Hepatitis B in the Northern Territory: insights into the changing epidemiology of an ancient condition.
Aboriginal and Torres Strait Islander people are disproportionately affected by hepatitis B virus (HBV) infection. A proposed mismatch between standard vaccines and the HBV/C4 sub-genotype prevalent in Aboriginal people in the Northern Territory (NT) may reduce vaccine effectiveness. To determine HBV prevalence in the NT by Indigenous status and to explore patterns of immunity following implementation of universal vaccination, using a large longitudinal diagnostic dataset. A retrospective analysis of all available HBV serology results in the NT from 1991 to 2011 was conducted, with HBV prevalence and vaccination status analysed according to adigenous status, age and sex using individuals' patterns of HBsAg, anti-HBs and anti-HBc serology over repeated tests. 100 790 individuals were tested (33.4% Indigenous) between 1991 and 2011 (26.1% of the 2011 NT population), with a total of 211 802 tests performed. In 2011, the proportion of HBV positive individuals in the NT was 3.17% (5.22% in Indigenous populations) compared to previous 2011 estimates of 1.70% (3.70% in Indigenous populations). The vaccine failure rate was lower than expected with only one presumed vaccinated person subsequently developing HBsAg positivity (0.02%). Evidence of suboptimal vaccine efficacy by breakthrough anti-HBc positivity in vaccinated individuals was demonstrated in 3.1% of the vaccinated cohort, of which 86.4% identified as Indigenous (HR 1.17). No difference in HBeAg positivity or seroconversion was observed between Indigenous and non-Indigenous individuals living with CHB. The burden of CHB in Indigenous people in the NT has previously been underestimated. A higher HBV prevalence in the NT than described in previous cross-sectional studies was found, including a higher prevalence in Indigenous people. Evidence of suboptimal vaccine efficacy was demonstrated predominantly in Indigenous individuals.


Single-Cell RNA-Sequencing From Mouse Incisor Reveals Dental Epithelial Cell-Type Specific Genes.
Dental epithelial stem cells give rise to four types of dental epithelial cells: inner enamel epithelium (IEE), outer enamel epithelium (OEE), stratum intermedium (SI), and stellate reticulum (SR). IEE cells further differentiate into enamel-forming ameloblasts, which play distinct roles, and are essential for enamel formation. These are conventionally classified by their shape, although their transcriptome and biological roles are yet to be fully understood. Here, we aimed to use single-cell RNA sequencing to clarify the heterogeneity of dental epithelial cell types. Unbiased clustering of 6,260 single cells from incisors of postnatal day 7 mice classified them into two clusters of ameloblast, IEE/OEE, SI/SR, and two mesenchymal populations. Secretory-stage ameloblasts expressed Amel and Enam were divided into Dspp + and Ambn + ameloblasts. Pseudo-time analysis indicated Dspp + ameloblasts differentiate into Ambn + ameloblasts. Further, Dspp and Ambn could be stage-specific markers of ameloblasts. Gene ontology analysis of each cluster indicated potent roles of cell types: OEE in the regulation of tooth size and SR in the transport of nutrients. Subsequently, we identified novel dental epithelial cell marker genes, namely Pttg1, Atf3, Cldn10, and Krt15. The results not only provided a resource of transcriptome data in dental cells but also contributed to the molecular analyses of enamel formation.


e-Learning for the elderly on drug utilization: A pilot study.
This study explores the attitudes of elderly people to the use of electronic educational technology (e-learning) on drug utilization, with particular emphasis on the layout, usability, content, and level of knowledge in the tool. e-Learning modules were evaluated by a group of elderly people (aged ⩾65 years, n = 16) via a questionnaire comprising closed and open-ended questions. Both qualitative and quantitative analyses of the responses showed mostly positive reviews. The results indicate that the e-learning modules are a suitable tool for distributing information and education and that they can be managed by elderly individuals who are familiar with computers, allowing them to learn more about medication use.


The effects of acute exercise-induced cortisol on CCR2 expression on human monocytes.
CC-chemokine receptor 2 (CCR2) and its ligand, monocyte chemotactic protein-1 (MCP-1, also known as CCL2), are crucial for the recruitment of monocytes/macrophages to sites of inflammation. We conducted a series of experiments to investigate the relationship between stress, monocyte CCR2 expression and migration activity. First, we collected peripheral blood mononuclear cells (PBMC) from untrained subjects (n=8) and measured CCR2 expression on CD14(+) monocytes cultured with cortisol, epinephrine and norepinephrine. Second, we collected PBMC from the subjects before and after they cycled for 60 min at 70% peak O(2) uptake (VO2(peak)), and measured alterations in CCR2 expression on monocytes following exercise. Third, we cultured PBMC with serum obtained before and after exercise and the glucocorticoid antagonist RU-486 to determine the effect of cortisol on CCR2 expression in vitro. Last, we measured the ability of PBMC treated with serum or cortisol to migrate through membrane filters in response to CCL2. Cortisol (but not epinephrine or norepinephrine) increased CCR2 expression on monocytes in a dose- and time-dependent manner. Exercise did not influence CCR2 expression on PBMC, whereas incubation of PBMC with post-exercise serum significantly increased CCR2 expression. Both cortisol and post-exercise serum increased the migration of PBMC toward CCL2. The increase in CCR2 expression on PBMC following stimulation with cortisol and serum was blocked by the glucocorticoid receptor antagonist RU-486. In conclusion, cortisol released during exercise increased monocyte CCR2 expression and migration activity in vitro. These alterations may influence inflammation and regeneration of damaged tissue after acute stress.


What can imaging tell us about physiology? Lung growth and regional mechanical strain.
The interplay of mechanical forces transduces diverse physico-biochemical processes to influence lung morphogenesis, growth, maturation, remodeling and repair. Because tissue stress is difficult to measure in vivo, mechano-sensitive responses are commonly inferred from global changes in lung volume, shape, or compliance and correlated with structural changes in tissue blocks sampled from postmortem-fixed lungs. Recent advances in noninvasive volumetric imaging technology, nonrigid image registration, and deformation analysis provide valuable tools for the quantitative analysis of in vivo regional anatomy and air and tissue-blood distributions and when combined with transpulmonary pressure measurements, allow characterization of regional mechanical function, e.g., displacement, strain, shear, within and among intact lobes, as well as between the lung and the components of its container-rib cage, diaphragm, and mediastinum-thereby yielding new insights into the inter-related metrics of mechanical stress-strain and growth/remodeling. Here, we review the state-of-the-art imaging applications for mapping asymmetric heterogeneous physical interactions within the thorax and how these interactions permit as well as constrain lung growth, remodeling, and compensation during development and following pneumonectomy to illustrate how advanced imaging could facilitate the understanding of physiology and pathophysiology. Functional imaging promises to facilitate the formulation of realistic computational models of lung growth that integrate mechano-sensitive events over multiple spatial and temporal scales to accurately describe in vivo physiology and pathophysiology. Improved computational models in turn could enhance our ability to predict regional as well as global responses to experimental and therapeutic interventions.


Staying innate: transcription factor maintenance of innate lymphoid cell identity.
Innate and adaptive lymphocytes are characterized by phenotypic and functional characteristics that result from genomic rearrangements (in the case of antigen-specific B and T cells) coupled with selective gene expression patterns that are generated in a context-dependent fashion. Cell-intrinsic expression of transcription factors (TFs) play a critical role in the regulation of gene expression that establish the distinct lymphoid subsets but also have been proposed to play an ongoing role in the maintenance of lineage-associated transcriptional signatures that comprise lymphocyte identity. This is the case for CD19(+) B cells that require Pax5 expression throughout their lifespan, as well as for diverse T-helper subsets that have specialized immune functions. Innate lymphoid cells (ILCs) comprise diverse effectors cells that differentiate under TF control and have critical roles in the early stages of immune responses. In this review, ILC development is reviewed and the requirement for persistent TF expression in the maintenance of transcriptional signatures that define ILC identity is explored.


Psychotic-like experiences in the general population: characterizing a high-risk group for psychosis.
Recent research shows that psychotic symptoms, or psychotic-like experiences (PLEs), are reported not only by psychosis patients but also by healthy members of the general population. Healthy individuals who report these symptoms are considered to represent a non-clinical psychosis phenotype, and have been demonstrated to be at increased risk of schizophrenia-spectrum disorder. Converging research now shows that this non-clinical psychosis phenotype is familial, heritable and covaries with familial schizophrenia-spectrum disorder. A review of the research also shows that the non-clinical phenotype is associated extensively with schizophrenia-related risk factors, including social, environmental, substance use, obstetric, developmental, anatomical, motor, cognitive, linguistic, intellectual and psychopathological risk factors. The criterion and construct validity of the non-clinical psychosis phenotype with schizophrenia demonstrates that it is a valid population in which to study the aetiology of psychosis. Furthermore, it suggests shared genetic variation between the clinical and non-clinical phenotypes. Much remains to be learned about psychosis by broadening the scope of research to include the non-clinical psychosis phenotype.


Predictable patterns of trait mismatches between interacting plants and insects.
There are few predictions about the directionality or extent of morphological trait (mis)matches between interacting organisms. We review and analyse studies on morphological trait complementarity (e.g. floral tube length versus insect mouthpart length) at the population and species level. Plants have consistently more exaggerated morphological traits than insects at high trait magnitudes and in some cases less exaggerated traits than insects at smaller trait magnitudes. This result held at the population level, as well as for phylogenetically adjusted analyses at the species-level and for both pollination and host-parasite interactions, perhaps suggesting a general pattern. Across communities, the degree of trait mismatch between one specialist plant and its more generalized pollinator was related to the level of pollinator specialization at each site; the observed pattern supports the "life-dinner principle" of selection acting more strongly on species with more at stake in the interaction. Similarly, plant mating system also affected the degree of trait correspondence because selfing reduces the reliance on pollinators and is analogous to pollination generalization. Our analyses suggest that there are predictable "winners" and "losers" of evolutionary arms races and the results of this study highlight the fact that breeding system and the degree of specialization can influence the outcome.


A phase II trial of prolonged, continuous infusion of low-dose gemcitabine plus cisplatin in patients with advanced malignant pleural mesothelioma.
Low-dose, prolonged infusion of gemcitabine has effects similar to standard doses in several cancers. We evaluated the toxicity and efficacy of low-dose gemcitabine in prolonged infusion plus cisplatin in patients with advanced pleural mesothelioma. Patients with mesothelioma received gemcitabine (250 mg/m(2)) in a 6-h infusion plus cisplatin (35 mg/m(2)) on days 1 and 8 every three weeks. We used the modified response evaluation criteria in solid tumours. This study is registered in clinical trials (NCT01869023). We included 39 patients; 82.1 % were low risk according to the European Organisation for Research and Treatment of Cancer prognostic group. Partial response was observed in 53.8 % (21/39), stable disease in 33.3 % (13/39) and progression in 12.8 % (5/39). The median progression-free survival was 6.9 months (95 % CI 3.2-10.6 months), and the associated factors were the EORTC risk and histology. The median overall survival was 20.7 months (95 % CI 10.7-30.8 months). The functional, physical and emotional roles and dyspnoea, insomnia and pain symptom scales improved. The most commonly graded 3/4 side effects were neutropenia (24.4 %), lymphopenia (14.6 %), thrombocytopenia (14.7 %) and anaemia (12.2 %). Low-dose, prolonged gemcitabine infusion plus cisplatin has acceptable toxicity and high efficacy with improved quality of life, representing an affordable regimen for the low-income population.


Understanding cisplatin resistance using cellular models.
Many mechanisms of cisplatin resistance have been proposed from studies of cellular models of resistance including changes in cellular drug accumulation, detoxification of the drug, inhibition of apoptosis and repair of the DNA adducts. A series of resistant models were developed from CCRF-CEM leukaemia cells with increasing doses of cisplatin from 100 ng/ml. This produced increasing resistance up to 7-fold with a treatment dose of 1.6 microg/ml. Cisplatin resistance in these cells correlated with increases in the antioxidant glutathione, yet treatment with buthionine sulphoximine, an inhibitor of glutathione synthesis, had no effect on resistance, suggesting that the increase in glutathione was not directly involved in cisplatin resistance. Two models were developed from H69 SCLC cells, H69-CP and H69CIS200 using 100 ng/ml or 200 ng/ml cisplatin respectively. Both cell models were 2-4 fold resistant to cisplatin, and have decreased expression of p21 which may increase the cell's ability to progress through the cell cycle in the presence of DNA damage. Both the H69-CP and H69CIS200 cells showed no decrease in cellular cisplatin accumulation. However, the H69-CP cells have increased levels of cellular glutathione and are cross resistant to radiation whereas the H69CIS200 cells have neither of these changes. This suggests that increases in glutathione may contribute to cross-resistance to other drugs and radiation, but not directly to cisplatin resistance. There are multiple resistance mechanisms induced by cisplatin treatment, even in the same cell type. How then should cisplatin-resistant cancers be treated? Cisplatin-resistant cell lines are often more sensitive to another chemotherapeutic drug paclitaxel (H69CIS200), or are able to be sensitized to cisplatin with paclitaxel pre-treatment (H69-CP). The understanding of this sensitization by paclitaxel using cell models of cisplatin resistance will lead to improvements in the clinical treatment of cisplatin resistant tumours.


Surveillance of Aedes albopictus Skuse breeding preference in selected dengue outbreak localities, peninsular Malaysia.
Entomological surveillance was conducted in order to determine the abundance and to evaluate any changes of biological vectors or ecology, especially in the dengue outbreak areas. The abundance and breeding preference of Aedes albopictus and Aedes aegypti were conducted in selected dengue outbreak localities in three states of peninsular Malaysia namely Selangor, Federal Territory of Kuala Lumpur, and Penang Island using ovitraps and larval survey method. It was determined that Ae. albopictus was predominant in most of the localities and found to breed more outdoor than indoor. A wide range of breeding foci were recorded in this study. It was also determined that ovitrap method was more effective to detect the presence of Aedes mosquitoes when the larval survey was at low rate of infestation. The abundance of Ae. albopictus in dengue outbreak localities emphasis that the vector control programme should also target this species together with the primary dengue vector, Ae. aegypti.


Coactivation of the Default Mode Network regions and Working Memory Network regions during task preparation.
The Default Mode Network (DMN) regions exhibit deactivation during a wide variety of resource demanding tasks. However, recent brain imaging studies reported that they also show activation during various cognitive activities. In addition, studies have found a negative correlation between the DMN and the working memory network (WMN). Here, we investigated activity in the DMN and WMN regions during preparation and execution phases of a verbal working memory task. Results showed that the core DMN regions, including the medial prefrontal cortex and posterior cingulate cortex, and WMN regions were activated during preparation. During execution, however, the WMN regions were activated but the DMN regions were deactivated. The results suggest that activation of these network regions is affected by allocation of attentional resources to the task relevant regions due to task demands. This study extends our previous results by showing that the core DMN regions exhibit activation during task preparation and deactivation during task execution.


Phosphatidylinositol-dependent activation of DNA polymerase alpha.
DNA polymerase alpha was activated in vitro by cAMP-independent, phospholipid-dependent, protein kinase catalytic subunit. Of the phospholipids examined, phosphatidylinositol showed the greatest potential for interaction with protein kinase and ATP to activate DNA polymerase alpha in vitro. DNA polymerase alpha was directly activated by phosphorylated phosphatidylinositol in the absence of protein kinase and ATP. Activation of DNA polymerase alpha as a function of phosphorylation was demonstrated using 32P-ATP as the phosphate donor. In vitro treatment of the enzyme with phosphatidylinositol produced Linweaver-Burk plots showing noncompetitive kinetics of enzyme activation, suggesting that activation occurs prior to binding of the enzyme to DNA template/primer. These data indicate that DNA polymerase alpha may be activated in vitro in the presence of protein kinase, ATP, and phosphatidylinositol, and suggest that phosphorylation of the enzyme may constitute an intracellular mechanism of enzyme activation.


Study of apoptosis in oral pemphigus vulgaris using immunohistochemical marker Bax and TUNEL technique.
Pemphigus vulgaris (PV) is an autoimmune mucocutaneous disease presenting clinically with blisters or erosions of the skin and mucous membrane. The main histopathologic characteristic of this disease is suprabasal vesicles due to loss of cell-cell adhesion between keratinocytes named acantholysis. Studies have shown that apoptosis is increased in PV. The purpose of this study is to investigate the role of apoptosis in blister formation in PV. This cross-sectional study was conducted on 25 specimens of oral PV. The presence of apoptosis was evaluated using the TUNEL technique in the normal perilesional region, vesicle area, and acantholytic cells. Also, the expression of Bax pro-apoptotic marker was assessed by the biotin-streptavidin immunohistochemical method. SPSS software was used for Wilcoxon test analysis. P values <0.05 were considered significant. The percentage and intensity staining of TUNEL-positive cells were noteworthy. There were statistically significant differences between basal and parabasal (P = 0.05), tombstone with vesicle roof (P = 0.038) and basal with tombstone (P = 0.038). However, the expression and staining intensity of pro-apoptotic marker Bax were weak, and no statistically significant differences were observed between the various areas. The results obtained in the present study suggest that the process of apoptosis occurs early in PV because it was observed in the perilesional normal appearing tissue. Also, the process of apoptosis may cause exacerbation or speeding of the bulla formation. In other words, inhibition of apoptosis in the patients could reduce the severity of the lesions.


Health-related quality of life in hypertrophic cardiomyopathy patients with implantable defibrillators.
Health-related quality of life (HRQL) in hypertrophic cardiomyopathy (HCM) patients with implantable cardioverter-defibrillators (ICDs) is largely unknown. The aim was to assess HRQL, including comparisons between groups, using the questionnaire SF-36, and compare it to a Swedish age- and sex-matched population. Validated data on adult HCM patients with ICDs were used. The SF-36 response rate was 82.5 % and 245 patients (mean age 55.9 years, 70.2 % men) were analyzed using the Mann-Whitney U-test, t-test, Spearman correlation and effect size calculations. In all SF-36 domains the patients' score was lower (p-value of <0.0001) than norms except for bodily pain. The general health domain showed the highest effect size (0.77) and the impact was more pronounced in the SF-36 physical component summary score (0.62) than the mental component summary score (0.46). Older age was correlated with lower scores on the physical component and higher scores on the mental component. Atrial fibrillation and/or systolic heart failure were associated with worse physical health. HRQL was similar in primary vs secondary prevention cases. Inappropriate ICD shock was associated with worse mental health while appropriate therapy trended toward better mental health. HCM patients with ICDs suffer from poor HRQL regardless of age, sex, or primary vs secondary prevention indication. Atrial fibrillation and systolic heart failure are determinants of poor physical health. Inappropriate shocks, but not appropriate therapies, are associated with poorer mental health.


Oral metformin-ascorbic acid co-administration ameliorates alcohol-induced hepatotoxicity in rats.
Alcoholic liver disease remains a major cause of liver failure worldwide with no available curative or prophylactic therapy as at present. High dose metformin is reported to ameliorate liver injuries in both human and animal models of acute and chronic alcoholic liver injuries. The aim of the present in vivo animal study was to determine whether metformin-ascorbic acid co-administration also prevents alcoholic hepatotoxicity in chronic alcohol exposure. In the present study, ameliorating effect of 200 mg/ kg/day of ascorbic acid (Asc), 500 mg/kg/day of metformin (Met) and their co-administration (Met-Asc) were investigated in 5 groups of 50% ethanol-treated male Wistar rats for 2 weeks of the experiment. The body weight of each rat was taken on days 1, 7, and 14 of the experiment, respectively. On day 15, fasted blood samples for plasma lipids and liver enzyme markers were collected via cardiac puncture from the rats under diethyl ether anaesthesia. Results showed that administration of graded oral doses of 50% ethanol for 14 days significantly (p<0.001) elevated the plasma liver enzymes--aspartate aminotransferase (AST), alanine aminotansferase (ALT) and alkaline phosphatase (ALP). Two weeks of ethanol treatment also induced alterations in the plasma triglycerides (PTG), total cholesterol (PTC), high density lipoprotein (HDL-c), and low density lipoprotein (LDL-c). However, these elevations were significantly (p<0.05) attenuated by Asc, Met, and Met-Asc after 14 days of oral treatment, with Met-Asc having higher significant (p<0.001) ameliorating effect than Asc alone but with comparative effect to that of Met alone. High dose metformin-ascorbic acid co-administration protected the liver against the deleterious effects of chronic high dose alcohol and the hepatoprotective effect of Met-Asc appeared to be due mainly to the metformin molecule of the drug combination. However, further studies would be required to evaluate the mechanisms underlying the observed effects.


Regional cerebral blood flow during mechanical hyperventilation in patients with fulminant hepatic failure.
Hyperventilation is frequently used to prevent or postpone the development of cerebral edema and intracranial hypertension in patients with fulminant hepatic failure (FHF). The influence of such therapy on regional cerebral blood flow (rCBF) remains, however, unknown. In this study the CBF-distribution pattern was determined within the first 12 hours after development of hepatic encephalopathy (HE) stage 4 before and during hyperventilation. Ten consecutive patients (median age 48 [range 33-57] years) with FHF and 9 healthy controls (median age 54 [24-58] years) had rCBF determined by single photon emission computed tomography (SPECT) using intravenous injection of 133Xenon. For determination of high resolution CBF pattern, the patients were also studied with 99mTc-hexa-methylpropyleneamine oxime (HMPAO) in the hyperventilation condition. There was no significant difference in the rCBF distribution pattern during normoventilation as compared with hyperventilation. The anterior to posterior (AP) ratio was significantly lower in patients as compared with healthy controls. After hepatic recovery and disappearance of HE, 3 patients had restored normal rCBF distribution pattern as compared with healthy controls. We conclude that in sedated patients with FHF, a relatively lower rCBF is found in the frontal regions and in the basal ganglia as compared with posterior regions. This rCBF-distribution pattern was not aggravated during hyperventilation. It is speculated that this change of rCBF in patients with FHF may render the frontal brain regions more susceptible to hypoxia. The relative frontal rCBF decrease was shown to be reversible with hepatic recovery and alleviation of HE.


An engineered cell line lacking OGG1 and MUTYH glycosylases implicates the accumulation of genomic 8-oxoguanine as the basis for paraquat mutagenicity.
Paraquat (1,1'-dimethyl, 4,4'-bipyridinium dichloride; PQ), a widely used herbicide, is toxic to mammals through ingestion, inhalation and skin contact. Epidemiological data suggest that PQ is also mutagenic and carcinogenic, especially in high doses. The toxic and mutagenic properties of PQ are attributed to the ability of the molecule to redox-cycle, which generates reactive oxygen species (ROS) and subsequent oxidative stress. ROS also cause oxidative DNA damage such as 8-oxoguanine (8OG), a mutagenic base that, when replicated, causes G to T transversion mutations. The present study employed the CHO-derived cell line AS52 to quantify the mutagenic properties of low doses of PQ. By containing a functional, chromosomally-integrated copy of the bacterial gpt gene, AS52 cells a facile system for evaluating the mutagenic properties of genotoxicants. To bolster the sensitivity of this system for detecting mutagenesis of weak mutagens like PQ, and to provide a tool for mechanistic evaluation of the mutagenic process, we constructed a new AS52-derived cell line defective for 8OG DNA repair. Specifically, we employed CRISPR-Cas9 technology to knock out 8-oxoguanine DNA glycosylase (OGG1) and MUTYH glycosylase, two key enzymes involved in the base excision repair of 8OG. The double knock-out (DKO) AS52 cells were found to be more sensitive to PQ toxicity than the parental (WT) AS52 cell line. They experienced higher levels of ROS, which translated into more DNA double-strand breaks, which explained the PQ toxicity. The increased ROS levels also led to more 8OG genomic accumulation, and a higher level of mutations in the DKO cells, suggesting that PQ mutagenesis is mediated primarily by 8OG genomic accumulation. Consistent with this view, antioxidant co-treatment lowered induced cellular ROS and PQ-induced mutagenesis. Taken together, our data demonstrate the strong protective role of OGG1 and MUTYH against PQ-induced mutagenesis. Moreover, our experiments establish the engineered OGG1-/-MUTYH-/- AS52 cell line and associated methods as a versatile cellular system for studying in quantitative terms the mutagenesis of other agents, environmental or endogenous, that induce oxidative stress.


Progressive femoroacetabular impingement after complete excision of osteoid osteoma in adolescents: a report of two cases.
This article highlights that the long-term and serial follow-up of adolescents with osteoid osteoma should be considered, even after complete excision of the nidus owing to the possibility of the delayed onset or progression of femur head and neck deformities or osteoarthritis. It is important to recognize the sequelae of osteoid osteomas, such as bone edema and new bone formation, which can alter the normal anatomy of the proximal femur. We report two cases of osteoid osteoma in the proximal femur, which showed progressive hypertrophy of the femoral neck after excision of the nidus and subsequent cam-type femoroacetabular impingement (FAI), requiring additional osteochondroplasty procedures. Even though hip pain was relieved immediately after excision of the nidus in both cases, cam-type FAI developed during postoperative follow-up of 18 months (case 1) and 6.5 years (case 2). Hip pain subsided within 1 month of osteochondroplasty, and the full range of motion of the hip joint was achieved and was being maintained after postoperative follow-up of 1 year (case 1) and 6 months (case 2).


The effect of occlusion of the skin with transdermal therapeutic system on Langerhans' cells and the induction of skin irritation.
Sensitization to drugs in transdermal therapeutic systems is a common unwanted event. We investigated whether prolonged occlusion of the skin causes skin irritation, and in this way might play a role in the possible induction of sensitization to drugs from these systems. Occlusion was effected with a placebo transdermal therapeutic system and silver-patch test in a time span ranging from eight hours to seven days in five groups of five volunteers. Skin irritation was judged on clinical aspects, histopathologic and immunofluorescence findings, and changes in the Langerhans' cell systems. The results indicate that occlusion with the systems used in this experiment provokes only slight or no skin irritation.


A multiplicity of factors contributes to selective RNA polymerase III occupancy of a subset of RNA polymerase III genes in mouse liver.
The genomic loci occupied by RNA polymerase (RNAP) III have been characterized in human culture cells by genome-wide chromatin immunoprecipitations, followed by deep sequencing (ChIP-seq). These studies have shown that only ∼40% of the annotated 622 human tRNA genes and pseudogenes are occupied by RNAP-III, and that these genes are often in open chromatin regions rich in active RNAP-II transcription units. We have used ChIP-seq to characterize RNAP-III-occupied loci in a differentiated tissue, the mouse liver. Our studies define the mouse liver RNAP-III-occupied loci including a conserved mammalian interspersed repeat (MIR) as a potential regulator of an RNAP-III subunit-encoding gene. They reveal that synteny relationships can be established between a number of human and mouse RNAP-III genes, and that the expression levels of these genes are significantly linked. They establish that variations within the A and B promoter boxes, as well as the strength of the terminator sequence, can strongly affect RNAP-III occupancy of tRNA genes. They reveal correlations with various genomic features that explain the observed variation of 81% of tRNA scores. In mouse liver, loci represented in the NCBI37/mm9 genome assembly that are clearly occupied by RNAP-III comprise 50 Rn5s (5S RNA) genes, 14 known non-tRNA RNAP-III genes, nine Rn4.5s (4.5S RNA) genes, and 29 SINEs. Moreover, out of the 433 annotated tRNA genes, half are occupied by RNAP-III. Transfer RNA gene expression levels reflect both an underlying genomic organization conserved in dividing human culture cells and resting mouse liver cells, and the particular promoter and terminator strengths of individual genes.


The Relationship Between Tryptophan Hydroxylase-2 Gene with Primary Insomnia and Depressive Symptoms in the Han Chinese Population
Insomnia often coexists with depression, and there is compelling evidence for a genetic component in the etiologies of both disorders. To investigate the relationship between exonic variant (rs4290270) in the tryptophan hydroxylase-2 gene and primary insomnia and symptoms of depression in Han Chinese. Case-control study. This study included 152 patients with primary insomnia and 164 age- and gender-matched normal controls. All patients were investigated by polysomnography for 2 consecutive nights. The depressive symptoms were measured by using a 20-item Zung Self-rating Depression Scale. Sleep quality was assessed with the Pittsburgh Sleep Quality index. The genotypes of the TPH-2 gene polymorphism rs4290270 were determined by the polymerase chain reaction-restriction fragment length polymorphism method. The genotype distributions of the tryptophan hydroxylase-2 gene polymorphism rs4290270 were in Hardy-Weinberg equilibrium in both patients and controls (p>0.05). The allele and genotype distributions of this variant were comparable between patients and controls in all subjects and between genders (all p>0.05). The impact of rs4290270 on self-rating depression scale score changes was statistically significant (p=0.002), with carriers of the A/A genotype having the highest self-rating depression scale score (mean ± standard deviation: 52.73±12.88), followed by the A/T genotype (50.94±11.29, p=0.35) and the T/T genotype (43.48±7.78, p<0.01), and this impact was more obvious in women (p<0.001). The tryptophan hydroxylase-2 gene polymorphism rs4290270 may not be a susceptibility locus for primary insomnia in Han Chinese, but it may be a marker of depressive symptoms.


Evidence for distinct rate-limiting steps in the cleavage of alkenes by carotenoid cleavage dioxygenases.
Carotenoid cleavage dioxygenases (CCDs) use a nonheme Fe(II) cofactor to split alkene bonds of carotenoid and stilbenoid substrates. The iron centers of CCDs are typically five-coordinate in their resting states, with solvent occupying an exchangeable site. The involvement of this iron-bound solvent in CCD catalysis has not been experimentally addressed, but computational studies suggest two possible roles. 1) Solvent dissociation provides a coordination site for O2, or 2) solvent remains bound to iron but changes its equilibrium position to allow O2 binding and potentially acts as a proton source. To test these predictions, we investigated isotope effects (H2O versus D2O) on two stilbenoid-cleaving CCDs, Novosphingobium aromaticivorans oxygenase 2 (NOV2) and Neurospora crassa carotenoid oxygenase 1 (CAO1), using piceatannol as a substrate. NOV2 exhibited an inverse isotope effect (kH/kD ∼ 0.6) in an air-saturated buffer, suggesting that solvent dissociates from iron during the catalytic cycle. By contrast, CAO1 displayed a normal isotope effect (kH/kD ∼ 1.7), suggesting proton transfer in the rate-limiting step. X-ray absorption spectroscopy on NOV2 and CAO1 indicated that the protonation states of the iron ligands are unchanged within pH 6.5-8.5 and that the Fe(II)-aquo bond is minimally altered by substrate binding. We pinpointed the origin of the differential kinetic behaviors of NOV2 and CAO1 to a single amino acid difference near the solvent-binding site of iron, and X-ray crystallography revealed that the substitution alters binding of diffusible ligands to the iron center. We conclude that solvent-iron dissociation and proton transfer are both associated with the CCD catalytic mechanism.


Bombesin may stimulate proliferation of human pancreatic cancer cells through an autocrine pathway.
Bombesin is trophic to normal pancreas and acinar cell adenocarcinoma, but its effects on ductal cell tumors are undetermined. The autocrine growth effects of bombesin on well-differentiated (HPAF, CD11) and poorly differentiated (CD18, PANC-1) human ductal pancreatic cancer cell lines were investigated. Receptor binding of labeled bombesin was measured in a whole-cell microplate assay. Bombesin production was measured by radioimmunoassay. Proliferative responses were quantified using the MTT assay. Messenger RNA for bombesin and its receptor were identified by primer extension analysis. A single class of high-affinity binding sites was detected on HPAF and CD18 cells. Similar affinities and high receptor densities were found on the 2 cell lines. Bombesin was secreted by all 4 cell lines during 24-hr culture in serum-free media, and its recovery was enhanced in the presence of protease inhibitors. Primer extension analysis demonstrated the presence of mRNA for both bombesin and its receptor in HPAF, CD18, CD11 and PANC-1 cells, even though no functional receptor was found in the latter 2 lines. Bombesin significantly stimulated the proliferation of HPAF and CD18 cells. This trophic effect was inhibited by the specific bombesin antagonist RC-3095. Bombesin may act as an autocrine growth factor in some human pancreatic cancer cell lines. Furthermore, other cell lines transcribe mRNA for bombesin receptors but have no functional bombesin receptors, suggesting a genetic or post-translational change in the receptor for these cells. Bombesin may be involved as a growth factor in the development of pancreatic ductal adenocarcinoma in humans. This possible autocrine growth pathway may provide an avenue for therapeutic intervention in this malignant disease.


Accuracy of piezoelectric accelerometers measuring displacement of a spinal adjusting instrument.
The accuracy and reproducibility of an electronic system to measure the displacement of a spring-loaded chiropractic adjusting instrument was examined. The electronic system included a piezoelectric force transducer, piezoelectric accelerometer transducers and a digital oscilloscope. Accuracy was studied by comparing electronic measurements with the expansion allowed by the mechanically limiting expansion-control knob of the instrument. The results suggested improvements for future accuracy verification checks and detected accuracy within about 10% of the expansion of the commonly used expansion-control-knob revolutions. Preliminary experiments are presented to show application of the system to studies on thrusts into the spine. The impedance-head-equipped spring-loaded Activator chiropractic adjusting instrument had a low velocity when used on the patient and appeared to cause bone movement and a measurable EMG response.


Synthesis, properties, and biomedical applications of gelatin methacryloyl (GelMA) hydrogels.
Gelatin methacryloyl (GelMA) hydrogels have been widely used for various biomedical applications due to their suitable biological properties and tunable physical characteristics. GelMA hydrogels closely resemble some essential properties of native extracellular matrix (ECM) due to the presence of cell-attaching and matrix metalloproteinase responsive peptide motifs, which allow cells to proliferate and spread in GelMA-based scaffolds. GelMA is also versatile from a processing perspective. It crosslinks when exposed to light irradiation to form hydrogels with tunable mechanical properties. It can also be microfabricated using different methodologies including micromolding, photomasking, bioprinting, self-assembly, and microfluidic techniques to generate constructs with controlled architectures. Hybrid hydrogel systems can also be formed by mixing GelMA with nanoparticles such as carbon nanotubes and graphene oxide, and other polymers to form networks with desired combined properties and characteristics for specific biological applications. Recent research has demonstrated the proficiency of GelMA-based hydrogels in a wide range of tissue engineering applications including engineering of bone, cartilage, cardiac, and vascular tissues, among others. Other applications of GelMA hydrogels, besides tissue engineering, include fundamental cell research, cell signaling, drug and gene delivery, and bio-sensing.


Seeing through biological tissues using the fly eye principle.
During the past decade, optical imaging through scattering medium has proved to be a powerful technique for many applications. It is especially effective in medical diagnostic, since it is safe, noninvasive and low-cost compared with the conventional radiation techniques. Based on a similar principle of the fly's visual system, we show a novel method of optical imaging through scattering medium. An image of bones hidden between two biological tissues (chicken breast) is recovered from many noisy speckle pictures obtained on the output of a multi-channeled optical imaging system. The operation of multiple imaging is achieved using a microlens array. Each lens from the array projects a different speckled image on a digital camera. The set of speckled images from the entire array are first shifted to a common center and then accumulated to a single average picture in which the concealed object is exposed.


Moebius sequence -a multidisciplinary clinical approach.
Moebius Sequence (MS) is a rare disorder defined by bilateral congenital paralysis of the abducens and facial nerves in combination with various odontological, craniofacial, ophthalmological and orthopaedic conditions. The aetiology is still unknown; but both genetic (de novo mutations) and vascular events in utero are reported. The purpose of present study was through a multidisciplinary clinical approach to examine children diagnosed with Moebius-like symptoms. Ten children underwent odontological, ophthalmological, obstetric, paediatric, orthopaedic, genetic, radiological and photographical evaluation. Five patients maintained the diagnosis of MS according to the diagnostic criteria. All five patients had bilateral facial and abducens paralysis confirmed by ophthalmological examination. Three of five had normal brain MR imaging. Two had missing facial nerves and one had missing abducens nerves. The Strengths and Difficulties Questionnaire (SDQ) showed normal scores in three of five patients. Interestingly, two of five children were born to mothers with uterine abnormalities (unicornuate/bicornuate uterus). In the odontological examination three of five showed enamel hypomineralisation. All five had abnormal orofacial motor function and maxillary prognathism. Two patients had adactyly, syndactyly and brachydactyly. None of the five patients had Poland anomaly, hip dislocation or dysplasia but all had a mild degree of scoliosis. We observed congenital club-feet, calcaneovalgus deformities, macrodactyly of one or more toes or curly toes. Pedobarography showed plantar pressures within normal ranges. Adherence to standard diagnostic criteria is central in the diagnosis of MS. An accurate diagnosis is the basis for correct discussion of other relevant concomitant symptoms of MS, genetic testing and evaluation of prognosis. The multidisciplinary approach and adherence to diagnostic criteria taken in present study increases the knowledge on the relationship between genotype, phenotype and symptomatology of MS.


SOS response induction by beta-lactams and bacterial defense against antibiotic lethality.
The SOS response aids bacterial propagation by inhibiting cell division during repair of DNA damage. We report that inactivation of the ftsI gene product, penicillin binding protein 3, by either beta-lactam antibiotics or genetic mutation induces SOS in Escherichia coli through the DpiBA two-component signal transduction system. This event, which requires the SOS-promoting recA and lexA genes as well as dpiA, transiently halts bacterial cell division, enabling survival to otherwise lethal antibiotic exposure. Our findings reveal defective cell wall synthesis as an unexpected initiator of the bacterial SOS response, indicate that beta-lactam antibiotics are extracellular stimuli of this response, and demonstrate a novel mechanism for mitigation of antimicrobial lethality.


The Assessment of Blood Flow Velocities in Retinal Collaterals in Diabetic Retinopathy.
Diabetic retinopathy (DR) is a microvascular disease characterized by capillary dropout and resultant retinal ischemia which then leads to retinal vascular remodeling. Our goal was to assess blood flow velocities in retinal collateral vessels in healthy and diabetic subjects with various stages of DR. In our pilot study, we enrolled five eyes of five healthy subjects (H), five eyes of four subjects with diabetes and no retinopathy (DM), three eyes of three subjects with mild non-proliferative diabetic retinopathy (MDR), and five eyes of four subjects with proliferative diabetic retinopathy (PDR). Following routine ophthalmic examination, all subjects were imaged using a retinal function imager (RFI; Optical Imaging Inc., Rehovot, Israel). The built-in software of the RFI was used to identify and segment retinal collaterals with measurement of the blood flow velocities (BFV). One-way ANOVA was performed for BFV, followed by Newman-Keuls post hoc test. The level of significance was set at 5%. The total number of collateral segments involved in the study was 30, 31, 21, and 39 in the H, DM, MDR, and PDR groups, respectively. The BFVs in the collaterals were significantly lower in PDR (H: 1.86 ± 0.67, DM: 1.91 ± 0.71, MDR: 1.71 ± 0.53, PDR: 1.37 ± 0.58 mm/s). The PDR group showed a statistically significant difference in the comparisons to all groups (p = 0.012, p = 0.008, and p = 0.043 for the H, DM, and MDR groups, respectively), while no other comparisons between the groups were significant. We observed decreased BFV in retinal collaterals in PDR that may be due to the extensive capillary dropout and retinal ischemia. Further studies are needed for the noninvasive functional assessment of retinal microvascular changes in DR to better understand the underlying pathophysiology.


Spleen Tyrosine Kinase-Mediated Autophagy Is Required for Epithelial-Mesenchymal Plasticity and Metastasis in Breast Cancer.
The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here, we compare a reversible model of epithelial-mesenchymal transition (EMT) induced by TGFβ to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGFβ-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal-epithelial transition (MET). Genetic knockout of autophagy-related 7 (ATG7) or pharmacologic inhibition of SYK activity with fostamatinib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, this study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells. SIGNIFICANCE: These findings present inhibition of spleen tyrosine kinase as a therapeutic option to limit breast cancer metastasis by promoting systemic tumor dormancy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/8/1831/F1.large.jpg.See related commentary by Farrington and Narla, p. 1756.


A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia.
Magnesium sulfate may prevent eclampsia by reducing cerebral vasoconstriction and ischemia. Nimodipine is a calcium-channel blocker with specific cerebral vasodilator activity. Our objective was to determine whether nimodipine is more effective than magnesium sulfate for seizure prophylaxis in women with severe preeclampsia. We conducted an unblinded, multicenter trial in which 1650 women with severe preeclampsia were randomly assigned to receive either nimodipine (60 mg orally every 4 hours) or intravenous magnesium sulfate (given according to the institutional protocol) from enrollment until 24 hours post partum. High blood pressure was controlled with intravenous hydralazine as needed. The primary outcome measure was the development of eclampsia, as defined by a witnessed tonic-clonic seizure. Demographic and clinical characteristics were similar in the two groups. The women who received nimodipine were more likely to have a seizure than those who received magnesium sulfate (21 of 819 [2.6 percent] vs. 7 of 831 [0.8 percent], P=0.01). The adjusted risk ratio for eclampsia associated with nimodipine, as compared with magnesium sulfate, was 3.2 (95 percent confidence interval, 1.1 to 9.1). The antepartum seizure rates did not differ significantly between groups, but the nimodipine group had a higher rate of postpartum seizures (9 of 819 [1.1 percent] vs. 0 of 831, P=0.01). There were no significant differences in neonatal outcome between the two groups. More women in the magnesium sulfate group than in the nimodipine group needed hydralazine to control blood pressure (54.3 percent vs. 45.7 percent, P<0.001). Magnesium sulfate is more effective than nimodipine for prophylaxis against seizures in women with severe preeclampsia.


Suicide in doctors. A psychological autopsy study.
Doctors are at higher risk of suicide than many other occupational groups. This study was conducted to investigate factors associated with suicide in doctors. Psychological autopsy study of 38 working doctors who died by suicide in England and Wales between January 1991 and December 1993. Psychiatric illness was present in 25 of the doctors. Depressive illness and drug or alcohol abuse were the most common diagnoses. Twenty-five doctors had significant problems related to work, 14 had relationship problems and 10 had financial problems. Multiple and interrelated problems were often present. The most common method of suicide was self-poisoning, often with drugs taken from work. Prevention of suicide in doctors requires a range of strategies, including improved management of psychiatric disorder, measures to reduce occupational stress and restriction of access to means of suicide when doctors are depressed.


Skeletal muscle metabolism in the chronic fatigue syndrome. In vivo assessment by 31P nuclear magnetic resonance spectroscopy.
Previous study of patients with chronic fatigue syndrome (CFS) has demonstrated a markedly reduced dynamic exercise capacity, not limited by cardiac performance and in the absence of clinical neuromuscular dysfunction, suggesting the possibility of a subclinical defect of skeletal muscle. The in vivo metabolism of the gastrocnemius muscles of 22 CFS patients and 21 normal control subjects was compared during rest, graded dynamic exercise to exhaustion and recovery, using 31P nuclear magnetic resonance (NMR) spectroscopy to reflect minute-to-minute intracellular high-energy phosphate metabolism. Duration of exercise was markedly shorter in the CFS patients (8.1 +/- 2.8 min) compared with the normal subjects (11.3 +/- 4.3 min) (p = 0.005). There were large changes in phosphocreatine (PCr), inorganic phosphate (Pi), and pH from rest to clinical fatigue in all subjects, reflecting the high intensity of the exercise. The temporal metabolic patterns were qualitatively similar in the CFS patients and normal subjects. There were early and continuous changes in PCr and Pi that peaked at the point of fatigue and rapidly reversed after exercise. In contrast, pH was relatively static in early exercise, not declining noticeably until 50 percent of total exercise duration was achieved, and reaching a nadir at 2 min postexercise, before rapidly reversing. There were no differences in pH at rest (7.08 +/- 0.04 vs 7.10 +/- 0.04), exhaustion (6.85 +/- 0.17 vs 6.76 +/- 0.17) or early (6.64 +/- 0.25 vs 6.56 +/- 0.24) or late recovery (7.09 +/- 0.04 vs 7.10 +/- 0.05), CFS patients vs normal subjects, respectively (NS). Neither were there intergroup differences (NS) in PCr or Pi. Although, quantitatively, the changes in PCr, Pi, and pH were marked and similar in both groups from rest to exhaustion, the changes all occurred much more rapidly in the CFS patients. Moreover, adenosine triphosphate (ATP) was significantly (p = 0.007) less at exhaustion in the CFS group. Patients with CFS and normal control subjects have similar skeletal muscle metabolic patterns during dynamic exercise and reach similar clinical and metabolic end points. However, CFS patients reach exhaustion much more rapidly than normal subjects, at which point they also have relatively reduced intracellular concentrations of ATP. These data suggest a defect of oxidative metabolism with a resultant acceleration of glycolysis in the working skeletal muscles of CFS patients. This metabolic defect may contribute to the reduced physical endurance of CFS patients. Its etiology is unknown. Whether CFS patients' overwhelming tiredness at rest has a similar metabolic pathophysiology or etiology also remains unknown.


A case of an acromegalic patient resistant to the recommended maximum GH receptor antagonist dosage.
The competitive GH receptor antagonist pegvisomant is reported to normalise IGF-1 levels in up to 97 % of acromegalic patients at a maximum dosage of 40 mg/d. Description of Case: We present an acromegalic patient resistant to the recommended maximum GH receptor antagonist dosage. The 60-year-old male patient presenting with typical clinical signs of acromegaly has underwent multiple transsphenoidal surgeries and pituitary irradiation, while currently available pharmacological therapies for acromegaly have been exhausted. Biochemical control of the disease could only be achieved until uptitration of pegvisomant to 60 mg/d which was tolerated well. The current treatment algorithm for acromegaly should be modified to treat cases of persistent and uncontrolled disease.


Kappa opioid receptor antagonists: A possible new class of therapeutics for migraine prevention.
Background Stress is the most commonly reported migraine trigger. Dynorphin, an endogenous opioid peptide acting preferentially at kappa opioid receptors (KORs), is a key mediator of stress responses. The aim of this study was to use an injury-free rat model of functional cephalic pain with features of migraine and medication overuse headache (MOH) to test the possible preventive benefit of KOR blockade on stress-induced cephalic pain. Methods Following sumatriptan priming to model MOH, rats were hyper-responsive to environmental stress, demonstrating delayed cephalic and extracephalic allodynia and increased levels of CGRP in the jugular blood, consistent with commonly observed clinical outcomes during migraine. Nor-binaltorphimine (nor-BNI), a long-acting KOR antagonist or CYM51317, a novel short-acting KOR antagonist, were given systemically either during sumatriptan priming or immediately before environmental stress challenge. The effects of KOR blockade in the amygdala on stress-induced allodynia was determined by administration of nor-BNI into the right or left central nucleus of the amygdala (CeA). Results KOR blockade prevented both stress-induced allodynia and increased plasma CGRP. Stress increased dynorphin content and phosphorylated KOR in both the left and right CeA in sumatriptan-primed rats. However, KOR blockade only in the right CeA prevented stress-induced cephalic allodynia as well as extracephalic allodynia, measured in either the right or left hindpaws. U69,593, a KOR agonist, given into the right, but not the left, CeA, produced allodynia selectively in sumatriptan-primed rats. Both stress and U69,593-induced allodynia were prevented by right CeA U0126, a mitogen-activated protein kinase inhibitor, presumably acting downstream of KOR. Conclusions Our data reveal a novel lateralized KOR circuit that mediated stress-induced cutaneous allodynia and increased plasma CGRP in an injury-free model of functional cephalic pain with features of migraine and medication overuse headache. Selective, small molecule, orally available, and reversible KOR antagonists are currently in development and may represent a novel class of preventive therapeutics for migraine.


Sizing a trial to alter the trajectory of health behaviours: methods, parameter estimates, and their application.
Group-randomized trials often involve repeat observations on the same participants. When there are no more than two observations from each participant, standard mixed-model regression methods for a pretest-posttest design can be used. When there are more than two observations from each participant, random coefficients models may be useful. This paper describes the random coefficients analysis appropriate to data from an extended nested cohort design and presents the methods for power analysis and sample size calculations based on that analysis. We provide estimates for the parameters required for those calculations for a number of adolescent health behaviours. We also show how the estimates can be used to plan a future trial.


Intestinal Dilation and Platelet:Albumin Ratio Are Predictors of Surgery in Stricturing Small Bowel Crohn's Disease.
It is a challenge to predict how patients with small bowel Crohn's disease (CD) will respond to intensified medical therapy. We aimed to identify factors that predicted surgery within 2 years of hospitalization for CD, to guide medical versus surgical management decisions. We performed a retrospective review of adults hospitalized for small bowel CD from 2004 through 2012 at a single academic referral center. Subjects underwent abdominal computed tomography or magnetic resonance imaging within 3 weeks of hospitalization. Imaging characteristics of small bowel dilation, bowel wall thickness, and disease activity were assessed by a single, blinded radiologist. Multivariate analysis by Cox proportional hazards regression techniques was used to generate a prediction model of intestinal resection within 2 years. A total of 221 subjects met selection criteria, with 32.6% undergoing surgery within 2 years of index admission. Bivariate analysis showed high-dose steroid use (>40 mg), ongoing treatment with anti-tumor necrosis factor agents at admission, platelet count, platelet:albumin ratio, small bowel dilation (≥35 mm), and bowel wall thickness to predict surgery (P ≤ .01). Multivariate modeling demonstrated small bowel dilation >35 mm (hazard ratio, 2.92; 95% confidence interval, 1.73-4.94) and a platelet:albumin ratio ≥125 (hazard ratio, 2.13; 95% confidence interval, 1.15-3.95) to predict surgery. Treatment with anti-tumor necrosis factor agents at admission conferred a nonsignificant increased trend for risk of surgery (hazard ratio, 1.61; 95% confidence interval, 0.994-2.65). Small bowel dilation >35 mm and high platelet:albumin ratios are independent and synergistic risk factors for future surgery in patients with structuring small bowel CD. Platelet:albumin ratios may capture the relationship between acute inflammation and cumulative damage and serve as markers of intestinal disease that cannot be salvaged with medical therapy.


The cell-cell adhesion molecule E-cadherin.
This review is dedicated to E-cadherin, a calcium-dependent cell-cell adhesion molecule with pivotal roles in epithelial cell behavior, tissue formation, and suppression of cancer. As founder member of the cadherin superfamily, it has been extensively investigated. We summarize the structure and regulation of the E-cadherin gene and transcript. Models for E-cadherin-catenin complexes and cell junctions are presented. The structure of the E-cadherin protein is discussed in view of the diverse functions of this remarkable protein. Homophilic and heterophilic adhesion are compared, including the role of E-cadherin as a receptor for pathogens. The complex post-translational processing of E-cadherin is reviewed, as well as the many signaling activities. The role of E-cadherin in embryonic development and morphogenesis is discussed for several animal models. Finally, we review the multiple mechanisms that disrupt E-cadherin function in cancer: inactivating somatic and germline mutations, epigenetic silencing by DNA methylation and epithelial to mesenchymal transition-inducing transcription factors, and dysregulated protein processing.


Management of non-gonococcal urethritis.
Non-gonococcal urethritis (NGU), or inflammation of the urethra, is the most common treatable sexually transmitted syndrome in men, with approximately 20-50 % of cases being due to infection with Chlamydia trachomatis and 10-30 % Mycoplasma genitalium. Other causes are Ureaplasma urealyticum, Trichomonas vaginalis, anaerobes, Herpes simplex virus (HSV) and adenovirus. Up to half of the cases are non-specific. Urethritis is characterized by discharge, dysuria and/or urethral discomfort but may be asymptomatic. The diagnosis of urethritis is confirmed by demonstrating an excess of polymorpho-nuclear leucocytes (PMNLs) in a stained smear. An excess of mononuclear leucocytes in the smear indicates a viral etiology. In patients presenting with symptoms of urethritis, the diagnosis should be confirmed by microscopy of a stained smear, ruling out gonorrhea. Nucleid acid amplifications tests (NAAT) for Neisseria gonorrhoeae, C. trachomatis and for M. genitalium. If viral or protozoan aetiology is suspected, NAAT for HSV, adenovirus and T. vaginalis, if available. If marked symptoms and urethritis is confirmed, syndromic treatment should be given at the first appointment without waiting for the laboratory results. Treatment options are doxycycline 100 mg x 2 for one week or azithromycin 1 gram single dose or 1,5 gram distributed in five days. However, azithromycin as first line treatment without test of cure for M. genitalium and subsequent Moxifloxacin treatment of macrolide resistant strains will select and increase the macrolide resistant strains in the population. If positive for M. genitalium, test of cure samples should be collected no earlier than three weeks after start of treatment. If positive in test of cure, moxifloxacin 400 mg 7-14 days is indicated. Current partner(s) should be tested and treated with the same regimen. They should abstain from intercourse until both have completed treatment. Persistent or recurrent NGU must be confirmed with microscopy. Reinfection and compliance must be considered. Evidence for the following recommendations is limited, and is based on clinical experience and guidelines. If doxycycline was given as first therapy, azithromycin five days plus metronidazole 4-500 mg twice daily for 5-7 days should be given. If azithromycin was prescribed as first therapy, doxycycline 100 mg x 2 for one week plus metronidazole, or moxifloxacin 400 mg orally once daily for 7-14 days should be given.


Evaluating order-constrained hypotheses for circular data using permutation tests.
Psychological researchers in different fields sometimes encounter circular or directional data. Circular data are data measured in the form of angles or two-dimensional orientations. As an example, experiments investigating the development of spatial memory and the influence of visual experience on haptic orientation perception are presented. Three permutation tests are proposed for the evaluation of ordered hypotheses. The quality of the permutation tests is investigated by means of several simulation studies. The results of these studies show the expected increase in power when the permutation tests for ordered hypotheses are compared to a common non-directional test for circular data. The differences in power between the three tests for ordered alternatives are small.


A galaxy lacking dark matter.
Studies of galaxy surveys in the context of the cold dark matter paradigm have shown that the mass of the dark matter halo and the total stellar mass are coupled through a function that varies smoothly with mass. Their average ratio Mhalo/Mstars has a minimum of about 30 for galaxies with stellar masses near that of the Milky Way (approximately 5 × 1010 solar masses) and increases both towards lower masses and towards higher masses. The scatter in this relation is not well known; it is generally thought to be less than a factor of two for massive galaxies but much larger for dwarf galaxies. Here we report the radial velocities of ten luminous globular-cluster-like objects in the ultra-diffuse galaxy NGC1052-DF2, which has a stellar mass of approximately 2 × 108 solar masses. We infer that its velocity dispersion is less than 10.5 kilometres per second with 90 per cent confidence, and we determine from this that its total mass within a radius of 7.6 kiloparsecs is less than 3.4 × 108 solar masses. This implies that the ratio Mhalo/Mstars is of order unity (and consistent with zero), a factor of at least 400 lower than expected. NGC1052-DF2 demonstrates that dark matter is not always coupled with baryonic matter on galactic scales.


Pupillary effects of alfentanil and morphine.
We have measured the onset and extent of the miotic effect of morphine and alfentanil in conscious patients. Forty unpremedicated ASA I and II patients were allocated randomly to four groups to receive either i.v. saline (control group), morphine 0.1 mg kg-1, alfentanil 4.0 micrograms kg-1 or a combination of these doses, and pupil diameters were measured for the next 30 min. There were no significant differences in the control diameters. In the opioid groups, a significant decrease in diameter (about 1 mm), occurred 4 min after administration of the drug and persisted throughout the study. The opioid groups behaved similarly for 25 min. After 10 min the mean diameter of the alfentanil group began to increase, but this did not reach statistical significance until after 25 min.


A bacterial size law revealed by a coarse-grained model of cell physiology.
Universal observations in Biology are sometimes described as "laws". In E. coli, experimental studies performed over the past six decades have revealed major growth laws relating ribosomal mass fraction and cell size to the growth rate. Because they formalize complex emerging principles in biology, growth laws have been instrumental in shaping our understanding of bacterial physiology. Here, we discovered a novel size law that connects cell size to the inverse of the metabolic proteome mass fraction and the active fraction of ribosomes. We used a simple whole-cell coarse-grained model of cell physiology that combines the proteome allocation theory and the structural model of cell division. This integrated model captures all available experimental data connecting the cell proteome composition, ribosome activity, division size and growth rate in response to nutrient quality, antibiotic treatment and increased protein burden. Finally, a stochastic extension of the model explains non-trivial correlations observed in single cell experiments including the adder principle. This work provides a simple and robust theoretical framework for studying the fundamental principles of cell size determination in unicellular organisms.


Chinese herbal medicines as adjuvant treatment during chemo- or radio-therapy for cancer.
Numerous studies have indicated that in cancer treatment Chinese herbal medicines in combination with chemo- or radio-therapy can be used to enhance the efficacy of and diminish the side effects and complications caused by chemo- and radio-therapy. Therefore, an understanding of Chinese herbal medicines is needed by physicians and other health care providers. This review provides evidence for use of Chinese herbal medicines as adjuvant cancer treatment during chemo- or radio-therapy. First, Chinese herbal medicines (e.g. Astragalus, Turmeric, Ginseng, TJ-41, PHY906, Huachansu injection, and Kanglaite injection) that are commonly used by cancer patients for treating the cancer and/or reducing the toxicity induced by chemo- or radio-therapy are discussed. Preclinical and clinical studies have shown that these Chinese herbal medicines possess great advantages in terms of suppressing tumor progression, increasing the sensitivity of chemo- and radio-therapeutics, improving an organism's immune system function, and lessening the damage caused by chemo- and radio-therapeutics. Second, clinical trials of Chinese herbal medicines as adjuvant cancer treatment are reviewed. By reducing side effects and complications during chemo- and radio-therapy, these Chinese herbal medicines have a significant effect on reducing cancer-related fatigue and pain, improving respiratory tract infections and gastrointestinal side effects including diarrhea, nausea, and vomiting, protecting liver function, and even ameliorating the symptoms of cachexia. This review should contribute to an understanding of Chinese herbal medicines as adjuvant treatment for cancer and provide useful information for the development of more effective anti-cancer drugs.


Evaluation of the use of surface electromyography in the diagnosis, documentation, and treatment of dental patients.
The use of electromyography as an aid in the differential diagnosis and treatment of dental patients is carefully examined in this literature review. Electromyography has been advocated for the establishment of rest and occlusal positions, and for the detection of muscle hyperactivity and hypoactivity, spasm, fatigue, and muscle imbalance. However, these claims were often based on studies that failed to include a control group when comparing various clinical parameters and EMG activity of the muscles of mastication. When a control group was incorporated, the authors usually failed to match the patients by such variables as age, sex, facial morphology, and history of bruxism. These variables have a significant influence on the level of EMG activity and may account for the high degree of variability observed between groups. Controlled trials evaluating the efficacy of biofeedback using electromyography found significant reductions of diurnal parafunctional activity during treatment, but the low symptom levels were not maintained after cessation of biofeedback. Based upon this extensive literature review, there is no convincing evidence to support the use of electromyography in the diagnosis or treatment of dental patients except in the treatment of parafunction.


Signal peptide peptidase-like 2c impairs vesicular transport and cleaves SNARE proteins.
Members of the GxGD-type intramembrane aspartyl proteases have emerged as key players not only in fundamental cellular processes such as B-cell development or protein glycosylation, but also in development of pathologies, such as Alzheimer's disease or hepatitis virus infections. However, one member of this protease family, signal peptide peptidase-like 2c (SPPL2c), remains orphan and its capability of proteolysis as well as its physiological function is still enigmatic. Here, we demonstrate that SPPL2c is catalytically active and identify a variety of SPPL2c candidate substrates using proteomics. The majority of the SPPL2c candidate substrates cluster to the biological process of vesicular trafficking. Analysis of selected SNARE proteins reveals proteolytic processing by SPPL2c that impairs vesicular transport and causes retention of cargo proteins in the endoplasmic reticulum. As a consequence, the integrity of subcellular compartments, in particular the Golgi, is disturbed. Together with a strikingly high physiological SPPL2c expression in testis, our data suggest involvement of SPPL2c in acrosome formation during spermatogenesis.


All-optical observation and reconstruction of spin wave dispersion.
To know the properties of a particle or a wave, one should measure how its energy changes with its momentum. The relation between them is called the dispersion relation, which encodes essential information of the kinetics. In a magnet, the wave motion of atomic spins serves as an elementary excitation, called a spin wave, and behaves like a fictitious particle. Although the dispersion relation of spin waves governs many of the magnetic properties, observation of their entire dispersion is one of the challenges today. Spin waves whose dispersion is dominated by magnetostatic interaction are called pure-magnetostatic waves, which are still missing despite of their practical importance. Here, we report observation of the band dispersion relation of pure-magnetostatic waves by developing a table-top all-optical spectroscopy named spin-wave tomography. The result unmasks characteristics of pure-magnetostatic waves. We also demonstrate time-resolved measurements, which reveal coherent energy transfer between spin waves and lattice vibrations.


Release of decay-accelerating factor (DAF) from the cell membrane by phosphatidylinositol-specific phospholipase C (PIPLC). Selective modification of a complement regulatory protein.
Decay-accelerating factor (DAF) is a 70,000 Mr membrane protein that inhibits amplification of the complement cascade on the cell surface, and protects cells from damage. Purified DAF can be reincorporated into the membrane of red cells and is functional. DAF is deficient in paroxysmal nocturnal hemoglobinuria (PNH), a disease characterized by increased sensitivity of erythrocytes to complement lysis. We show here that DAF is part of a newly described family of membrane proteins anchored to the lipid bilayer by means of phosphatidylinositol (PI). Treatment with PI-specific phospholipase C (PIPLC) releases 70-80, 60, and 10% of cell surface DAF from mononuclear cells, neutrophils, and erythrocytes, respectively. The PIPLC-released DAF (DAF-S) is slightly smaller (67,000 Mr) than the membrane form. DAF and DAF-S cannot be distinguished antigenically. Furthermore, DAF-S has lost its ability to significantly inhibit the C3-convertase, as well as its ability to incorporate into cell membranes. Since DAF can only inhibit C3-convertase endogenously, i.e., within the membrane of the same cell, it is likely that the loss of activity of DAF-S is causally related to its inability to reincorporate in the lipid bilayer. As shown by others, the complement-sensitive red cells from PNH patients lack acetylcholinesterase, which is also anchored to the membrane by PI (9). Thus it is possible that the molecular defect in PNH lies in the biosynthetic pathways leading to the attachment of PI to the polypeptide chains, in the transport of these proteins to the surface, or in their release by the action of endogenous phospholipases. From a practical standpoint the specific release of DAF by PIPLC could facilitate killing of tumor cells by amplifying the effects of the complement cascade on the surface of antibody-sensitized cells.


[Study on antiinflammatory effect of different chemotype of Cinnamomum camphora on rat arthritis model induced by Freund's adjuvant].
To study the antiinflammatory effects of naphtha from different chemotypes of Cinnamomum camphora and natural borneol on the rat arthritis model induced by Freund's adjuvant. The arthritis model was induced by injecting Freund's adjuvant in rat voix pedis dermis and the rats were randomly divided into seven groups: normal control group, model control group, triptergium wilfordii control group, borneol chemotype naphtha group, camphor chemotype naphtha group, isocamphane chemotype naphtha group and natural borneol group. Rats of the triptergium wilfordii control group were given orally 8.1 mg x kg(-1) triptergium wilfordii for 35 days, rats of the normal control group and model control group were given same volume water, and rats of other groups were given 80 mg x kg(-1) corresponding drug. We observed the rat common condition, weighed the rat body weight weekly, measured the degree of swelling of voix pedis every 4 days, weighed the thymus and spleen on the end of life, and measured the contents of cell factor TNF-alpha, IL-2, and IL-6 in rat blood serum. As far as the arthrosis degree of swelling and the contents of cell factor TNF-alpha, IL-2, IL-6 were concerned, rats of model control group were higher than normal control group, and rats of other drug groups were lower than the model control group. The order of inhibition ratios of the arthrosis degree of swelling from high to low principle was isocamphane chemotype naphtha group, camphor chemotype naphtha group, borneol chemotype naphtha group and natural borneol group. All medication administration teams evidently reduced the contents of the IL-2 and IL-6, and the inhibition ratios were higher than 38%. In the case of the contents of TNF-alpha and IL-2, all groups were not evidently different. In the case of inhibition of IL-6, camphor chemotype naphtha group was better than borneol chemotype naphtha group and natural borneol group, the latter was better than isocamphane chemotype naphtha group. As far as the weight, thymus index and spleen index were concerned, all medication administration groups were not different. The different chemotypes of C. camphora have anti-inflammatory effect on the rat arthritis model induced by Freund's adjuvant, but pharmacological activity and mechanism of action are different. The study points out the clinical curative effects of the chemotypes of the kindred medicinal plant are different, and please consider the difference of chemotype in clinical application.


Structured treatment interruptions (STI) in chronic unsuppressed HIV infection in adults.
Structured treatment interruptions (STI) of antiretroviral therapy (ART) have been investigated as part of novel treatment strategies, with different aims and objectives depending on the populations involved. These populations include: 1) patients who initiate ART during acute HIV infection; 2) patients with chronic HIV infection, on ART, with successfully suppressed viremia; and 3) patients with chronic HIV infection and treatment failure, with persistent viremia due to multi-drug resistant HIV (Hirschel 2001; Deeks 2002; Miller 2003). In an earlier Cochrane review (Pai 2005), we had summarized the evidence about the effects of STI in chronic suppressed HIV infection. In this review, we summarize the evidence on STI in patients with chronic unsuppressed HIV infection due to drug-resistant HIV. Unsuppressed HIV infection describes those patients who cannot suppress viremia, due to the presence of multi-drug-resistant virus. It is also referred to as treatment failure. Drug resistance is identified by the presence of resistant mutations at baseline.STI as a treatment strategy in HIV-infected patients with chronic unsuppressed viremia involves interrupting ART in controlled clinical settings, for a pre-specified duration of time. These interruptions have various aims, including the following: 1) to allow wild virus to re-emerge and replace the resistant mutant virus, with the hope of improving the efficacy of a subsequent ART regimen; 2) to halt development of drug resistance and to preserve subsequent treatment options; 3) to alleviate treatment fatigue and reduce drug-related adverse effects; and 4) to improve quality of life (Miller 2003; Montaner 2001; Vella 2000;). The objective of our systematic review was to synthesize the evidence on the effect of structured treatment interruptions in adult patients with chronic unsuppressed HIV infection. We included all available intervention studies (randomized controlled trials and non-randomized trials) conducted in HIV-infected patients worldwide. We searched nine databases, covering the period from January 1996 to February 2006. We also scanned bibliographies of relevant studies and contacted experts in the field to identify unpublished research, abstracts and ongoing trials. In the first screen, a total of 3186 potentially eligible citations from nine databases and sources were identified, of which 2047 duplicate citations were excluded. The remaining 1139 citations were examined in detail, and we further excluded 951 citations that were modeling studies, animal studies, case reports, and opinion pieces. As shown in Figure 01, 188 citations were identified in the second screen as relevant for full-text screening. Of these, 60 basic science studies, editorials and abstracts were excluded and 128 full-text articles were retrieved. In the third screen, all full-text articles were examined for eligibility in our review. These were subclassified into three categories: 1) chronic suppressed HIV infection; 2) chronic unsuppressed HIV infection; and 3) acute HIV infection. Studies were further excluded if their abstracts did not contain enough information for inclusion in our reviews. A total of 62 studies were finally classified into chronic suppressed, acute, and chronic unsuppressed categories. Of these, 17 trials met the eligibility criteria for this review. Inclusion criteriaAll available randomized or non-randomized controlled trials investigating planned treatment interruptions among patients with chronic unsuppressed HIV infection. Early pilot non-randomized prospective studies on treatment interruptions of fixed and variable durations were also included. Relevant abstracts on randomized controlled trials were also included if they contained sufficient information. Exclusion criteriaEditorials, reviews, modeling studies, and basic science studies were excluded. Studies on STI among patients with chronic suppressed HIV infection were summarized in a separate review. Studies on STI in primary HIV infection were beyond the scope of this review. Two reviewers independently extracted data, evaluated study eligibility and quality. Disagreements were resolved in consultation with a third reviewer.A total of seventeen studies on STI were included in our review. However, due to significant heterogeneity across studies (i.e. in study design, populations, baseline characteristics, and reported outcomes; and in reporting of measures of effect, hazard ratios, and risk ratios), we considered it inappropriate to perform a meta-analysis. In early pilot non-randomized trials, a pattern was evident across studies. During treatment interruption, a decline in CD4 cell counts, increase in viral load, and a shift in the level of genotypic drug resistance towards more of a wild-type HIV virus was reported. This suggests that STI may be used to increase drug susceptibility to an optimized salvage regimen upon treatment re-initiation. These studies generated useful data and hypotheses that were later tested in randomized controlled trials. Randomized controlled trials rated high on quality. Of the eight randomized controlled trials reviewed, seven had been completed while one was ongoing and remains blinded. Of the seven completed randomized controlled trials, six have reported consistent virologic and immunologic patterns, and found no significant benefit in virologic response to subsequent ART in the STI arm, compared to the control arm. In addition, the largest completed randomized trial reported greater numbers of clinical disease progression events and evidence of prolonged negative impact on CD4 cell counts in the STI arm (Beatty 2005; Benson 2004; Deeks 2001; Lawrence 2003; Walmsley 2005; Ruiz 2003). The single RCT with divergent findings from the others (GigHAART), reporting a significant virologic and immunologic benefit due to STI, was different in prescribing a shorter STI duration and a salvage ART regimen of 8-9 drugs. There were also differences in the patient population characteristics with this study, targeting those with very advanced HIV disease (Katlama 2004). Although we await the unblinded results of the eighth RCT (OPTIMA), the evidence so far does not support STI in the setting of chronic unsuppressed HIV infection with antiretroviral treatment failure (Brown 2004; Holodniy 2004; Kyriakides 2002; Singer 2006). The current available evidence primarily supports a lack of benefit of STI before switching therapy in patients with unsuppressed HIV viremia despite ART. There is evidence of harm in attempting STI in patients with relatively advanced HIV disease, due to the associated CD4 cell decline and the increased risk of clinical disease progression. At this time, there is no evidence to recommend the use of STI in this clinical category of patients with treatment failure.


Endoscopic Endonasal Approach for Complex Macroadenoma with Suprasellar and Retrochiasmatic Extension.
In this video, we describe the technical nuances of an endoscopic endonasal approach (EEA) for a complex macroadenoma with suprasellar and retrochiasmatic extension. The patient is a 51-year-old male with several years' history of progressive visual loss. Neuro-ophthalmology assessment revealed a profound visual loss with homonymous hemianopsia and left optic nerve atrophy. His pituitary hormonal profile was normal. The options for surgical approach included transcranial, endoscopic endonasal, or a combination of both. An EEA was the preferred surgical option, because it allows for early identification of the pituitary gland, and provides access to the suprasellar region including pre- and retrochiasmatic spaces, which facilitates tumor removal while minimizing manipulation of the optic apparatus. While most pituitary adenomas do not require extracapsular subarachnoidal dissection, there are complex adenomas with subarachnoidal invasion and multilobulated morphology, such as the one presented here, that require a combination of internal debulking, extracapsular and subarachnoidal dissection. The technique presented here allows for complete tumor resection, avoiding the risk of postoperative apoplexy of residual adenoma, and facilitates identification of perforating branches and neural structures that require meticulous preservation. Here, we also illustrate the proper management of reconstruction-related complications. Postoperative course was complicated with meningitis with necrotic nasoseptal flap and required surgical debridement, new inferior turbinate flap, fascia lata, lumbar drain, and 6-week antibiotic treatment. Imaging follow-up showed complete removal of tumor. The patient had significant improvement in visual fields and left visual acuity, and no postoperative hormonal dysfunction. The link to the video can be found at: https://youtu.be/9T5b167bVJA .


Pseudomonas aeruginosa corneal infection affects cholinergic enzymes in rat lacrimal gland.
Since the increased use of extended-wear contact lenses, Pseudomonas aeruginosa has emerged as a primary etiological agent of ulcerative keratitis. Clinical isolates have been classified into two types: cytotoxic and non-cytotoxic. This study revealed significant immune and neuro-enzymatic changes elicited by the two types of P. aeruginosa in the lacrimal gland of rats. The humoral immune response in the lacrimal gland to the non-cytotoxic strain was significantly lower than to the cytotoxic strain, possibly due to the immunogenicity of the extracellular toxin; however, the same effect was not seen in the serum. Choline acetyltransferase and acetylcholinesterase are known to be responsible for synthesis and degradation of acetylcholine, respectively, binding receptors on acini and plasma cells, modulating their activity, and constituting the principle regulator of tear secretion. Following infection, neuro-enzyme activities were significantly modified to reduce the concentration of acetylcholine and therefore potentially reduce secretion from the glands. The data lead to the hypothesis that P. aeruginosa may have the potential to reduce the protective barrier provided by the lacrimal gland to benefit pathogenicity. It was also observed that the neuro-enzyme response of the lacrimal glands of uninfected eyes of the test animals was the same as that of infected eyes, implying that the signal may be relayed by common lymphoidal tissue or the central nervous system and a measurable response returned to both eyes.


Developments in waste tyre thermochemical conversion processes: gasification, pyrolysis and liquefaction.
Fossil fuels, particularly crude oil, have proven to be a source of energy to households, transportation and power industries over the past decades. This natural reserve is diminishing at an alarming rate with crude oil having reserves to last the earth for the next half a century. As a result, researchers are constantly seeking remedial technologies to close this gap. Thermochemical conversion processes such as pyrolysis, gasification and liquefaction (PGL) offer an alternative solution to mitigating the world's high reliance on crude oil. These processes can be employed to provide energy, fuel and high-end value-added products. This paper aims to highlight all the research and development advancements and trends that have been made over the past three decades while employing waste tyres and other feedstock. In addition, the prominent countries and their associated researchers who have made novel discoveries in the field of thermochemical conversion are extensively discussed. The research findings show that significant research outputs such as the utilization of vast types of feed materials, the reaction mechanisms, the factors affecting the processes, and the application of the different end-products for thermochemical processes are well documented in the literature. Also, the collected data showed that significant advancements have been achieved in developing PGL technologies. The following conclusions were drawn: (i) PGL technologies show a generally increasing percentage interest from 1990 to 2020, (ii) many authors have identified the end-products obtained from waste feedstocks, such as; waste tyres, biomass, plastics, food waste, microalgae and animal manure to yield promising application benefits, (iii) China has shown the greatest interest in investing into waste to energy initiatives and has demonstrated the vast applications of waste derived products and, (iv) employing waste tyres as a feedstock has shown potential for producing high-end value products in their crude form or refined form. Some of the shortcomings identified during the study are the modest interest shown by most African regions as well as the lack of regulatory frameworks developed by certain countries.


Nanostructured anti-bacterial poly-lactic-co-glycolic acid films for skin tissue engineering applications.
Major issues faced with the use of today's skin grafts are infection, scar tissue formation, insufficient keratinocyte (or skin producing cells) proliferation and high production costs. To overcome these limitations, we propose here for the first time, a nanofeatured poly(lactide-co-glycolide) (PLGA) membrane as a next generation antibacterial skin graft material. An alkaline surface treatment method was used to create random nanofeatures on PLGA membranes where sodium hydroxide (NaOH) concentration and exposure times were altered to control surface morphology. Most significantly, and without the use of antibiotics, results showed a decrease in Staphylococcus aureus (a dangerous pathogen infecting skin grafts) growth for up to ∼40% after 2 days of culture on nanofeatured PLGA membranes compared to untreated controls. Results also showed that while bacteria growth was stunted, mammalian cell growth was not. Specifically, cell culture results showed an increase in human epidermal keratinocyte density, while the density of scar tissue forming human dermal fibroblasts, did not change on nanofeatured PLGA surfaces compared to the untreated controls after 3 days of culture. These findings indicate that the alkaline treatment of PLGA membranes is a promising quick and effective manner to limit scar tissue formation and bacterial invasion while increasing skin cell proliferation for improving numerous wound-healing applications.


Sexual maturation protects against development of lung inflammation through estrogen.
Increasing levels of estrogen and progesterone are suggested to play a role in the gender switch in asthma prevalence during puberty. We investigated whether the process of sexual maturation in mice affects the development of lung inflammation in adulthood and the contributing roles of estrogen and progesterone during this process. By inducing ovalbumin-induced lung inflammation in sexually mature and immature (ovariectomized before sexual maturation) adult mice, we showed that sexually immature adult mice developed more eosinophilic lung inflammation. This protective effect of "puberty" appears to be dependent on estrogen, as estrogen supplementation at the time of ovariectomy protected against development of lung inflammation in adulthood whereas progesterone supplementation did not. Investigating the underlying mechanism of estrogen-mediated protection, we found that estrogen-treated mice had higher expression of the anti-inflammatory mediator secretory leukoprotease inhibitor (SLPI) and lower expression of the proasthmatic cytokine IL-33 in parenchymal lung tissue and that their expressions colocalized with type II alveolar epithelial cells (AECII). Treating AECII directly with SLPI significantly inhibited IL-33 production upon stimulation with ATP. Our data suggest that estrogen during puberty has a protective effect on asthma development, which is accompanied by induction of anti-inflammatory SLPI production and inhibition of proinflammatory IL-33 production by AECII.


GPER as a Receptor for Endocrine-Disrupting Chemicals (EDCs).
Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that interfere with endogenous hormonal systems at various levels, resulting in adverse health effects. EDCs belong to diverse chemical families and can accumulate in the environment, diet and body fluids, with different levels of persistence. Their action can be mediated by several receptors, including members of the nuclear receptor family, such as estrogen and androgen receptors. The G protein-coupled estrogen receptor (GPER), a seven-transmembrane domain receptor, has also attracted attention as a potential target of EDCs. This review summarizes our current knowledge concerning GPER as a mediator of EDCs' effects.


Nest suitability, fine-scale population structure and male-mediated dispersal of a solitary ground nesting bee in an urban landscape.
Bees are the primary pollinators of flowering plants in almost all ecosystems. Worldwide declines in bee populations have raised awareness about the importance of their ecological role in maintaining ecosystem functioning. The naturally strong philopatric behavior that some bee species show can be detrimental to population viability through increased probability of inbreeding. Furthermore, bee populations found in human-altered landscapes, such as urban areas, can experience lower levels of gene flow and effective population sizes, increasing potential for inbreeding depression in wild bee populations. In this study, we investigated the fine-scale population structure of the solitary bee Colletes inaequalis in an urbanized landscape. First, we developed a predictive spatial model to detect suitable nesting habitat for this ground nesting bee and to inform our field search for nests. We genotyped 18 microsatellites in 548 female individuals collected from nest aggregations throughout the study area. Genetic relatedness estimates revealed that genetic similarity among individuals was slightly greater within nest aggregations than among randomly chosen individuals. However, genetic structure among nest aggregations was low (Nei's GST = 0.011). Reconstruction of parental genotypes revealed greater genetic relatedness among females than among males within nest aggregations, suggesting male-mediated dispersal as a potentially important mechanism of population connectivity and inbreeding avoidance. Size of nesting patch was positively correlated with effective population size, but not with other estimators of genetic diversity. We detected a positive trend between geographic distance and genetic differentiation between nest aggregations. Our landscape genetic models suggest that increased urbanization is likely associated with higher levels of inbreeding. Overall, these findings emphasize the importance of density and distribution of suitable nesting patches for enhancing bee population abundance and connectivity in human dominated habitats and highlights the critical contribution of landscape genetic studies for enhanced conservation and management of native pollinators.


Effect of hyperbaric oxygen therapy on chronic neurocognitive deficits of post-traumatic brain injury patients: retrospective analysis.
The aim of the study is to evaluate the effect of hyperbaric oxygen therapy (HBOT) in participants suffering from chronic neurological deficits due to traumatic brain injury (TBI) of all severities in the largest cohort evaluated so far with objective cognitive function tests and metabolic brain imaging. A retrospective analysis was conducted of 154 patients suffering from chronic neurocognitive damage due to TBI, who had undergone computerised cognitive evaluations pre-HBOT and post-HBOT treatment. The average age was 42.7±14.6 years, and 58.4% were men. All patients had documented TBI 0.3-33 years (mean 4.6±5.8, median 2.75 years) prior to HBOT. HBOT was associated with significant improvement in all of the cognitive domains, with a mean change in global cognitive scores of 4.6±8.5 (p<0.00001). The most prominent improvements were in memory index and attention, with mean changes of 8.1±16.9 (p<0.00001) and 6.8±16.5 (p<0.0001), respectively. The most striking changes observed in brain single photon emission computed tomography images were in the anterior cingulate and the postcentral cortex, in the prefrontal areas and in the temporal areas. In the largest published cohort of patients suffering from chronic deficits post-TBI of all severities, HBOT was associated with significant cognitive improvements. The clinical improvements were well correlated with increased activity in the relevant brain areas.