Ultrasound B-scans for clinical evaluation of neoplastic neck nodes.
As an attemp to improve the quantitative and qualitative evaluation of neoplastic neck nodes, we are evaluating ultrasound B-scans. Clinical examples are presented to demonstrate how "B-scans" may be used to evaluate lymph node size and response to therapy. Qualitatively, such scans may also be of value as a means of establishing lymph node boundaries and position with respect to other neck structures.


An electronic oral health record to document, plan and educate.
The University of British Columbia (UBC) in collaboration with a software developer (Planmeca Oy, Finland) created an electronic oral health record based on the principles of cognitive ergonomics rooted in the European research and development project 'ORQUEST' to guide students through medical, dental, social histories, examinations, treatment planning and progress notes. Clinicians in each dental specialty of the Faculty of Dentistry and software engineers cooperated to define the clinical content and workflow of clinical procedures in three phases: (i) development of a radiographic module, (ii) development of medical, dental, social and family histories, intra- and extra-oral examinations, progress notes and treatment planning and (iii) development of the orthodontic section accompanied by an optimisation phase to correct technical problems and clinical content issues. From a practical perspective, this EOHR enhances the clinical performance of students and the quality assurance capacity of the institution. It facilitates audits of clinical productivity and research, and it can be modified with relative ease to suit similar educational and clinical environments in either public or private healthcare settings.


Protein and mRNA expression of folic acid-associated enzymes as biomarkers for the cytotoxicity of the thymidylate synthase-targeted drugs, pemetrexed and S-1, in non-small cell lung cancer.
The thymidylate synthase (TS)-targeted drugs, pemetrexed and S-1, exert an important role in advanced non-small cell lung cancer (NSCLC) treatment; folic acid-associated enzymes are expected to behave as biomarkers, although their role has yet to be fully elucidated. In the present study, a single-institutional prospective analysis, in which the mRNA and protein expression levels of five folic acid-associated enzymes were evaluated with surgical specimens of NSCLC, was performed. Drug sensitivity was evaluated using a collagen gel droplet-embedded culture drug sensitivity test (CD-DST) in vitro. A total of 50 patients with NSCLC were enrolled, and the mRNA and protein expression levels of five enzymes were assessed in 47 and 46 patients, respectively. A significant association was identified between mRNA and protein expression in TS (r=0.6266), but the correlation between mRNA and protein expression levels for the other four enzymes was poor. TS mRNA expression was significantly higher in poorly differentiated tumors compared with moderately differentiated tumors (P=0.0399). TS protein expression was significantly higher in patients with pleural invasion or lymphatic invasion compared with those lacking them (P=0.027 and 0.030, respectively). CD-DST revealed that none of the tumors that were sensitive to pemetrexed, but not to S-1, were well differentiated, whereas none of the tumors that were sensitive to S-1, but not to pemetrexed, were poorly differentiated. More prominent vascular invasion was observed in the tumors that were sensitive to S-1. The only factors that exhibited the potential to discriminate the cytotoxicity of pemetrexed from S-1 were tumor differentiation grade and vascular invasion.


[Enoxacin for type III A prostatitis: a clinical observation].
Chronic prostatitis, especially type III A, is a common disease in adult males, for which there are quite a few therapeutic methods. This study aimed to investigate the clinical efficacy of enoxacin in the treatment of III A prostatitis. We selected 198 cases of III A prostatitis with complete treatment and follow-up data from the outpatients, all treated by enoxacin injection for 1 week, followed by oral medication of enoxacin for 2 weeks. Then we evaluated the therapeutic effect based on the NIH-CPSI scores and changes in the indexes of expressed prostatic secretions (EPS). The rate of total effectiveness was 86.4%, cure 8.6% (17/198), remarkable effectiveness 58.1% (115/198), improvement 19.7% (39/198), and ineffectiveness 13.6% (27/198). Only 16 cases (8.1%) complained of transitory gastrointestinal tract discomfort and/or skin itching. Enoxacin has desirable efficacy and few adverse effects on type III A prostatitis.


[Treatment of serious subtalar joint osteoarthritis and stage II posterior tibial tendon dysfunction by subtalar arthrodesis].
To assess the curative effect of the subtalar arthrodesis on the serious subtalar joint with the posterior tibial tendon dysfunction. From October 2000 to February 2006, 31 patients (18 males, 13 females; age 23-62 years, averaged 36.4 years) with serious subtalar joint osteoarthrisis and stage II posterior tibial tendon dysfunction were treated by the subtalar arthrodesis. The tibial tendon dysfunction involved 15 right and 16 left lower extremities, which were caused by retrograde osteoarthritis in 14 patients, sequel of an injury in 8 patients, infection in 7 patients, and anatomic structural abnormity in 2 patients. The treatment course averaged 9. 5 months (range, 6-30 months). Before the subtalar arthrodesis, the injured tendons were repaired, and then the bone grafting was performed in the tarsus sinus. All of the patients were assessed before and after operation according to the Hindfoot scores system (American Orthopedics Foot and Ankle Society, AOFAS). Among the patients, 28 were followed up on an average of 23.6 months (range, 8-61 months). The AOFAS scores ranged from 45.30+/-1.08 before operation to 79.60+/-2.14 after operation. The pain indexes ranged from 15.40+/-2.23 before operation to 38.50+/-2.61 after operation. The functional indexes of the foot and ankle joint ranged from averaged 21.60+/-3.01 before operation to averaged 37.40+/-2.83 after operation. The statistical analysis of the t-test on all the above data showed that there was a significant difference between before operation and after operation (P<0.01). The angles between the longitudinal line of the talar and the calcaneal bone were 43.70+/-1.06 degrees before operation and 29.40+/-0.98 degrees after operation, and the deviation angles between the calcaneal line and the talus were 48.20+/- 0.85 degrees before operation and 39.40+/-1.02 degrees after operation. There was a significant difference between before operation and after operation (P<0.01). The subtalar arthrodesis combined with the bone grafting in the tarsus sinus and the repair of the injured tendons can effectively correct the deformity of the deformity of the metapodium, relieve the pain, retain the adjacent joint motion ability, and this method can be recommended for the adult patient who suffers from serious subtalar osteoarthritis and stage II osterior tibial tendon dysfunction.


Preliminary crystallographic study of cyclohexadienyl dehydratase from Pseudomonas aeruginosa.
Single crystals of cyclohexadienyl dehydratase from Pseudomonas aeruginosa have been obtained by vapour diffusion from ammonium sulphate solution (pH 6.0) at 4 degrees C. The crystals belong to the tetragonal space group P4(3)2(1)2 or P4(1)2(1)2 with a = b = 105.5 A and c = 165.0 A. The asymmetric unit contains at least one dimeric protein molecule with M(r) = 72 kDa. The crystals diffract to 3 A resolution and are suitable for an X-ray analysis.


Monoclonal Antibodies in Multiple Myeloma: A New Wave of the Future.
In 2015, 2 monoclonal antibodies were approved for the treatment of relapsed or refractory multiple myeloma (RRMM), elotuzumab and daratumumab. Elotuzumab is a monoclonal IgG-κ antibody directed against SLAMF7 (signaling lymphocytic activation molecule F7), a cell surface receptor involved in natural killer cell activation. Daratumumab is a monoclonal IgG-κ antibody that binds to CD38, a transmembrane protein found on the surface of myeloma cells and responsible for cellular adhesion and ectoenzymatic activity. Both elotuzumab and daratumumab act through recruitment of the immune system to enhance cellular cytotoxicity directed against myeloma cells. Elotuzumab requires lenalidomide and dexamethasone combined to enhance progression-free survival in patients with RRMM, and daratumumab has both single-agent and combination activity with either lenalidomide or the proteasome inhibitor bortezomib in RRMM. The adverse effect profile of both agents mainly consists of allergic-type infusion reactions. Other considerations for monoclonal antibody use in the treatment of MM include the potential for interference in serum protein electrophoresis testing and cross-reactivity of daratumumab with CD38 present on red blood cells. In the present report, we discussed the clinical development of daratumumab and elotuzumab and newer immunologic approaches to the treatment of MM.


Multiple Myeloma with Foamy Mott Cells.
Intracytoplasmic assorted vacuoles containing immunoglobulin collections are occasionally seen in multiple myeloma. When abundant, they impart a foamy appearance to the tumor cells, which is a potential source for diagnostic pitfalls. Herein, we report the case of a patient who presented with skeletal pain and CT confirmed lytic lesions. A bone marrow biopsy revealed multiple myeloma with unusual foamy Mott cells. The patient was subsequently treated with four cycles of cyclophosphamide, bortezomib, and dexamethasone induction therapy, followed by 3 cycles of lenalidomide with dexamethasone. A biopsy performed following initial biological and immunomodulatory drugs revealed different morphological and clonal characteristics. These features were modified again, five years later, and again, after two years of close monitoring. Hematopathologists should be aware of this morphologic variant of myeloma as well as for the capacity of clonal characteristics, such as light chain monotype, to fluctuate subsequent to treatment.


Efficacy and safety of low dose desmopressin orally disintegrating tablet in men with nocturia: results of a multicenter, randomized, double-blind, placebo controlled, parallel group study.
We investigated the efficacy and safety of 50 and 75 μg desmopressin orally disintegrating tablets in men with nocturia (2 or more nocturnal voids). In this 3-month, randomized, double-blind, parallel study 50 and 75 μg desmopressin were compared with placebo. The co-primary efficacy end points were changes from baseline in mean number of nocturnal voids and proportions of patients achieving at least a 33% reduction from baseline in nocturnal voids (33% responders) during a 3-month treatment period. The full analysis set comprised 385 men (age range 20 to 87 years). The 50 and 75 μg doses significantly reduced the number of nocturnal voids (-0.37, p <0.0001 and -0.41, p = 0.0003, respectively) and increased the odds of a 33% or greater response (OR 1.98, p = 0.0009 and OR 2.04, p = 0.0004, respectively) compared with placebo during 3 months. Desmopressin 50 and 75 μg increased the time to first void from baseline by approximately 40 minutes compared to placebo (p = 0.006 and p = 0.003, respectively). The response to desmopressin was seen by 1 week of treatment and was sustained. Significant increases in health related quality of life and sleep quality were observed compared to placebo. Desmopressin was well tolerated as only 2 subjects (age 74 and 79 years) on 50 μg had a serum sodium level of less than 130 mmol/L (vs 9 subjects on 75 μg). Desmopressin (orally disintegrating tablet) is an effective and well tolerated treatment for men with nocturia. Treatment with 50 μg desmopressin, the minimum effective dose, provided sustained improvement of nocturia throughout the study and meaningful benefits to patients with an improved safety profile.


Effects of hPMSCs on granulosa cell apoptosis and AMH expression and their role in the restoration of ovary function in premature ovarian failure mice.
This study was performed to determine the effects of human placenta mesenchymal stem cell (hPMSC) transplantation on granulosa cell apoptosis and anti-Müllerian hormone (AMH) and follicle-stimulating hormone receptor (FSHR) expression in autoimmune drug-induced premature ovarian failure (POF) mice. The aim of this research is to investigate the mechanisms of hPMSCs on ovarian reserve capacity. The POF mice model was established by injection of zona pellucida 3 peptide (pZP3). hPMSC transplantation was conducted by intravenous injection into mice following pZP3 treatment. The follicle number was examined by histopathology. The serum levels of FSH, LH, E2, AMH and anti-zona pellucida antibody (AzpAb) were measured by enzyme-linked immunosorbent assay. AMH and FSHR expression in the ovary was analyzed by immunohistochemistry and western blot analysis. Granulosa cell apoptosis of the ovaries was examined by In Situ Cell Death Detection Kit. Granulosa cells were isolated and treated with SiAmh interference and hPMSC supernatant to observe the effects of AMH expression on granulosa cell apoptosis in vitro. The results showed that hPMSC transplantation can significantly recover the estrus cycle in the POF group. Morphological staining showed that the basal follicles and sinus follicles after hPMSC transplantation were higher in POF mice than in those without treatment, and the follicle number was significantly decreased with atresia. The serum levels of FSH, LH and AzpAb in the hPMSC transplantation group were reduced considerably, but the E2 and AMH levels were significantly increased. After hPMSC transplantation, the AMH and FSHR expression in ovarian tissue was significantly higher than in the POF group as determined by immunochemistry and western blot analysis. The FSHR expression was shown in granulosa cells only, and FSHR expression increases with AMH expressed in the ovary; granulosa cell apoptosis was decreased following hPMSC transplantation. The same results were observed from the in-vitro study. hPMSC transplantation can significantly improve the serum levels of high gonadotropin and low estrogen of POF mice, promote follicular development, inhibit excessive follicular atresia and granulosa cell apoptosis, and improve the ovarian reserve capacity. The mechanism may be achieved by increasing the expression of AMH and FSHR in ovaries.


Phase I/II clinical trial of a Wilms' tumor 1-targeted dendritic cell vaccination-based immunotherapy in patients with advanced cancer.
Dendritic cell (DC)-based immunotherapies have been created for a broad expanse of cancers, and DC vaccines prepared with Wilms' tumor protein 1 (WT1) peptides have shown great therapeutic efficacy in these diseases. In this paper, we report the results of a phase I/II study of a DC-based vaccination for advanced breast, ovarian, and gastric cancers, and we offer evidence that patients can be effectively vaccinated with autologous DCs pulsed with WT1 peptide. There were ten patients who took part in this clinical study; they were treated biweekly with a WT1 peptide-pulsed DC vaccination, with toxicity and clinical and immunological responses as the principal endpoints. All of the adverse events to DC vaccinations were tolerable under an adjuvant setting. The clinical response was stable disease in seven patients. Karnofsky Performance Scale scores were enhanced, and computed tomography scans revealed tumor shrinkage in three of seven patients. Human leukocyte antigen (HLA)/WT1-tetramer and cytoplasmic IFN-γ assays were used to examine the induction of a WT-1-specific immune response. The immunological responses to DC vaccination were significantly correlated with fewer myeloid-derived suppressor cells (P = 0.045) in the pretreated peripheral blood. These outcomes offered initial clinical evidence that the WT1 peptide-pulsed DC vaccination is a potential treatment for advanced cancer.


Key role of glycogen storage in high K+-induced contraction of the smooth muscles of the bovine trachea.
To elucidate the role of glycogen in the contraction of tracheal smooth muscle, we investigated the changes in the glycogen contents of the bovine trachea during contractions induced by high K(+) and hypoxia (achieved by bubbling N(2) instead of O(2)), either in a glucose-free condition or in the presence of iodoacetic acid (IAA), an inhibitor of glycolysis. Hyperosmotic addition of 65 mM KCl (H-65 K(+)) induced a sustained contraction. A glucose-free condition did not affect H-65 K(+)-induced contraction. However, hypoxia slightly inhibited the contraction, and glucose-free PSS with hypoxia or IAA remarkably inhibited the H-65 K(+)-induced contraction. H-65 K(+) induced a sustained increase in reduced pyridine nucleotide (PNred) fluorescence, representing glycolysis activity. Hypoxia alone slightly enhanced PNred fluorescence, and when combined with a glucose-free condition, it remarkably enhanced the H-65 K(+)-induced PNred fluorescence. IAA inhibited PNred fluorescence. In the presence of H-65 K(+), a glucose-free condition, hypoxia and the combination of glucose-free PSS and hypoxia decreased the glycogen contents. However, IAA had no effect on glycogen contents. Although hypoxia or glucose-free PSS did not affect PCr and ATP contents, the combination of hypoxia and glucose-free PSS or IAA induced a gradual decrease of PCr content. In conclusion, we suggest that endogenous glycogen was utilized to increase the activity of glycolysis for maintaining high K(+)-induced contraction of the bovine trachea in the glucose -free and/or hypoxic condition.


Relevance of biochemical tumor markers and lymphadenectomy in management of non-seminomatous testis tumors: current perspective.
Radioimmunoassay determinations of the biochemical tumor markers, alpha-fetoprotein or human chorionic gonadotropin, revealed elevated serum levels in 94 per cent of the patients with advanced disease. No falsely positive values have been observed. The markers are useful in monitoring the response to therapy and, when persistently elevated after therapy, indicate the presence of residual malignant tumor, usually embryonal carcinoma. However, they have a more limited role in the management and followup of the great majority of new patients with non-seminomatous germ cell tumors of the testis (stages A and B) owing to a falsely negative incidence of 38 per cent in patients found to have retroperitoneal metastases at lymphadenectomy. Furthermore, marker levels obtained during chemotherapy, even in the presence of residual tumor, frequently are normal. Thus, they have a limited role in the early detection of residual disease in patients treated systematically with prophylactic chemotherapy. A meticulous retroperitoneal lymphadenectomy remains the single most important factor in dictating the use of adjuvant chemotherapy, the specific agent and the combination and duration of therapy. The prophylactic use of actinomycin D in stage A and the early aggressive use of vinblastine sulfate and bleomycin in stage B2 have reduced the incidence of recurrence substantially. A prospective plan of management used in 95 consecutive patients since 1974 has resulted in survival free of tumor of 100 per cent for patients with stage A disease, 91 per cent for stage B and 61 per cent for stage C.


Social influences among young drivers on talking on the mobile phone while driving.
This study set out to measure the influence of injunctive, subjective, verbal, and behavioral norms on talking on a mobile phone while driving. In particular it examines social influences that have been neglected in past research, namely, injunctive norms and explicit verbal and behavioral norms communicated by law enforcers with regard to using a mobile phone when driving. All four types of social norms have rarely been used in studies of this social phenomenon, except for occasional exceptions drawing on Ajzen's theory of planned behavior, which addresses only one: subjective norms. Regression analysis of data collected from young drivers from 217 questionnaires is used to predict the intention of motorists to continue talking on their mobile phones while driving. Selective interaction effects, the purpose of the call, and injunctive and subjective norms were included. The results show that the explicit verbal and behavioral law enforcement norms, the subjective norms, and the interaction of the injunctive norm with the purpose of the call are significant predictors of the unlawful behavior. The results taken together seem to imply that social marketing is likely to encounter difficulty in changing behavior because the subjective norm (what others think I should do) coupled with the lack of enforcement (verbal norms) play important roles in maintaining the unlawful behavior. Moreover, the perception that talking on the mobile phone while driving is acceptable behavior (injunctive norm) in conjunction with the purpose of the call create further challenges to social marketers. The results have implications on policy makers and enforcers. Law enforcers should do their job to prevent the wrong behavior in the first place. In addition, campaigns may be directed to convince the target audience about the false norms and use persuasive communication to emphasize the potential costs of maintaining the unlawful behavior.


Specific in situ hybridization of the intracellular organism of porcine proliferative enteropathy.
The identity of the intracellular bacteria found in the enterocytes of pigs with proliferative enteropathy was investigated using specific DNA probes to various Campylobacter species and to a novel organism, ileal symbiont intracellularis. The ilea from pigs (Nos. 1-7) that were diagnosed by routine histopathology as having proliferative enteropathy were used. Diagnosis was made on the basis of proliferation of the enterocytes on hematoxylin and eosin-stained sections and the presence of large numbers of intracellular curved organisms on Warthin-Starry silver-stained sections. Four of these pigs (Nos. 1-4) had the chronic form of the disease, porcine intestinal adenomatosis, and three (Nos. 5-7) had the acute form, proliferative hemorrhagic enteropathy. An additional three normal pigs (Nos. 8-10) were obtained from three separate farms with no history of proliferative enteropathy. Frozen ileal sections were examined by in situ hybridization with DNA probes specific for ileal symbiont intracellularis and the three porcine intestinal Campylobacter species, C. coli, C. hyointestinalis, and C. mucosalis. In all seven pigs with either the intestinal adenomatosis or hemorrhagic enteropathy form of the disease, a DNA probe specific for ileal symbiont intracellularis hybridized to localized foci in the apical cytoplasm of ileal enterocytes. These hybridization sites corresponded to the location of intracellular bacteria in silver-stained sections of adjacent tissue. Sections from the three normal pigs tested with this probe and from all pigs tested with the Campylobacter species-specific DNA probes showed no specific hybridization reactions. The identity of the intracellular organism in these diseased pigs is ileal symbiont intracellularis.


artbin: Extended sample size for randomized trials with binary outcomes.
We describe the command artbin, which offers various new facilities for the calculation of sample size for binary outcome variables that are not otherwise available in Stata. While artbin has been available since 2004, it has not been previously described in the Stata Journal. artbin has been recently updated to include new options for different statistical tests, methods and study designs, improved syntax, and better handling of noninferiority trials. In this article, we describe the updated version of artbin and detail the various formulas used within artbin in different settings.


Results of early surgery for sagittal suture synostosis: long-term follow-up and the occurrence of raised intracranial pressure.
Numerous techniques are used to correct sagittal synostosis. Although cosmetic results and operative complications are well documented, little is known about functional outcome. In our institution, the technique for extended strip craniectomy evolved over time. This study compares cosmetic results, complications, and signs of raised intracranial pressure (ICP) between the variants of the extended strip craniectomy. Seventy-nine consecutive patients undergoing early extended strip craniectomy for scaphocephaly (2002-2008) were included. Four techniques were used: A, a simple bilateral parietal flap with out-fracturing of the bone flap; B, C, and D included remodeling of the parietal flap by adding triangular cuts and bending or suturing the resulting fingers. In technique D, the sagittal strip was rotated and fixed between the parietal flaps. Data on head circumference (HC), skull X-ray, and fundoscopy were collected prospectively. For all patients, the average cranial index (CI) was 74 after 3 months and 72 after 2 years. Although technique D resulted in the best initial improvement, there was no significant percentage increase in CI after 24 months between the four techniques. Postoperatively, 9 % of the patients developed papilledema, 42 % developed a fontanel bulge, and 57 % had diminished HC. Four patients were reoperated on because of raised ICP. Postoperative CI is mainly determined by preoperative CI and hardly affected by type of extended strip craniectomy. Signs of raised ICP occurred more frequently than expected, therefore structural follow-up is required to detect such signs. Technique and timing of surgery should aim at creating sufficient intracranial volume.


Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat.
Hepatic morphological abnormalities were examined in rats whose bile ducts had been either cannulated and then obstructed or irreversibly ligated for 5, 10, 15 and 28 days or longer. Throughout the experiment most of the morphological changes observed in the cannulated group were comparable to those in the ligated group. Portal inflammation and marginal bile duct proliferation were noted with the same frequency in both groups. Biliary obstruction for 15 days or more led to cirrhosis. After 28 days obstruction, five out of six cannulated rats and four out of six ligated animals respectively developed cirrhosis. The development of cirrhosis was progressive and associated with ascites. It is concluded that in the rat the morphological sequelae of long term cholestasis induced by either cannulation and obstruction or ligation of bile ducts are similar and are accompanied by cirrhosis. The advantages of this experimental model for the study of human cirrhosis are discussed.


A Case of Effective Balloon Fenestration for Localized Aortic Dissection Complicated with Acute Renal and Bilateral Limb Ischemia in a Thoracoabdominal Aortic Aneurysm.
An 85-year-old man visited our hospital with bilateral leg weakness. Blood tests revealed an abrupt deterioration of renal function. Computed tomography revealed a 53-mm aortic aneurysm at the level of the diaphragm with an aortic dissection after branching of the superior mesenteric artery. An emergency left axillary-left femoral artery bypass surgery was performed to secure blood flow to the kidneys and lower limbs. Five days later, a transcatheter balloon fenestration for the stenosis was performed, and the blood pressure of the infrarenal aorta was improved. Both the dorsal pedis and posterior tibial arteries became palpable, and renal function was improved.


Linagliptin inhibits high glucose-induced transdifferentiation of hypertrophic scar-derived fibroblasts to myofibroblasts via IGF/Akt/mTOR signalling pathway.
Hypertrophic scar (HS) is a fibroproliferative disease after serious burns; the underlying mechanism remains unknown. The study was performed to clarify the effect of high glucose (HG) on HS. The expression of Col1, Col3 and α-SMA was upregulated in HS-derived fibroblasts (HSF) exposed to HG (20 and 30 mmol/L), and HG activated the phosphorylated protein expression of IGF/Akt/mTOR signalling pathway in HSF. Dpp4, a marker targeted the treatment of diabetes mellitus, was overexpressed in HG-induced HSF. Linagliptin, a Dpp4 inhibitor, played the antifibrotic role in HSF exposed to HG, the levels of Col1, Col3 and α-SMA were significantly downregulated, and the cell proliferation and migration were also inhibited. Furthermore, linagliptin alleviated the phosphorylated protein expression of IGF/Akt/mTOR signalling pathway. Moreover, the mTOR inhibitor (rapamycin) mimicked the effect of linagliptin on the collagen and α-SMA that means linagliptin may inhibit HG-induced transdifferentiation of HSF to myofibroblasts via IGF/Akt/mTOR signalling pathway.


Comprehensive bioinformatics and machine learning analysis identify VCAN as a novel biomarker of hepatitis B virus-related liver fibrosis.
Hepatitis B virus (HBV) infection remains the leading cause of liver fibrosis (LF) worldwide, especially in China. Identification of decisive diagnostic biomarkers for HBV-associated liver fibrosis (HBV-LF) is required to prevent chronic hepatitis B (CHB) from progressing to liver cancer and to more effectively select the best treatment strategy. We obtained 43 samples from CHB patients without LF and 81 samples from CHB patients with LF (GSE84044 dataset). Among these, 173 differentially expressed genes (DEGs) were identified. Functional analysis revealed that these DEGs predominantly participated in immune-, extracellular matrix-, and metabolism-related processes. Subsequently, we integrated four algorithms (LASSO regression, SVM-RFE, RF, and WGCNA) to determine diagnostic biomarkers for HBV-LF. These analyses and receive operating characteristic curves identified the genes for phosphatidic acid phosphatase type 2C (PPAP2C) and versican (VCAN) as potentially valuable diagnostic biomarkers for HBV-LF. Single-sample gene set enrichment analysis (ssGSEA) further confirmed the immune landscape of HBV-LF. The two diagnostic biomarkers also significantly correlated with infiltrating immune cells. The potential regulatory mechanisms of VCAN underlying the occurrence and development of HBV-LF were also analyzed. These collective findings implicate VCAN as a novel diagnostic biomarker for HBV-LF, and infiltration of immune cells may critically contribute to the occurrence and development of HBV-LF.


An Optimized Uncertainty-Aware Training Framework for Neural Networks.
Uncertainty quantification (UQ) for predictions generated by neural networks (NNs) is of vital importance in safety-critical applications. An ideal model is supposed to generate low uncertainty for correct predictions and high uncertainty for incorrect predictions. The main focus of state-of-the-art training algorithms is to optimize the NN parameters to improve the accuracy-related metrics. Training based on uncertainty metrics has been fully ignored or overlooked in the literature. This article introduces a novel uncertainty-aware training algorithm for classification tasks. A novel predictive uncertainty estimate-based objective function is defined and optimized using the stochastic gradient descent method. This new multiobjective loss function covers both accuracy and uncertainty accuracy (UA) simultaneously during training. The performance of the proposed training framework is compared from different aspects with other UQ techniques for different benchmarks. The obtained results demonstrate the effectiveness of the proposed framework for developing the NN models capable of generating reliable uncertainty estimates.


Potentiation of gamma-aminobutyric acidA receptor Cl- current correlates with in vivo anesthetic potency.
Ten general anesthetics of varying structure and potency were investigated for possible modulatory effects on gamma-aminobutyric acid, (GABAA) receptors, using the voltage clamp technique. All 10 anesthetics studied were observed to prolong the duration of responses to exogenously applied GABA recorded in cultured rat hippocampal neurons. These modulatory effects of the anesthetics occurred at pharmacologically relevant concentrations. An excellent correlation exists between drug potency as modulators of the GABAA receptor and anesthetic potency in vivo. These data suggest an alternative interpretation of the historical association between anesthetic potency and lipophilicity. It is proposed that hydrophobic binding sites on ligand-gated ion channel proteins, such as the GABAA receptors, constitute a molecular target site for many general anesthetics.


Neurological adverse events of immune checkpoint inhibitors: An update of clinical presentations, diagnosis, and management.
The use of immune checkpoint inhibitors (ICIs) has represented a major advance in cancer treatment. By enhancing endogenous immune responses to destroy cancer cells, ICIs can cause immune-related adverse events (irAEs), with possible involvement of any organ system. IrAEs are frequent, particularly those involving the skin or the endocrine system, and usually completely reversible after temporary immunosuppression, while neurological irAEs (n-irAEs) are relatively rare, often severe, and they carry a considerable risk of mortality and long-term disability. They usually affect the peripheral nervous system, mainly manifesting as myositis, polyradiculoneuropathy, or cranial neuropathy, and, less frequently, involve the central nervous system, causing encephalitis, meningitis, or myelitis. Although somehow reminiscent of the disorders that neurologists are familiar to deal with in their daily practice, n-irAEs are characterized by distinctive features from their idiopathic counterparts; for instance, myositis may have a predominant oculo-bulbar involvement reminiscent of myasthenia gravis and frequently associates with myocarditis; peripheral neuropathy, although often resembling Guillain-Barré syndrome, usually responds to corticosteroids. Remarkably, several associations between the neurological phenotype and the type of ICIs or the type of cancer have emerged in the last few years, and the growing administration of ICIs in patients with neuroendocrine cancers has led to an increased number of reports of paraneoplastic neurological syndromes (triggered or worsened by ICIs). This review aims to update current knowledge regarding the clinical presentation of n-irAEs. We also discuss the essential parts of the diagnostic approach, and we provide general recommendations for the management of these disorders.


Secondary Leiomyosarcoma of the Lower Limb Following Uterine Smooth Muscle Tumor of Uncertain Malignant Potential.
This report presents uterine smooth muscle tumors of uncertain malignant potential course with an unpredictable clinical behavior and late metastases. Metastases have been described to the humerus, lung, and peritoneum. Hereby we present the case of a 71-year-old woman with a past surgical history of hysterectomy and bilateral adnexectomy due to a smooth muscle tumor of unknown malignant potential, who was evaluated 6 years later after the appearance of a mass in the proximal third of the right lower limb. The mass was diagnosed as a G1 epithelioid leiomyosarcoma and was surgically removed with immediate reconstruction with a tendinous transfer to the tibialis posterior muscle to maintain foot dorsiflexion. Patients diagnosed with smooth uterine muscle tumors of uncertain malignant potential should be closely followed up given the possibility of recurrence and late metastases, bearing in mind uncommon locations as well, such as the lower limb.


Venom-derived peptide inhibitors of voltage-gated potassium channels.
Voltage-gated potassium channels play a key role in human physiology and pathology. Reflecting their importance, numerous channelopathies have been characterised that arise from mutations in these channels or from autoimmune attack on the channels. Voltage-gated potassium channels are also the target of a broad range of peptide toxins from venomous organisms, including sea anemones, scorpions, spiders, snakes and cone snails; many of these peptides bind to the channels with high potency and selectivity. In this review we describe the various classes of peptide toxins that block these channels and illustrate the broad range of three-dimensional structures that support channel blockade. The therapeutic opportunities afforded by these peptides are also highlighted. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.'


Alcohol and Drug Use and Aberrant Drug-Related Behavior Among Patients on Chronic Opioid Therapy.
To better identify individuals on chronic opioid therapy (COT) at high risk for aberrant-drug related behavior (ADRB). We examine whether patients with low level alcohol and drug use have similar characteristics to those with alcohol and drug disorders. We then examined the relationship of alcohol and drug use to ADRBs among COT patients. The sample was 972 randomly selected COT patients (age 21-80 years old) from a large health system in Northern California, USA, and interviewed in 2009. Logistic regression models were used to model the dependent variables of: alcohol use, illicit drug use, alcohol disorders, illicit drug disorders, and ADRBs. The odds of daily/weekly alcohol use were lower for those with a high daily opioid dose (120+ mg/day vs. <20 mg/day) (OR = 0.32, p < 0.010). Illicit drug disorders were associated with depression (OR = 2.31, p < .001) and being on a high daily opioid dose (OR = 5.51, p < .01). Participants with illicit drug use had higher odds of giving (OR = 2.57, p < 0.01) and receiving opioids from friends or family (OR = 3.25, p < 0.001), but disorder diagnoses were not associated with ADRBs. Findings reinforce that illicit drug use should be of high concern to clinicians prescribing opioids, and suggest it should be considered separately from alcohol use and alcohol disorders in the evaluation of ADRBs. Frequent alcohol use is low, but not uncommon, and suggests a need to discuss specific issues regarding safe use of opioids among persons who use alcohol that may differ from their risk of drug use.


IGF-1 assessed by pubertal status has the best positive predictive power for GH deficiency diagnosis in peripubertal children.
Background When evaluating peripubertal short stature patients, the interpretation of insulin-like growth factor 1 (IGF-1) levels based on chronological age (CA) can be inaccurate due to the influence of sex steroids and, presently, there is no evidence to support the assessment of IGF-1 values according to bone age (BA) and pubertal status (PS). Our objective was to assess the discriminatory performance of IGF-1 levels based on CA, BA and PS in the diagnosis of growth hormone (GH) deficiency. Methods We evaluated IGF-1 levels from 154 peripubertal short stature patients classified as GH deficient (GHD, n=23) or non-GHD (n=131). IGF-1 was assayed by a chemiluminescent immunometric assay and transformed into standard deviation scores (SDS) according to CA (IGF-1-SDS-CA), BA (IGF-1-SDS-BA) and PS (IGF-1-SDS-PS). Results The performances of IGF-1-SDS-CA, IGF-1-SDS-BA and IGF-1-SDS-PS in the receiver operator characteristics (ROC) curves were similar. There were greater accuracy and specificity of IGF-1-SDS-PS (98.4% and 93.3%, respectively) and IGF-1-SDS-BA (92.7% and 90.1%, respectively) when compared to IGF-1-SDS-CA (65.6% and 69.5%, respectively). The post-test probability of the IGF-1-SDS was also improved when compared to PS and BA - 44.8% (IGF-1-SDS-PS), 16.8% (IGF-1-SDS-BA) and 5.1% (IGF-1-SDS-CA), with similar negative predictive values. Conclusions The evaluation of IGF-1 levels based on CA has a higher sensitivity than those based on BA or PS, which justify its use as a screening tool. Additionally, IGF-1 assessed by PS has the best positive predictive power for GHD diagnosis in peripubertal age and could reduce the necessity of a second GH stimulation test.


Intestinal parasitic infection alters bone marrow derived dendritic cell inflammatory cytokine production in response to bacterial endotoxin in a diet-dependent manner.
Giardia lamblia is a common intestinal parasitic infection that although often acutely asymptomatic, is associated with debilitating chronic intestinal and extra-intestinal sequelae. In previously healthy adults, a primary sporadic Giardia infection can lead to gut dysfunction and fatigue. These symptoms correlate with markers of inflammation that persist well after the infection is cleared. In contrast, in endemic settings, first exposure occurs in children who are frequently malnourished and also co-infected with other enteropathogens. In these children, Giardia rarely causes symptoms and associates with several decreased markers of inflammation. Mechanisms underlying these disparate and potentially enduring outcomes following Giardia infection are not presently well understood. A body of work suggests that the outcome of experimental Giardia infection is influenced by the nutritional status of the host. Here, we explore the consequences of experimental Giardia infection under conditions of protein sufficiency or deficiency on cytokine responses of ex vivo bone marrow derived dendritic cells (BMDCs) to endotoxin stimulation. We show that BMDCs from Giardia- challenged mice on a protein sufficient diet produce more IL-23 when compared to uninfected controls whereas BMDCs from Giardia challenged mice fed a protein deficient diet do not. Further, in vivo co-infection with Giardia attenuates robust IL-23 responses in endotoxin-stimulated BMDCs from protein deficient mice harboring enteroaggregative Escherichia coli. These results suggest that intestinal Giardia infection may have extra-intestinal effects on BMDC inflammatory cytokine production in a diet dependent manner, and that Giardia may influence the severity of the innate immune response to other enteropathogens. This work supports recent findings that intestinal microbial exposure may have lasting influences on systemic inflammatory responses, and may provide better understanding of potential mechanisms of post-infectious sequelae and clinical variation during Giardia and enteropathogen co-infection.


Evidence for diversity of Plasmodium falciparum sporozoite surface antigens derived from analysis of antibodies elicited in humans.
We have compared the reactivities of antibodies developed by individuals frequently exposed to Plasmodium falciparum infections with the epitopes contained within the repeats of the circumsporozoite (CS) protein and their reactivities with the epitopes of a native molecule(s) accessible on the sporozoite surface. Results of direct-binding assays and competition assays between artificial and native molecules or between human antibodies and anti-CS monoclonal antibodies suggest that humans respond preferentially to epitopes not contained within the repeats of the CS protein and probably not contained in the whole CS protein. Human monoclonal antibodies reactive with P. falciparum sporozoite surface antigens were produced by Epstein-Barr virus transformation of human lymphocytes. Their pattern of reactivity with sporozoites from a number of different isolates indicates the existence of several distinct epitopes on the parasite surface. Differences between isolates and between sporozoites within a given sample were observed. No single human monoclonal antibody capable of detecting an epitope expressed in all the parasites studied was found.


Degradation profile and preliminary clinical testing of a resorbable device for ligation of blood vessels.
A resorbable device for ligation of blood vessels was developed and tested in vitro to reveal the degradation profile of the device and to predict the clinical performance in terms of adequate mechanical support during a healing period of 1week. In addition, preliminary clinical testing was performed that showed complete hemostasis and good tissue grip of renal arteries in five pigs. The device was made by injection molding of poly(glycolide-co-trimethylene carbonate) triblock copolymer, and it consisted of a case with a locking mechanism connected to a partly perforated flexible band. A hydrolytic degradation study was carried out for 7, 30 and 60days in water and buffer medium, following the changes in mass, water absorption, pH and mechanical properties. A new rapid matrix-free laser desorption ionization-mass spectrometry (LDI-MS) method was developed for direct screening of degradation products released into the degradation medium. The combination of LDI-MS and electrospray ionization-mass spectrometry analyses enabled the comparison of the degradation product patterns in water and buffer medium. The identified degradation products were rich in trimethylene carbonate units, indicating preferential hydrolysis of amorphous regions where trimethylene units are located. The crystallinity of the material was doubled after 60days of hydrolysis, additionally confirming the preferential hydrolysis of trimethylene carbonate units and the enrichment of glycolide units in the remaining solid matrix. The mechanical performance of the perforated band was followed for the first week of hydrolysis and the results suggest that sufficient strength is retained during the healing time of the blood vessels.


Functional morphology of the forelimb of tupaiids (Mammalia, Scandentia) and its phylogenetic implications.
In this study, the forelimb of 12 species of tupaiids was analyzed functionally and compared to that of other archontan mammals. Several differences that relate to differential substrate use were found in the forelimb morphology of tupaiids. These differences included shape of the scapula, length and orientation of the coracoid process, size of the lesser tuberosity, shape of the capitulum, length of the olecranon process, and shape of the radial head and central fossa. The forelimb of the arboreal Ptilocercus lowii, the only ptilocercine, is better adapted for arboreal locomotion, while that of tupaiines is better adapted for terrestrial (or scansorial) locomotion. While the forelimb of the arboreal Ptilocercus appears to be habitually flexed and exhibits more mobility in its joints, a necessity for movement on uneven, discontinuous arboreal supports, all tupaiines are characterized by more extended forelimbs and less mobility in their joints. These restricted joints limit movements more to the parasagittal plane, which increases the efficiency of locomotion on a more even and continuous surface like the ground. Even the most arboreal tupaiines remain similar to their terrestrial relatives in their forelimb morphology, which probably reflects the terrestrial ancestry of Tupaiinae (but not Tupaiidae). The forelimb of Urogale everetti is unique among tupaiines in that it exhibits adaptations for scratch-digging. Several features of the tupaiid forelimb reflect the arboreal ancestry of Tupaiidae and it is proposed that the ancestral tupaiid was arboreal like Ptilocercus. Also, compared to the forelimb character states of tupaiines, those of Ptilocercus are more similar to those of other archontans and it is proposed that the attributes of the forelimb of Ptilocercus are primitive for the Tupaiidae. Hence, Ptilocercus should be considered in any phylogenetic analysis that includes Scandentia.


Cardiovascular imaging environment: will the future be cloud-based?
In cardiovascular CT and MR imaging large datasets have to be stored, post-processed, analyzed and distributed. Beside basic assessment of volume and function in cardiac magnetic resonance imaging e.g., more sophisticated quantitative analysis is requested requiring specific software. Several institutions cannot afford various types of software and provide expertise to perform sophisticated analysis. Areas covered: Various cloud services exist related to data storage and analysis specifically for cardiovascular CT and MR imaging. Instead of on-site data storage, cloud providers offer flexible storage services on a pay-per-use basis. To avoid purchase and maintenance of specialized software for cardiovascular image analysis, e.g. to assess myocardial iron overload, MR 4D flow and fractional flow reserve, evaluation can be performed with cloud based software by the consumer or complete analysis is performed by the cloud provider. However, challenges to widespread implementation of cloud services include regulatory issues regarding patient privacy and data security. Expert commentary: If patient privacy and data security is guaranteed cloud imaging is a valuable option to cope with storage of large image datasets and offer sophisticated cardiovascular image analysis for institutions of all sizes.


Interaction of 17β-estradiol and dietary fatty acids on energy and glucose homeostasis in female mice.
Fatty acid-induced hypothalamic inflammation (HI) is a potential cause of the obesity epidemic. It is unclear whether saturated or n-6 polyunsaturated fat is the primary driver of these effects. Premenopausal women are protected, in part, from obesity and associated comorbidities by circulating 17β-estradiol (E2). It is unknown how HI interacts with E2, because most studies of HI do not examine females despite the involvement of E2 in hypothalamic energy homeostasis. Our objective is to determine the effects of high-fat diets with varying levels of linoleic acid (LA) and saturated fat on the energy and glucose homeostasis in female mice with and without E2. Female C57BL/6J mice were fed either a control diet or a 45% kilocalories from fat diet with varying levels of LA (1, 15, or 22.5% kilocalories from LA) with or without E2 (300 μg/kg/day orally). After 8 weeks, the oil-treated high-fat groups gained more weight than control groups regardless of fat type. E2 reduced body fat accumulation in all high-fat groups. Glucose clearance from glucose challenge was impaired by LA. Nighttime O2 consumption was increased by E2, regardless of diet and independent of activity. Neuropeptides and HI genes were not affected by LA or SFA content. These data show that fatty acid type does not affect body weight, but does affect glucose metabolism in females, and these effects are not associated with an induction in HI gene expression.


Abnormal Mitochondria-Endoplasmic Reticulum Communication Promotes Myocardial Infarction.
Myocardial infarction is characterized by cardiomyocyte death, and can be exacerbated by mitochondrial damage and endoplasmic reticulum injury. In the present study, we investigated whether communication between mitochondria and the endoplasmic reticulum contributes to cardiomyocyte death after myocardial infarction. Our data demonstrated that hypoxia treatment (mimicking myocardial infarction) promoted cardiomyocyte death by inducing the c-Jun N-terminal kinase (JNK) pathway. The activation of JNK under hypoxic conditions was dependent on overproduction of mitochondrial reactive oxygen species (mtROS) in cardiomyocytes, and mitochondrial division was identified as the upstream inducer of mtROS overproduction. Silencing mitochondrial division activators, such as B cell receptor associated protein 31 (BAP31) and mitochondrial fission 1 (Fis1), repressed mitochondrial division, thereby inhibiting mtROS overproduction and preventing JNK-induced cardiomyocyte death under hypoxic conditions. These data revealed that a novel death-inducing mechanism involving the BAP31/Fis1/mtROS/JNK axis promotes hypoxia-induced cardiomyocyte damage. Considering that BAP31 is localized within the endoplasmic reticulum and Fis1 is localized in mitochondria, abnormal mitochondria-endoplasmic reticulum communication may be a useful therapeutic target after myocardial infarction.


[Evolvement of Acupuncture Needle Manipulation Techniques Described in Textbooks of Acupuncture and Moxibustion of Successive Editions].
This paper summarizes the evolvement of the needle manipulation techniques described in the textbooks of Acupuncture and Moxibustion of the past successive 10 editions in Chinese, analyzes the reasons for the evolvement and its impact on clinical treatment, and proposes future developing trends. After analyzing characteristics of needle-manipulation techniques of the well-known Chinese acupuncture specialists, and those described in multi-editions of the textbooks, we found that the currently evoluted contents primarily contain the definition and types of manipulating techniques. However, the reasons for the evolvement and connotation of needle manipulating are probably due to a) undefined descriptions in the history; b) changes in the academic studies and clinical application of acupuncture and moxibustion during the textbook compilation; c) the well-known specialists' and the participated editors' academic thoughts; d) the textbook content setting needs, etc. The evolvement reflects the changed preoccupations of factors affecting clinical efficacy of acupuncture manipulations, and facilitates the implementation of standardized clinical operative procedures. The development of current acupuncture needle manipulation techniques emphasizes the quantification of manual manipulations, fits clinical needs, and pays more attention to the pressing hand during needle insertion.


Hypertension among Asians and Pacific islanders in California.
Hypertension is investigated among Asians and Pacific islanders in California. Descriptive rates are provided for four Asian and Pacific islander ethnic-sex-age subgroupings. Overall, Filipinos have rates of hypertension nearly equal to those of American blacks and, in some large demographic categories, have prevalence rates comparable to blacks. Uncontrolled hypertension is shown to be related to overall health levels measured by life expectancy, chronologic age, and relative body weight. Change in dietary patterns toward the adoption of American foods increases both relative body weight and the risk of hypertension. The adjusted rates of hypertension are similar for men and women after the effects of relative body weight, alcohol consumption, and other variables are removed. A psychologic dimension of variables, including excess alcohol intake and proneness to depression and boredom, increases prevalence of high blood pressure. Social support mechanisms such as marriage, religious affiliation, and a large number of friends are associated with lower levels of hypertension. Many predictor variables are analyzed along with reasons for the high prevalence rates of hypertension for Filipinos and low rates for Japanese.


Spatial Dependence of Reduced Sulfur in Everglades Dissolved Organic Matter Controlled by Sulfate Enrichment.
Sulfate inputs to the Florida Everglades stimulate sulfidic conditions in freshwater wetland sediments that affect ecological and biogeochemical processes. An unexplored implication of sulfate enrichment is alteration of the content and speciation of sulfur in dissolved organic matter (DOM), which influences the reactivity of DOM with trace metals. Here, we describe the vertical and lateral spatial dependence of sulfur chemistry in the hydrophobic organic acid fraction of DOM from unimpacted and sulfate-impacted Everglades wetlands using X-ray absorption spectroscopy and ultrahigh-resolution mass spectrometry. Spatial variation in DOM sulfur content and speciation reflects the degree of sulfate enrichment and resulting sulfide concentrations in sediment pore waters. Sulfur is incorporated into DOM predominantly as highly reduced species in sulfidic pore waters. Sulfur-enriched DOM in sediment pore waters exchanges with overlying surface waters and the sulfur likely undergoes oxidative transformations in the water column. Across all wetland sites and depths, the total sulfur content of DOM correlated with the relative abundance of highly reduced sulfur functionality. The results identify sulfate input as a primary determinant on DOM sulfur chemistry to be considered in the context of wetland restoration and sulfur and trace metal cycling.


Localization of massless Dirac particles via spatial modulations of the Fermi velocity.
The electrons found in Dirac materials are notorious for being difficult to manipulate due to the Klein phenomenon and absence of backscattering. Here we investigate how spatial modulations of the Fermi velocity in two-dimensional Dirac materials can give rise to localization effects, with either full (zero-dimensional) confinement or partial (one-dimensional) confinement possible depending on the geometry of the velocity modulation. We present several exactly solvable models illustrating the nature of the bound states which arise, revealing how the gradient of the Fermi velocity is crucial for determining fundamental properties of the bound states such as the zero-point energy. We discuss the implications for guiding electronic waves in few-mode waveguides formed by Fermi velocity modulation.


Adolescents' parent and peer relationships.
High school seniors (N = 89) from a suburban private high school were administered a comprehensive questionnaire to determine differences between adolescents who rated the quality of their parent and peer relationships as high or low. Adolescents with high parent and high peer relationship scores had more friends, greater family togetherness, lower levels of depression and drug use, and a higher grade point average.


Impact of music type on motor coordination task performance among introverted and extroverted students.
Purpose. People are interested in music. In this study, we assessed the impact of music type on objective performance. Materials and methods. We distributed 64 medical science students in Tehran into four groups: Iranian pop music, traditional music, Mozart's classical music and control groups. All participants performed the two-arm coordination test once without music and once with music (except for the control group), with an interval of 1 week. In the music groups, music was playing during the performance of the test. Participants were categorized as either introverted or extroverted and were distributed equally in the groups. Results. There was a significant decrease of test time in the second trial, observed in all music groups, and no significant difference identified in the control group. The traditional music group had less difference of mean time compared to the pop music group. The differences in the traditional and classical groups were not significantly different. In the music groups, both extroverted and introverted students decreased their test time significantly after music intervention, but extroverted students decreased more. Conclusion. Listening to music would enhance the speed of performance. Music with a higher tempo, such as pop music, increased the speed more.


Synthesis of Novel Thieno[2,3-d]pyrimidine Derivatives and Evaluation of Their Cytotoxicity and EGFR Inhibitory Activity.
4-Substitutedaminoquinazoline scaffolds were reported to possess potent cytotoxic and EGFR inhibitory activity such as gefitinib (Iressa), erlotinib (Tarceva) and tandutinib. Synthesis of novel 4-substitutedaminothieno[2,3-d]pyrimidine derivatives as bioisosters of 4-substitutedaminoquinazoline derivatives with potential cytotoxic and EGFR inhibitory activity. Novel 4-substitutedaminothieno[2,3-d]pyrimidine derivatives 4a-i and 5a-c were synthesized via reacting corresponding 4-chlorothieno[2,3-d]pyrimidine derivatives 3a-c with N-methylpiperazine, morpholine, N-phenylpiperazine or 1,3-propanediamine. Six compounds (2a, 4d, 4e, 5a-c) were selected by the National Cancer Institute (USA) for evaluating their cytotoxic activity using 60 different human tumor cell lines using a single dose (10-5 Molar). The rest of the synthesized compounds (2b, 2c, 3a-c, 4a-c and 4f-i) were subjected to screening against T47D breast cancer cell line using a single dose (10-5 Molar) at Pharmacology lab., Cancer biology lab., Egyptian National Institute. Moreover, compounds 2a and 4b-e were subjected to further evaluation by IC50 determination. Finally, the inhibition of epidermal growth factor receptor (EGFR) was then investigated for the most active compounds 2a and 4d. Compounds 2a and 4b-e showed significant cytotoxic activity. Compound 2a was more potent than doxorubicin against lung cancer cell line A549 with IC50 = 13.40 μM and comparable activity against MCF7. Compound 4d exhibited more potent activity than Doxorubicin against prostate PC3 (IC50 = 14.13 µM) while showed comparable activity against MCF7 and T47D. 4-Substitutedaminothieno[2,3-d]pyrimidine is a promising backbone for the design and synthesis of potent cytotoxic leads.


Very high volume hemofiltration with the Cascade system in septic shock patients.
We compared hemodynamic and biological effects of the Cascade system, which uses very high volume hemofiltration (HVHF) (120 mL kg(-1) h(-1)), with those of usual care in patients with septic shock. Multicenter, prospective, randomized, open-label trial in three intensive care units (ICU). Adults with septic shock with administration of epinephrine/norepinephrine were eligible. Patients were randomized to usual care plus HVHF (Cascade group), or usual care alone (control group). Primary end point was the number of catecholamine-free days up to 28 days after randomization. Secondary end points were number of days free of mechanical ventilation, renal replacement therapy (RRT) or ICU up to 90 days, and 7-, 28-, and 90-day mortality. We included 60 patients (29 Cascade, 31 usual care). Baseline characteristics were comparable. Median number of catecholamine-free days was 22 [IQR 11-23] vs 20 [0-25] for Cascade vs control; there was no significant difference even after adjustment. There was no significant difference in number of mechanical ventilation-free days or ICU requirement. Median number of RRT-free days was 85 [46-90] vs 74 [0-90] for Cascade vs control groups, p = 0.42. By multivariate analysis, the number of RRT-free days was significantly higher in the Cascade group (up to 25 days higher after adjustment). There was no difference in mortality at 7, 28, or 90 days. Very HVHF using the Cascade system can safely be used in patients presenting with septic shock, but it was not associated with a reduction in the need for catecholamines during the first 28 days.


[A study on the prediction of long-term prognosis of adulthood epilepsy].
We report results of a study on the relation between the clinical findings 2 years after initiation of the therapy and the long-term prognosis of seizure control, and discuss the possibility of predicting the prognosis in the early stage of therapy. The subjects consisted of 141 patients, observed for 10 to 20 years at Hirosaki University Hospital. Regarding the epilepsy type, the prognosis of temporal lobe epilepsy was unfavorable. In temporal lobe epilepsy, only 21% were in remission (seizure-free for 3 years or more) at the time of the study. Also, the presence of organic brain lesions or neuropsychiatric complications at the early stage of treatment was associated with unfavorable prognosis. We are particularly interested in the possibility of predicting the long-term prognosis from the result of early response to anti-epileptic drug therapy. We found a significant correlation between the early excellent response to drug treatment and the good long-term prognosis. Using discriminant analysis (quantification theory II), we tried to find which factors would influence more to the long-term prognosis. As the result, an importance was found in the following order: (1) epilepsy type, (2) presence or absence of neuropsychiatric complications, (3) age at onset, (4) early response to treatment, (5) presence or absence of organic brain lesions and (6) the interval between the onset and the initiation of drug treatment. Correct identification rate by discriminant analysis was 73%.


Becoming men: Gender, disability, and transitioning to adulthood.
Children and youth with progressive conditions are living longer, and there is increased interest in designing programs that will assist them with "transitioning" to adulthood. Almost none of the transitions research to date, however, has attended to the experiences of disabled boys in "becoming men," nor has there been critical conceptual work problematizing notions of "normal" adulthood or theorizing the complex, diverse, and gendered experiences of transitioning. In this Canadian study, we investigated the intersectionality of gender, disability, and emerging adulthood with 15 young men with Duchenne muscular dystrophy. Participants created audio diaries and photographs that were explored in in-depth interviews. Using a Bourdieusian lens and Arthur Frank's notion of the narrative habitus, we examined how participants re/negotiated identities in everyday practices. Our analysis suggested that disability, masculinities, and generational (life stage) identities intersected through "narratives of nondifference," wherein participants worked to establish identities as typical "guys." Within limited fields of school and work, participants distanced themselves from the label of "disabled" and discussed their successes and challenges in terms of normative developmental trajectories. We suggest that the pursuit of "normal" is reproduced and reinforced in health and social programs and closes off other narratives and possibilities.


Animal Board Invited Review: Comparing conventional and organic livestock production systems on different aspects of sustainability.
To sustainably contribute to food security of a growing and richer world population, livestock production systems are challenged to increase production levels while reducing environmental impact, being economically viable, and socially responsible. Knowledge about the sustainability performance of current livestock production systems may help to formulate strategies for future systems. Our study provides a systematic overview of differences between conventional and organic livestock production systems on a broad range of sustainability aspects and animal species available in peer-reviewed literature. Systems were compared on economy, productivity, environmental impact, animal welfare and public health. The review was limited to dairy cattle, beef cattle, pigs, broilers and laying hens, and to Europe, North America and New Zealand. Results per indicators are presented as in the articles without performing additional calculations. Out of 4171 initial search hits, 179 articles were analysed. Studies varied widely in indicators, research design, sample size and location and context. Quite some studies used small samples. No study analysed all aspects of sustainability simultaneously. Conventional systems had lower labour requirements per unit product, lower income risk per animal, higher production per animal per time unit, higher reproduction numbers, lower feed conversion ratio, lower land use, generally lower acidification and eutrophication potential per unit product, equal or better udder health for cows and equal or lower microbiological contamination. Organic systems had higher income per animal or full time employee, lower impact on biodiversity, lower eutrophication and acidification potential per unit land, equal or lower likelihood of antibiotic resistance in bacteria and higher beneficial fatty acid levels in cow milk. For most sustainability aspects, sometimes conventional and sometimes organic systems performed better, except for productivity, which was consistently higher in conventional systems. For many aspects and animal species, more data are needed to conclude on a difference between organic and conventional livestock production systems.


Glucose variability and mortality in patients hospitalized with acute myocardial infarction.
Mean blood glucose (BG) during acute myocardial infarction (AMI) is an important predictor of inpatient mortality but does not capture glucose variability (GV), which has been shown to be independently associated with mortality in critically ill patients. Whether GV is associated with in-hospital mortality during AMI, after accounting for mean BG, is unknown. We analyzed 18 563 consecutive patients with AMI with ≥3 BGs in the first 48 hours admitted to 61 US hospitals from 2000 to 2008. Five different GV metrics were compared for their ability to predict in-hospital mortality (range, standard deviation, mean amplitude of glycemic excursions, mean absolute glucose change, and average daily risk range) using hierarchical logistic regression models that sequentially adjusted for mean BG, hypoglycemia (<70 mg/dL), and multiple patient characteristics. In unadjusted analyses, range and average daily risk range had the highest C-indices (0.620 for range, 0.635 for average daily risk range; both P<0.0001). Greater GV was associated with higher mortality for all metrics (eg, mortality was 3.8%, 5.5%, 7.1%, and 11.3% for increasing quartiles of range, P<0.0001); however, the association between GV and mortality for each metric was no longer significant after multivariable adjustment. In contrast, mean BG remained an important predictor of survival (P<0.001, all models). Although greater GV is associated with increased risk of in-hospital mortality in patients with AMI in unadjusted analyses, GV is no longer independently predictive after controlling for multiple patient factors, including mean BG. These findings suggest that GV does not provide additional prognostic value above and beyond already recognized risk factors for mortality during AMI.


[Exploration and reflection on evaluation methodology of human use experience for new Chinese drug development].
The "triple combination" review system provides an opportunity for the transformation of human use experience into new Chinese drugs. However, there are some methodological and technical limitations in the assessment of human experience. Hence, the efficacy and safety evaluation methods should be established in accordance with the characteristics of Chinese herbs. This study summarized some evidence-based methodology to promote the transformation of human use experience to new Chinese drugs, mainly including the individualized pragmatic randomized controlled trial(RCT), cluster RCT, single-case RCT, single arm RCT with objective performance criteria, and partially nested RCT. As the real world data can be used to support the transformation of human experience, attention should be paid to convenient and efficient collection of data, prudent selection of design types, and adoption of appropriate ana-lysis methods to deal with confounding bias, including multi-factor regression model and propensity score. The newly proposed mixed research method can also be utilized to assess the human use experience, which is suitable for mining the theory of traditional Chinese medicine(TCM) and expert experience from different aspects. Meanwhile, considering the study design requirements and TCM cha-racteristics, this study put forward the common problems and solutions in the development of new Chinese drugs based on human use experience, including how to select the feasible outcome indicators, how to collect prescription data in the case of herb and dosage adjustment, and how to evaluate the comprehensive effectiveness of TCM from the perspective of "combination of disease and syndrome".


Probiotics and Helicobacter pylori infection in children.
Approximately 50 percent of the world population is infected with Helicobacter pylori (H. pylori), with the highest prevalence rates in developing countries. The current guidelines suggest the use of triple therapy as first choice treatment of Helicobacter pylori infection, although the eradication failure rate is more than 30 percent. Current interest in probiotics as therapeutic agents against Helicobacter pylori is stimulated by the increasing resistance of pathogenic bacteria to antibiotics, thus the interest for alternative therapies is a real actual topic. Available data in children indicate that probiotics seem to be efficacious for the prevention of antibiotic associated side-effects, and might be of help for the prevention of Helicobacter pylori complications by decreasing Helicobacter pylori density and gastritis, and for the prevention of Helicobacter pylori colonization or re-infection by inhibiting adhesion to gastric epithelial cells. There is no clear evidence that probiotics may increase the Helicobacter pylori eradication rate.


Responses of dorsal spinal cord blood flow to noxious mechanical stimulation of the skin in anesthetized rats.
In urethane-anesthetized, artificially ventilated rats, alterations in dorsal spinal cord blood flow (SCBF) at the L4-6 level were measured with laser Doppler flowmetry in response to noxious mechanical cutaneous stimulation (pinching) of either a forepaw or a hindpaw. The stimulation was delivered ipsilaterally or contralaterally to the site of blood flow measurement. Pinching of the forepaw or the hindpaw on either side increased mean arterial pressure (MAP) to the same degree. However, the SCBF response to pinching of the ipsilateral hindpaw was significantly greater than that to other stimulations. These responses were not influenced by denervation of the baroreceptors. The responses of SCBF to pinching of the ipsilateral hindpaw persisted both after treatment with phenoxybenzamine and after spinalization at the C1-2 level, whereas the responses to pinching at other sites disappeared. The responses of MAP to stimulation at all four sites became negligible after treatment with phenoxybenzamine and after spinalization at the C1-2 level. These results indicate that noxious mechanical stimulation of the skin produces increases in SCBF via two mechanisms: one is via an elevation of systemic arterial pressure; the other is via a localized spinal mechanism evoked by ipsilateral, segmental inputs.


Loss of Ovarian Hormones and Accelerated Somatic and Mental Aging.
Bilateral oophorectomy in premenopausal women is a unique condition causing the abrupt and premature loss of ovarian hormones, primarily estrogen. Bilateral oophorectomy causes an alteration of several fundamental aging processes at the cellular, tissue, organ, and system levels, leading to multimorbidity, frailty, and reduced survival. However, many questions remain unanswered.


Population attributable fractions for risk factors and disability burden of dementia in Jiangxi Province, China: a cross-sectional study.
In view of the fact that there is no effective treatment for dementia, the number of years that dementia patients have to live with dementia will gradually increase for the rest of their lives, and the disability loss caused by dementia will increase. It is urgent to study the influence of risk factors on dementia by making use of the potential of prevention. The purpose of this study is to quantify the burden of dementia disability attributable to risk factors by assessing the population attributable fractions (PAFs) in Jiangxi Province, which is one of the regions of moderate aging process of China. The prevalence data of nine risk factors were obtained through the Sixth National Health Service Survey in 2018, which covered 2713 older people. Levin's formula was used to calculate the PAF for each risk factor for dementia. We adjusted the PAF for communality between risk factors, and used these values to calculate overall weighted PAFs and the years lived with disability (YLDs), which were attributable to nine risk factors. The number of dementia cases and their proportions that can theoretically be prevented by nine identified risk factors were 111636 (99595-120877) and 66.8% (59.6-72.3), respectively. The total YLDs of dementia were estimated to be 61136 (46463-78369) (males: 36434 [24100-49330], females: 23956 [14716-34589]). Physical inactivity (11639 [8845-14920]), low social contact (9324 [7086-11952]), and hearing loss (5668 [4307-7265] were the top three contributors to dementia. The moderate aging areas represented by Jiangxi Province have great potential in the prevention of dementia. Targeted interventions and management of risk factors can effectively reduce the disability burden of dementia.


The rubber tree genome reveals new insights into rubber production and species adaptation.
The Para rubber tree (Hevea brasiliensis) is an economically important tropical tree species that produces natural rubber, an essential industrial raw material. Here we present a high-quality genome assembly of this species (1.37 Gb, scaffold N50 = 1.28 Mb) that covers 93.8% of the genome (1.47 Gb) and harbours 43,792 predicted protein-coding genes. A striking expansion of the REF/SRPP (rubber elongation factor/small rubber particle protein) gene family and its divergence into several laticifer-specific isoforms seem crucial for rubber biosynthesis. The REF/SRPP family has isoforms with sizes similar to or larger than SRPP1 (204 amino acids) in 17 other plants examined, but no isoforms with similar sizes to REF1 (138 amino acids), the predominant molecular variant. A pivotal point in Hevea evolution was the emergence of REF1, which is located on the surface of large rubber particles that account for 93% of rubber in the latex (despite constituting only 6% of total rubber particles, large and small). The stringent control of ethylene synthesis under active ethylene signalling and response in laticifers resolves a longstanding mystery of ethylene stimulation in rubber production. Our study, which includes the re-sequencing of five other Hevea cultivars and extensive RNA-seq data, provides a valuable resource for functional genomics and tools for breeding elite Hevea cultivars.


Links Between the Amplitude Modulation of Low-Frequency Spontaneous Fluctuation Across Resting State Conditions and Thalamic Functional Connectivity.
A comparison of the different types of resting state reveals some interesting characteristics of spontaneous brain activity that cannot be found in a single condition. Differences in the amplitude of low-frequency fluctuation (ALFF) between the eyes open (EO) and the eyes closed (EC) almost have a spatially distinct pattern with traditional EO-EC activation within sensory systems, suggesting the divergent functional roles of ALFF and activation. However, the underlying mechanism is far from clear. Since the thalamus plays an essential role in sensory processing, one critical step toward understanding the divergences is to depict the relationships between the thalamus and the ALFF modulation in sensory regions. In this preliminary study, we examined the association between the changes of ALFF and the changes of thalamic functional connectivity (FC) between EO and EC. We focused on two visual thalamic nuclei, the lateral geniculate nucleus (LGN) and the pulvinar (Pu). FC results showed that LGN had stronger synchronization with regions in lateral but not in medial visual networks, while Pu had a weaker synchronization with auditory and sensorimotor areas during EO compared with EC. Moreover, the patterns of FC modulation exhibited considerable overlaps with the ALFF modulation, and there were significant correlations between them across subjects. Our findings support the crucial role of the thalamus in amplitude modulation of low-frequency spontaneous activity in sensory systems, and may pave the way to elucidate the mechanisms governing distinction between evoked activation and modulation of low-frequency spontaneous brain activity.


Understanding the Effects of Emergency Experience on Online First-Aid Learning Intention: The Mediating Role of Psychological Distances and Prosociality.
The fast-paced lifestyle resulting from China's rapid economic development has caused more than 500 million sudden cardiac deaths in 2020. Online first-aid education for the public is considered a key potential solution to avoid such incidents and would have great practical value. This study focuses on understanding the impact of past first-aid experience on the intention for online learning of first-aid knowledge and skills from the perspective of individual psychological factors based on the construction level and prosociality theories. More specifically, it tests the mediating roles of psychological distances and prosociality, which reflect psychological status, in the relationship between experience and learning intention along with a series of associated demographic variables. Primary data collected via a survey are analyzed through regression analysis. The results show that first-aid experience has a significant positive impact on online first-aid learning intention. In addition, psychological distances from first-aid events, and prosociality, play mediating roles in the relationship between first-aid experience and learning intention. Thus, this study contributes to understanding first-aid learning intention by revealing the impact of the individual factors of psychological distances and prosociality.


Inhibition of lymphocyte proliferation by antibodies to prolactin.
Recent in vivo studies have shown that treatments that decrease circulating prolactin (PRL) in rodents result in significant immunosuppression. Our attempts to demonstrate corresponding direct stimulatory effects of PRL on cultured lymphocytes were unsuccessful. However, antibodies against pituitary PRL potently inhibited both murine and human lymphocyte proliferation in response to both T and B cell mitogens. Further studies using IL 2 and IL 4 responsive cell lines (CTLL-2 and HT-2) demonstrated that the same anti-PRL antibodies inhibited the proliferative response to these cytokine growth factors. Thus, antibodies to PRL appear to block an event occurring in the G1 to GS phase transition of these cell lines, which constitutively express growth factor receptors. The inhibitory activity of anti-PRL antibodies could be adsorbed by addition of purified human PRL or by immobilized PRL on an affinity column. Antibodies to other pituitary hormones were without inhibitory effect on CTLL-2 cell proliferation. Proliferation of lymphocytes in serum-free medium was also potently inhibited by anti-PRL antibodies, suggesting that antibody effects were not due to neutralization of PRL or other factors contained in culture serum supplements. We suggest from these data that a protein with homology to PRL and recognized by these anti-PRL antibodies is produced by lymphocytes and plays a critical role in their progression through the cell cycle.


[Indications for surgery from the viewpoints of surgeon and juror].
Whether an operation is indicated or not is a question that is a frequent subject of discussion between physicians and the legal front. As the state has the duty to protect its citizens, any physical surgical operation is legally seen as a personal injury. Only if the patient completely agrees to the surgery after being carefully informed about it is the element of criminal offense (personal injury) revoked. The obligation to disclose medical information on the surgery applies to information on the operation itself and on the possible consequences to the patient in his/her physical and mental social environment. In particular, the patient must be given all information about the risks that could arise during and after the surgery. The legislative aim of this is not to treat a list of questions and to mention all possible risks, but the legislator wants to oblige physicians to give patients who have reached the age of majority full information on diagnosis and therapy and to enable them to consider the pros and cons of the surgery carefully and then to agree to the operation or to refuse it. Besides the obligation to disclose medical information in emergency cases, the obligation to disclose medical information to minors also makes heavy demands on the physician. Examples of contraindications are given.


Detection of antibodies in cats infected with filarial parasites by the indirect immunofluorescence technique.
The indirect immunofluorescence technique in cats infected with filarial parasites, Brugia malayi, B. pahangi and D. repens were studied. The antibody level in infected microfilaraemic cats was higher than that in infected amicrofilaraemic cats and uninfected cats. Papain-treated whole microfilariae appeared to be more sensitive than the sonicated antigen. The comparative IFA titres using papain-treated and sonicated microfilarial antigen, in the serodiagnosis of filariasis is presented.


Clinical and radiographic outcomes of an accelerometer-based system for the tibial resection in total knee arthroplasty.
The accelerometer-based system is a portable surgical navigation system for TKA that does not require the use of a large computer console for registration and alignment feedback as required in computer-assisted surgery (CAS). The purpose of this prospective study was to determine the accuracy of the accelerometer-based system in the tibial component positioning and also to evaluate clinical outcomes. Between December 2011 and July 2012, a total of 53 consecutive patients with primary gonarthrosis were prospectively enrolled for unilateral TKA using a handheld surgical navigation system to perform the tibial resection. Pre-operatively and postoperatively, patients were asked to fill out a visual analogue scale for pain (VAS) and a knee injury and osteoarthritis outcome score (KOOS). Standing antero-posterior (AP) hip-knee-ankle (HKA) and lateral knee-to-ankle radiographs were performed to determine the varus/valgus alignment and the posterior slope of the tibial components relative to the mechanical axis. The mean duration of follow-up was 23 months. Average preoperative VAS was 8.3 ± 0.67, which significantly improved to a mean 1.2 ± 0.57 at final follow up (P < 0.001). All scores significantly increased compared with pre-operative scores, except for the KOOS sport component (P = 0.075) and quality of life (P = 0.19). Intra-operatively, the average reading provided by the system with regard to varus/valgus alignment before performing the tibial resection was 0.55° ± 0.43. The average postoperative radiographic alignment of the tibial component in the coronal plane was 0.65° ± 0.59 of deviation by the ideal alignment (P > 0.05). This study demonstrates that the OrthAlign navigation system combines the accuracy of the computer-assisted surgery systems with the ease of use and familiarity of the traditional instruments while avoiding the drawbacks of the CAS technique and disadvantages of conventional IM femoral alignment systems. The system could demonstrate an improvement in the incidence of outliers in final coronal alignment, as compared with a patient-specific cutting guide.


Progressive cerebral degeneration of childhood with liver disease (Alpers Huttenlocher disease) with cytochrome oxidase deficiency presenting with epilepsia partialis continua as the first clinical manifestation.
A previously healthy and normally developed 17-year-old young female presented with a sudden onset of focal motor seizure status that proved to be refractory to anticonvulsive treatment. Severe encephalopathy with visual impairment leading to blindness, mental deterioration, and predominantly left spastic tetraparesis developed progressively. Hepatic disease evolved 4 months after onset of the first symptoms and led to death in hepatic failure 1 month later. Diagnostic studies revealed an elevated protein and lactate in the cerebrospinal fluid, slow-wave and intermittently continuous spike-wave activity in the EEG, and a complex i.v. (cytochrome-C oxidase) deficiency in the muscle biopsy. MRI scans revealed signal abnormalities in the occipital lobe, thalamus, and basal ganglia only after 3 months. Histopathological findings in liver biopsy and in postmortem brain examination displaying widespread predominantly right cortical spongiosis, neuronal loss and astrocytosis were consistent with the clinically suspected diagnosis of progressive neuronal degeneration of childhood with liver disease (PNDC) or Alpers Huttenlocher disease. This rare disorder of unknown origin is usually seen in infants and young children and is rarely reported in adolescence.


Diagnosis of stress.
Stress is defined as a disruption of normal homeostasis. During exposure to stress stimuli, the body responds physiologically by increased activity of both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathoadrenal system (SAS). Stress also gives rise to a number of characteristic behavioral responses. Diagnosis of stress, therefore, depends on a multitude of factors and is complex. A variety of approaches to the diagnosis of stress have been employed, including the use of questionnaires, biochemical measures, and physiologic techniques. Most of these methods are subject to experimental error and must be viewed with caution. A thorough, stress-oriented, face-to-face medical interview is currently the most practicable way to diagnose stress and its effects. It remains for future research to develop a cleaner methodology to diagnose this elusive, yet, all too common medical entity.


Pharmacogenomics: personalizing drug therapy.
Pharmacogenomics is a rapidly growing field of research into the ways in which genetic variation affects drug response. Its objective is to develop precisely targeted, optimal drug therapy. One area of pharmacogenomics focuses on identifying genetic markers for differences in the way people metabolize drugs; another concentrates on developing genetic tests that predict how specific patients will respond to agents such as statins or cancer therapies. Nurses are now called upon to interpret such information or services in order to provide appropriate patient teaching regarding drug selection.


Neural mechanisms of voluntary and involuntary recall: a PET study.
Neuropsychological and neuroimaging studies on episodic memory retrieval have primarily focused on volitional memory tasks. However, some conscious memories arise involuntarily, i.e. without a strategic retrieval attempt, yet little is known about the neural network underlying involuntary episodic memory. The aim of this study was to determine whether voluntary and involuntary recall are mediated by separate cortical networks. We used positron emission tomography (PET) to measure changes in regional cerebral blood flow (rCBF) in 12 healthy subjects during voluntary and involuntary cued recall of pictures and a control condition with no episodic memory requirements. Involuntary recall was elicited by using an incidental memory task. Compared to the control condition, voluntary and involuntary recall were both associated with significant regional cerebral blood flow (rCBF) increases in posterior cingulate gyrus (PCG; BA 23), left precuneus (BA 7), and right parahippocampal gyrus (BA 35/36). In addition, rCBF in right dorsolateral prefrontal cortex (PFC; BA 8/9) and left precuneus (BA 7) was significantly larger during voluntary compared to involuntary recall, while rCBF was enhanced in left dorsolateral PFC (BA 9) during involuntary recall. The findings corroborate an association of the right PFC with a strategic component of episodic memory retrieval. Moreover, they show for the first time that it is possible to activate the medial temporal lobe, the PCG, and the precuneus, regions normally associated with retrieval success, without this strategic element. The relatively higher activity in precuneus during voluntary compared to involuntary recall suggests that activity in this region co-varies not only with retrieval success but also with retrieval intentionality.


Hypoglycaemic effect of Artemisia sphaerocephala Krasch seed polysaccharide in alloxan-induced diabetic rats.
The purpose of this study was to examine the hypoglycaemic activity of a new polysaccharide extracted from seed polysaccharide (ASP) was administered orally for 4 weeks and the blood glucose changes were determined in fasted rats. Plasma insulin, cholesterol and triglycerides levels were also determined. The ASP at a dose of 200 mg/kg body weight (bw) produced a significant decrease in blood glucose levels in diabetic rats (P <0.01). In the other hand, the effect of the ASP on the plasma cholesterol were also significant in diabetic rats (P <0.05). Furthermore, there was a significant effect of ASP on plasma triglycerides in both normal and diabetic groups. In order to characterise the active principle(s), which could be responsible for the therapeutic effect, a preliminary phytochemical analysis of the ASP was performed. The monosaccharides of ASP were composed of L-Ara, D-Xyl, D-Lyx, D-Man, D-Glc, D-Gal. Their molar proportions were 1, 4.98, 1.69, 27.86, 3.76 and 13.92, respectively.


Effect of Lactobacillus strains (L. casei and L. Acidophillus Strains cerela) on bacterial overgrowth-related chronic diarrhea.
Small bowel bacterial overgrowth and related diarrhea is a condition that frequently accompanies anatomic disorders, surgically created blind loops or strictures with partial small bowel obstruction and although it is often controlled with antimicrobial therapy, alternative treatment may be needed. The aim of this study was to evaluate the efficacy of an oral probiotic preparation of 2 viable lyophilized strains of lactobacilli (1.5 g each) compared with placebo. Twenty two patients with proven overgrowth and chronic diarrhea are described. In random order and double-blind fashion, 2 groups of patients received identical capsules with both Lactobacillus casei and L. acidophillus strains CERELA (12 patients) (LC) and placebo (10 patients) (P) during three consecutive periods of 7 days each followed by a similar three periods of control after withdrawal. At the end of each period the mean daily number of stools, glucose breath H2 test, and symptoms were considered. Lactobacillus were investigated in feces in both groups at day 0 (baseline), on day 21 of treatment with LC and P and on day 21 after withdrawal. Compared with P a significant reduction in mean daily number of stools was achieved with LC (p < 0.005) at 15 days, and (p < 0.0005) at 21 days and the effect was sustained at 7 days and 15 days (p < 0.005) after withdrawal. With respect to breath H2 level a significant decrease in H2 concentration was noted at 7 days (p < 0.005) at 15 days, and 21 days (p < 0.0001) with LC and only a significant decrease (p < 0.005) was observed at 7 days after withdrawal. No significant changes were observed with respect to symptoms. The Lactobacillus CERELA strains were isolated from the feces in all patients LC (n = 12) on day 21, and by contrast no Lactobacillus were observed except in two patients out of seven patients after withdrawal. In summary, this study provides evidence that LC are effective for treatment of bacterial overgrowth--related chronic diarrhea, and suggest that probiotics must be used with continuity.


Cardiometabolic risk in obese children.
Obesity in childhood remains a significant and prevalent public health concern. Excess adiposity in youth is a marker of increased cardiometabolic risk (CMR) in adolescents and adults. Several longitudinal studies confirm the strong association of pediatric obesity with the persistence of adult obesity and the future development of cardiovascular disease, diabetes, and increased risk of death. The economic and social impact of childhood obesity is further exacerbated by the early onset of the chronic disease burden in young adults during their peak productivity years. Furthermore, rising prevalence rates of severe obesity in youth from disadvantaged and/or minority backgrounds have prompted the creation of additional classification schemes for severe obesity to improve CMR stratification. Current guidelines focus on primary obesity prevention efforts, as well as screening for clustering of multiple CMR factors to target interventions. This review summarizes the scope of the pediatric obesity epidemic, the new severe obesity classification scheme, and examines the association of excess adiposity with cardiovascular and metabolic risk. We will also discuss potential questions for future investigation.


Myocardial injury in patients with intracerebral hemorrhage treated with recombinant factor VIIa.
We report myocardial injury in 20 recombinant factor VIIa (rFVIIa) treated and 110 nontreated patients with intracerebral hemorrhage. Patients were treated or received standard medical management. All received EKG and cardiac enzyme testing. Elevated troponin occurred in 20% treated vs 3% nontreated (p = 0.02). Myocardial infarction occurred in 10% vs 1% (p = 0.01). We found a significant increase in myocardial injury in rFVIIa treated patients.


Subversion of Immune Response by Human Cytomegalovirus.
Human cytomegalovirus (HCMV) is the most common cause of congenital infections and is an important pathogen in immunocompromised individuals. Despite a robust host immune system, HCMV able to replicate, evade host defenses, establish latency for life. A significant portion of HCMV genome dedicated to encode gene products for modulation of host immune response. Growing number of HCMV gene products are being recognized to play role in immune evasion. Information on viral immune evasion mechanisms by which HCMV persists in host will be useful in devising antiviral intervention strategies and development of new vaccines. This minireview provides a brief overview of immune evasion strategy adapted by HCMV by utilizing its gene products in modulation of host immune response.


Host-microbiome interactions in nicotinamide mononucleotide (NMN) deamidation.
The nicotinamide adenine dinucleotide (NAD+ ) precursor nicotinamide mononucleotide (NMN) is a proposed therapy for age-related disease, whereby it is assumed that NMN is incorporated into NAD+ through the canonical recycling pathway. During oral delivery, NMN is exposed to the gut microbiome, which could modify the NAD+ metabolome through enzyme activities not present in the mammalian host. We show that orally delivered NMN can undergo deamidation and incorporation in mammalian tissue via the de novo pathway, which is reduced in animals treated with antibiotics to ablate the gut microbiome. Antibiotics increased the availability of NAD+ metabolites, suggesting the microbiome could be in competition with the host for dietary NAD+ precursors. These findings highlight new interactions between NMN and the gut microbiome.