoantigens correlate with protection.
Previous results with the Babesia divergens gerbil vaccination model were extended in studies with cattle. Two calves were vaccinated with culture-derived B. divergens exoantigens, and two others were treated with control supernatant; both preparations were adjuvanted with Quil-A saponin. A parasite-specific humoral response was observed after the first vaccine injection and was boosted by two succeeding vaccine injections. Sera from the two vaccinated calves immunoprecipitated eight major parasitic proteins (with molecular masses ranging between 17 and 110 kDa) whose patterns were close to those observed in gerbil vaccine assays. The cellular immune response, monitored by lymphoproliferation assays, was slightly delayed in comparison with the humoral response; a significant proliferation occurred only after the second vaccine injection. Mononuclear cell proliferation was dose dependent in the presence of (i) lysates of B. divergens-parasitized erythrocytes, (ii) exoantigens of the whole supernatant, or (iii) protective exoantigens of two low-molecular-mass fractions obtained after supernatant gel filtration chromatography. An infectious challenge was administered 3 weeks after the third vaccine injection, with 3.6 x 10(10) B. divergens-parasitized erythrocytes. Erythrocyte count, rectal temperature, and parasitemia of the animals were monitored daily until they returned to initial values. All parameters indicated that the exoantigens induced protection from B. divergens infection for the two vaccinated calves.


Density functional theory modeling of C-Au chemical bond formation in gold implanted polyethylene.
We have studied processes of gold ion implantation in polyethylene (PE) by theoretical chemistry methods. Car-Parrinello molecular dynamics (CPMD) simulations of collisions and following chemical kinetics considerations lead to the conclusion that chemical bonds between gold atoms and PE chains are formed. We have identified and characterized by a DFT method various stable structures with C-Au, C-Au-C, C-Au-H and C-AuH2 types of chemical bonds. The binding energies (BE) of C-Au bonds are as high as 227 kJ mol-1 and the bond analysis reveals a covalent bonding character. For the experimental detection of these structures in gold implanted PE, we predicted characteristic infra-red (IR) frequencies. The C-Au stretching vibrational modes lie around 500 cm-1. Other characteristic frequencies lie in a band between 730 cm-1 and 1500 cm-1.


Electrophysiological manifestation of luteinizing hormone-releasing hormone pulse generator activity in the rhesus monkey: influence of alpha-adrenergic and dopaminergic blocking agents.
Characteristic increases in neuronal electrical activity associated with the initiation of each LH pulse were recorded from ovariectomized rhesus monkeys bearing multiple chronic electrodes in the medial basal hypothalamus. These electrophysiological manifestations of hypothalamic LHRH pulse generator activity were inhibited by the alpha-adrenergic blocker phentolamine or the alpha 1-adrenoceptor blockers phenoxybenzamine and prazosin. At the dosages used, the effects of single injections of these drugs ranged from a reduction in the frequency of LHRH pulse generator activity to its complete arrest. This was faithfully reflected in the pattern of pulsatile LH discharges. The dopaminergic blocking agent metaclopramide similarly reduced the frequency of the pulse generator or arrested its activity altogether. The alpha 2-adrenoceptor blocker yohimbine had no demonstrable effect on hypothalamic electrical activity at the doses studied. These findings support the view of a central action of alpha 1-adrenergic and dopaminergic blockade on LHRH pulse generator activity and the concept that central adrenergic and dopaminergic inputs can modulate the frequency of the LHRH pulse generator.


Soft bounds on diffusion produce skewed distributions and Gompertz growth.
Constraints can affect dramatically the behavior of diffusion processes. Recently, we analyzed a natural and a technological system and reported that they perform diffusion-like discrete steps displaying a peculiar constraint, whereby the increments of the diffusing variable are subject to configuration-dependent bounds. This work explores theoretically some of the revealing landmarks of such phenomenology, termed "soft bound." At long times, the system reaches a steady state irreversibly (i.e., violating detailed balance), characterized by a skewed "shoulder" in the density distribution, and by a net local probability flux, which has entropic origin. The largest point in the support of the distribution follows a saturating dynamics, expressed by the Gompertz law, in line with empirical observations. Finally, we propose a generic allometric scaling for the origin of soft bounds. These findings shed light on the impact on a system of such "scaling" constraint and on its possible generating mechanisms.


Diastereoselective hydrophosphonylation of imines using (R,R)-TADDOL phosphite. Asymmetric synthesis of alpha-aminophosphonic acid derivatives.
Efficient synthesis of alpha-aminophosphonic acid derivatives is achieved, the key step being a diastereoselective hydrophosphonylation of N-diphenylphosphinyl imines using a readily available chiral cyclic (R,R)-TADDOL-phosphite derived from inexpensive natural tartaric acid.