Termite gut symbiotic archaezoa are becoming living metabolic fossils.
Over the course of several million years, the eukaryotic gut symbionts of lower termites have become adapted to a cellulolytic environment. Up to now it has been believed that they produce nutriments using their own cellulolytic enzymes for the benefit of their termite host. However, we have now isolated two endoglucanases with similar apparent molecular masses of approximately 36 kDa from the not yet culturable symbiotic Archaezoa living in the hindgut of the most primitive Australian termite, Mastotermes darwiniensis. The N-terminal sequences of these cellulases exhibited significant homology to cellulases of termite origin, which belong to glycosyl hydrolase family 9. The corresponding genes were detected not in the mRNA pool of the flagellates but in the salivary glands of M. darwiniensis. This showed that cellulases isolated from the flagellate cells originated from the termite host. By use of a PCR-based approach, DNAs encoding cellulases belonging to glycosyl hydrolase family 45 were obtained from micromanipulated nuclei of the flagellates Koruga bonita and Deltotrichonympha nana. These results indicated that the intestinal flagellates of M. darwiniensis take up the termite's cellulases from gut contents. K. bonita and D. nana possess at least their own endoglucanase genes, which are still expressed, but without significant enzyme activity in the nutritive vacuole. These findings give the impression that the gut Archaezoa are heading toward a secondary loss of their own endoglucanases and that they use exclusively termite cellulases.


Task-specific role of ipsilateral pathways: somatosensory evoked potentials during cooperative hand movements.
Task-specific neural coupling during cooperative hand movements has been described in healthy volunteers, manifested by bilateral reflex electromyographic responses in forearm muscles following unilateral ulnar nerve stimulation and by task-specific activation of secondary somatosensory cortical areas (S2) in functional MRI. The aim of this study was to investigate the role of sensory input to the ipsilateral and contralateral cortex during a cooperative task. Somatosensory evoked potentials from the ulnar nerve were recorded over the ipsilateral and contralateral cortex during resting and during cooperative and noncooperative hand movements. Ipsilateral potentials with smaller amplitude were present under all conditions in almost all participants. In relation to the resting condition, the amplitudes of both the ipsilateral and the contralateral potential were reduced during the cooperative and the noncooperative tasks. Nevertheless, the reduction in amplitude was similar for the ipsilateral and the contralateral potentials in the noncooperative task, but less on the ipsilateral compared with the contralateral side during the cooperative task. The ratio of ipsilateral/contralateral somatosensory evoked potential amplitude was thus significantly larger during the cooperative task compared with the control task and the resting condition. This indicates a functional role of ipsilateral pathways connecting the cervical spinal cord with the cortex during the cooperative task. These observations favor the idea of a task-specific mediation of sensory input from both hands to the ipsilateral and contralateral hemispheres as the basis of neuronal coupling.


Photorefractive BaTiO(3) spheres and spherical disks.
We have produced single-crystal spheres and spherical disks of photorefractive barium titanate (BaTiO(3)) . The spheres and disks allow direct fiber-to-fiber two-beam coupling without additional optical elements. We also investigate the spontaneous oscillation of triangles and other whispering-gallery modes in these spherical structures.


Brain aging differs with cognitive ability regardless of education.
Higher general cognitive ability (GCA) is associated with lower risk of neurodegenerative disorders, but neural mechanisms are unknown. GCA could be associated with more cortical tissue, from young age, i.e. brain reserve, or less cortical atrophy in adulthood, i.e. brain maintenance. Controlling for education, we investigated the relative association of GCA with reserve and maintenance of cortical volume, -area and -thickness through the adult lifespan, using multiple longitudinal cognitively healthy brain imaging cohorts (n = 3327, 7002 MRI scans, baseline age 20-88 years, followed-up for up to 11 years). There were widespread positive relationships between GCA and cortical characteristics (level-level associations). In select regions, higher baseline GCA was associated with less atrophy over time (level-change associations). Relationships remained when controlling for polygenic scores for both GCA and education. Our findings suggest that higher GCA is associated with cortical volumes by both brain reserve and -maintenance mechanisms through the adult lifespan.


A quinazoline-based HDAC inhibitor affects gene expression pathways involved in cholesterol biosynthesis and mevalonate in prostate cancer cells.
Chronic inflammation can lead to the development of cancers and resolution of inflammation is an ongoing challenge. Inflammation can result from dysregulation of the epigenome and a number of compounds that modify the epigenome are in clinical use. In this study the anti-inflammatory and anti-cancer effects of a quinazoline epigenetic-modulator compound were determined in prostate cancer cell lines using a non-hypothesis driven transcriptomics strategy utilising the Affymetrix PrimeView® Human Gene Expression microarray. GATHER and IPA software were used to analyse the data and to provide information on significantly modified biological processes, pathways and networks. A number of genes were differentially expressed in both PC3 and DU145 prostate cancer cell lines. The top canonical pathways that frequently arose across both cell lines at a number of time points included cholesterol biosynthesis and metabolism, and the mevalonate pathway. Targeting of sterol and mevalonate pathways may be a powerful anticancer approach.


Specialized transcription factories.
We have previously suggested a model for the eukaryotic genome based on the structure of the bacterial nucleoid where active RNA polymerases cluster to loop the intervening DNA. This organization of polymerases into clusters--which we call transcription 'factories'--has important consequences. For example, in the nucleus of a HeLa cell the concentration of soluble RNA polymerase II is approximately 1 mM, but the local concentration in a factory is 1000-fold higher. Because a promoter can diffuse approximately 100 nm in 15 s, one lying near a factory is likely to initiate; moreover, when released at termination, it will still lie near a factory, and the movement and modifications (e.g. acetylation) accompanying elongation will leave it in an 'open' conformation. Another promoter out in a long loop is less likely to initiate, because the promoter concentration falls off with the cube of the distance from the factory. Moreover, a long tether will buffer it from transcription-induced movement, making it prone to deacetylation, deposition of HP1 (heterochromatin protein 1), and incorporation into heterochromatin. The context around a promoter will then be self-sustaining: productive collisions of an active promoter with the factory will attract factors increasing the frequency of initiation, and the longer an inactive promoter remains inactive, the more it becomes embedded in heterochromatin. We review here the evidence that different factories may specialize in the transcription of different groups of genes.


Optical restoration of photorefractive holograms through self-enhanced diffraction.
For the first time to our knowledge, we demonstrate the use of self-enhanced diffraction to optically restore weak dynamic volume holograms. This restoration process is achieved through the use of a novel beam-toggling scheme that significantly enhances the steady-state diffraction efficiency of volume index gratings stored in photorefractive media. Experiments demonstrating and confirming theory are presented and discussed.


Calcium - how and why?
Calcium is among the most commonly used ions, in a multitude of biological functions, so much so that it is impossible to imagine life without calcium. In this article I have attempted to address the question as to how calcium has achieved this status with a brief mention of the history of calcium research in biology. It appears that during the origin and early evolution of life the Ca2+ ion was given a unique opportunity to be used in several biological processes because of its unusual physical and chemical properties.


A microfluidic-based hydrodynamic trap: design and implementation.
We report an integrated microfluidic device for fine-scale manipulation and confinement of micro- and nanoscale particles in free-solution. Using this device, single particles are trapped in a stagnation point flow at the junction of two intersecting microchannels. The hydrodynamic trap is based on active flow control at a fluid stagnation point using an integrated on-chip valve in a monolithic PDMS-based microfluidic device. In this work, we characterize device design parameters enabling precise control of stagnation point position for efficient trap performance. The microfluidic-based hydrodynamic trap facilitates particle trapping using the sole action of fluid flow and provides a viable alternative to existing confinement and manipulation techniques based on electric, optical, magnetic or acoustic force fields. Overall, the hydrodynamic trap enables non-contact confinement of fluorescent and non-fluorescent particles for extended times and provides a new platform for fundamental studies in biology, biotechnology and materials science.


The role of root apoplastic barriers in cadmium translocation and accumulation in cultivars of rice (Oryza sativa L.) with different Cd-accumulating characteristics.
The radial translocation of cadmium (Cd) from the root to the shoot is one of the major processes affecting Cd accumulation in rice (Oryza sativa L.) grains, but few studies have focused on Cd apoplastic transport in rice. The aim of this study was to determine how apoplastic barriers affect Cd translocation via the apoplastic pathway, Cd accumulation levels in upper parts (shoot and grains) of rice cultivars, and the possible mechanism involved. Hydroponic and soil pot trials were conducted to study the development and chemical constituents of apoplastic barriers and their permeability to bypass flow, and to determine Cd localization in the roots of rice cultivars with different Cd-accumulating characteristics. The Cd accumulation in upper parts was positively correlated with bypass flow in the root and the apparent Cd concentration in the xylem, indicating that the apoplastic pathway may play an important role in Cd root-shoot translocation in rice. Apoplastic barriers were deposited closer to the root tip and were thicker in low Cd-accumulating cultivars than in high Cd-accumulating cultivars. The amounts and rates of increase in lignin and suberin were significantly higher in ZD14 (a low Cd-accumulating cultivar) than in FYXZ (a high Cd-accumulating cultivar) under Cd stress, indicating that stronger barriers were induced by Cd in ZD14. The stronger and earlier formation of barriers in the low Cd-accumulating cultivar decreased bypass flow more efficiently, so that more Cd was retained in the root during apoplastic translocation. This was confirmed by localization analyses of Cd in root transverse sections. These results suggest that apoplastic barriers reduce Cd root-to-shoot translocation via the apoplastic pathway, leading to lower Cd accumulation in the upper parts of rice plants. Bypass flow may have the potential to be used as a rapid screening indicator for low Cd-accumulating rice cultivars.


The influence of marital status on stage at diagnosis and survival of older persons with melanoma.
Melanoma incidence and mortality had a sustained increase in the last 3 decades in the United States, especially among white older men. Little is known about the relationship between marital status and melanoma outcomes in older people. The objective of this study was to determine the association between marital status and stage at diagnosis and survival of older persons with cutaneous melanoma. Data are from the Surveillance, Epidemiology and End Results (SEER) registries-Medicare-linked database (1991-1999). The sample consisted of 14,630 men and women 65 years old and older. The outcomes were melanoma stage at diagnosis and melanoma specific survival. The main independent variable, marital status, was used in four categories: married, single, separated or divorced, and widowed. Other covariates include sociodemographics, stage at diagnosis, tumor characteristics (body site and histology), and comorbidity index. Logistic regression and survival analyses techniques were used. Multivariate analyses showed that, compared with married persons, widowed persons were more likely to be diagnosed with late-stage (regional or distant) versus early-stage (in situ or localized) melanoma (odds ratio = 1.31, 95% confidence interval [CI], 1.13-1.52). In addition, after controlling for all other variables (sociodemographics, stage at diagnosis, tumor characteristics, and comorbidity), widowed persons were at increased risk of death from melanoma (hazard ratio = 1.23, 95% CI, 1.06-1.44). Older widowed persons were more likely to be diagnosed at late stage and to die from melanoma than were older married persons.


Iridescence in Meat Caused by Surface Gratings.
The photonic structure of cut muscle tissues reveals that the well-ordered gratings diffract light, producing iridescent colours. Cut fibrils protruding from the muscle surface create a two-dimensional periodic array, which diffract light at specific wavelengths upon illumination. However, this photonic effect misleads consumers in a negative way to relate the optical phenomenon with the quality of the product. Here we discuss the fundamentals of this optical phenomenon and demonstrate a methodology for quantitatively measuring iridescence caused by diffraction gratings of muscle tissue surface of pork (Sus scrofa domesticus) using reflection spectrophotometry. Iridescence was discussed theoretically as a light phenomenon and spectral measurements were taken from the gratings and monitored in real time during controlled drying. The findings show that the intensity of diffraction diminishes as the surface grating was dried with an air flow at 50 °C for 2 min while the diffracted light wavelength was at 585 ± 9 nm. Our findings indicate that the diffraction may be caused by a blazed surface grating. The implications of the study include providing guidelines to minimise the iridescence by altering the surface microstructure, and in consequence, removing the optical effect.


Venobiliary fistula with haemobilia: a rare complication of percutaneous liver biopsy.
We describe a case of a 36-year-old man with a history of chronic hepatitis C who presented with abdominal pain 3 days after undergoing a percutaneous ultrasound-guided liver biopsy. Initial investigations revealed a venobiliary fistula with haemobilia and obstructive jaundice with direct bilirubin peaking at 9.2 mg/dL. He underwent an endoscopic retrograde cholangiopancreatography with sphincterotomy and stent placement, bilirubin decreased to 3.7 mg/dL, and the patient was discharged. The patient returned with recurrent abdominal pain and upper gastrointestinal bleeding with haemoglobin of 8.6 g/dL, requiring multiple transfusions. He underwent transcatheter arterial embolisation but continued bleeding. Radiofrequency ablation was pursued and was able to achieve haemostasis. The patient was discharged. The patient returned again with a fever of 39.2 °C and was found to have a large right hepatic lobe abscess. The patient underwent abscess drainage with drain placement and was treated with antibiotics for 6 weeks. He followed up in the clinic with resolution of symptoms and infection.


Characterization of HPV16 L1 loop domains in the formation of a type-specific, conformational epitope.
Virus-like particles (VLPs) formed by the human papillomavirus (HPV) L1 capsid protein are currently being tested in clinical trials as prophylactic vaccines against genital warts and cervical cancer. The efficacy of these vaccines is critically dependent upon L1 type-specific conformational epitopes. To investigate the molecular determinants of the HPV16 L1 conformational epitope recognized by monoclonal antibody 16A, we utilized a domain-swapping approach to generate a series of L1 proteins composed of a canine oral papillomavirus (COPV) L1 backbone containing different regions of HPV16 L1. Gross domain swaps, which did not alter the ability of L1 to assemble into VLPs, demonstrated that the L1 N-terminus encodes at least a component of the 16A antigenic determinant. Finer epitope mapping, using GST-L1 fusion proteins, mapped the 16A epitope to the L1 variable regions I and possibly II within the N-terminus. These results suggest that non-contiguous loop regions of L1 display critical components of a type-specific, conformational epitope.


Long-term reinfection of the human genome by endogenous retroviruses.
Endogenous retrovirus (ERV) families are derived from their exogenous counterparts by means of a process of germ-line infection and proliferation within the host genome. Several families in the human and mouse genomes now consist of many hundreds of elements and, although several candidates have been proposed, the mechanism behind this proliferation has remained uncertain. To investigate this mechanism, we reconstructed the ratio of nonsynonymous to synonymous changes and the acquisition of stop codons during the evolution of the human ERV family HERV-K(HML2). We show that all genes, including the env gene, which is necessary only for movement between cells, have been under continuous purifying selection. This finding strongly suggests that the proliferation of this family has been almost entirely due to germ-line reinfection, rather than retrotransposition in cis or complementation in trans, and that an infectious pool of endogenous retroviruses has persisted within the primate lineage throughout the past 30 million years. Because many elements within this pool would have been unfixed, it is possible that the HERV-K(HML2) family still contains infectious elements at present, despite their apparent absence in the human genome sequence. Analysis of the env gene of eight other HERV families indicated that reinfection is likely to be the most common mechanism by which endogenous retroviruses proliferate in their hosts.


Specialty preferences of 1(st) year medical students in a Saudi Medical School - Factors affecting these choices and the influence of gender.
In recent years there has been a growing appreciation of the issues of career preference in medicine as it affects student learning and academic performance. Various factors influence the specialty choices of medical students. Some specialties tend to attract students more than others. One possible consequence of this would be a mismatch between health needs and specialist numbers in the region. This study investigated the career preferences of 1(st) year medical students in a Saudi medical school and to assess factors affecting these choices. The study was a cross-sectional survey carried out on the 1(st) year undergraduate students in the college of medicine, King Faisal University, Saudi Arabia. A total of 109 students (57 female and 52 males) responded to the questionnaire which was initially administered to all the students of the 1(st) year - A total of 120 students (response rate was 90.8%). A mixed method approach was used and qualitative data from open-ended questions were analyzed based on thematic analysis. The top choices were general surgery, internal medicine, and pediatrics. Among female students; the top specialty choices were: General surgery (23%), pediatrics (18%), and dermatology (15%). Among the male students; the top choices were: General surgery (54%) and internal medicine (23%). Of the total, 57% of the students agreed or strongly agreed that primary aptitude was the main factor affecting the choice. Only 31% felt that there was a significant influence of role model, 48% felt that the advice of others - peers and family, would be a factor influencing their choices, and 53% agreed that specialty choice would influence their future learning patterns. Males were more likely to choose a specialty based on actual aptitude for the specialty, financial rewards, and scope for research; and this gender difference was statistically significant. Surgery was the top-choice in both genders. Other popular choices included internal medicine, pediatrics, and dermatology. Important factors affecting these choices included - primary aptitude, advice of peers, reputation, financial rewards, and the challenge involved.


Conservation of the metabolomic response to starvation across two divergent microbes.
We followed 68 cellular metabolites after carbon or nitrogen starvation of Escherichia coli and Saccharomyces cerevisiae, using a filter-culture methodology that allows exponential growth, nondisruptive nutrient removal, and fast quenching of metabolism. Dynamic concentration changes were measured by liquid chromatography-tandem mass spectrometry and viewed in clustered heat-map format. The major metabolic responses anticipated from metabolite-specific experiments in the literature were observed as well as a number of novel responses. When the data were analyzed by singular value decomposition, two dominant characteristic vectors were found, one corresponding to a generic starvation response and another to a nutrient-specific starvation response that is similar in both organisms. Together these captured a remarkable 72% of the metabolite concentration changes in the full data set. The responses described by the generic starvation response vector (42%) included, for example, depletion of most biosynthetic intermediates. The nutrient-specific vector (30%) included key responses such as increased phosphoenolpyruvate signaling glucose deprivation and increased alpha-ketoglutarate signaling ammonia deprivation. Metabolic similarity across organisms extends from the covalent reaction network of metabolism to include many elements of metabolome response to nutrient deprivation as well.


Patch-clamp characterisation of somatostatin-secreting -cells in intact mouse pancreatic islets.
The perforated patch whole-cell configuration of the patch-clamp technique was applied to superficial cells in intact mouse pancreatic islets. Three types of electrical activity were observed corresponding to alpha-, beta- and delta-cells. The delta-cells were electrically active in the presence of glucose but lacked the oscillatory pattern seen in the beta-cells. By contrast, the alpha-cells were electrically silent at high glucose concentrations but action potentials could be elicited by removal of the sugar. Both alpha- and beta-cells contained transient voltage-activated K+ currents. In the delta-cells, the K+ currents activated above -20 mV and were completely blocked by TEA (20 mM). The alpha-cells differed from the delta-cells in possessing a TEA-resistant K+ current activating already at -40 mV. Immunocytochemistry revealed the presence of Kv3.4 channels in delta-cells and TEA-resistant Kv4.3 channels in alpha-cells. Thus the presence of a transient TEA-resistant current can be used to functionally separate the delta- and alpha-cells. A TTX-sensitive Na+ current developed in delta-cells during depolarisations beyond -30 mV and reached a peak amplitude of 350 pA. Steady-state inactivation of this current was half-maximal at -28 mV. The delta-cells were also equipped with a sustained Ca2+ current that activated above -30 mV and reached a peak of 60 pA when measured at 2.6 mM extracellular Ca2+. A tolbutamide-sensitive KATP channel conductance was observed in delta-cells exposed to glucose-free medium. Addition of tolbutamide (0.1 mM) depolarised the delta-cell and evoked electrical activity. We propose that the KATP channels in delta-cells serve the same function as in the beta-cell and couple an elevation of the blood glucose concentration to stimulation of hormone release.


Can Social Anxiety Impact Facial Emotion Recognition in Schizophrenia?
Social anxiety is highly prevalent in individuals with schizophrenia, with studies suggesting rates of 30%. This study aimed at determining if social anxiety is linked to specific emotion recognition deficits and to specific social functioning deficits. A total of 47 participants with a diagnosis of schizophrenia and receiving outpatient services answered measures of facial recognition (Ekman; Facial Emotion Identification Test), facial discrimination (Facial Emotion Discrimination Test), role-play, social anxiety (Social Interaction Anxiety Scale and Brief Social Phobia Scale), psychiatric symptoms (Brief Psychiatric Rating Scale), self-esteem (Self-Esteem Rating Scale-Short Form), and social functioning (Social Functioning Scale). A total of 22 (47%) participants were rated as socially anxious. Those with social anxiety had worse social functioning in the domains of interpersonal communication (t[45] = 2.28, p = 0.025) and engagement (in conversations) (t[45] = 2.89, p = 0.000) and had lower self-esteem (t[45] = 4.05, p = 0.001). Participants with social anxiety also had more difficulties in recognizing neutral emotional faces (t[31] = 2.19, p = 0.036). More studies are warranted to better understand the link between neutral expression recognition and social anxiety in schizophrenia.


Associations of serum and dietary magnesium with cardiovascular disease, hypertension, diabetes, insulin, and carotid arterial wall thickness: the ARIC study. Atherosclerosis Risk in Communities Study.
The objective of this study was to examine the relationships of serum and dietary magnesium (Mg) with prevalent cardiovascular disease (CVD), hypertension, diabetes mellitus, fasting insulin, and average carotid intimal-medial wall thickness measured by B-mode ultrasound. A cross-sectional design was used. The setting was the Atherosclerosis Risk in Communities (ARIC) Study in four US communities. A total of 15,248 participants took part, male and female, black and white, aged 45-64 years. Fasting serum Mg, lipids, fasting glucose and insulin were measured; as was usual dietary intake by food frequency questionnaire and carotid intima-media thickness by standardized B-mode ultrasound methods. The results showed that serum Mg levels and dietary Mg intake were both lower in blacks than whites. Mean serum Mg levels were significantly lower in participants with prevalent CVD, hypertension, and diabetes than in those free of these diseases. In participants without CVD, serum Mg levels were also inversely associated with fasting serum insulin, glucose, systolic blood pressure and smoking. Dietary Mg intake was inversely associated with fasting serum insulin, plasma high density lipoprotein-cholesterol, systolic and diastolic blood pressure. Adjusted for age, race, body mass index, smoking, hypertension, Low density lipoprotein-cholesterol, and field center, mean carotid wall thickness increased in women by 0.0118 mm (p = 0.006) in diuretic users and 0.0048 mm (p = 0.017) in nonusers for each 0.1 mmol/l decrease in serum Mg level; the multivariate association in men was not significant. In conclusion, low serum and dietary Mg may be related to the etiologies of CVD, hypertension, diabetes, and atherosclerosis.


Cellular regulation of ribonucleotide reductase in eukaryotes.
Synthesis of deoxynucleoside triphosphates (dNTPs) is essential for both DNA replication and repair and a key step in this process is catalyzed by ribonucleotide reductases (RNRs), which reduce ribonucleotides (rNDPs) to their deoxy forms. Tight regulation of RNR is crucial for maintaining the correct levels of all four dNTPs, which is important for minimizing the mutation rate and avoiding genome instability. Although allosteric control of RNR was the first discovered mechanism involved in regulation of the enzyme, other controls have emerged in recent years. These include regulation of expression of RNR genes, proteolysis of RNR subunits, control of the cellular localization of the small RNR subunit, and regulation of RNR activity by small protein inhibitors. This review will focus on these additional mechanisms of control responsible for providing a balanced supply of dNTPs.


Complete and sustained remission of hypercortisolism with pasireotide treatment of an adrenocorticotropic hormone (ACTH)-secreting thoracic neuroendocrine tumor: an n-of-1 trial.
N-of-1 trials can serve as useful tools in managing rare disease. We describe a patient presenting with a typical clinical picture of Cushing's Syndrome (CS). Further testing was diagnostic of ectopic Adrenocorticotropic Hormone (ACTH) secretion, but its origin remained occult. The patient was offered treatment with daily pasireotide at very low doses (300 mg bid), which resulted in clinical and biochemical control for a period of 5 years, when a pulmonary typical carcinoid was diagnosed and dissected. During the pharmacological treatment period, pasireotide was tentatively discontinued twice, with immediate flare of symptoms and biochemical markers, followed by remission after drug reinitiation. This is the first report of clinical and biochemical remission of an ectopic CS (ECS) with pasireotide used as first line treatment, in a low-grade lung carcinoid, for a prolonged period of 5 years. In conclusion, the burden of high morbidity caused by hypercortisolism can be effectively mitigated with appropriate pharmacological treatment, in patients with occult tumors. Pasireotide may lead to complete and sustained remission of hypercortisolism, until surgical therapy is feasible. The expression of SSTR2 from typical carcinoids may be critical in allowing the use of very low drug doses for achieving disease control, while minimizing the risk of adverse events.


Successful in utero transesophageal pacing for severe drug-resistant tachyarrhythmia.
Sustained fetal tachyarrhythmia can evolve into a life-threatening condition in 40% of cases when hydrops develops, with a 27% risk of perinatal death. Several antiarrhythmic drugs can be given solely or in combination to the mother to achieve therapeutic transplacental concentrations. Therapeutic failure could lead to progressive cardiac insufficiency and restrict therapeutic options to either elective delivery or direct fetal administration of antiarrhythmic drugs, which may increase the risk of death. We report for the first time successful fetal transesophageal pacing to treat a hydropic fetus with drug-resistant tachyarrhythmia.


The human IgE repertoire.
IgE is a key mediator in allergic diseases. However, in strong contrast to other antibody isotypes, many details of the composition of the human IgE repertoire are poorly defined. The low levels of human IgE in the circulation and the rarity of IgE-producing B cells are important reasons for this lack of knowledge. In this review, we summarize the current knowledge on these repertoires both in terms of their complexity and activity, i.e. knowledge which despite the difficulties encountered when studying the molecular details of human IgE has been acquired in recent years. We also take a look at likely future developments, for instance through improvements in sequencing technology and methodology that allow the isolation of additional allergen-specific human antibodies mimicking IgE, as this certainly will support our understanding of human IgE in the context of human disease in the years to come.


Three-dimensional vision with dual acousto-optic deflection encoding.
We report a new method of sensing a three-dimensional (3D) object surface with an arbitrary geometric shape. In this approach, the first-order beams diffracted from two acousto-optic deflectors (AODs) interfere with each other to form a spatial carrier that is used to encode the depth information from the 3D object surface. A direct digital synthesizer is utilized to control two AODs to generate sequentially spatial carriers with different spatial frequencies so that a modified temporal phase-unwrapping technique can be applied for decoding the shape information of the test surface. Preliminary experimental results are presented to demonstrate the effectiveness of this method.


An overexpression screen of Toxoplasma gondii Rab-GTPases reveals distinct transport routes to the micronemes.
The basic organisation of the endomembrane system is conserved in all eukaryotes and comparative genome analyses provides compelling evidence that the endomembrane system of the last common eukaryotic ancestor (LCEA) is complex with many genes required for regulated traffic being present. Although apicomplexan parasites, causative agents of severe human and animal diseases, appear to have only a basic set of trafficking factors such as Rab-GTPases, they evolved unique secretory organelles (micronemes, rhoptries and dense granules) that are sequentially secreted during invasion of the host cell. In order to define the secretory pathway of apicomplexans, we performed an overexpression screen of Rabs in Toxoplasma gondii and identified Rab5A and Rab5C as important regulators of traffic to micronemes and rhoptries. Intriguingly, we found that not all microneme proteins traffic depends on functional Rab5A and Rab5C, indicating the existence of redundant microneme targeting pathways. Using two-colour super-resolution stimulated emission depletion (STED) we verified distinct localisations of independent microneme proteins and demonstrate that micronemal organelles are organised in distinct subsets or subcompartments. Our results suggest that apicomplexan parasites modify classical regulators of the endocytic system to carryout essential parasite-specific roles in the biogenesis of their unique secretory organelles.


THE BEHAVIOR OF THE LEUCOCYTES DURING COINCIDENT REGENERATION AND THYROID-INDUCED METAMORPHOSIS IN THE FROG LARVA, WITH A CONSIDERATION OF GROWTH FACTORS.
1. Coincident progressive and regressive changes are induced in the tail of the frog larva by simultaneous thyroid administration and removal of a portion of the tail. The rate of growth of the regenerating tail is greatest in animals not treated with thyroid, next greatest in animals treated with thyroid 2 days after tail removal, somewhat less in animals treated with thyroid simultaneously with tail removal, and least in those treated with thyroid 2 days before removal of the tail. 2. The leucocytes chiefly concerned are neutrophilic granulocytes, lymphocytes, hemoblasts, and lymphoid phagocytes (monocytes, macrophages). The neutrophils further tissue lysis, the lymphoid phagocytes remove tissue débris. The lymphocytes are apparently not numerous enough to exert any important growth-promoting influence. The hemoblasts represent merely a part of the general reaction to thyroid treatment. Eosinophils are absent except for a few that appear in the late stages. Basophils of mesenchymal origin are present in the later stages of thyroid-treated animals. These appear to differentiate further into eosinophils. 3. The rate and amount of growth are correlated directly with the degree of crowding of cells, and inversely with the degree of vascularity. The greatest crowding and least vascularity occur in animals not treated with thyroid, somewhat less crowding and greater vascularity in those treated with thyroid 2 days after tail removal, still less crowding and somewhat greater vascularity in those treated with thyroid at the time of tail removal, and finally, least crowding and greatest vascularity occur in animals treated with thyroid 2 days before tail removal. These results support the views of Burrows (4) upon the mechanism of growth stimulation of cells.


Low-dose naltrexone suppresses ovarian cancer and exhibits enhanced inhibition in combination with cisplatin.
Ovarian cancer is the leading cause of death from gynecological malignancies. Although initial therapeutic modalities are successful, 65% of these women relapse with only palliative treatments available thereafter. Endogenous opioids repress the proliferation of human ovarian cancer cells in vitro, and do so in a receptor-mediated manner. The present study examined whether modulation of opioid systems by the opioid antagonist naltrexone (NTX), alone or in combination with standard of care therapies (taxol/paclitaxel, cisplatin), alters human ovarian cancer cell proliferation in tissue culture and tumor progression in mice. Administration of NTX for six hours every two days, but not continuously, reduced DNA synthesis and cell replication from vehicle-treated controls in tissue culture. Moreover, brief exposure to NTX in combination with taxol or cisplatin had an enhanced anticancer action. Mice with established ovarian tumors and treated with a low dosage of NTX (LDN), which invokes a short period of opioid receptor blockade, repressed tumor progression in a non-toxic fashion by reducing DNA synthesis and angiogenesis but not altering cell survival. The combination of LDN with cisplatin, but not taxol, resulted in an additive inhibitory effect on tumorigenesis with enhanced depression of DNA synthesis and angiogenesis. LDN combined with cisplatin alleviated the toxicity (e.g. weight loss) associated with cisplatin. LDN treatment upregulated the expression of the opioid growth factor (OGF, chemical term ([Met(5)]-enkephalin) and its receptor, OGFr. Previous tissue culture studies have reported that OGF is the only opioid peptide with antiproliferative activity on ovarian cancer cells, with OGF action mediated by OGFr. Thus, the common denominator of intermittent opioid receptor blockade by short-term NTX or LDN on ovarian cancer proliferation and tumorigenesis recorded herein appears to be related to the OGF-OGFr axis. These preclinical data may offer a non-toxic and efficacious pathway-related treatment that can benefit patients with ovarian cancer.


Information and communication technology in patient education and support for people with schizophrenia.
Poor compliance with treatment often means that many people with schizophrenia or other severe mental illness relapse and may need frequent and repeated hospitalisation. Information and communication technology (ICT) is increasingly being used to deliver information, treatment or both for people with severe mental disorders. To evaluate the effects of psychoeducational interventions using ICT as a means of educating and supporting people with schizophrenia or related psychosis. We searched the Cochrane Schizophrenia Group Trials Register (2008, 2009 and September 2010), inspected references of identified studies for further trials and contacted authors of trials for additional information. All clinical randomised controlled trials (RCTs) comparing ICT as a psychoeducational and supportive tool with any other type of psychoeducation and supportive intervention or standard care. We selected trials and extracted data independently. For homogenous dichotomous data we calculated fixed-effect risk ratios (RR) with 95% confidence intervals (CI). For continuous data, we calculated mean differences (MD). We assessed risk of bias using the criteria described in the Cochrane Handbook for Systematic Reviews of Interventions. We included six trials with a total of 1063 participants. We found no significant differences in the primary outcomes (patient compliance and global state) between psychoeducational interventions using ICT and standard care.Technology-mediated psychoeducation improved mental state in the short term (n = 84, 1 RCT, RR 0.75, 95% CI 0.56 to 1.00; n = 30, 1 RCT, MD -0.51, 95% CI -0.90 to -0.12) but not global state (n = 84, 1 RCT, RR 1.07, 95% CI 0.82 to 1.42). Knowledge and insight were not effected (n = 84, 1 RCT, RR 0.89, 95% CI 0.68 to 1.15; n = 84, 1 RCT, RR 0.77, 95% CI 0.58 to 1.03). People allocated to technology-mediated psychoeducation perceived that they received more social support than people allocated to the standard care group (n = 30, 1 RCT, MD 0.42, 95% CI 0.04 to 0.80).When technology-mediated psychoeducation was used as an adjunct to standard care it did not improve general compliance in the short term (n = 291, 3 RCTs, RR for leaving the study early 0.81, 95% CI 0.55 to 1.19) or in the long term (n = 434, 2 RCTs, RR for leaving the study early 0.70, 95% CI 0.39 to 1.25). However, it did improve compliance with medication in the long term (n = 71, 1 RCT, RR 0.45, 95% CI 0.27 to 0.77). Adding technology-mediated psychoeducation on top of standard care did not clearly improve either general mental state, negative or positive symptoms, global state, level of knowledge or quality of life. However, the results were not consistent regarding level of knowledge and satisfaction with treatment.When technology-mediated psychoeducation plus standard care was compared with patient education not using technology the only outcome reported was satisfaction with treatment. There were no differences between groups. Using ICT to deliver psychoeducational interventions has no clear effects compared with standard care, other methods of delivering psychoeducation and support, or both. Researchers used a variety of methods of delivery and outcomes, and studies were few and underpowered. ICT remains a promising method of delivering psychoeducation; the equivocal findings of this review should not postpone high-quality research in this area.


Lovastatin-Mediated Changes in Human Tendon Cells.
Statins are among the most widely prescribed drugs worldwide. Numerous studies have shown their beneficial effects in prevention of cardiovascular disease through cholesterol-lowering and anti-atherosclerotic properties. Although some statin patients may experience muscle-related symptoms, severe side effects of statin therapy are rare, primarily due to extensive first-pass metabolism in the liver. Skeletal muscles appear to be the main site of side effects; however, recently some statin-related adverse effects have been described in tendon. The mechanism behind these side effects remains unknown. This is the first study that explores tendon-specific effects of statins in human primary tenocytes. The cells were cultured with different concentrations of lovastatin for up to 1 week. No changes in cell viability or morphology were observed in tenocytes incubated with therapeutic doses. Short-term exposure to lovastatin concentrations outside the therapeutic range had no effect on tenocyte viability; however, cell migration was reduced. Simvastatin and atorvastatin, two other drug family members, also reduced the migratory properties of the cells. Prolonged exposure to high concentrations of lovastatin induced changes in cytoskeleton leading to cell rounding and decreased levels of mRNA for matrix proteins, but increased BMP-2 expression. Gap junctional communication was impaired but due to cell shape change and separation rather than direct gap junction inhibition. These effects were accompanied by inhibition of prenylation of Rap1a small GTPase. Collectively, we showed that statins in a dose-dependent manner decrease migration of human tendon cells, alter their expression profile and impair the functional network, but do not inhibit gap junction function.


Normal human dermis contains distinct populations of CD11c+BDCA-1+ dendritic cells and CD163+FXIIIA+ macrophages.
We used a panel of monoclonal antibodies to characterize DCs in the dermis of normal human skin. Staining for the CD11c integrin, which is abundant on many kinds of DCs, revealed cells in the upper dermis. These cells were positive for blood DC antigen-1 (BDCA-1; also known as CD1c), HLA-DR, and CD45, markers that are also expressed by circulating myeloid DCs. A small subset of CD11c+ dermal cells expressed DEC-205/CD205 and DC-lysosomal-associated membrane glycoprotein/CD208 (DC-LAMP/CD208), suggesting some differentiation or maturation. When BDCA-1+ cells were selected from collagenase digests of normal dermis, they proved to be strong stimulators for T cells in a mixed leukocyte reaction. A second major population of cells located throughout the dermis was positive for factor XIIIA (FXIIIA), but lacked CD11c and BDCA-1. They expressed the macrophage scavenger receptor CD163 and stained weakly for HLA-DR and CD45. Isolated CD163+ dermal cells were inactive in stimulating T cell proliferation, but in biopsies of tattoos, these cells were selectively laden with granular pigments. Plasmacytoid DCs were also present in the dermis, marked by CD123 and BDCA-2. In summary, the normal dermis contains typical immunostimulatory myeloid DCs identified by CD11c and BDCA-1, as well as an additional population of poorly stimulatory macrophages marked by CD163 and FXIIIA.


Longitudinal study of diagnoses in children of women with unipolar and bipolar affective disorder.
School-age children of unipolar depressed, bipolar, chronically medically ill, or normal women were diagnosed every 6 months for up to 3 years. Offspring of unipolar women had the highest rates of disorder at all evaluations, but children of bipolar and medically ill mothers also experienced significant rates of disorder. Observing diagnoses from both past lifetime and prospective follow-up assessments, it appeared that most children who had diagnoses had onsets in preadolescence and continued a chronic or intermittent course of disorder. Thus, risk to offspring of ill mothers is not transitory and indicates a pernicious course that commonly includes effective disorders alone or in combination with behavior and anxiety disorders.


Sleep disturbance in heavy marijuana users.
To determine if recently abstinent, heavy marijuana (MJ) users show differences in polysomnographic (PSG) measures compared with a drug-free control group. A group of carefully selected heavy MJ users were chosen for study inclusion and matched to a drug-free control group. Questionnaire data were collected prior to cessation of MJ use. PSG studies were conducted during 2 consecutive nights after discontinuation of MJ use in our core sleep laboratory. Baltimore Maryland, General Clinical Research Center (GCRC) core sleep lab. 17 heavy MJ users discontinuing MJ use and 14 drug-free controls. Men and women were studied, 18 to 30 years. The MJ users reported no other drug use and alcohol use was negligible in both groups. Urine was positive for metabolites of cannabis only. The MJ users showed differences in PSG measures (lower total sleep times, and less slow wave sleep than the control group) on both nights; they also showed worse sleep efficiency, longer sleep onset, and shorter REM latency than the control group on Night 2. More sleep continuity parameters were significantly worse for the MJ group than the control group on Night 2 versus Night 1, indicating that sleep in the MJ group was relatively worse on Night 2 compared to Night 1. The MJ group did not show improved sleep after an adaptation night as expected. Withdrawal symptoms, craving, and depression did not appear to influence these findings. During discontinuation of heavy MJ use, PSG measures of sleep disturbance were detected in MJ users compared with a drug-free control group. While this preliminary study cannot identify the extent to which these group differences were present before abstinence, poor sleep quality either prior to or after MJ discontinuation could result in treatment failure for MJ users. Further investigation is necessary to determine the association between the use and cessation of MJ and sleep disturbance.


A new species of Asthenocotyle Robinson, 1961 (Monogenea: Microbothriidae), a skin parasite of the great lanternshark Etmopterus princeps Collett from the Azores, with a redescription of A. kaikourensis Robinson, 1961 and observations on A. taranakiensis Beverley-Burton, Klassen & Lester, 1987.
Asthenocotyle azorensis n. sp. (Monogenea: Microbothriidae) is described from the dermal denticles of the great lanternshark Etmopterus princeps Collett off the Azores. The type-species of the genus, A. kaikourensis Robinson, 1961, is redescribed and additional observations are made on A. taranakiensis Beverley-Burton, Klassen & Lester, 1987. The generic diagnosis is revised. The new species is distinguished from its two congeners by the large size of the pharynx and fewer testes. The ejaculatory bulb of A. kaikourensis is much larger than those of A. taranakiensis and A. azorensis and is supplied with many ducts from an extensive field of male accessory gland-cells located outside the genital pouch and extending posteriorly to the region of the germarium and external seminal vesicle. Asthenocotyle taranakiensis is distinguished from the other two species by its copulatory sclerite, which forms a double loop, although this may not be the case when the copulatory organ is extended. The bodies of A. azorensis and A. kaikourensis are similar in shape, with the maximum width approximately 37% and 25%, respectively, of the total length from the anterior end. In addition to the relatively small size of the genital pouch and ejaculatory bulb in A. azorensis and A. taranakiensis, the vaginal opening is adjacent to the common genital opening. In A. kaikourensis, the vaginal opening is distant from and posterior to the common genital opening. The functional morphology of the copulatory organ of A. azorensis is considered. The relative importance, for the taxonomy of microbothriids, of the number of testes versus the anatomy of the copulatory complex is discussed.


Steady-State Motion Visual Evoked Potential (SSMVEP) Based on Equal Luminance Colored Enhancement.
Steady-state visual evoked potential (SSVEP) is one of the typical stimulation paradigms of brain-computer interface (BCI). It has become a research approach to improve the performance of human-computer interaction, because of its advantages including multiple objectives, less recording electrodes for electroencephalogram (EEG) signals, and strong anti-interference capacity. Traditional SSVEP using light flicker stimulation may cause visual fatigue with a consequent reduction of recognition accuracy. To avoid the negative impacts on the brain response caused by prolonged strong visual stimulation for SSVEP, steady-state motion visual evoked potential (SSMVEP) stimulation method was used in this study by an equal-luminance colored ring-shaped checkerboard paradigm. The movement patterns of the checkerboard included contraction and expansion, which produced less discomfort to subjects. Feature recognition algorithms based on power spectrum density (PSD) peak was used to identify the peak frequency on PSD in response to visual stimuli. Results demonstrated that the equal-luminance red-green stimulating paradigm within the low frequency spectrum (lower than 15 Hz) produced higher power of SSMVEP and recognition accuracy than black-white stimulating paradigm. PSD-based SSMVEP recognition accuracy was 88.15±6.56%. There was no statistical difference between canonical correlation analysis (CCA) (86.57±5.37%) and PSD on recognition accuracy. This study demonstrated that equal-luminance colored ring-shaped checkerboard visual stimulation evoked SSMVEP with better SNR on low frequency spectrum of power density and improved the interactive performance of BCI.


Cybersecurity vulnerabilities in medical devices: a complex environment and multifaceted problem.
The increased connectivity to existing computer networks has exposed medical devices to cybersecurity vulnerabilities from which they were previously shielded. For the prevention of cybersecurity incidents, it is important to recognize the complexity of the operational environment as well as to catalog the technical vulnerabilities. Cybersecurity protection is not just a technical issue; it is a richer and more intricate problem to solve. A review of the factors that contribute to such a potentially insecure environment, together with the identification of the vulnerabilities, is important for understanding why these vulnerabilities persist and what the solution space should look like. This multifaceted problem must be viewed from a systemic perspective if adequate protection is to be put in place and patient safety concerns addressed. This requires technical controls, governance, resilience measures, consolidated reporting, context expertise, regulation, and standards. It is evident that a coordinated, proactive approach to address this complex challenge is essential. In the interim, patient safety is under threat.


The Saccharomyces cerevisiae homologue of mammalian translation initiation factor 6 does not function as a translation initiation factor.
Eukaryotic translation initiation factor 6 (eIF6) binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit. The Saccharomyces cerevisiae gene that encodes the 245-amino-acid eIF6 (calculated Mr 25,550), designated TIF6, has been cloned and expressed in Escherichia coli. The purified recombinant protein prevents association between 40S and 60S ribosomal subunits to form 80S ribosomes. TIF6 is a single-copy gene that maps on chromosome XVI and is essential for cell growth. eIF6 expressed in yeast cells associates with free 60S ribosomal subunits but not with 80S monosomes or polysomal ribosomes, indicating that it is not a ribosomal protein. Depletion of eIF6 from yeast cells resulted in a decrease in the rate of protein synthesis, accumulation of half-mer polyribosomes, reduced levels of 60S ribosomal subunits resulting in the stoichiometric imbalance in the 40S/60S subunit ratio, and ultimately cessation of cell growth. Furthermore, lysates of yeast cells depleted of eIF6 remained active in translation of mRNAs in vitro. These results indicate that eIF6 does not act as a true translation initiation factor. Rather, the protein may be involved in the biogenesis and/or stability of 60S ribosomal subunits.


Withdrawal of Life-Support in Neonatal Hypoxic-Ischemic Encephalopathy.
We describe the frequency and timing of withdrawal of life-support (WLS) in moderate or severe hypoxic-ischemic encephalopathy (HIE) and examine its associations with medical and sociodemographic factors. We undertook a secondary data analysis of a prospective multicenter data registry of regional level IV Neonatal Intensive Care Units participating in the Children's Hospitals Neonatal Database. Infants ≥36 weeks gestational age with HIE admitted to a Children's Hospitals Neonatal Database Neonatal Intensive Care Unit between 2010 and 2016, who underwent therapeutic hypothermia were categorized as (1) infants who died following WLST and (2) survivors with severe HIE (requiring tube feedings at discharge). Death occurred in 267/1,925 (14%) infants with HIE, 87.6% following WLS. Compared to infants with WLS (n = 234), the survived severe group (n = 74) had more public insurance (73% vs 39.3%, P = 0.00001), lower household income ($37,020 vs $41,733, P = 0.006) and fewer [20.3% vs 35.0%, P = 0.0212] were from the South. Among infants with WLS, electroencephalogram was performed within 24 hours in 75% and was severely abnormal in 64% cases; corresponding rates for MRI were 43% and 17%, respectively. Private insurance was independently associated with WLS, after adjustment for HIE severity and center. In a multicenter cohort of infants with HIE, WLS occurred frequently and was associated with sociodemographic factors. The rationale for decision-making for WLS in HIE require further exploration.


Neurobiology of autism gene products: towards pathogenesis and drug targets.
The genetic heterogeneity of autism spectrum disorders (ASDs) is enormous, and the neurobiology of proteins encoded by genes associated with ASD is very diverse. Revealing the mechanisms on which different neurobiological pathways in ASD pathogenesis converge may lead to the identification of drug targets. The main objective is firstly to outline the main molecular networks and neuronal mechanisms in which ASD gene products participate and secondly to answer the question how these converge. Finally, we aim to pinpoint drug targets within these mechanisms. Literature review of the neurobiological properties of ASD gene products with a special focus on the developmental consequences of genetic defects and the possibility to reverse these by genetic or pharmacological interventions. The regulation of activity-dependent protein synthesis appears central in the pathogenesis of ASD. Through sequential consequences for axodendritic function, neuronal disabilities arise expressed as behavioral abnormalities and autistic symptoms in ASD patients. Several known ASD gene products have their effect on this central process by affecting protein synthesis intrinsically, e.g., through enhancing the mammalian target of rapamycin (mTOR) signal transduction pathway or through impairing synaptic function in general. These are interrelated processes and can be targeted by compounds from various directions: inhibition of protein synthesis through Lovastatin, mTOR inhibition using rapamycin, or mGluR-related modulation of synaptic activity. ASD gene products may all feed into a central process of translational control that is important for adequate glutamatergic regulation of dendritic properties. This process can be modulated by available compounds but may also be targeted by yet unexplored routes.


Success of free flap anastomoses performed within the zone of trauma in acute lower limb reconstruction.
Traditionally, in free flap cover of lower limb injuries, every attempt is made to perform anastomoses proximal to the zone of injury. We report on the success of anastomoses within the zone of trauma, at the level of the fracture, avoiding further dissection and exposure. The records of free flap reconstructions for fractures of the lower extremity at a tertiary trauma centre between 2004 and 2010 were retrospectively reviewed. A total of 48 lower limb fractures required free flap reconstruction, performed at 28 days post injury (0-275 days). Anastomoses were proximal (21), distal (5) or within the zone of trauma (22). There was no significant difference (p > 0.05) in return to theatre, revision of anastomosis or flap survival between groups. Of the 22 performed within the zone of injury, five returned to theatre but only two for revision of anastomosis and 20 (91%) of these flaps survived. Of the 48 free flaps, arterial anastomoses were end to end in 34 (71%) and end to side in 14 (30%). There was no significant difference (p > 0.05) in return to theatre, revision of anastomosis or flap survival between the end-to-end and end-to-side groups. There was a tendency for arterial anastomoses to be performed end to end outside the zone of trauma (23/26) compared to within the zone of trauma (11/22). Our data suggest that free flap anastomoses can be performed safely in the zone of trauma in lower limb injuries.


Fibroscan and FibroTest/FibroMax to assess liver fibrosis/cirrhosis in patients with chronic HBV and HCV infection in Georgia.
Although, liver biopsy is the gold standard in assessment of the degree of liver damage, the method has some limitations. For this reason, assessment of liver damage using non-invasive methods is currently an important topic in hepatology. The aim of the study was to evaluate liver fibrosis/cirrhosis using Transient Elastography and FibroTest/FibroMax in patients with chronic HCV and HBV infection in Georgia and to compare Fibroscan and FibroTest/FibroMax results. 252 patients were included in the study, among them 185 with chronic HCV infection and 67 with chronic HBV infection. These patients were investigated at the Georgian-French Joint Hepatology Clinic "Hepa", from December 2007 to November 2008. In patients with chronic HCV or HBV infection Fibroscan and Fibrotest/FibroMax results were correlated in 127 (68.6%) and 45 (67.2%) cases, respectively. Discordance in one degree of fibrosis stage was found in 36 (19.5%) patients with chronic HCV infection and in 14 (20.9%) patients with chronic HBV infection. Discordance in more then one degree of fibrosis stage was found in 22 (11.9%) and 8 (11.9%) cases. In patients with Fibroscan and Fibrotest/FibroMax concordant results liver biopsy might be avoided. Fibroscan and Fibrotest/Max appear to be very valuable methods for detecting early stages of fibrosis among patients with chronic HCV and HBV infection, allowing to avoid the progression of liver damage, as well as end-stage liver disease. These methods are easy to perform and therefore allows regular follow-up of the course of LF.


Characterization of a specific interaction between Escherichia coli thymidylate synthase and Escherichia coli thymidylate synthase mRNA.
Previous studies have shown that human TS mRNA translation is controlled by a negative autoregulatory mechanism. In this study, an RNA electrophoretic gel mobility shift assay confirmed a direct interaction between Escherichia coli (E.coli) TS protein and its own E.coli TS mRNA. Two cis-acting sequences in the E.coli TS mRNA protein-coding region were identified, with one site corresponding to nucleotides 207-460 and the second site corresponding to nucleotides 461-807. Each of these mRNA sequences bind TS with a relative affinity similar to that of the full-length E.coli TS mRNA sequence (IC50 = 1 nM). A third binding site was identified, corresponding to nucleotides 808-1015, although its relative affinity for TS (IC50 = 5.1 nM) was lower than that of the other two cis-acting elements. E.coli TS proteins with mutations in amino acids located within the nucleotide-binding region retained the ability to bind RNA while proteins with mutations at either the nucleotide active site cysteine (C146S) or at amino acids located within the folate-binding region were unable to bind TS mRNA. These studies suggest that the regions on E.coli TS defined by the folate-binding site and/or critical cysteine sulfhydryl groups may represent important RNA binding domains. Further evidence is presented which demonstrates that the direct interaction with TS results in in vitro repression of E.coli TS mRNA translation.


Curcumin attenuates oxidative stress induced NFκB mediated inflammation and endoplasmic reticulum dependent apoptosis of splenocytes in diabetes.
The present study was aimed to determine the curative role of curcumin against diabetes induced oxidative stress and its associated splenic complications. Diabetes was induced in the experimental rats via the intraperitoneal administration of a single dose of STZ (65mgkg-1body weight). Increased blood glucose and intracellular ROS levels along with decreased body weight, the activity of cellular antioxidant enzymes and GSH/GSSG ratio were observed in the diabetic animals. Histological assessment showed white pulp depletion and damaged spleen anatomy in these animals. Oral administration of curcumin at a dose of 100mgkg-1 body weight daily for 8weeks, however, restored these alterations. Investigation of the mechanism of hyperglycemia induced oxidative stress mediated inflammation showed upregulation of inflammatory cytokines, chemokines, adhesion molecules and increased translocation of NFκB into the nucleus. Moreover, ER stress dependent cell death showed induction of eIF2α and CHOP mediated signalling pathways as well as increment in the expression of GRP78, Caspase-12, Calpain-1, phospho JNK, phospho p38 and phospho p53 in the diabetic group. Alteration of Bax/Bcl-2 ratio; disruption of mitochondrial membrane potential, release of cytochrome-C from mitochondria and upregulation of caspase 3 along with the formation of characteristic DNA ladder in the diabetic animals suggest the involvement of mitochondria dependent apoptotic pathway in the splenic cells. Treatment with curcumin could, however, protect cells from inflammatory damage and ER as well as mitochondrial apoptotic death by restoring the alterations of these parameters. Our results suggest that curcumin has the potential to act as an anti-diabetic, anti-oxidant, anti-inflammatory and anti-apoptotic therapeutic against diabetes mediated splenic damage.


Screening of the chemical composition and bioactivity of Waldheimia glabra (Decne.) Regel essential oil.
This research aimed at improving knowledge as to the chemical composition and the antibacterial and anti-cancer activities of the essential oil of Waldheimia glabra, a wild plant from the Himalayan Mountains. The results obtained by GC-MS showed that spathulenol, 9-tetradecenol, thujopsene, α-thujone, santolina alcohol and terpinen-4-ol were the main constituents of Waldheimia glabra essential oil. These results were confirmed by HS-SPME GC-MS analysis that also reported high amounts of artemisia alcohol and camphor. Disc diffusion assay suggested a mild antibacterial activity against both Escherichia coli and Staphylococcus aureus. Finally, a dose-response correlation was observed between Waldhemia glabra essential oil concentration and viability of human breast adenocarcinoma cells MDA-MB-231 and MCF-7. Together with the GC-MS method, HS-SPME GC-MS proved to be a reliable technique to characterise the chemical composition of essential oil obtained from aromatic plants. Further studies will focus on W. glabra phytochemicals and their biological activity, in order to support traditional uses of the plant. © 2015 Society of Chemical Industry.


Using real-time ultrasound imaging as adjunct teaching tools to enhance physical therapist students' ability and confidence to perform traction of the knee joint.
Often, physical therapy students struggle with the skill and the confidence to perform manual techniques for musculoskeletal examination. Current teaching methods lack concurrent objective feedback. Real-time ultrasound imaging (RTUI) has the advantage of generating visualization of anatomical structures in real-time in an efficient and safe manner. We hypothesize that the use of RTUI to augment teaching with concurrent objective visual feedback will result in students' improved ability to create a change in joint space when performing a manual knee traction and higher confidence scores. Eighty-six students were randomly allocated to a control or an experimental group. All participants received baseline instructions on how to perform knee traction. The control group received standardized lab instruction (visual, video, and instructor/partner feedback). The experimental group received standardized lab instruction augmented with RTUI feedback. Pre-data and post-data collection consisted of measuring participants' ability to create changes in joint space when performing knee traction, a confidence survey evaluating perceived ability and a reflection paper. Joint space changes between groups were compared using a paired t-test. Surveys were analyzed with descriptive statistics and compared using Wilcoxon Rank Sum and for the reflection papers, themes were identified and descriptive statistics reported. Although there were no statistically significant differences between the control and the experimental group, overall scores improved. Qualitative data suggests students found the use of ultrasound imaging beneficial and would like more exposure. This novel approach to teaching knee traction with RTUI has potential and may be a basis for further studies.


Genomewide location analysis of Candida albicans Upc2p, a regulator of sterol metabolism and azole drug resistance.
Upc2p, a transcription factor of the zinc cluster family, is an important regulator of sterol biosynthesis and azole drug resistance in Candida albicans. To better understand Upc2p function in C. albicans, we used genomewide location profiling to identify the transcriptional targets of Upc2p in vivo. A triple hemagglutinin epitope, introduced at the C terminus of Upc2p, conferred a gain-of-function effect on the fusion protein. Location profiling identified 202 bound promoters (P < 0.05). Overrepresented functional groups of genes whose promoters were bound by Upc2p included 12 genes involved in ergosterol biosynthesis (NCP1, ERG11, ERG2, and others), 18 genes encoding ribosomal subunits (RPS30, RPL32, RPL12, and others), 3 genes encoding drug transporters (CDR1, MDR1, and YOR1), 4 genes encoding transcription factors (INO2, ACE2, SUT1, and UPC2), and 6 genes involved in sulfur amino acid metabolism (MET6, SAM2, SAH1, and others). Bioinformatic analyses suggested that Upc2p binds to the DNA motif 5'-VNCGBDTR that includes the previously characterized Upc2p binding site 5'-TCGTATA. Northern blot analysis showed that increased binding correlates with increased expression for the analyzed Upc2p targets (ERG11, MDR1, CDR1, YOR1, SUT1, SMF12, and CBP1). The analysis of ERG11, MDR1, and CDR1 transcripts in wild-type and upc2Delta/upc2Delta strains grown under Upc2p-activating conditions (lovastatin treatment and hypoxia) showed that Upc2p regulates its targets in a complex manner, acting as an activator or as a repressor depending upon the target and the activating condition. Taken together, our results indicate that Upc2p is a key regulator of ergosterol metabolism. They also suggest that Upc2p may contribute to azole resistance by regulating the expression of drug efflux pump-encoding genes in addition to ergosterol biosynthesis genes.


Personalized Prediction of Psychosis: External Validation of the NAPLS-2 Psychosis Risk Calculator With the EDIPPP Project.
As part of the second phase of the North American Prodrome Longitudinal Study (NAPLS-2), Cannon and colleagues report, concurrently with the present article, on a risk calculator for the individualized prediction of a psychotic disorder in a 2-year period. The present study represents an external validation of the NAPLS-2 psychosis risk calculator using an independent sample of patients at clinical high risk for psychosis collected as part of the Early Detection, Intervention, and Prevention of Psychosis Program (EDIPPP). Of the total EDIPPP sample of 210 subjects rated as being at clinical high risk based on the Structured Interview for Prodromal Syndromes, 176 had at least one follow-up assessment and were included in the construction of a new prediction model with six predictor variables in the NAPLS-2 psychosis risk calculator (unusual thoughts and suspiciousness, symbol coding test performance, verbal learning test performance, decline in social functioning, baseline age, and family history). Discrimination performance was assessed with the area under the receiver operating characteristic curve (AUC). The NAPLS-2 risk calculator was then used to generate a psychosis risk estimate for each case in the external validation sample. The external validation model showed good discrimination, with an AUC of 0.790 (95% CI=0.644-0.937). In addition, the personalized risk generated by the risk calculator provided a solid estimation of the actual conversion outcome in the validation sample. Two independent samples of clinical high-risk patients converge to validate the NAPLS-2 psychosis risk calculator. This prediction calculator represents a meaningful step toward early intervention and the personalized treatment of psychotic disorders.


NDE of two-layered mortar samples using high-frequency Rayleigh waves.
The Spectral Analysis of Surface Waves (SASW) is a popular technique in seismics for imaging the ground subsurface. It uses the dispersive properties of Rayleigh waves in a transversely homogeneous, multilayered medium. The SASW approach is being transposed into the civil engineering domain to characterize subsurface damage in concrete structures. Such a damage consists in a few millimeters thick surface layer with porosity slightly higher than in the sound material. It is induced by contact with moisture or chemicals at the surface of the structure and may facilitate penetration of aggressive agents. In this study, two-layered mortar samples are made to mimic concrete cover damage in real structures. The dispersive behavior of Rayleigh waves arises when the wavelength is comparable to the thickness of the first layer. Given the small thickness of this layer, it requires increasing the frequency up to several hundreds of kHz, which means high attenuation and low signal-to-noise ratio. Rayleigh waves with 0.5 MHz central frequency are generated into the samples by the wedge method. Phase velocity dispersion curves are obtained by broadband phase spectroscopy from signals received at various distances from the source. The signal processing is first validated on simulated signals with known dispersion law. Then, the measured dispersion curves are compared with the theoretical curve for a two-layered medium, following Haskell's approach. The measured curve displays the general behavior expected from theory. However, a three-layered, visco-elastic model would be necessary to get a better fit and to estimate more accurately the parameters of each layer.


Sequence capture of ultraconserved elements from bird museum specimens.
New DNA sequencing technologies are allowing researchers to explore the genomes of the millions of natural history specimens collected prior to the molecular era. Yet, we know little about how well specific next-generation sequencing (NGS) techniques work with the degraded DNA typically extracted from museum specimens. Here, we use one type of NGS approach, sequence capture of ultraconserved elements (UCEs), to collect data from bird museum specimens as old as 120 years. We targeted 5060 UCE loci in 27 western scrub-jays (Aphelocoma californica) representing three evolutionary lineages that could be species, and we collected an average of 3749 UCE loci containing 4460 single nucleotide polymorphisms (SNPs). Despite older specimens producing fewer and shorter loci in general, we collected thousands of markers from even the oldest specimens. More sequencing reads per individual helped to boost the number of UCE loci we recovered from older specimens, but more sequencing was not as successful at increasing the length of loci. We detected contamination in some samples and determined that contamination was more prevalent in older samples that were subject to less sequencing. For the phylogeny generated from concatenated UCE loci, contamination led to incorrect placement of some individuals. In contrast, a species tree constructed from SNPs called within UCE loci correctly placed individuals into three monophyletic groups, perhaps because of the stricter analytical procedures used for SNP calling. This study and other recent studies on the genomics of museum specimens have profound implications for natural history collections, where millions of older specimens should now be considered genomic resources.


Ice cover extent drives phytoplankton and bacterial community structure in a large north-temperate lake: implications for a warming climate.
Mid-winter limnological surveys of Lake Erie captured extremes in ice extent ranging from expansive ice cover in 2010 and 2011 to nearly ice-free waters in 2012. Consistent with a warming climate, ice cover on the Great Lakes is in decline, thus the ice-free condition encountered may foreshadow the lakes future winter state. Here, we show that pronounced changes in annual ice cover are accompanied by equally important shifts in phytoplankton and bacterial community structure. Expansive ice cover supported phytoplankton blooms of filamentous diatoms. By comparison, ice free conditions promoted the growth of smaller sized cells that attained lower total biomass. We propose that isothermal mixing and elevated turbidity in the absence of ice cover resulted in light limitation of the phytoplankton during winter. Additional insights into microbial community dynamics were gleaned from short 16S rRNA tag (Itag) Illumina sequencing. UniFrac analysis of Itag sequences showed clear separation of microbial communities related to presence or absence of ice cover. Whereas the ecological implications of the changing bacterial community are unclear at this time, it is likely that the observed shift from a phytoplankton community dominated by filamentous diatoms to smaller cells will have far reaching ecosystem effects including food web disruptions.


Near-Patient Thrombin Generation in Patients Undergoing Elective Cardiac Surgery.
Measuring thrombin generation (TG) in plasma increasingly gained attention as a diagnostic tool in the field of thrombosis and hemostasis. To include the contribution of all blood cells, recently, the whole blood TG method was developed. We changed the calculation method of the standard calibrated automated thrombography (CAT) to a method only taking into account the data until the peak of TG, thereby considerably reducing the time from blood draw to result. By redesigning the method, the blood volume per test was reduced to 15 μL. For all TG parameters, the interassay variation proved to be below 15%. The interindividual variation of all parameters was comparable to the CAT method. Thirty-three patients undergoing cardiothoracic surgery were included to investigate whether our assay correlates with postoperative blood loss. On dividing patients into severe and mild bleeders, significant differences between both groups were found for the peak endogenous thrombin potential (peakETP) and peak values determined by our near-patient device. Importantly, patients with a peakETP below the median experienced significantly more blood loss compared to those with a peakETP above the median. A similar division based on the peak as well as the body mass index of the patient yielded similar significant differences. A combination of the peakETP, the body mass index, and the lag time even resulted in a better predictor of blood loss compared to each parameter separately. Our adapted whole blood TG assay can be used near patients and is indicative for the amount of blood loss post cardiothoracic surgery.


The coevolution of ova defensiveness with sperm competitiveness in house mice.
Theoretical models have suggested that sperm competition can lead to increased ova resistance to fertilization. While there is some comparative evidence that this might be true, there is no experimental evidence to show that ova defensiveness evolves in response to sperm competition. We performed a series of in vitro fertilization assays to gauge the fertilizability of ova produced by female house mice from experimental populations that evolved either with or without sperm competition. Our analysis revealed that after 24 generations of experimental evolution, females that evolved under a polygamous regime produced more defensive ova than females that evolved under a monogamous regime. We therefore provide the first direct line of evidence that sperm competition can generate sexual conflict at the gametic level and lead to asymmetries in fertilization rates among populations. Our results show that females respond to sperm competition via fertilization barriers that have the potential to mediate sperm entry.


Stabilization of a 4.5 V Cr4+/Cr3+ redox reaction in NASICON-type Na3Cr2(PO4)3 by Ti substitution.
The development of high-voltage cathode materials composed of abundant metals for rechargeable batteries is a crucial task to realize higher energy density in large-scale electrical energy storage systems. Here we report a reversible Cr4+/Cr3+ redox reaction at 4.5 V vs. Na/Na+ in NASICON-type Na2CrTi(PO4)3 (NCTP). An unstable Cr4+/Cr3+ redox in Na3Cr2(PO4)3 is successfully stabilized by the substitution of Ti with Cr. The charge/discharge mechanism of NCTP was studied by powder X-ray diffraction and soft X-ray absorption spectroscopy.


Oxytocin receptor blockade reduces acquisition but not retrieval of taste aversion and blunts responsiveness of amygdala neurons to an aversive stimulus.
When gastrointestinal sickness induced by toxin injection is associated with exposure to novel food, the animal acquires a conditioned taste aversion (CTA). Malaise is accompanied by a surge in oxytocin release and in oxytocin neuronal activity; however, it is unclear whether oxytocin is a key facilitator of aversion or merely its marker. Herein we investigated whether blockade of the oxytocin receptor with the blood-brain barrier penetrant oxytocin receptor antagonist L-368,899 is detrimental for the acquisition and/or retrieval of lithium chloride (LiCl)-dependent CTA to a saccharin solution in mice. We also examined whether L-368,899 given prior to LiCl affects neuronal activity defined through c-Fos immunohistochemistry in select brain sites facilitating CTA acquisition. L-368,899 given prior to LiCl caused a 30% increase in saccharin solution intake in a two-bottle test, but when the antagonist was administered before the two-bottle test, it failed to diminish the retrieval of an existing CTA. LiCl administration increased c-Fos expression in the hypothalamic paraventricular and supraoptic nuclei, area postrema, nucleus of the solitary tract and basolateral and central (CNA) nuclei of the amygdala. L-368,899 injected before LiCl reduced the number of c-Fos positive CNA neurons and brought it down to levels similar to those observed in mice treated only with L-368,899. We conclude that oxytocin is one of the key components in acquisition of LiCl-induced CTA and the aversive response can be alleviated by the oxytocin receptor blockade. Oxytocin receptor antagonism blunts responsiveness of CNA to peripherally injected LiCl.


Modifying the body: motivations for getting tattooed and pierced.
Body modifications have been prevalent for centuries and are practiced for a great variety of reasons. Lately, tattoos and body piercings have become increasingly popular. Thus, a profound understanding of the underlying motivations behind obtaining tattoos and body piercings nowadays is required. A considerable body of research on motivational aspects already exists, mainly using explorative approaches to describe motivations. In this paper we provide a review of the existing relevant literature. Furthermore, we establish ten broad motivational categories, comprising motivations for getting tattooed and body pierced, for reference in future research.


Inhibition of mammalian target of rapamycin signaling pathway decreases retinoic acid stimulated gene 8 expression in adult mouse testis.
To evaluate the expression of mammalian target of rapamycin (mTOR) pathway molecules in mouse spermatogenesis and as well as its role during proliferation and meiotic initiation of spermatogenic cells. Experimental animal study. University. C57Balb-C adult male mice. Expressions of mTOR signaling pathway proteins in adult testis were evaluated. Then the effect of inhibition of this pathway on proliferation and differentiation of spermatogonial stem cells was investigated using seminiferous tubule culture. Immunohistochemistry was performed to evaluate the expressions of mTOR signaling pathway proteins. To inhibit mTOR signaling pathway by rapamycin, seminiferous tubule culture was done. Viability assay and terminal deoxynucleotidyl transferase dUTP nick end labeling was performed to evaluate the culture conditions and to examine cell death, respectively. Western blot was used to determine the expressions of the PCNA, STRA8, and VASA proteins. Our results showed that spermatogonial stem cells and preleptotene spermatocytes express total mTOR, p-mTOR, total p70S6K, p-p70S6K, and p-4EBP1. Expressions of p-p70S6K, p-4EBP1, PCNA, and STRA8 decreased significantly in the rapamycin-treated group, where no difference was observed in VASA expression. Cell viability and the number of apoptotic cells were similar for all groups. Our findings suggest that the mTOR signaling pathway may have role in the proliferation and stimulation of meiotic initiation of spermatogonial stem cells. To the best of our knowledge, this is the first ex vivo study that reports the function of the mTOR pathway in adult mouse spermatogenesis.


Bone mineral density at the hip predicts mortality in elderly men.
Low bone density as assessed by calcaneal ultrasound has been associated with mortality in elderly men and women. We examined the relationship between bone density measured at the hip and all cause and cardiovascular mortality in elderly men. Men aged 65-76 years from the general community were recruited from general practices in Cambridge between 1991 and 1995. At baseline survey, data collection included health questionnaires, measures of anthropometry and cardiovascular risk factors, as well as bone mineral density (BMD) measured using dual energy X-ray absorptiometry. All men have been followed up for vital status up to December 1999. BMD was significantly inversely related to mortality from all causes and cardiovascular disease, with decreasing rates with increasing bone density quartile, and an approximate halving of risk between the bottom and top quartile (p < 0.002, test for trend all causes and p < 0.025, test for trend for cardiovascular deaths). In multivariate analyses using the Cox proportional hazards model, an increase of 1 standard deviation (0.144 g/cm2) in total hip bone density was significantly associated with an age-adjusted 0.77 relative risk (95% CI 0.66-0.91) for all-cause mortality and 0.76 relative risk (95% CI 0.62-0.93) for cardiovascular disease mortality. The association remained significant after adjusting for age, body mass index, cigarette smoking status, serum cholesterol, systolic blood pressure, past history of heart attack, stroke or cancer and other lifestyle factors which included use of alcohol, physical activity and general health status. Low bone density at the hip is thus a strong and independent predictor of all-cause and cardiovascular mortality in older men.


Rheumatic Heart Disease Prophylaxis in Older Patients: A Register-Based Audit of Adherence to Guidelines.
Prevention of rheumatic heart disease (RHD) remains challenging in high-burden settings globally. After acute rheumatic fever (ARF), secondary antibiotic prophylaxis is required to prevent RHD. International guidelines on recommended durations of secondary prophylaxis differ, with scope for clinician discretion. Because ARF risk decreases with age, ongoing prophylaxis is generally considered unnecessary beyond approximately the third decade. Concordance with guidelines on timely cessation of prophylaxis is unknown. We undertook a register-based audit to determine the appropriateness of antibiotic prophylaxis among clients aged ≥35 years in Australia's Northern Territory. Data on demographics, ARF episode(s), RHD severity, prophylaxis type, and relevant clinical notes were extracted. The determination of guideline concordance was based on whether (1) national guidelines were followed; (2) a reason for departure from guidelines was documented; (3) lifelong continuation was considered appropriate in all cases of severe RHD. We identified 343 clients aged ≥35 years prescribed secondary prophylaxis. Guideline concordance was 39% according to national guidelines, 68% when documented reasons for departures from guidelines were included and 82% if patients with severe RHD were deemed to need lifelong prophylaxis. Shorter times since last echocardiogram or cardiologist review were associated with greater likelihood of guideline concordance (P < .001). The median time since last ARF was 5.9 years in the guideline-concordant group and 24.0 years in the nonconcordant group (P < .001). Thirty-two people had an ARF episode after age 40 years. In this setting, appropriate discontinuation of RHD prophylaxis could be improved through timely specialist review to reduce unnecessary burden on clients and health systems.


Antibacterial properties of antimicrobial-finished textile products.
The antibacterial properties of five kinds of antimicrobial-finished textile products (AFTPs) were examined against Staphylococcus aureus, including methicillin-resistant (MRSA) strains and Pseudomonas aeruginosa, under wet and dry conditions. Textile products containing Ag. Zn. ammonium Zeolite and chitosan were found to be effective against methicillin-sensitive S. aureus (MSSA) for up to 6 hr of incubation under wet and dry conditions, and effective against MRSA for up to 24 hr of incubation only under wet conditions. Under dry conditions, however, all AFTPs were ineffective against one MRSA strain. When organic matter was added to the incubation mixture, textile products containing Ag. Zn. ammonium Zeolite and chitosan still showed antibacterial activities, but not as strongly. The results of this study suggested the following: (1) There are differences in antibacterial properties among commercially available AFTPs; (2) Determining effectiveness requires several hours of incubation; (3) Water content as an environmental factor can affect effectiveness; and (4) Some bacterial species and strains are not affected by AFTPs. The antibacterial properties of AFTPs in the clinical setting may be of limited value.


Hyperoxia increases the uptake of 5-fluorouracil in mammary tumors independently of changes in interstitial fluid pressure and tumor stroma.
Hypoxia is associated with increased resistance to chemo- and radiation-therapy. Hyperoxic treatment (hyperbaric oxygen) has previously been shown to potentiate the effect of some forms of chemotherapy, and this has been ascribed to enhanced cytotoxicity or neovascularisation. The aim of this study was to elucidate whether hyperoxia also enhances any actual uptake of 5FU (5-fluorouracil) into the tumor tissue and if this can be explained by changes in the interstitium and extracellular matrix. One group of tumor bearing rats was exposed to repeated hyperbaric oxygen (HBO) treatment (2 bar, pO(2)= 2 bar, 4 exposures à 90 min), whereas one group was exposed to one single identical HBO treatment. Animals housed under normal atmosphere (1 bar, pO(2) = 0.2 bar) served as controls. Three doses of 5FU were tested for dose response. Uptake of [3H]-5FU in the tumor was assessed, with special reference to factors that might have contributed, such as interstitial fluid pressure (Pif), collagen content, oxygen stress (measured as malondialdehyd levels), lymphatics and transcapillary transport in the tumors. The uptake of the cytostatic agent increases immediately after a single HBO treatment (more than 50%), but not 24 hours after the last repeated HBO treatment. Thus, the uptake is most likely related to the transient increase in oxygenation in the tumor tissue. Factors like tumor Pif and collagen content, which decreased significantly in the tumor interstitium after repeated HBO treatment, was without effect on the drug uptake. We showed that hyperoxia increases the uptake of [3H]-5FU in DMBA-induced mammary tumors per se, independently of changes in Pif, oxygen stress, collagen fibril density, or transendothelial transport alone. The mechanism by which such an uptake occur is still not elucidated, but it is clearly stimulated by elevated pO(2).


Skeletal age in idiopathic short stature: An analytical study by the TW3 method, Greulich and Pyle method.
The skeletal age in short stature and in various other growth abnormalities is well documented. We lack the study pertaining to the analysis of the skeletal age in idiopathic short stature or analyzing the difference in skeletal age delay or advancement between the familial short stature (FSS) and non-familial short stature (non-FSS) groups, hence this study. Present retrospective study is designed to study the variation in patterns of skeletal age in ISS. One hundred and eighty six patients, 95 males and 91 females of idiopathic short stature were examined to assess the skeletal age deviation in relation to chronological age. The radiographs of the left hand and wrist were done. The skeletal age was assessed using Tanner and Whitehouse (TW3) method and Greulich and Pyle (GP) atlas. The patients were divided into two groups based on the parental heights. Group A (Familial Short Stature; FSS) with 100 patients (55 males, 45 females) included patients whose at least one parent was short and Group B (non-Familial Short Stature; non-FSS) with 86 patients (40 males, 46 females), included patients whose parental height was normal. The carpal scores, RUS (Radius, Ulna and Short bone) scores and GP age were determined and the respective delay or advances were calculated. The skeletal age in Group A was delayed relative to chronological age by a mean of 1.9 years in males and 2.3 years in females (P<0.05) by RUS method, mean of 2.7 years in males and 2.6 years in females by Carpal score (P<0.05), 2.2 years in males and 2.7 years in females by GP atlas age (P<0.05). The skeletal age in Group B was advanced by a mean of 0.9 years in males and 1.4 years in females (P<0.05) by RUS method, mean of 0.4 years in males and 0.35 years in females by Carpal score (P<0.05), mean of 1.1 years in males and 0.2 years in females by GP atlas method (P<0.05). The Pearson's coefficient of correlation (P<.001) demonstrated good agreement association between all three scores. There is definite age delay in both males and females in the FSS group while the bone maturation is accelerated in the non-FSS group. Both RUS and GP show good correlation amongst both the genders in both the groups and there is good inter observer correlation for both the methods. We can hypothesize that while treatment protocols to accelerate bone age will be beneficial in the FSS group, these should be avoided in the non-FSS group. Our study also indicates that there definitely exists a difference in normal growth curves in both these groups and a detailed study is required to plot their respective normal growth lines so as to make proper adjustments in the assessment of the remaining growth and limb lengthening protocols.


Stress-dependent morphogenesis: continuum mechanics and truss systems.
A set of equilibrium equations is derived for the stress-controlled shape change of cells due to the remodelling and growth of their internal architecture. The approach involves the decomposition of the deformation gradient into an active and a passive component; the former is allowed to include a growth process, while the latter is assumed to be hyperelastic and mass-preserving. The two components are coupled with a control function that provides the required feedback mechanism. The balance equations for general continua are derived and, using a variational approach, we deduce the equilibrium equations and study the effects of the control function on these equations. The results are applied to a truss system whose function is to simulate the cytoskeletal network constituted by myosin microfilaments and microtubules, which are found experimentally to control shape change in cells. Special attention is paid to the conditions that a thermodynamically consistent formulation should satisfy. The model is used to simulate the multicellular shape changes observed during ventral furrow invagination of the Drosophila melanogaster embryo. The results confirm that ventral furrow invagination can be achieved through stress control alone, without the need for other regulatory or signalling mechanisms. The model also reveals that the yolk plays a distinct role in the process, which is different to its role during invagination with externally imposed strains. In stress control, the incompressibility constraint of the yolk leads, via feedback, to the generation of a pressure in the ventral zone of the epithelium that eventually eases its rise and internalisation.


Self-organized permeability in carbonate aquifers.
Advances over the past 40 years have resulted in a clear understanding of how dissolution processes in carbonate rocks enhance aquifer permeability. Laboratory experiments on dissolution rates of calcite and dolomite have established that there is a precipitous drop in dissolution rates as chemical equilibrium is approached. These results have been incorporated into numerical models, simulating the effects of dissolution over time and showing that it occurs along the entire length of pathways through carbonate aquifers. The pathways become enlarged and integrated over time, forming self-organized networks of channels that typically have apertures in the millimeter to centimeter range. The networks discharge at point-located springs. Recharge type is an important factor in determining channel size and distribution, resulting in a range of aquifer types, and this is well demonstrated by examples from England. Most carbonate aquifers have a large number of small channels, but in some cases large channels (i.e., enterable caves) can also develop. Rapid velocities found in ground water tracer tests, the high incidence of large-magnitude springs, and frequent microbial contamination of wells all support the model of self-organized channel development. A large majority of carbonate aquifers have such channel networks, where ground water velocities often exceed 100 m/d.


Solvent-induced dimensional changes in EDTA-demineralized dentin matrix.
The purpose of this study was to test the null hypothesis that the re-expansion of dried matrix and the shrinkage of moist, demineralized dentin is not influenced by polar solvents. Dentin disks were prepared from midcoronal dentin of extracted human third molars. After complete demineralization in 0.5M of EDTA (pH 7), the specimens were placed in the well of a device that measures changes in matrix height in real time. Dry, collapsed matrices were created by blowing dry N(2) on the specimens until they shrank to a stable plateau. Polar solvents [water, methanol, ethanol, n-propanol, n-butanol, formamide, ethylene glycol, hydroxyethyl methacrylate (HEMA), or mixtures of water-HEMA] as model primers then were added and the degree of re-expansion measured. These same solvents also were applied to moist, expanded matrices and the solvent-induced shrinkages measured. Regression analysis was used to test the correlations between matrix height and Hansen's dispersive, polar, hydrogen bonding, and total solubility parameters (delta(d), delta(p), delta(h), delta(t)). The results indicate that water-free polar solvents of low hydrogen bonding (H-bond) ability (e.g., neat HEMA) do not re-expand dried matrices and that they shrink moist matrices. When HEMA was mixed with progressively higher water concentrations, the model water-HEMA primers expanded the dried matrix in proportion to their water concentrations and they produced less shrinkage of moist matrices. Solvents with higher H-bonding capacities (methanol, ethanol, ethylene glycol, formamide, and water) re-expanded the dried matrix in proportion to their solubility parameters for H-bonding (delta(h)). They also induced small transient shrinkages of moist matrices, which slowly re-expanded. The results require rejection of the null hypothesis.