Management of hepatitis B: Pakistan Society for the Study of Liver Diseases (PSSLD) practice guidelines.
Pakistan remains in the intermediate prevalence area for Hepatitis B with an estimated carrier rate of 2.5%. Chronic Hepatitis B patients should be considered for treatment if Alanine transaminase (ALT) is persistently elevated in the last 6 months and HBV DNA is > 2000 IU/ml, irrespective of HBeAg status. In case of normal ALT and HBV DNA > 2000 IU/ml, treatment should only be considered if there is advanced fibrosis or cirrhosis on liver biopsy. HBV DNA positive cirrhotic patients should receive treatment irrespective of ALT status. Medicine available for the treatment of Hepatitis B in Pakistan are lamivudine, adefovir, telbivudine, entecavir, standard and pegylated interferon and thymosin. Patients who fail to achieve primary response as evidenced by < 2 log decrease in serum HBV DNA level after 6 months of nucleos(t)ide analogue therapy should have modification of treatment. Add-on adefovir therapy is indicated in those showing resistance to lamivudine or else switch to entecavir. For lamivudine-naïve patients who develop drug resistance while on adefovir, add-on or switching to lamivudine, telbivudine or entecavir is indicated. Treatment should be stopped in HBeAg positive patients on oral antiviral agents who seroconvert (disappearance of HBeAg and appearance of anti-HBe antibody) with undetectable HBVDNA documented on two separate occasions at least 6 months apart. In HBeAg negative patients, discontinuation may be considered if undetectable HBV-DNA has been documented on three separate occasions 6 months apart although current evidence seems to support long term therapy in this group.


Transforming growth Factor-beta1 induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway.
Myofibroblasts play an important role in the fibrogenic process of pulmonary fibrosis. Transforming growth factor (TGF)-beta is well known to induce the phenotypic modulation of fibroblasts to myofibroblasts; however, the intracellular signal regulating induction of the myofibroblastic phenotype of human lung fibroblasts (HLF) has not been determined. In the present study, we examined the role of the mitogen-activated protein kinase (MAPK) superfamily in inducing the phenotypic modulation of HLF to myofibroblasts characterized by alpha-smooth-muscle actin expression, in order to clarify this issue. The results showed that: (1) TGF-beta1 caused the phenotypic modulation of HLF to myofibroblasts in a dose- and a time-dependent manner; (2) TGF-beta1 induced increases in c-Jun-NH2- terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (Erk) phosphorylation and activity; (3) the inhibitors CEP-1347, SB 203580, and PD 98059 attenuated TGF-beta1-induced JNK, p38 MAPK, and Erk activity, respectively; and (4) CEP-1347, but not SB 203580 or PD 98059, attenuated the TGF-beta1-induced phenotypic modulation of HLF to myofibroblasts in a dose-dependent manner. These results indicate that TGF-beta1 is capable of inducing the myofibroblastic phenotype of HLF, and that JNK regulates the phenotypic modulation of TGF-beta1-stimulated HLF to myofibroblasts.


Invasive mammal eradication on islands results in substantial conservation gains.
More than US$21 billion is spent annually on biodiversity conservation. Despite their importance for preventing or slowing extinctions and preserving biodiversity, conservation interventions are rarely assessed systematically for their global impact. Islands house a disproportionately higher amount of biodiversity compared with mainlands, much of which is highly threatened with extinction. Indeed, island species make up nearly two-thirds of recent extinctions. Islands therefore are critical targets of conservation. We used an extensive literature and database review paired with expert interviews to estimate the global benefits of an increasingly used conservation action to stem biodiversity loss: eradication of invasive mammals on islands. We found 236 native terrestrial insular faunal species (596 populations) that benefitted through positive demographic and/or distributional responses from 251 eradications of invasive mammals on 181 islands. Seven native species (eight populations) were negatively impacted by invasive mammal eradication. Four threatened species had their International Union for the Conservation of Nature (IUCN) Red List extinction-risk categories reduced as a direct result of invasive mammal eradication, and no species moved to a higher extinction-risk category. We predict that 107 highly threatened birds, mammals, and reptiles on the IUCN Red List-6% of all these highly threatened species-likely have benefitted from invasive mammal eradications on islands. Because monitoring of eradication outcomes is sporadic and limited, the impacts of global eradications are likely greater than we report here. Our results highlight the importance of invasive mammal eradication on islands for protecting the world's most imperiled fauna.


Generation of a New Model Rat: Nrf2 Knockout Rats Are Sensitive to Aflatoxin B1 Toxicity.
THE TRANSCRIPTION FACTOR NRF2: (NF-E2-related-factor 2) REGULATES A BATTERY OF ANTIOXIDATIVE STRESS-RESPONSE GENES AND DETOXICATION GENES, AND NRF2 KNOCKOUT LINES OF MICE HAVE BEEN CONTRIBUTING CRITICALLY TO THE CLARIFICATION OF ROLES THAT NRF2 PLAYS FOR CELL PROTECTION HOWEVER, THERE ARE APPARENT LIMITATIONS IN USE OF THE MOUSE MODELS FOR INSTANCE, RATS EXHIBIT MORE SUITABLE FEATURES FOR TOXICOLOGICAL OR PHYSIOLOGICAL EXAMINATIONS THAN MICE IN THIS STUDY, WE GENERATED 2 LINES OF NRF2 KNOCKOUT RATS BY USING A GENOME EDITING TECHNOLOGY; 1 LINE HARBORS A 7-BP DELETION Δ7 AND THE OTHER LINE HARBORS A 1-BP INSERTION +1 IN THE NRF2 GENE IN THE LIVERS OF RATS HOMOZYGOUSLY DELETING THE NRF2 GENE, AN ACTIVATOR OF NRF2 SIGNALING, CDDO-IM, COULD NOT INDUCE EXPRESSION OF REPRESENTATIVE NRF2 TARGET GENES TO EXAMINE ALTERED TOXICOLOGICAL RESPONSE, WE TREATED THE NRF2 KNOCKOUT RATS WITH AFLATOXIN B1 AFB1, A CARCINOGENIC MYCOTOXIN THAT ELICITS GENE MUTATIONS THROUGH BINDING OF ITS METABOLITES TO DNA AND FOR WHICH THE RAT HAS BEEN PROPOSED AS A REASONABLE SURROGATE FOR HUMAN TOXICITY INDEED, IN THE NRF2 KNOCKOUT RAT LIVERS THE ENZYMES OF THE AFB1 DETOXICATION PATHWAY WERE SIGNIFICANTLY DOWNREGULATED SINGLE DOSE ADMINISTRATION OF AFB1 INCREASED HEPATOTOXICITY AND BINDING OF AFB1-N7-GUANINE TO HEPATIC DNA IN NRF2 KNOCKOUT RATS COMPARED WITH WILD-TYPE NRF2 KNOCKOUT RATS REPEATEDLY TREATED WITH AFB1 WERE PRONE TO LETHALITY AND CDDO-IM WAS NO LONGER PROTECTIVE THESE RESULTS DEMONSTRATE THAT NRF2 KNOCKOUT RATS ARE QUITE SENSITIVE TO AFB1 TOXICITIES AND THIS RAT GENOTYPE EMERGES AS A NEW MODEL ANIMAL IN TOXICOLOGY.


Recombinant human erythropoietin for the treatment of anemia in the myelodysplastic syndromes: a clinical and erythrokinetic assessment.
The clinical and ferrokinetic effects of escalating doses of subcutaneously administered recombinant human erythropoietin (rh-EPO) were studied in ten patients with myelodysplastic syndromes and severe transfusion-dependent anemia. Red blood cell transfusion requirements diminished in four patients, and one of the patients eventually became transfusion independent with an EPO-induced rise of Hb from 7.7 g/dl to 12.3 g/dl. Endogenous serum levels of EPO were significantly increased in all patients (100-5700 mU/ml), but three of four responders had a relatively low baseline level. The effective red cell iron turnover (RCIT) improved in two responding patients and even normalized in one patient. This increase in RCIT was accompanied with a decline in the ineffective red cell iron turnover (IIT). The other responding patients had a relatively preserved RCIT before EPO treatment. EPO therapy further increased the fraction of IIT in the latter patients. Red cell survival time did not increase during EPO therapy, even in the responding patients. One transient and one maintained increase in platelet count were observed. Disease progression with a sustained increase in blast cells in one patient and a transient elevation of blasts in another patient was seen. No other side effects of EPO therapy were observed. These results suggest that anemic MDS patients with low serum EPO levels and relatively spared effective erythropoiesis as measured by ferrokinetic studies may be the best candidates for treatment with recombinant human EPO.


CD103+ tumor-infiltrating lymphocytes are tumor-reactive intraepithelial CD8+ T cells associated with prognostic benefit and therapy response in cervical cancer.
Human papilloma virus (HPV)-induced cervical cancer constitutively expresses viral E6/E7 oncoproteins and is an excellent target for T cell-based immunotherapy. However, not all tumor-infiltrating T cells confer equal benefit to patients, with epithelial T cells being superior to stromal T cells. To assess whether the epithelial T cell biomarker CD103 could specifically discriminate the beneficial antitumor T cells, association of CD103 with clinicopathological variables and outcome was analyzed in the TCGA cervical cancer data set (n = 304) and by immunohistochemistry (IHC) in an independent cohort (n = 460). Localization of CD103+ cells in the tumor was assessed by immunofluorescence. Furthermore, use of CD103 as a response biomarker was assessed in an in vivo E6/E7+ tumor model. Our results show that CD103 gene expression was strongly correlated with cytotoxic T cell markers (e.g. CD8/GZMB/PD1) in the TCGA series. In line with this, CD103+ cells in the IHC series co-expressed CD8 and were preferentially located in cervical tumor epithelium. High CD103+ cell infiltration was strongly associated with an improved prognosis in both series, and appeared to be a better predictor of outcome than CD8. Interestingly, the prognostic benefit of CD103 in both series seemed limited to patients receiving radiotherapy. In a preclinical mouse model, HPV E6/E7-targeted therapeutic vaccination in combination with radiotherapy increased the intratumoral number of CD103+ CD8+ T cells, providing a potential mechanistic basis for our results. In conclusion, CD103 is a promising marker for rapid assessment of tumor-reactive T cell infiltration of cervical cancers and a promising response biomarker for E6/E7-targeted immunotherapy.


Effect of secretin on glomerular dynamics in dogs.
These studies were performed to determine whether a role for increased renal plasma flow (RPF) in the regulation of glomerular filtration rate (GFR) could be demonstrated in dogs by infusing the polypeptide hormone secretin, a vasodilator that has been reported to increase GFR. Differences between control and recollection periods were compared by paired t test in five time-control dogs (group 1) and 10 secretin dogs (group 2). In group 2, secretin (100 mU . kg-1 . min-1, ia) significantly increased single-nephron glomerular filtration rate (SNGFR) 11.1 +/- 3.1 nl/min (20%) and glomerular plasma flow 59 +/- 11 nl/min (26%). Similar increases in GFR (26%) and RPF (29%) were observed. Secretin also increased glomerular capillary pressure 5.2 +/- 0.8 mmHg and free-flow proximal tubule pressure 5.5 +/- 1.0 mmHg. Secretin did not significantly affect average effective filtration pressure (EFP) but significantly increased the ultrafiltration coefficient (Kf) 0.74 +/- 0.14 nl . min-1 . mmHg-1. These differences were significantly greater than those observed in group 2. It is concluded that secretin increased SNGFR primarily by an effect on Kf. This is consistent with the marked effect that Kf is predicted to have on glomerular filtration in dogs. The maintenance of EFP agrees with other vasodilator studies and indicates that GFR is only moderately dependent on plasma flow in dogs.


Predictability and parallelism in the contemporary evolution of hybrid genomes.
Hybridization between species is widespread across the tree of life. As a result, many species, including our own, harbor regions of their genome derived from hybridization. Despite the recognition that this process is widespread, we understand little about how the genome stabilizes following hybridization, and whether the mechanisms driving this stabilization tend to be shared across species. Here, we dissect the drivers of variation in local ancestry across the genome in replicated hybridization events between two species pairs of swordtail fish: Xiphophorus birchmanni × X. cortezi and X. birchmanni × X. malinche. We find unexpectedly high levels of repeatability in local ancestry across the two types of hybrid populations. This repeatability is attributable in part to the fact that the recombination landscape and locations of functionally important elements play a major role in driving variation in local ancestry in both types of hybrid populations. Beyond these broad scale patterns, we identify dozens of regions of the genome where minor parent ancestry is unusually low or high across species pairs. Analysis of these regions points to shared sites under selection across species pairs, and in some cases, shared mechanisms of selection. We show that one such region is a previously unknown hybrid incompatibility that is shared across X. birchmanni × X. cortezi and X. birchmanni × X. malinche hybrid populations.


Stability analysis of a class of noise perturbed neural networks.
We establish robustness stability results for a specific type of artificial neural networks for associative memories under parameter perturbations and determine conditions that ensure the existence of asymptotically stable equilibria of the perturbed neural system that are the asymptotically stable equilibria of the original unperturbed neural network. The proposed stability analysis tool is the sliding mode control and it facilitates the analysis by considering only a reduced-order system instead of the original one and time-dependent external stimuli.


Ligand-directed targeting of lymphatic vessels uncovers mechanistic insights in melanoma metastasis.
Metastasis is the most lethal step of cancer progression in patients with invasive melanoma. In most human cancers, including melanoma, tumor dissemination through the lymphatic vasculature provides a major route for tumor metastasis. Unfortunately, molecular mechanisms that facilitate interactions between melanoma cells and lymphatic vessels are unknown. Here, we developed an unbiased approach based on molecular mimicry to identify specific receptors that mediate lymphatic endothelial-melanoma cell interactions and metastasis. By screening combinatorial peptide libraries directly on afferent lymphatic vessels resected from melanoma patients during sentinel lymphatic mapping and lymph node biopsies, we identified a significant cohort of melanoma and lymphatic surface binding peptide sequences. The screening approach was designed so that lymphatic endothelium binding peptides mimic cell surface proteins on tumor cells. Therefore, relevant metastasis and lymphatic markers were biochemically identified, and a comprehensive molecular profile of the lymphatic endothelium during melanoma metastasis was generated. Our results identified expression of the phosphatase 2 regulatory subunit A, α-isoform (PPP2R1A) on the cell surfaces of both melanoma cells and lymphatic endothelial cells. Validation experiments showed that PPP2R1A is expressed on the cell surfaces of both melanoma and lymphatic endothelial cells in vitro as well as independent melanoma patient samples. More importantly, PPP2R1A-PPP2R1A homodimers occur at the cellular level to mediate cell-cell interactions at the lymphatic-tumor interface. Our results revealed that PPP2R1A is a new biomarker for melanoma metastasis and show, for the first time to our knowledge, an active interaction between the lymphatic vasculature and melanoma cells during tumor progression.


Size-specific ligands for RNA hairpin loops.
The targeting of one mRNA in the transcriptome requires small molecules that bind with substantial affinity and specificity. As such, compounds with specificity for individual RNA secondary structural motifs could be useful for targeting RNA. Described herein is the synthesis of a combinatorial library of 105 dimers of deoxystreptamine and the subsequent identification of compounds with specificity for specific RNA hairpin loop sizes, including tetraloops and octaloops. Such compounds will be useful for the perturbation of RNA function in vivo.


Evaluating Educational Needs of Parents at Newborn Discharge: A Pilot Study.
The delivery of anticipatory guidance regarding newborn care is a standard practice for pediatricians. The purpose of this prospective study was to analyze the preexisting knowledge of routine newborn care in postpartum mothers. Inclusion criteria included all postpartum mothers of live-born infants at least two hours following delivery that had not yet received formal instruction in newborn care. Each eligible mother that agreed to the voluntary survey was asked four multiple-choice questions which evaluated her knowledge of newborn care. The four questions addressed knowledge of safe sleep, car seat position, feeding behavior, and neonatal fever. A standardized template was used to ensure validity. Results were recorded in Microsoft Excel. Of the study population, 42% (55/131) of surveyed mothers were first-time mothers. Overall, results of the survey demonstrated that postpartum mothers answered the surveyed questions correctly 88% of the time previous to receiving anticipatory guidance. Postpartum mothers appear to have a high preexisting knowledge of routine newborn care in this study. Further studies are needed to determine if postpartum mothers' knowledge base increases with inpatient education.


Production of filmable medium-chain-length polyhydroxyalkanoates produced from glycerol by Pseudomonas mediterranea.
Glycerol is an effective carbon source for the production of scl- and mcl-polyhydroxyalkanoates (PHAs) by Pseudomonas spp. P. mediterranea 9.1 (CFBP 5447) synthesizes an amorphous mcl-PHA when grown on crude glycerol, whereas on both reagent grade (RG) and partially refined (PR) glycerol, it produces two very similar distinctive mcl-PHAs with the unusual property of producing, with the appropriate treatment, a transparent film. Mcl-PHAs recovered after biomass extraction have an average molecular weight of approximately 56,000/63,000 Da. The monomer composition and physicochemical properties of such mcl-PHAs suggest their potential application as a softener of biopolymeric blends for food packaging and medical devices.


Seneca Valley Virus Degrades STING via PERK and ATF6-Mediated Reticulophagy.
Seneca Valley Virus (SVV), a member of the Picornaviridae family, is an emerging porcine virus that can cause vesicular disease in pigs. However, the immune evasion mechanism of SVV remains unclear, as does its interaction with other pathways. STING (Stimulator of interferon genes) is typically recognized as a critical factor in innate immune responses to DNA virus infection, but its role during SVV infection remains poorly understood. In the present study, we observed that STING was degraded in SVV-infected PK-15 cells, and SVV replication in the cells was affected when STING was knockdown or overexpressed. The STING degradation observed was blocked when the SVV-induced autophagy was inhibited by using autophagy inhibitors (Chloroquine, Bafilomycin A1) or knockdown of autophagy related gene 5 (ATG5), suggesting that SVV-induced autophagy is responsible for STING degradation. Furthermore, the STING degradation was inhibited when reticulophagy regulator 1 (FAM134B), a reticulophagy related receptor, was knocked down, indicating that SVV infection induces STING degradation via reticulophagy. Further study showed that in eukaryotic translation initiation factor 2 alpha kinase 3 (PERK)/activating transcription factor 6 (ATF6) deficient cells, SVV infection failed to induce reticulophagy-medaited STING degradation, indicating that SVV infection caused STING degradation via PERK/ATF6-mediated reticulophagy. Notably, blocking reticulophagy effectively hindered SVV replication. Overall, our study suggested that SVV infection resulted in STING degradation via PERK and ATF6-mediated reticulophagy, which may be an immune escape strategy of SVV. This finding improves the understanding of the intricate interplay between viruses and their hosts and provides a novel strategy for the development of novel antiviral drugs.


Differential regulation of Epstein-Barr virus (EBV) latent gene expression in Burkitt lymphoma cells infected with a recombinant EBV strain.
Epstein-Barr virus (EBV)-negative Burkitt lymphomas (BLs) can be infected in vitro with prototype EBV strains to study how the virus may affect the phenotype of tumor cells. Studies thus far have concentrated on the use of transforming B95-8 and nontransforming P3HR1 strains. Immunological and phenotypic differences between the sublines infected with these two strains were reported. The majority of these differences, if not all, can be attributed to the lack of EBNA-2 coding sequences in the P3HR1 strain. The recent development of a selectable Akata strain has opened up new possibilities for infecting epithelial and T cells as well. We infected five EBV-negative BL lines with the recombinant Akata virus. Our results indicate that the infected cell lines BL28, Ramos, and DG75 express EBNA-1, EBNA-2, and LMP1, the viral proteins associated with type III latency, and use both YUK and QUK splices. In contrast, two EBV-negative variants of Akata and Mutu when reinfected displayed restricted type I latency and expressed only EBNA-1. All clones of infected Mutu cells used the QUK splice exclusively. The usage of Qp was observed in a majority of Akata clones. Some Akata clones, however, were found to have double promoter usage (Qp and C/Wp) but at 4 months after infection did not express EBNA-2. The results demonstrate differential regulation of EBV latency in BLs with the same recombinant viral strain and suggest that the choice of latency type may be cell dependent. The restricted latency observed for infected Akata and Mutu cells indicates that a BL may opt for type I latency in the absence of immune pressure as well.


Associations of motility and auto-aggregation with biofilm-formation capacity levels in Clostridioidesdifficile.
Clostridioides difficile (C. difficile) is responsible for one of the most common nosocomial infections worldwide. This work assessed associations between biofilm-formation capacity levels of C. difficile and cell viability, motility, flagella, motility and auto-aggregation in 118 clinical isolates. Biofilm production was assessed by the crystal violet method. Cell viability was determined by BacTiter-Glo™ Microbial Cell Viability Assay and live-imaging microscopy. Expression levels of LuxS, Cwp84, Spo0A, PilA, and FliC were measured by real-time PCR. Motility was visually assessed in agar tubes. Auto-aggregation levels were determined by OD600 measurements. Out of 118 isolates, 66 (56 %) were biofilm producers, with most being strong or moderate producers. Cell viability, motility and auto-aggregation positively correlated with biofilm-production capacity (p = 0.0001, p = 0.036 and p < 0.0001, respectively). Positive associations were found between pilA, fliC and luxS expression levels and biofilm-production capacity (p = 0.04, p = 0.01, p = 0.036, respectively). This is the first report of associations between biofilm-formation capacity and cell viability, pilA, fliC, and luxS gene expression, auto-aggregation and motility. These correlations should be further explored to expand knowledge on the regulation of C. difficile biofilm formation, and pathogenesis, which will have notable implications on treatment options.


Studying Medicine and being a doctor in Spain.
This article was migrated. The article was marked as recommended. In Spain, and probably around the world, the degree of Medicine is one of the most appreciated studies by the students. Not only the influence of job prospects, better than in other University careers, but also the study of a scientific career with many specialization areas or the joy felt by doctors when they manage to help a very sick patient, are some reasons to undertake the adventure to become a doctor. Since the demand to study Medicine is so high, it is not strange that most people with interest stay out of the process, since, at least in Spain, only the high school students with the best records are able to enter into a School of Medicine. But becoming a doctor is more than the study of a University Degree for 6 years. They need also a postgraduate specialization (MIR), in Hospitals of the National Health System, as a necessary step in order to be able to practice Medicine, either in public or private institutions. However, this road is not free from problems since there has been a decrease in the number of MIR specialization places offered without a similar reduction in the number of undergraduate positions. Moreover, the number of medical schools has not stopped growing and places Spain as one of the countries with the highest ratio of Medical Schools per inhabitant. This situation can lead to a scenario similar to that experienced in the 80s and 90s, where we witnessed an increase in the number of Specialist Physicians without Official Title (called MESTOS). As of November 2018, around 4,000 medical graduates cannot access specialized health training and may be forced into unemployment or emigration.


PostExcision Events in Human Nucleotide Excision Repair.
The nucleotide excision repair system removes a wide variety of DNA lesions from the human genome, including photoproducts induced by ultraviolet (UV) wavelengths of sunlight. A defining feature of nucleotide excision repair is its dual incision mechanism, in which two nucleolytic incision events on the damaged strand of DNA at sites bracketing the lesion generate a damage-containing DNA oligonucleotide and a single-stranded DNA gap approximately 30 nucleotides in length. Although the early events of nucleotide excision repair, which include lesion recognition and the dual incisions, have been explored in detail and are reasonably well understood, the fate of the single-stranded DNA gaps and excised oligonucleotide products of repair have not been as extensively examined. In this review, recent findings that address these less-explored aspects of nucleotide excision repair are discussed and support the concept that postincision gap and excised oligonucleotide processing are critical steps in the cellular response to DNA damage induced by UV light and other environmental carcinogens. Defects in these latter stages of repair lead to cell death and other DNA damage signaling responses and may therefore contribute to a number of human disease states associated with exposure to UV wavelengths of sunlight, including skin cancer, aging and autoimmunity.


Steam quality and effective sterilization.
Faced with using steam from a commercial utility having boilers greater than 5 miles distant and being the last user on the system resulted in ineffective sterilization. A three phase testing program was established utilizing: Direct physical measurements - an Ellison model 915A portable steam calorimeter. Direct microbiology - Autoclaved feed pellets were aseptically placed in fluid thioglycolate medium and incubated at 37 degrees C. Indirect microbiology - Feces from "defined flora" mice fed the autoclaved pelleted feed were tested. Colorimetric measurements verified that the steam sometimes contained greater than 5% entrained water. During periods of wet steam it was impossible to maintain consistent sterility of the mouse pellets even using a cycle of 126 degrees C for 60 minutes. One spore-forming Gram positive rod, Clostridium perfringens type D was the predominant bacterium isolated. Lactating mice, or mice stressed experimentally came down with diarrhea within days of eating pellets treated with wet steam (calorimetric measurements) and a subsequent positive culture. These mice voided stools predominantly showing Clostridium perfringens type D.


Analysis of regional timelines to set up a global phase III clinical trial in breast cancer: the adjuvant lapatinib and/or trastuzumab treatment optimization experience.
This study measured the time taken for setting up the different facets of adjuvant lapatinib and/or trastuzumab treatment optimization (ALTTO), an nternational phase III study being conducted in 44 participating countries. Time to regulatory authority (RA) approval, time to ethics committee/institutional review board (EC/IRB) approval, time from study approval by EC/IRB to first randomized patient, and time from first to last randomized patient were prospectively collected in the ALTTO study. Analyses were conducted by grouping countries into either geographic regions or economic classes as per the World Bank's criteria. South America had a significantly longer time to RA approval (median: 236 days, range: 21-257 days) than Europe (median: 52 days, range: 0-151 days), North America (median: 26 days, range: 22-30 days), and Asia-Pacific (median: 62 days, range: 37-75 days). Upper-middle economies had longer times to RA approval (median: 123 days, range: 21-257 days) than high-income (median: 47 days, range: 0-112 days) and lower-middle income economies (median: 57 days, range: 37-62 days). No significant difference was observed for time to EC/IRB approval across the studied regions (median: 59 days, range 0-174 days). Overall, the median time from EC/IRB approval to first recruited patient was 169 days (range: 26-412 days). This study highlights the long time intervals required to activate a global phase III trial. Collaborative research groups, pharmaceutical industry sponsors, and regulatory authorities should analyze the current system and enter into dialogue for optimizing local policies. This would enable faster access of patients to innovative therapies and enhance the efficiency of clinical research.


Cognitive-behavioral therapy for body dysmorphic disorder: a review of its efficacy.
The aim of this study was to review the efficacy of different methods of cognitive and/or behavioral therapies used to treat body dysmorphic disorder. We evaluated all case series, open studies, controlled trials, and meta-analyses of cognitive and/or behavioral treatment approaches to body dysmorphic disorder published up to July 2012, identified through a search in the PubMed/Medline, PsycINFO, ISI Web of Knowledge, and Scopus databases. Our findings indicate that individual and group cognitive behavioral therapies are superior to waiting list for the treatment of body dysmorphic disorder. While the efficacy of cognitive therapy is supported by one controlled trial, utility of behavioral therapy is suggested by one open study and one controlled relapse prevention follow-up study. There is a pressing need to conduct head-to-head studies, with appropriate, active, control treatment groups, in order to examine further the efficacy of cognitive and/or behavioral therapies for body dysmorphic disorder.


Transient MPK6 activation in response to oxygen deprivation and reoxygenation is mediated by mitochondria and aids seedling survival in Arabidopsis.
Mitogen-activated protein kinases (MPKs) are regulated by diverse stresses with a reactive oxygen species (ROS) component. Here, we report the rapid and transient activation of MPK3, MPK4 and MPK6 upon oxygen deprivation as well as reoxygenation in seedlings of Arabidopsis thaliana. MPK activation peaked within 2 h of oxygen deprivation and again at a higher magnitude within 5 min of reoxygenation. MPK6 was the predominant kinase regulated by oxygen availability in both aerial and root tissue, except in mpk6 mutants, which displayed compensatory activation of MPK3. A universal consequence of oxygen deprivation in eukaryotes is inhibition of the terminal step of the mitochondrial electron transport chain (mETC). We demonstrate that treatment of seedlings with the mETC inhibitors antimycin A and potassium cyanide under normoxia promotes transient MPK6 and MPK3 activation. Confocal imaging of seedlings provided evidence that both oxygen deprivation and mETC inhibitors stimulate mitochondria-associated ROS production. We found that seedling survival of prolonged oxygen deprivation was improved in transgenics that ectopically overexpress MPK3, MPK4 and MPK6, but the induction of mRNAs associated with low oxygen acclimation responses were not markedly altered in MPK6 overexpression lines or mpk6 loss-of-function mutants. However, distinctions in MPK6 activation potential were correlated with other differences in mRNAs accumulation. Our findings suggest that oxygen deprivation and reoxygenation trigger mitochondrial ROS production to activate MPK signaling, which in turn regulate reversible processes that aid survival of transient oxygen deprivation.


In vivo fluorescence reflectance imaging of protease activity in a mouse model of post-traumatic osteoarthritis.
Joint injuries initiate a surge of inflammatory cytokines and proteases that contribute to cartilage and subchondral bone degeneration. Detecting these early processes in animal models of post-traumatic osteoarthritis (PTOA) typically involves ex vivo analysis of blood serum or synovial fluid biomarkers, or histological analysis of the joint. In this study, we used in vivo fluorescence reflectance imaging (FRI) to quantify protease, matrix metalloproteinase (MMP), and Cathepsin K activity in mice following anterior cruciate ligament (ACL) rupture. We hypothesized that these processes would be elevated at early time points following joint injury, but would return to control levels at later time points. Mice were injured via tibial compression overload, and FRI was performed at time points from 1 to 56 days after injury using commercially available activatable fluorescent tracers to quantify protease, MMP, and cathepsin K activity in injured vs uninjured knees. PTOA was assessed at 56 days post-injury using micro-computed tomography and whole-joint histology. Protease activity, MMP activity, and cathepsin K activity were all significantly increased in injured knees relative to uninjured knees at all time points, peaking at 1-7 days post-injury, then decreasing at later time points while still remaining elevated relative to controls. This study establishes FRI as a reliable method for in vivo quantification of early biological processes in a translatable mouse model of PTOA, and provides crucial information about the time course of inflammation and biological activity following joint injury. These data may inform future studies aimed at targeting these early processes to inhibit PTOA development.


High pretreatment cognitive impulsivity predicts response of oppositional symptoms to methylphenidate in patients with attention-deficit hyperactivity disorder/oppositional defiant disorder.
The aim of this study was to compare impulsivity levels, as assessed by a continuous performance test (CPT), and the correlations between baseline CPT performance and response to methylphenidate (MPH), as assessed by the conjunctive CPT (CCPT), in children with only Diagnostic and Statistical Manual of Mental Disorders, 5th ed. attention-deficit hyperactivity disorder with no oppositional defiant disorder (ADHD/noODD) or with comorbid ODD (ADHD/ODD). Fifty-three children and adolescents were included in the study (ADHD/noODD group, n = 25, 12 women/13 men and ADHD/ODD group, n = 28, eight females/20 males). Attention was assessed at baseline using CCPT. ADHD and ODD severities were assessed at baseline and following a 12-week MPH treatment using the ADHD-rating scale (ADHD-RS) completed by the parent and by a teacher and the Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Age Children-ODD (K-SADS-ODD) completed by the treating psychiatrist. Higher baseline commission-errors rates (P = 0.0031) in ADHD-RS/parent-child, ADHD-RS/teacher, and K-SADS-ODD scores were detected in ADHD/ODD compared with the ADHD/noODD. Significant improvements in ADHD-RS/parent-child, ADHD-RS/teacher, and K-SADS-ODD scores were achieved following MPH treatment in both groups. Significant correlations were found between baseline CCPT commission-error rates and improvement in ADHD-RS-teacher in ADHD/noODD, but not in ADHD/ODD. Among the ADHD/ODD, but not the ADHD/noODD, a significant correlation was found between baseline CCPT commission-error rates and improvement in K-SADS-ODD. Baseline cognitive impulsivity (as measured by the CCPT) can predict response of ODD to MPH treatment in ADHD/ODD patients.


Effects of nano-encapsulated curcumin-chrysin on telomerase, MMPs and TIMPs gene expression in mouse B16F10 melanoma tumour model.
Due to the high rate of drug resistance among malignant melanoma cases, it seems necessary to introduce an efficient pharmaceutical approach to melanoma treatment. For this purpose, Curcumin (Cur) and Chrysin (Chr), two natural anti-cancers, were co-encapsulated in PLGA-PEG nanoparticles (NPs), characterized by DLS, FTIR and FE-SEM and investigated for their effects on MMPs, TIMPs and TERT genes expression in C57B16 mice bearing B16F10 melanoma tumours. The results showed that the expression of MMP-9, MMP-2 and TERT genes were significantly decreased in all treated groups compared to the control. This reduction had the highest amount in CurChr NPs group and then CurChr group for each three genes. Likewise, the expression of TIMP-1 and TIMP-2 genes was significantly increased in all treated groups, compared to the control. Combination groups showed the highest rise in expression of these two genes and the observed increase was greater in nano groups. Moreover, the highest melanoma tumour growth inhibition was detected for CurChr NPs, followed by CurChr = Cur NPs > Cur > Chr NP > Chr. Overall, it is speculated that the nano-combination of Cur and Chr into polymeric NPs with a one-step fabricated co-delivery system may be a promising and convenient approach to improve their efficiency in melanoma cancer therapy.


Childhood sexual abuse moderates the relationship between sexual functioning and eating disorder psychopathology in anorexia nervosa and bulimia nervosa: a 1-year follow-up study.
Sexual dysfunctions that affect all aspects of sexuality are common in patients with eating disorders. However, only few studies have provided longitudinal information on sexual functioning in patients with eating disorders. To evaluate the longitudinal course of sexual functioning, and how changes in psychopathology and history of childhood abuse interact with sexual functioning in patients with anorexia nervosa (AN) and bulimia nervosa (BN). A total of 27 patients with AN and 31 with BN were assessed at baseline and at 1-year follow-up after a standard individual cognitive behavioral therapy (CBT). Subjects were studied by means of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders IV, Female Sexual Function Index (FSFI), Eating Disorder Examination Questionnaire, Beck Depression Inventory, Spielberg's State-Trait Anxiety Inventory, Symptom Checklist-90, and Childhood Experience of Care and Abuse Questionnaire. After treatment, both patients with AN and BN showed a significant improvement in the FSFI total score (P < 0.01 for both AN and BN) and all FSFI subscales, without significant between groups differences. Patients reporting childhood sexual abuse did not show a significant improvement in sexual functioning (β = 0.05; P = 0.58). Reduction in eating disorder severity was directly associated with FSFI improvement, but only in those subjects with no history of sexual abuse (β = 0.28; P = 0.01). Eating disorder-specific psychopathology could be considered as a specific maintaining factor for sexual dysfunction in eating disorders subjects. Subjects reporting a history of childhood sexual abuse represent a subpopulation of patients with a profound uneasiness, involving body perception, as well as sexual functioning, which appeared not to be adequately challenged during standard CBT intervention. The results, though original, should be considered as preliminary, given the relatively small sample size.


Possible progression of subacute lupus erythematosus--case report.
Subacute lupus erythematosus (SLE) is a specific form of lupus erythematosus characterized by prevalently cutaneous manifestations usually with a good prognosis. It is more common in patients aged 15 to 70 years, and there is a female predilection. This form accounts for 10% of all lupus erythematosus cases. We present the case of a 57-year-old male patient diagnosed at age 35 with chronic psoriasiform subacute lupus erythematosus, pathologically confirmed at the Iaşi Dermatology Clinic. At the age of 54 years he had multiple ischemic strokes, followed by deterioration of general status, and at 56 years deep vein thrombosis in the right leg. The patient presented the erythematous-squamous lesions specific to psoriasiform SLE localized both on the upper third of the body and knees and associated with submucosal lesions of the lower lip, oral mucosa and appendages. The patient also presented hypo- and hyperpigmentated atrophic scar-like lesions. Laboratory tests performed during the last two admissions showed the presence of anti-ds DNA and antiphospholipid antibodies, inflammatory syndrome, and nitrogen retention syndrome. Treatment consisted of systemic and local dermatocorticoids and associated medication, emollient lotions and creams with SPF 50+, with slowly favorable progression. The peculiarity of the case lies in the chronic progression without significant systemic involvement for 19 years, and then in 2 years the antiphospholipid antibody syndrome and a shift to systemic lupus erythematosus to occur.


Electron microscopic detection of salivary alpha-amylase in the pellicle formed in situ.
Immunological and biochemical analyses have shown that alpha-amylase is an essential component of the acquired pellicle. After adsorption, this enzyme might act as a receptor for bacterial adherence. However, data indicating that amylase is bound to the pellicle surface in vivo and thus available for adhering bacteria are rare. Therefore, the present study focused on alpha-amylase within the pellicle formed in situ, using gold-immunolabeling electron microscopic techniques. Pellicles were formed by intra-oral exposure of enamel specimens for 30 and 120 min in six subjects. The results obtained by transmission electron microscopy indicate that amylase was randomly distributed in the pellicle layer without any preferential localization within the pellicle. Thus, salivary alpha-amylase might be considered as an important structural component that is even involved in the early stages of pellicle formation. The findings of field emission in-lens scanning electron microscopy provided evidence that the enzyme is located on the pellicle surface. It could be concluded that alpha-amylase might act as a receptor for bacterial adherence to the pellicle in vivo.


Cell-specific actions of a human LHX3 gene enhancer during pituitary and spinal cord development.
The LIM class of homeodomain protein 3 (LHX3) transcription factor is essential for pituitary gland and nervous system development in mammals. In humans, mutations in the LHX3 gene underlie complex pediatric syndromes featuring deficits in anterior pituitary hormones and defects in the nervous system. The mechanisms that control temporal and spatial expression of the LHX3 gene are poorly understood. The proximal promoters of the human LHX3 gene are insufficient to guide expression in vivo and downstream elements including a conserved enhancer region appear to play a role in tissue-specific expression in the pituitary and nervous system. Here we characterized the activity of this downstream enhancer region in regulating gene expression at the cellular level during development. Human LHX3 enhancer-driven Cre reporter transgenic mice were generated to facilitate studies of enhancer actions. The downstream LHX3 enhancer primarily guides gene transcription in α-glycoprotein subunit -expressing cells secreting the TSHβ, LHβ, or FSHβ hormones and expressing the GATA2 and steroidogenic factor 1 transcription factors. In the developing nervous system, the enhancer serves as a targeting module active in V2a interneurons. These results demonstrate that the downstream LHX3 enhancer is important in specific endocrine and neural cell types but also indicate that additional regulatory elements are likely involved in LHX3 gene expression. Furthermore, these studies revealed significant gonadotrope cell heterogeneity during pituitary development, providing insights into the cellular physiology of this key reproductive regulatory cell. The human LHX3 enhancer-driven Cre reporter transgenic mice also provide a valuable tool for further developmental studies of cell determination and differentiation in the pituitary and nervous system.


Transcription factor TEAD1 is essential for vascular development by promoting vascular smooth muscle differentiation.
TEAD1 (TEA domain transcription factor 1), a transcription factor known for the functional output of Hippo signaling, is important for tumorigenesis. However, the role of TEAD1 in the development of vascular smooth muscle cell (VSMC) is unknown. To investigate cell-specific role of Tead1, we generated cardiomyocyte (CMC) and VSMC-specific Tead1 knockout mice. We found CMC/VSMC-specific deletion of Tead1 led to embryonic lethality by E14.5 in mice due to hypoplastic cardiac and vascular walls, as a result of impaired CMC and VSMC proliferation. Whole transcriptome analysis revealed that deletion of Tead1 in CMCs/VSMCs downregulated expression of muscle contractile genes and key transcription factors including Pitx2c and myocardin. In vitro studies demonstrated that PITX2c and myocardin rescued TEAD1-dependent defects in VSMC differentiation. We further identified Pitx2c as a novel transcriptional target of TEAD1, and PITX2c exhibited functional synergy with myocardin by directly interacting with myocardin, leading to augment the differentiation of VSMC. In summary, our study reveals a critical role of Tead1 in cardiovascular development in mice, but also identifies a novel regulatory mechanism, whereby Tead1 functions upstream of the genetic regulatory hierarchy for establishing smooth muscle contractile phenotype.


Decomposing bias in different types of simple decisions.
The ability to adjust bias, or preference for an option, allows for great behavioral flexibility. Decision bias is also important for understanding cognition as it can provide useful information about underlying cognitive processes. Previous work suggests that bias can be adjusted in 2 primary ways: by adjusting how the stimulus under consideration is processed, or by adjusting how the response is prepared. The present study explored the experimental, behavioral, and theoretical distinctions between these biases. Different bias manipulations were employed in parallel across perceptual and memory-based decisions to assess the generality of the 2 biases. This is the 1st study to directly test whether conceptually similar bias instructions can induce dissociable bias effects across different decision tasks. The results show that stimulus and response biases can be separately induced in both tasks, suggesting that the biases generalize across different types of decisions. When analyzing behavioral data, the 2 biases can be differentiated by focusing on the time course of bias effects and/or by fitting choice reaction time models to the data. These findings have strong theoretical implications about how observed bias relates to underlying cognitive processes and how it should be used when testing cognitive theories. Guidelines are presented to help researchers identify how to induce the biases experimentally, how to dissociate them in the behavioral data, and how to quantify them using drift diffusion models. Because decision bias is pervasive across many domains of cognitive science, these guidelines can be useful for future work exploring decision bias and choice preferences.


Cdk5 mediates changes in morphology and promotes apoptosis of astrocytoma cells in response to heat shock.
The cyclin-dependent kinase member, Cdk5, is expressed in a variety of cell types, but neuron-specific expression of its activator, p35, is thought to limit its activity to neurons. Here we demonstrate that both Cdk5 and p35 are expressed in the human astrocytoma cell line, U373. Cdk5 and p35 are present in the detergent-insoluble cytoskeletal fraction of this cell line and Cdk5 localizes to filopodia and vinculin-rich regions of cell-matrix contact in lamellopodia. When exposed to a 46(o)C heat shock, U373 cells change shape, lose cell-matrix contacts and show increased levels of apoptosis. To test whether Cdk5 activation might play a role in these events, U373 cells were stably transfected with histidine-tagged or green fluorescent protein-tagged constructs of Cdk5 or a dominant negative mutation, Cdk5T33. Under normal growth conditions, growth characteristics of the stably transfected lines were indistinguishable from untransfected U373 cells and Cdk5 localization was not changed. However, when subjected to heat shock, cells stably transfected with Cdk5-T33 remained flattened, showed little loss of cell-matrix adhesion, and exhibited significantly lower levels of apoptosis. In contrast, cells that overexpressed wild-type Cdk5 showed morphological changes similar to those seen in untransfected U373 cells in response to heat shock and had significantly higher levels of apoptosis. Heat-shocked cells showed changes in p35 mobility and stability of the Cdk5/p35 complex consistent with endogenous Cdk5 activity. Together these findings suggest that endogenous Cdk5 activity may play a key role in regulating morphology, attachment, and apoptosis in U373 cells, and raise the possibility that Cdk5 may be a general regulator of cytoskeletal organization and cell adhesion in both neuronal and non-neuronal cells.


Testing the environment for dispersed mutagens: use of plant bioconcentrators coupled with microbial mutagen assays.
Mutagens dispersed in ecosystems are usually in low concentration and episodic in occurrence. The possibility of detecting such dispersed mutagens by utilizing indigenous bioconcentrator organisms coupled with a microbial mutagen assay offer a useful screening protocol. There are numerous examples of plant and animal species which concentrate toxic substances from the environment. Body extracts of these bioconcentrators can be suitably fractioned and tested for mutagens with various microbial mutagen assays. The fractions may be tested with a broad range of microbial assays covering numerous genetic end points as well as both with and without mammalian microsomal activation. This kind of environmental screening has an advantage over physicochemical techniques, in that sampling techniques are simpler and a wider chemical spectrum can be screened. There are problems inherent with testing a complex biological extract, however. If a reversion assay is used, the metabolite necessary for growth may be present. Toxins may be introduced, either concentrated from the environment in the same way as the mutagen, or produced by the concentrator itself. Finally, the concentrator may also produce an endogenous mutagen which will give spuriously active extracts. Methods for minimizing some of these difficulties are discussed.


Comprehensive human urine standards for comparability and standardization in clinical proteome analysis.
Urine proteomics is emerging as a powerful tool for biomarker discovery. The purpose of this study is the development of a well-characterized "real life" sample that can be used as reference standard in urine clinical proteomics studies. We report on the generation of male and female urine samples that are extensively characterized by different platforms and methods (CE-MS, LC-MS, LC-MS/MS, 1-D gel analysis in combination with nano-LC MS/MS (using LTQ-FT ultra), and 2-DE-MS) for their proteome and peptidome. In several cases analysis involved a definition of the actual biochemical entities, i.e. proteins/peptides associated with molecular mass and detected PTMs and the relative abundance of these compounds. The combination of different technologies allowed coverage of a wide mass range revealing the advantages and complementarities of the different technologies. Application of these samples in "inter-laboratory" and "inter-platform" data comparison is also demonstrated. These well-characterized urine samples are freely available upon request to enable data comparison especially in the context of biomarker discovery and validation studies. It is also expected that they will provide the basis for the comprehensive characterization of the urinary proteome.


A retention index calculator simplifies identification of plant volatile organic compounds.
Plant volatiles (PVOCs) are important targets for studies in natural products, chemotaxonomy and biochemical ecology. The complexity of PVOC profiles often limits research to studies targeting only easily identified compounds. With the availability of mass spectral libraries and recent growth of retention index (RI) libraries, PVOC identification can be achieved using only gas chromatography coupled to mass spectrometry (GCMS). However, RI library searching is not typically automated, and until recently, RI libraries were both limited in scope and costly to obtain. To automate RI calculation and lookup functions commonly utilised in PVOC analysis. Formulae required for calculating retention indices from retention time data were placed in a spreadsheet along with lookup functions and a retention index library. Retention times obtained from GCMS analysis of alkane standards and Koeberlinia spinosa essential oil were entered into the spreadsheet to determine retention indices. Indices were used in combination with mass spectral analysis to identify compounds contained in Koeberlinia spinosa essential oil. Eighteen compounds were positively identified. Total oil yield was low, with only 5 ppm in purple berries. The most abundant compounds were octen-3-ol and methyl salicylate. The spreadsheet accurately calculated RIs of the detected compounds. The downloadable spreadsheet tool developed for this study provides a calculator and RI library that works in conjuction with GCMS or other analytical techniques to identify PVOCs in plant extracts.


The functions of medical care.
Medical care has several important functions other than restoring or maintaining health. These other functions are assessment and certification of health status, prognostication, segregation of the ill to limit communication of illness, and helping to cope with the problems of illness--the caring function. Medical care serving these "paracurative" functions may legitimately be given indepedently, without associated curing or preventive intent of the provider of care. Although such services do not result in benefits to health, such as extension of life or reduction of disability, they do have other valued outcomes, outcomes not measurable as a gain in personal health status. For example, caring activities may result in satisfaction, comfort, or desirable affective states, even while the patient's health status deteriorates during an incurable illness. The physician's approach to patients, the economist's analysis of the benefits of health services, the planner's decisions about health programs, the evaluator's judgments about the quality of care, or the patient's expectations about treatment are strongly influenced by his assumptions about the purpose of medical care or the proper outcome of the process. When the health worker assumes that the only useful outcome is health, he may consider the paracurative services to be ineffective, inefficient, or undesirable. In contrast, when he recognizes and understands the paracurative functions of medical care, he may better perform his function in the medical care system.


Imaging port wine stains by fiber optical coherence tomography.
We develop a fiber optical coherence tomography (OCT) system in the clinical utility of imaging port wine stains (PWS). We use our OCT system on 41 patients with PWS to document the difference between PWS skin and contralateral normal skin. The system, which operates at 4 frames with axial and transverse resolutions of 10 and 9 mum, respectively, in the skin tissue, can clearly distinguish the dilated dermal blood vessels from normal tissue. We present OCT images of patients with PWS and normal human skin. We obtain the structural parameters, including epidermal thickness and diameter and depth of dilated blood vessels. We demonstrate that OCT may be a useful tool for the noninvasive imaging of PWS. It may help determine the photosensitizer dose and laser parameters in photodynamic therapy for treating port wine stains.


Lung function after bilateral lower lobe lung volume reduction surgery for alpha1-antitrypsin emphysema.
This study explores the mechanism(s) of airflow limitation following lung volume reduction surgery (LVRS) in patients with emphysema due to homozygous alpha1-antitrypsin (AT) deficiency. Bilateral targeted lower lobe stapled LVRS using video thoracoscopy was performed in six patients (five males) aged 61+/-9 yrs (mean+/-SD) with alpha1-AT emphysema. Two patients received only a 6-month follow-up. However, four patients, at 22, 24, 27 and 36 months post-LVRS, noted relief from dyspnoea and increased walk tolerance. At 27+/-6 months (mean+/-SD) post-LVRS, their forced expiratory volume in one second improved only from 30+/-2% of the predicted value (mean+/-SEM) before surgery to 33+/-1% pred after surgery. Yet, total lung capacity (TLC) decreased from 151+/-13 to 127+/-10% pred; diffusing capacity increased from 35+/-9 to 59+/-9% pred; and vital capacity increased from 68+/-10 to 88+/-5% pred. In three patients, static lung elastic recoil at TLC increased from 1.1+/-0.15 to 1.2+/-0.10 kPa. Using flow/pressure curves, the mechanism for expiratory airflow limitation pre-LVRS and the improvement noted post-LVRS could be primarily accounted for by the initial loss and subsequent increase in lung elastic recoil. Bilateral lung volume reduction surgery provides modest physiologic improvement for 2-3 yrs in patients with alpha1-antitrypsin emphysema due to increases in lung elastic recoil.


Construction of a shuttle expression vector with a promoter functioning in both halophilic Archaea and Bacteria.
A shuttle expression vector, designated as pAJ, was constructed based on the Haloferax volcanii-Escherichia coli shuttle vector pSY1. This new construct contains the amyH promoter from Haloarcula hispanica and was able to confer the promoter activity in both Hfx. volcanii and E. coli. pAJ successfully expressed proteins in Hfx. volcanii or E. coli, rendering it feasible to express target proteins in corresponding domains. In addition, pAJ contains a multiple cloning site with 11 restriction sites and a 6×His tag sequence, and the vector size was decreased to 8903 bp. To the best of our knowledge, pAJ is the first reported shuttle expression vector that can express proteins in both Bacteria and Archaea. Importantly, pAJ can even express the haloarchaeal heat shock protein DnaK in both domains. In conclusion, this novel vector only provides researchers with a new means to manipulate genes or express proteins in Haloarchaea but also serves as a convenient tool for the comparative study of the function of some highly conserved genes in Haloarchaea and in Bacteria.


[Evolution of cardiovascular disease mortality in the Toledo Province, 1975-1994].
Cardiovascular diseases are the leading cause of death in the developed countries. The cardiovascular mortality varies throughout the different parts of Spain. In this study, an analysis is made of the 1975-1994 trend in the cardiovascular death rate due to heart disease and ischemic heart disease among those falling within the 35-74 age range in the province of Toledo. Based on the deaths recorded by the Spanish National Statistics Institute, standardized rates were calculated by the direct method for the causes selected. The trend is assessed based on the mean percentage variance in the rates. The male gender-related ratios are given by causes. A markedly downward trend is found for the cardiovascular death rate as a whole, showing an average drop of 2.58% among males and of 4.78% among females. The decrease is less for heart disease in general, 1.13% among men and 2.68% among women. The trend in the mortality due to ischemic heart disease shows no specific trend, it being possible to term these rates as being stable. For all of the causes, a greater number of deaths among males are recorded, especially with regard to ischemic heart disease, showing a male/female ratio = 1.75. The cardiovascular mortality in Toledo is dropping similarly to the nationwide rate. The heart disease group as a whole is undergoing a gradual decrease. The stabilization of the death rate due to ischemic heart disease can be explained by the fact that Toledo has low rates as compared to the rest of Spain.


Kinematic analysis of wrist motion during simulated colonoscopy in first-year gastroenterology fellows.
Gastroenterology trainees acquire skill and proficiency in performing colonoscopies at different rates. The cause for heterogeneous competency among the trainees is unclear. Kinematic analysis of the wrist joint while performing colonoscopy can objectively assess the variation in wrist motion. Our objective was to test the hypothesis that the time spent by the trainees in extreme ranges of wrist motion will decrease as the trainees advance through the fellowship year. Five first-year gastroenterology fellows were prospectively studied at four intervals while performing simulated colonoscopies. The setting was an endoscopy simulation laboratory at a tertiary care center. Kinematic assessment of wrist motion was done using a magnetic position/orientation tracker held in place by a custom-made arm sleeve and hand glove. The main outcome measure was time spent performing each of four ranges of wrist motion (mid, center, extreme, and out) for each wrist degree of freedom (pronation/supination, flexion/extension, and adduction/abduction). There were no statistically significant differences in the time spent for wrist movements across the three degrees of freedom throughout the study period. However, fellows spent significantly less time in extreme range (1.47 ± 0.34 min vs. 2.44 ± 0.34 min, P = 0.004) and center range (1.02 ± 0.34 min vs 1.9 ± 0.34 min, P = 0.01) at the end of the study compared to the baseline evaluation. The study was limited by the small number of subjects and performance of colonoscopies on a simulator rather than live patients. Gastroenterology trainees alter the time spent at the extreme range of wrist motion as they advance through training. Endoscopy training during the first 10 months of fellowship may have beneficial effects on learning ergonomically correct motion patterns.


Using a voucher system to extend health services to migrant farmworkers.
FAMILY HEALTH/LA CLINICA de los Campesinos, Inc., is a federally funded migrant health clinic in the heart of Wisconsin's farmland that has offered outpatient health care since 1973 and an accompanying "voucher" program since 1988. The charges for outpatient care are based on the ability to pay. The clinic issues vouchers not only to migrant workers living and working in remote parts of the State but also to patients needing services the clinic does not offer. Between 1 April 1992 and 30 March 1993, 677 participants submitted 1,794 vouchers that provided for $83,833 in partial health care payments. La Clinica paid a median amount of $22 for each voucher, its reimbursement value ranging from $1 to $979. Hospitals received the highest median payment and pharmacies the lowest. Voucher payments generally covered 60% of the bill, but dentists commanded a higher percentage(70%) and clinics and medical groups a lower one (42%). Most vouchers paid for procedures and services La Clinica could not provide. This program shows how a health care provider in one location, with a patient population scattered throughout a sizeable geographic area, can coordinate services not offered at its facility. With the national spotlight on health care reform, the concept of vouchers for people in outlying or underserved regions deserves further investigation.


After SARS-CoV-2, will H5N6 and other influenza viruses follow the pandemic path?
While the world is focused on attending, controlling, and mitigating the current pandemic of COVID-19, caused by the SARS-CoV-2, other viral threats are possibly emerging and reemerging especially in Asia, posing a risk for the spread in that region and beyond. A predictable threat is the avian influenza virus, especially H5N6, which has recently led to significant outbreaks in China and the Philippines, deserving more attention and control. In the current review, we assess the history of this highly pathogenic reemerging virus, as well as the contemporary implications of poultry outbreaks occurring in some Asian countries. We also look at outbreaks due to other strains not only in Asia but also across Europe and Africa, according to recent reports from the World Organization of Animal Health (OIE).


First investigation on ultrasound-assisted preparation of food products: sensory and physicochemical characteristics.
This paper presents a comparison between manufactured food products using conventional and ultrasound-assisted procedures. Three different foam-type products, chocolate Genoise, basic sponge cake, and chocolate mousse were prepared using both methods with subsequent evaluation of the samples using both sensory and physicochemical methods. Ultrasound-assisted preparations were considered superior according to the sensory analysis, and physicochemical data confirmed this finding. This approach of applying an emerging piece of equipment, with potential industrial application to assist food preparation, consists of a new technique that could be of great interest for the development of not only other food products created by molecular gastronomy but also for practical work carried out by students.


Mimic Phosphorylation of a βC1 Protein Encoded by TYLCCNB Impairs Its Functions as a Viral Suppressor of RNA Silencing and a Symptom Determinant.
Phosphorylation of the βC1 protein encoded by the betasatellite of tomato yellow leaf curl China virus (TYLCCNB-βC1) by SNF1-related protein kinase 1 (SnRK1) plays a critical role in defense of host plants against geminivirus infection in Nicotiana benthamiana However, how phosphorylation of TYLCCNB-βC1 impacts its pathogenic functions during viral infection remains elusive. In this study, we identified two additional tyrosine residues in TYLCCNB-βC1 that are phosphorylated by SnRK1. The effects of TYLCCNB-βC1 phosphorylation on its functions as a viral suppressor of RNA silencing (VSR) and a symptom determinant were investigated via phosphorylation mimic mutants in N. benthamiana plants. Mutations that mimic phosphorylation of TYLCCNB-βC1 at tyrosine 5 and tyrosine 110 attenuated disease symptoms during viral infection. The phosphorylation mimics weakened the ability of TYLCCNB-βC1 to reverse transcriptional gene silencing and to suppress posttranscriptional gene silencing and abolished its interaction with N. benthamiana ASYMMETRIC LEAVES 1 in N. benthamiana leaves. The mimic phosphorylation of TYLCCNB-βC1 had no impact on its protein stability, subcellular localization, or self-association. Our data establish an inhibitory effect of phosphorylation of TYLCCNB-βC1 on its pathogenic functions as a VSR and a symptom determinant and provide a mechanistic explanation of how SnRK1 functions as a host defense factor.IMPORTANCE Tomato yellow leaf curl China virus (TYLCCNV), which causes a severe yellow leaf curl disease in China, is a monopartite geminivirus associated with the betasatellite (TYLCCNB). TYLCCNB encodes a single pathogenicity protein, βC1 (TYLCCNB-βC1), which functions as both a viral suppressor of RNA silencing (VSR) and a symptom determinant. Here, we show that mimicking phosphorylation of TYLCCNB-βC1 weakens its ability to reverse transcriptional gene silencing, to suppress posttranscriptional gene silencing, and to interact with N. benthamiana ASYMMETRIC LEAVES 1. To our knowledge, this is the first report establishing an inhibitory effect of phosphorylation of TYLCCNB-βC1 on its pathogenic functions as both a VSR and a symptom determinant and to provide a mechanistic explanation of how SNF1-related protein kinase 1 acts as a host defense factor. These findings expand the scope of phosphorylation-mediated defense mechanisms and contribute to further understanding of plant defense mechanisms against geminiviruses.


Wnt/β-Catenin Small-Molecule Inhibitor CWP232228 Preferentially Inhibits the Growth of Breast Cancer Stem-like Cells.
Breast cancer stem cells (BCSC) are resistant to conventional chemotherapy and radiotherapy, which may destroy tumor masses but not all BCSC that can mediate relapses. In the present study, we showed that the level of Wnt/β-catenin signaling in BCSC is relatively higher than in bulk tumor cells, contributing to a relatively higher level of therapeutic resistance. We designed a highly potent small-molecule inhibitor, CWP232228, which antagonizes binding of β-catenin to T-cell factor (TCF) in the nucleus. Notably, although CWP232228 inhibited the growth of both BCSC and bulk tumor cells by inhibiting β-catenin-mediated transcription, BCSC exhibited greater growth inhibition than bulk tumor cells. We also documented evidence of greater insulin-like growth factor-I (IGF-I) expression by BCSC than by bulk tumor cells and that CWP232228 attenuated IGF-I-mediated BCSC functions. These results suggested that the inhibitory effect of CWP232228 on BCSC growth might be achieved through the disruption of IGF-I activity. Taken together, our findings indicate that CWP232228 offers a candidate therapeutic agent for breast cancer that preferentially targets BCSC as well as bulk tumor cells.


[Assisted reproductive technologies and the embryo status].
The status of the human embryo has always be a subject of philosophical and theological thoughts with major social consequences, but, until the 19th century, it has been mainly an abstraction. The arrival of the human embryo in vitro, materialized by Louise Brown's birth in 1978 and above all by the supernumerary embryos produced by the Australian team of Trounson and Wood following the introduction of ovarian stimulation, will turn theoretical thoughts into a reality. Nobody may ignore the hidden intentions behind the debate, as to recognise a status to a few days old embryo will immediately have a major impact on the status of a few weeks old foetus and therefore on the abortion rights. We will see that the embryo status, essentially based as well on a vision on the good and evil as on social order, cannot be based on a scientific analysis of the reproduction process but comes from a society's choice, by essence " arbitrary " and always disputable. This does not preclude the collectivity right and legitimacy to give a precise status and it is remarkable to observe the law is careful not to specify which status to give to the human embryo. It is more thru handling procedures and functioning rules that the law designed the embryo position, neither with a status of a person, nor of a thing. It nevertheless remains true that there is a constant risk that the legislation gives the embryo a status that would call into question it's unique characteristic of early reproductive stage, jeopardizing at once the hard-won reproductive freedom (reproductive choice) as well as freedom of research on embryonic stem cells, one of the most promising field of medical research.


Fast transformation of 2D nanofiber membranes into pre-molded 3D scaffolds with biomimetic and oriented porous structure for biomedical applications.
The ability to transform two-dimensional (2D) structures into three-dimensional (3D) structures leads to a variety of applications in fields such as soft electronics, soft robotics, and other biomedical-related fields. Previous reports have focused on using electrospun nanofibers due to their ability to mimic the extracellular matrix. These studies often lead to poor results due to the dense structures and small poor sizes of 2D nanofiber membranes. Using a unique method of combining innovative gas-foaming and molding technologies, we report the rapid transformation of 2D nanofiber membranes into predesigned 3D scaffolds with biomimetic and oriented porous structure. By adding a surfactant (pluronic F-127) to poly(ε-caprolactone) (PCL) nanofibers, the rate of expansion is dramatically enhanced due to the increase in hydrophilicity and subsequent gas bubble stability. Using this novel method together with molding, 3D objects with cylindrical, hollow cylindrical, cuboid, spherical, and irregular shapes are created. Interestingly, these 3D shapes exhibit anisotropy and consistent pore sizes throughout entire object. Through further treatment with gelatin, the scaffolds become superelastic and shape-recoverable. Additionally, gelatin-coated, cube-shaped scaffolds were further functionalized with polypyrrole coatings and exhibited dynamic electrical conductivity during cyclic compression. Cuboid-shaped scaffolds have been demonstrated to be effective for compressible hemorrhage in a porcine liver injury model. In addition, human neural progenitor cells can be uniformly distributed and differentiated into neurons throughout the cylinder-shaped nanofiber scaffolds, forming ordered 3D neural tissue constructs. Taken together, the approach presented in this study is very promising in the production of pre-molded 3D nanofiber scaffolds for many biomedical applications.


Comprehensive Analysis of the Genetic and Epigenetic Mechanisms of Osteoporosis and Bone Mineral Density.
Osteoporosis is a skeletal disorder characterized by a systemic impairment of bone mineral density (BMD). Genome-wide association studies (GWAS) have identified hundreds of susceptibility loci for osteoporosis and BMD. However, the vast majority of susceptibility loci are located in non-coding regions of the genome and provide limited information about the genetic mechanisms of osteoporosis. Herein we performed a comprehensive functional analysis to investigate the genetic and epigenetic mechanisms of osteoporosis and BMD. BMD and osteoporosis are found to share many common susceptibility loci, and the corresponding susceptibility genes are significantly enriched in bone-related biological pathways. The regulatory element enrichment analysis indicated that BMD and osteoporosis susceptibility loci are significantly enriched in 5'UTR and DNase I hypersensitive sites (DHSs) of peripheral blood immune cells. By integrating GWAS and expression Quantitative Trait Locus (eQTL) data, we found that 15 protein-coding genes are regulated by the osteoporosis and BMD susceptibility loci. Our analysis provides new clues for a better understanding of the pathogenic mechanisms and offers potential therapeutic targets for osteoporosis.


The Involvement of Hypothalamus-Pituitary-Adrenal (HPA) Axis in Suicide Risk.
Stress and Hypothalamic-Pituitary-Adrenal (HPA) axis dysregulation play a major role in various pathophysiological processes associated with both mood disorders and suicidal behavior. We conducted a systematic review with the primary aim of clarifying the nature and extent of HPA axis activity and suicidal behavior. The second aim of this review was to investigate whether potential biomarkers related to HPA axis abnormalities act as individual susceptibility factors for suicide. The PRISMA statement for reporting systematic reviews was used. Only articles published in English peer-reviewed journals were considered for possible inclusion; we excluded case reports, meta-analyses, and systematic reviews, and studies that did not clearly report statistical analysis, diagnostic criteria, or the number of patients included. Overall, 36 articles on HPA axis and suicide risk met inclusion criteria and were reviewed. Studies that investigated tests detecting biomarkers and the role of early life stressors in suicide risk were also included. We found that HPA axis activity is involved in suicide risk, regardless of the presence or absence of psychiatric conditions. The HPA axis abnormalities, mainly characterized by hyperactivity of the HPA axis, may exert an important modulatory influence on suicide risk. Impaired stress response mechanisms contribute to suicide risk. Targeting HPA axis dysregulation might represent a fruitful strategy for identifying new treatment targets and improving suicide risk prediction.


Survival and extinction results for a patch model with sexual reproduction.
We consider a version of the contact process with sexual reproduction on a graph with two levels of interactions modeling metapopulations. The population is spatially distributed into patches and offspring are produced in each patch at a rate proportional to the number of pairs of individuals in the patch (sexual reproduction) rather than simply the number of individuals as in the basic contact process. Offspring produced at a given patch either stay in their parents' patch or are sent to a nearby patch with some fixed probabilities. As the patch size tends to infinity, we identify a mean-field limit consisting of an infinite set of coupled differential equations. For the mean-field equations, we find explicit conditions for survival and extinction that we call expansion and retreat. Using duality techniques to compare the stochastic model to its mean-field limit, we find that expansion and retreat are also precisely the conditions needed to ensure survival and extinction of the stochastic model when the patch size is large. In addition, we study the dependence of survival on the dispersal range. We find that, with probability close to one and for a certain set of parameters, the metapopulation survives in the presence of nearest neighbor interactions while it dies out in the presence of long range interactions, suggesting that the best strategy for the population to spread in space is to use intermediate dispersal ranges.


Gas-phase structure of the histone multimers characterized by ion mobility mass spectrometry and molecular dynamics simulation.
The minimum structural unit of chromatin is the nucleosome core particle (NCP), consisting of 146 bp of DNA wrapped around a histone octamer, which itself contains two H2A/H2B dimers and one (H3/H4)2 tetramer. These multimers possess functionally important tail regions that are intrinsically disordered. In order to elucidate the mechanisms behind NCP assembly and disassembly processes, which are highly related to gene expression, structural characterization of the H2A/H2B dimer and (H3/H4)2 tetramer will be of importance. In the present study, human histone multimers with disordered tail regions were characterized by electrospray ionization (ESI) ion mobility-mass spectrometry (IM-MS) and molecular dynamics (MD) simulation. Experimentally obtained arrival times of these histone multimer ions showed rather wide distributions, implying that multiple conformers exist for each histone multimer in the gas phase. To examine their structures, MD simulations of the histone multimers were performed first in solution and then in vacuo at four temperatures, resulting in a variety of histone multimer structures. Theoretical collision cross-section (CCS) values calculated for the simulated structures revealed that structural models with smaller CCS values had more compact tail regions than those with larger CCS values. This implied that variation of the CCS values of the histone multimers were primarily due to the random behaviors of the tail regions in the gas phase. The combination of IM-MS and MD simulation enabled clear and comprehensive characterization of the gas-phase structures of histone multimers containing disordered tails.


[Anti-Helicobacter therapy for duodenal peptic ulcer complicated by pyloroduodenal stenosis].
The rate of persistence of and susceptibility of Helicobacter pylori (HP) to antibacterial drugs (ABDs) and the results of eradication therapy were studied in patients with duodenal peptic ulcer complicated by pyloroduodenal stenosis (PDS). The patients with PDS exhibited a high (97.1%) rate of anthral mucosal infection with HP showing a high resistance to ABDs. The efficiency of eradication therapy performed with the susceptibility of HP to ABDs kept in mind was 92.5%. The use of eradication therapy in the complex preoperative preparation of patients with ulcerative PDS increases the latter.


Combination of diet, exercise and intermittent treatment of cimetidine on body weight and maintenance of weight loss. A 42 months follow-up study.
The aim of the study was to investigate the long term effect of diet, exercise and intermittent treatment of cimetidine on body weight and maintenance of weight lost during treatment. Fifty women and five men who had completed a 8 week randomized double-blind, placebo-controlled trial of cimetidine for weight loss were invited to participate in an open, non-randomized follow-up study of 42 months. The study was designed to compare weight loss and/or weight gain in subjects who, dependent on their level of motivation, volunteered to participate in an intervention or non-intervention group. In the intervention group the subjects were treated with cimetidine for 8 weeks twice a year, followed a diet restriction and performed regular exercise. In the non-intervention group the subjects had no behavioral treatment. Twenty two subjects volunteered to participate in the intervention program whereas 33 subjects volunteered to participate in the non-intervention group. In the intervention group, non-significant reductions in body weight (1.9 +/- 5.5 kg), BMI (0.6 +/- 1.7 kg/m2), body fat% (1.7 +/- 2.9) and waist circumference (2.1 +/- 5.9 cm) were found. In the non-intervention group there was a significant increase in body weight (7.5 +/- 5.3 kg), BMI (2.6 +/- 1.8 kg/m2), body fat% (3.0 +/- 3.3) and waist circumference (6.7 +/- 5.1 cm). Among the group of subjects initially treated with cimetidine for 8 weeks and who followed a subsequent intervention of additional 42 months (n = 16), there was a 15.1% weight loss. Among the group initially treated with placebo for 8 weeks and who volunteered to participate in the non-intervention group (n = 22), there was a weight gain of 8.6%. In conclusion, the combination of diet restriction, regular exercise and intermittent treatment of cimetidine appears to have long term effects on body weight and maintenance of weight loss.


Potential applicability of cytokines as biomarkers of disease activity in rheumatoid arthritis: Enzyme-linked immunosorbent spot assay-based evaluation of TNF-α, IL-1β, IL-10 and IL-17A.
Biomarkers play a pivotal role in the management of rheumatoid arthritis (RA) by facilitating early diagnosis and 'treat to the target.' However, no gold standard biomarker has been identified for monitoring the disease activity in RA. Cytokines, a diverse group of small protein molecules secreted by peripheral blood mononuclear cells (PBMCs), play a pivotal role in pathogenesis and disease progression in RA. Research is currently underway to find out the applicability of cytokines as biomarkers in RA. This study aimed to quantify the PBMCs that secrete four types of cytokines; TNF-α, IL-1β, IL-10 and IL-17A in two cohorts of active RA patients (early RA patients and established RA patients), compared to healthy controls (HC), using the enzyme-linked immunosorbent spot (ELISPOT) assay, and to assess their association with measures of disease activity of RA. Patients were recruited from outpatient rheumatology clinics, and the disease activity was assessed using single and composite measures of disease activity. The cytokine expression was evaluated using freshly separated PBMCs from whole blood of RA patients using the ELISPOT assay. The number of PBMCs (counted as spot-forming cells (SFCs) per 105 PBMCs) that secreted the cytokine of interest were statistically significantly higher in early RA patients, compared to HC, for IL-17A (P<0.05). Such an increased number of SFCs was not observed in the established RA group, compared to controls, for any of the cytokines tested. The correlation analysis showed that IL-17A is having a moderate correlation (Spearman`s ρ, p <0.05) with five clinical measures of disease activity, including disease activity score 28 (DAS28). According to the multivariable linear regression models, IL17A was a good predictor of both the disease activity score 28 (DAS28) and clinical disease activity index (CDAI). In conclusion, IL-17A has potential applicability as a biomarker of disease activity of RA.


Plasma osteopontin concentrations in preeclampsia - is there an association with endothelial injury?
Abstract Background: It has been previously reported that plasma osteopontin (OPN) concentrations are increased in cardiovascular disorders. The goal of the present study was to determine plasma OPN concentrations in healthy pregnant women and preeclamptic patients, and to investigate their relationship to the clinical characteristics of the study subjects and to markers of inflammation [C-reactive protein (CRP)], endothelial activation [von Willebrand factor antigen (VWF:Ag)] or endothelial injury (fibronectin), oxidative stress [malondialdehyde (MDA)] and trophoblast debris (cell-free fetal DNA). Forty-four patients with preeclampsia and 44 healthy pregnant women matched for age and gestational age were involved in this case-control study. Plasma OPN concentrations were measured with ELISA. Serum CRP concentrations were determined with an autoanalyzer using the manufacturer's reagents. Plasma VWF:Ag was quantified by ELISA, while plasma fibronectin concentrations were measured by nephelometry. Plasma MDA concentrations were estimated by the thiobarbituric acid-based colorimetric assay. The amount of cell-free fetal DNA in maternal plasma was determined by quantitative real-time PCR analysis of the sex-determining region Y (SRY) gene. For statistical analyses, non-parametric methods were applied. Serum levels of CRP, as well as plasma concentrations of VWF:Ag, fibronectin, MDA and cell-free fetal DNA were significantly higher in preeclamptic patients than in healthy pregnant women. There was no significant difference in plasma OPN concentrations between controls and the preeclamptic group. However, preeclamptic patients with plasma fibronectin concentrations in the upper quartile had significantly higher plasma OPN concentrations than those below the 75th percentile, as well as healthy pregnant women [median (interquartile range): 9.38 (8.10-11.99) vs. 7.54 (6.31-9.40) and 7.40 (6.51-8.80) ng/mL, respectively, p<0.05 for both]. Furthermore, in preeclamptic patients, plasma OPN concentrations showed a significant positive linear association with plasma fibronectin (Spearman R=0.38, standardized regression coefficient (beta)=0.41, p<0.05 for both). Plasma OPN concentrations are increased in preeclamptic patients with extensive endothelial injury. However, further studies are warranted to explore the relationship between OPN and endothelial damage. Clin Chem Lab Med 2010;48:181-7.


Function of arginase in lactating mammary gland.
The potential for a considerable formation of ornithine exists in lactating mammary gland because of its arginase content. Late in lactation arginase reaches an activity in the gland higher than that present in any rat tissue except liver. Occurrence of the urea cycle can be excluded since two enzymes for the further reaction of ornithine in the cycle, carbamoyl phosphate synthetase I and ornithine carbamoyltransferase, are both absent from this tissue. Instead, carbamoyl phosphate synthetase II appears early in lactation, associated with accumulation of aspartate carbamoyltransferase and DNA, consistent with the proposed role of these enzymes in pyrimidine synthesis. The facts require another physiological role for arginase apart from its known function in the urea cycle. Significant activity of ornithine aminotransferase develops in mammary gland in close parallel with the arginase. By this reaction, ornithine can be converted into glutamic semialdehyde and subsequently into proline. The enzymic composition of the lactating mammary gland is therefore appropriate for the major conversion of arginine into proline that is known to occur in the intact gland.


Heterozygous loss of TSC2 alters p53 signaling and human stem cell reprogramming.
Tuberous sclerosis complex (TSC) is a pediatric disorder of dysregulated growth and differentiation caused by loss of function mutations in either the TSC1 or TSC2 genes, which regulate mTOR kinase activity. To study aberrations of early development in TSC, we generated induced pluripotent stem cells using dermal fibroblasts obtained from patients with TSC. During validation, we found that stem cells generated from TSC patients had a very high rate of integration of the reprogramming plasmid containing a shRNA against TP53. We also found that loss of one allele of TSC2 in human fibroblasts is sufficient to increase p53 levels and impair stem cell reprogramming. Increased p53 was also observed in TSC2 heterozygous and homozygous mutant human stem cells, suggesting that the interactions between TSC2 and p53 are consistent across cell types and gene dosage. These results support important contributions of TSC2 heterozygous and homozygous mutant cells to the pathogenesis of TSC and the important role of p53 during reprogramming.


A correlation analysis on the postpartum anxiety disorder and influencing factors in puerperae with gestational diabetes mellitus.
The aim of this study is to discuss the postpartum anxiety disorder and influencing factors in puerperae with gestational diabetes mellitus (GDM) to provide a clinical basis for better early identification and intervention of adverse mood. Convenient sampling method was adopted to investigate 205 pregnant women as the observation group and 201 normal healthy pregnant women in the same period as the control group. The self-rating anxiety scale (SAS) was used to investigate and observe the respondents, evaluate the postpartum anxiety status of patients with GDM, and analyze the related influencing factors. Statistical analysis of the data was performed using SAS 3.0 software. A proposed P < 0.05 was considered as statistically significant. Patients with GDM had a higher risk than normal maternal anxiety, related to years of education, triglycerides, 1-h postprandial blood glucose, and a history of induced abortion. GDM can lead to the occurrence of postpartum anxiety, and the poor psychological state is not conducive to the maternal and infant health. Early identification and early intervention can reduce the harm caused by anxiety and promote the progress of maternal and infant health and clinical research.


Hematologic changes in man during decompression: relations to overt decompression sickness and bubble scores.
In order to determine whether asymtomatic gas phase separation causes hematologic abnormalities, studies were carried out following two dive series, one to 210 feet of sea water (FSW) for 50 min and the other to 132 FSW for 30 min. Studies included white and red cell count, red cell indices, platelet count, ESR, fibrinogen, fibrin split products, prothrombin time, partial thromboplastin time, coagulation factors II, V, VII, VIII, and X, clot retraction, platelet aggregation and adhesion, euglobulin lysis time, and platelet factor III. Changes were seen in platelet and white cell count, prothrombin time and partial thrombo-plastin time. White cell count was the only variable which correlated with total bubble score. The results are presented and implications of the findings discussed.


Uptake and utilization of institutional voluntary HIV testing and counseling services among students aged 18-24 in Kenya's public Universities.
Kenya is home to an estimated 1.7 million people living with HIV/AIDS. According to the Kenya AIDS Indicator survey KAIS 2012, HIV prevalence in the age group 15-24 stood at 2.2%. Globally, young people aged 15-24 are a highly vulnerable population with respect to HIV/AIDS infection and transmission. HIV testing and counseling services play a critical role as an entry point to care and treatment. However, uptake of HIV testing and counseling services among the youth in Kenya has been reportedly low. Youths at Universities are among the priority populations in HIV/AIDS programs. This study aimed to determine the barriers to uptake and utilization of institution-based voluntary counseling and testing VCT services among students aged 18-24 in selected public universities in Kenya. The specific objectives were to determine the factors associated with uptake and utilization and the association between various socio-demographic factors and service uptake in institutional VCT facilities. This research utilized a descriptive cross-sectional study design where primarily, data was collected using semi-structured questionnaires and through focus group discussions held with the students in the sampled Universities. Data available at Jomo Kenyatta University of Agriculture and Technology JKUAT Hospital VCT were reviewed for the period 2010 and 2016 to give an insight into service utilization rates among students. Multi-stage sampling technique was utilized to reach a student sample size of 305 from the selected public Universities in Kenya. Uptake of institutional VCT services among University students sampled stood at 45% from a population where 84.4% were aware of the presence of these services on their campuses. More males than females utilized the services. Emerging themes from the study indicated that participants utilized the services for different reasons. Accessibility to test site, testing hours, fear to be seen at site and fear of test result were also identified as factors affecting service uptake. These factors also were also reported when students were asked about their desired characteristics of a VCT facility on campus. This study has unraveled the factors that are associated with testing and counseling in institutional facilities. University students seem to seek and utilize VCT services for different reasons. It is also clear that patterns of services utilization vary from group to another as observed in the case of year of study, gender and age category. It is necessary for policy makers in institutions of higher learning together with those tasked with managing healthcare services in these institutions to adopt approaches that will overcome the barriers to utilization of VCT services among students. With knowledge of the factors associated with uptake and utilization of VCT services in institutional facilities, efforts to tackle the barriers and maximize on enhancers should be utilized fully in order to improve uptake and utilization of services. More research should also focus on the persisting risky sexual behaviors among University students despite the high knowledge they have on HIV/AIDS.


[Diagnostic aspects of anxiety disorders].
A concise review is presented of epidemiological, family- and genetic studies in anxiety disorders. Special emphasis is given to recent developments in the classification of anxiety disorders. The literature in which a more central role of panic attacks is suggested, is critically reviewed. Based upon the studies reviewed it is questionable whether the diagnosis agoraphobia without panic attacks is justified.


Basis for Immunotherapy for Treatment of Meningiomas.
Meningiomas are common tumors that account for approximately one third of CNS tumors diagnosed every year. They are classified by the World Health Organization in grades I-III. Higher grades have an increased rate of growth, invasiveness, rate of recurrence, and worse outcomes than lower grades. Most meningiomas are grade I, while ~18% of meningiomas are grade II and III in hospital-based series. Meningiomas are typically "benign" tumors that are treated with surgery and radiation. However, when they recur or are unresectable, treatment options are very limited, especially since they are chemotherapy-resistant. Recent advances in the treatment of cancers with immunotherapy have focused on checkpoint blockade as well as other types of immunotherapy. There is emerging evidence supporting the use of immunotherapy as a potentially effective treatment strategy for meningioma patients. The immune microenvironment of meningiomas is a complex interplay of genetic alterations, immunomodulatory protein expression, and tumor-immune cell interactions. Meningiomas are known to be infiltrated by immune cells including microglia, macrophages, B-cells, and T-cells. Several mechanisms contribute to decreased an ti-tumor immune response, allowing tumor growth and evasion of the immune system. We discuss the most current knowledge on the immune micro-environment of meningiomas, preclinical findings of immunotherapy in meningiomas, meningioma immunotherapy clinical trials, and also offer insight into future prospects for immunotherapies in meningiomas.