Fabry-Perot filter using grating structures.
Grating structures are designed at the inner wall of the Fabry-Perot (FP) resonator to enhance the performance of an FP optical filter. The rectangular grating or triangular grating (TG) structures allows the light to be propagated effectively through the FP resonator. Attributed to the grating structures, the spectrum intensity of a FP resonator with grating structures is calculated to be 4.5-fold higher than that of a FP resonator with slot. In addition, the Q-factor of the resonant peak for a FP resonator with hybrid TG structure and two slots is 9.5-fold and 4.7-fold higher than that of a FP resonator with one slot and TG configurations, respectively.


Age relative to school class peers and emotional well-being in 10-year-olds.
The aim of this study was to investigate the effect of age relative to school (i.e., class or grade level) peers on emotional well-being and the role of possible mediators of this effect in early adolescence using a large set of individual-level data from a community survey. A large community-based survey of 10-year-old children and their primary parents was conducted in Tokyo, where the school entry cutoff date is fixed. Emotional well-being was assessed by the WHO (Five) Well-Being Index (WHO-5). Academic performance and the experience of being bullied at school were also evaluated as potential mediators of the effect of relative age. A total of 4,478 children participated in the study. In a univariate linear regression analysis, the relative birthdate (continuous variable starting from the school entry date and ending at the last date of the academic grade) was negatively associated with emotional well-being (β = -0.043, p = .005). The path analyses suggested that academic performance and bullying mediated the relationship between the relative birthdate and emotional well-being (both p < .01). Among a sample of 10-year-olds, children who were younger compared to class peers had lower levels of emotional well-being. Academic performance and victimization by peers mediated the relationship.


Cdk5 is essential for synaptic vesicle endocytosis.
Synaptic vesicle endocytosis (SVE) is triggered by calcineurin-mediated dephosphorylation of the dephosphin proteins. SVE is maintained by the subsequent rephosphorylation of the dephosphins by unidentified protein kinases. Here, we show that cyclin-dependent kinase 5 (Cdk5) phosphorylates dynamin I on Ser 774 and Ser 778 in vitro, which are identical to its endogenous phosphorylation sites in vivo. Cdk5 antagonists and expression of dominant-negative Cdk5 block phosphorylation of dynamin I, but not of amphiphysin or AP180, in nerve terminals and inhibit SVE. Thus Cdk5 has an essential role in SVE and is the first dephosphin kinase identified in nerve terminals.


Stretchability of the rectus femoris muscle: investigation of validity and intratester reliability of two methods including X-ray analysis of pelvic tilt.
Validity and intratester reliability of two test methods designed to identify stretchability of the rectus femoris muscle (RFM) was investigated, combined with x-ray analysis of pelvic tilt in the sagittal plane. The first method is commonly used in clinical practice. The second is a new technique supposed to tilt the pelvis posteriorly and thus further separate the origin and insertion of the muscle. Investigation of validity and intratester reliability of the two methods was made by testing and retesting a random sample of 71 persons. The tests were performed with an equipment that automatically recorded the angle of knee flexion from a previously determined applied torque, indicating the end point of motion for that particular subject. Angle of knee flexion and subjective estimation of pain sensation due to stretch were recorded at each measurement. The pelvic tilt-analysis consisted of test-retest reliability of x-ray measurements, comparison between the methods in both starting and final position, and x-ray and electronic goniometer measurements. All applied torques were measured with a strain gauge. Two out of three criteria of validity favored the new method and the third pointed out the two methods as equal. The two methods as well as the x-ray measurements showed high reliability, and the hypothesis of a more posterior tilted pelvis in the new method was confirmed. The electronic goniometer was less sensitive than x-ray, but proposed to analyse pelvic tilt clinically. Methodology procedures for joint angle measurements are discussed.


Germline mutations in shelterin complex genes are associated with familial glioma.
Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma.


Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia.
Tolerance to antifungal drug concentrations above the minimal inhibitory concentration (MIC) is rarely quantified, and current clinical recommendations suggest it should be ignored. Here, we quantify antifungal tolerance in Candida albicans isolates as the fraction of growth above the MIC, and find that it is distinct from susceptibility/resistance. Instead, tolerance is due to the slow growth of subpopulations of cells that overcome drug stress more efficiently than the rest of the population, and correlates inversely with intracellular drug accumulation. Many adjuvant drugs used in combination with fluconazole, a widely used fungistatic drug, reduce tolerance without affecting resistance. Accordingly, in an invertebrate infection model, adjuvant combination therapy is more effective than fluconazole in treating infections with highly tolerant isolates and does not affect infections with low tolerance isolates. Furthermore, isolates recovered from immunocompetent patients with persistent candidemia display higher tolerance than isolates readily cleared by fluconazole. Thus, tolerance correlates with, and may help predict, patient responses to fluconazole therapy.


Brain networks of social action-outcome contingency: The role of the ventral striatum in integrating signals from the sensory cortex and medial prefrontal cortex.
Social interactions can be facilitated by action-outcome contingency, in which self-actions result in relevant responses from others. Research has indicated that the striatal reward system plays a role in generating action-outcome contingency signals. However, the neural mechanisms wherein signals regarding self-action and others' responses are integrated to generate the contingency signal remain poorly understood. We conducted a functional MRI study to test the hypothesis that brain activity representing the self modulates connectivity between the striatal reward system and sensory regions involved in the processing of others' responses. We employed a contingency task in which participants made the listener laugh by telling jokes. Participants reported more pleasure when greater laughter followed their own jokes than those of another. Self-relevant listener's responses produced stronger activation in the medial prefrontal cortex (mPFC). Laughter was associated with activity in the auditory cortex. The ventral striatum exhibited stronger activation when participants made listeners laugh than when another did. In physio-physiological interaction analyses, the ventral striatum showed interaction effects for signals extracted from the mPFC and auditory cortex. These results support the hypothesis that the mPFC, which is implicated in self-related processing, gates sensory input associated with others' responses during value processing in the ventral striatum.


To Fear Is to Gain? The Role of Fear Recognition in Risky Decision Making in TBI Patients and Healthy Controls.
Fear is an important emotional reaction that guides decision making in situations of ambiguity or uncertainty. Both recognition of facial expressions of fear and decision making ability can be impaired after traumatic brain injury (TBI), in particular when the frontal lobe is damaged. So far, it has not been investigated how recognition of fear influences risk behavior in healthy subjects and TBI patients. The ability to recognize fear is thought to be related to the ability to experience fear and to use it as a warning signal to guide decision making. We hypothesized that a better ability to recognize fear would be related to a better regulation of risk behavior, with healthy controls outperforming TBI patients. To investigate this, 59 healthy subjects and 49 TBI patients were assessed with a test for emotion recognition (Facial Expression of Emotion: Stimuli and Tests) and a gambling task (Iowa Gambling Task (IGT)). The results showed that, regardless of post traumatic amnesia duration or the presence of frontal lesions, patients were more impaired than healthy controls on both fear recognition and decision making. In both groups, a significant relationship was found between better fear recognition, the development of an advantageous strategy across the IGT and less risk behavior in the last blocks of the IGT. Educational level moderated this relationship in the final block of the IGT. This study has important clinical implications, indicating that impaired decision making and risk behavior after TBI can be preceded by deficits in the processing of fear.


Coagulant and fibrinolytic status in tuberculous meningitis.
The long-term neurologic sequelae of childhood tuberculous meningitis (TBM) mainly result from ischemia owing to cerebral vasculitis. Deep vein thrombosis occurs in adults with pulmonary tuberculosis owing to hypercoaguability. The present study aimed to investigate coagulation status during acute childhood TBM. Coagulation status, including the natural anticoagulants, antithrombin, protein C and protein S; procoagulant FVIII; fibrinolytic factors, tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1) as well as anticardiolipin antibodies (ACA), was determined in 16 children with TBM before and during treatment. A prothrombotic profile was found as expressed by a decrease of anticoagulant (protein S) and increase of the procoagulant (factor VIII) activity. Raised PAI-1 and normal tissue plasminogen activator values indicated deficient fibrinolysis. This hypercoagulable state was more pronounced in stage 3 patients than in stage 2 patients. The bleeding time on admission ranged from 1.2 to 10 minutes [mean 4.2 minutes]. The mean platelet count on admission was 577.9 +/- 188.6 x 10/L and increased further during the course of the treatment. The hypercoagulable state in childhood TBM is comparable to that described in adults with pulmonary tuberculosis and may further increase the risk for infarction. Therapeutic measures that reduce the risk for thrombosis could therefore be potentially beneficial in childhood TBM.


Understanding Primary Care Provider Attitudes and Behaviors Regarding Cardiovascular Disease Risk and Diabetes Prevention in the Northern Midwest.
IN BRIEF We sought to fill critical gaps in understanding primary care providers' (PCPs') beliefs regarding diabetes prevention and cardiovascular disease risk in the prediabetes population, including through comparison of attitudes between rural and non-rural PCPs. We used data from a 2016 cross-sectional survey sent to 299 PCPs practicing in 36 primary clinics that are part of a randomized control trial in a predominately rural northern Midwestern integrated health care system. Results showed a few significant, but clinically marginal, differences between rural and non-rural PCPs. Generally, PCPs agreed with the importance of screening for prediabetes and thoroughly and clearly discussing CV risk with high-risk patients.


Persistent primary hyperparathyroidism caused by adenomas identified in pharyngeal or adjacent structures.
Abnormalities in the normal migration of the parathyroid glands during embryological development of the head and neck may result in considerable variability in the location of parathyroid tissue. Ectopic parathyroid adenomas present diagnostic and technical challenges and are frequently the cause of persistent primary hyperparathyroidism (HPT) after unsuccessful initial parathyroid surgery. We report a series of eight patients with persistent primary HPT who had adenomas in rare and unusual locations associated with various pharyngeal structures. Four were located within the epineurium of the vagus nerve at or above the level of the carotid bifurcation, and four were located within the paranasopharyngeal space or oropharynx. Noninvasive and invasive preoperative imaging studies were crucial in localizing the neoplasms in these patients and permitted the use of a direct surgical approach, resulting in cure in all patients and a low complication rate. The location of parathyroid glands in high pharyngeal and cervical structures is a consequence of anomalous or arrested descent through developing pharyngeal structures and illustrates the remarkable spectrum of ectopic parathyroid adenomas that occur secondary to this phenomenon.


Stage-specific requirement of cysteine during in vitro maturation of porcine oocytes for glutathione synthesis associated with male pronuclear formation.
The present study was designed to clarify the duration of maturation of porcine oocytes when cysteine promotes male pronuclear (MPN) formation through oocyte glutathione (GSH) synthesis. When cumulus-oocyte complexes (COCs) were cultured in a serum-free maturation medium supplemented or not supplemented with 0.57 mM cysteine, about 90% of oocytes reached metaphase I (M-I) to metaphase II (M-II) and M-II at 36 and 48 h of culture, respectively. When cysteine was added to medium at 0, 12, 24, and 36 h of culture and COCs were cultured for a total of 48 h, oocyte GSH concentrations at the end of culture and the incidence of MPN formation after sperm penetration in vitro were both higher than the values in oocytes cultured for 48 h without cysteine. In contrast, the GSH concentration at 48 h and the incidence of MPN formation were not increased when cysteine was present only during the first 24 h of maturation culture. When cysteine was added to medium every 3 h from 36 h of culture on, a higher incidence of MPN formation was obtained in oocytes cultured in the presence of cysteine from 36 to 42 h than from 36 to 45 h of culture, although GSH concentrations were higher in oocytes cultured with cysteine from 36 to 42 h than from 39 to 42 h of culture. These results suggest that the presence of cysteine in maturation medium is critical only between 42 and 48 h of culture when porcine oocytes are in the late M-I to M-II stage of development. At that time cysteine is utilized for GSH synthesis, which is subsequently instrumental in the formation of MPN after sperm penetration in vitro.


Service delivery for people with hereditary spastic paraparesis living in the South West of England.
Hereditary Spastic Paraplegia (HSP) is an inherited nervous system disorder characterized by development of leg weakness, spasms and stiffness. While generally acknowledged that health and social care services can minimise symptoms and improve quality of life, there is a lack of research exploring this from the perspective of people affected by HSP. This qualitative study explored the users and providers experience of using rural services. Focus groups and interviews were undertaken of people with HSP (n = 14), carers (n = 6) and professionals (n = 12), to describe their experience of service provision and to suggest improvements for care. These were taped, transcribed and analysed. Four themes emerged: (1) Diagnosis, symptoms and finding support; (2) Therapy, treatment and the delivery of care; (3) Managing the disease together; and (4) The way forward. Rehabilitation and support for self-management is valued by those affected with HSP throughout the disease trajectory from diagnosis onwards. Key to this is the development of a partnership approach which includes carers. Single point, well-informed, gatekeepers may enhance the coordination and delivery of care in rural areas. These findings underline current guidance promoting a holistic approach for people with neurological conditions.


Odorant receptor expressed sequence tags demonstrate olfactory expression of over 400 genes, extensive alternate splicing and unequal expression levels.
The olfactory receptor gene family is one of the largest in the mammalian genome. Previous computational analyses have identified approximately 1,500 mouse olfactory receptors, but experimental evidence confirming olfactory function is available for very few olfactory receptors. We therefore screened a mouse olfactory epithelium cDNA library to obtain olfactory receptor expressed sequence tags, providing evidence of olfactory function for many additional olfactory receptors, as well as identifying gene structure and putative promoter regions. We identified more than 1,200 odorant receptor cDNAs representing more than 400 genes. Using real-time PCR to confirm expression level differences suggested by our screen, we find that transcript levels in the olfactory epithelium can differ between olfactory receptors by up to 300-fold. Differences for one gene pair are apparently due to both unequal numbers of expressing cells and unequal transcript levels per expressing cell. At least two-thirds of olfactory receptors exhibit multiple transcriptional variants, with alternative isoforms of both 5' and 3' untranslated regions. Some transcripts (5%) utilize splice sites within the coding region, contrary to the stereotyped olfactory receptor gene structure. Most atypical transcripts encode nonfunctional olfactory receptors, but can occasionally increase receptor diversity. Our cDNA collection confirms olfactory function of over one-third of the intact mouse olfactory receptors. Most of these genes were previously annotated as olfactory receptors based solely on sequence similarity. Our finding that different olfactory receptors have different expression levels is intriguing given the one-neuron, one-gene expression regime of olfactory receptors. We provide 5' untranslated region sequences and candidate promoter regions for more than 300 olfactory receptors, valuable resources for computational regulatory motif searches and for designing olfactory receptor microarrays and other experimental probes.


PDLIM2 repression by ROS in alveolar macrophages promotes lung tumorigenesis.
One of the most fundamental and challenging questions in the field of cancer is how immunity is transformed from tumor immunosurveillance to tumor-promoting inflammation. Here, we identified the tumor suppressor PDZ-LIM domain-containing protein 2 (PDLIM2) as a checkpoint of alveolar macrophages (AMs) important for lung tumor suppression. During lung tumorigenesis, PDLIM2 expression in AMs is downregulated by ROS-activated transcription repressor BTB and CNC homology 1 (BACH1). PDLIM2 downregulation leads to constitutive activation of the transcription factor STAT3, driving AM protumorigenic polarization/activation and differentiation from monocytes attracted from the circulation to suppress cytotoxic T lymphocytes and promote lung cancer. PDLIM2 downregulation also decreases AM phagocytosis. These findings establish ROS/BACH1/PDLIM2/STAT3 as a signaling pathway driving AMs for lung tumor promotion.


Mammography diffusion and trends in late-stage breast cancer: evaluating outcomes in a population.
The purpose of this study was to assess mammography diffusion in a population offered an organized breast cancer screening program, using intervals of 1-3 years, and to evaluate its effect on the late-stage cancer (tumors > or = 3 cm2) rates compared to rates in the surrounding community. We measured "ever-use" of mammography (1986-1992) among women enrollees of a consumer-controlled health care organization (n > or = 60,000/year; ages > or = 40), Group Health Cooperative of Puget Sound (GHC). Among these same women and the surrounding community (n = > or = 745,000/year), we measured late-stage cancer rates. Using unconditional logistic regression, we compared annual rates of ever-use among GHC women ages 40-49 and > or = 50 (1986-1992) and late-stage breast cancer (1983/84-1991/92) among all women. Among all GHC women ages 40 to 49, and 50 years of age and older, 67.4 and 82.8%, respectively, ever-used mammography by 1992. By 1992, approximately one-third of the mammograms among GHC women occurred in each of the three previous years. The rate of late-stage tumors declined significantly in the GHC and non-GHC populations among women 50 years of age and older (P < 0.001) but not among women ages 40 to 49. In conclusion, implementing a system of automated reminders was not sufficient to maximize mammography use in a population. Reductions in late-stage disease occurred among women ages > or = 50, even when regular" was not synonymous with "annual."


Voices from the front lines. Four leaders on the cross-border challeng they've faced.
Executives on the front lines of managing across borders share their insights: Luc Minguet, of France's Michelin, talks about the importance of cultural training not just for managers taking on assignments abroad but also for local employees who work with colleagues from around the world. He describes how his own experience learning to communicate across cultures reflects the tire-maker's broader practices. Eduardo Caride, of Madrid-based Telefónica, explains how the relatively young multinational is investing in a diverse talent mix as it strives to become a truly global company. Whereas early on, leaders relied on exporting Spanish managers abroad, he notes, the street now runs both ways. Takeo Yamaguchi, of Japan's Hitachi, details his efforts to create standardized global HR systems and processes across the conglomerate's 948 separate companies. "Three years ago, we had no systematic way of tracking employees, evaluating performance, or identifying future leaders," Yamaguchi says. "Today we do." And Shane Tedjarati, from the United States' Honeywell, talks about how the industrial powerhouse is shifting its strategy toward new regions, such as China, India, vietnam, and Indonesia. "We call these markets 'high-growth regions' instead of emerging markets," says Tedjarati, "because they now account for more than half of Honeywell's total growth."


Injection of recombinant adenovirus for delivery of genetically encoded calcium indicators into astrocytes of the cerebellar cortex.
The cerebellar cortex contains two astrocyte types: the Bergmann glia of the molecular layer and the velate protoplasmic astrocytes of the granule cell layer. In vivo, these cell types generate both subcellular calcium transients and trans-glial calcium waves. This protocol outlines a method for in vivo calcium imaging in cerebellar astrocytes, using the injection of a replication-incompetent recombinant adenovirus for gene transfer of the fluorescent calcium indicator protein (FCIP) G-CaMP2. The adenovirus contains a cytomegalovirus (CMV) immediate-early (IE) promoter which confines expression of G-CaMP2 to astrocytes. Expression is sufficiently high to allow calcium signals to be recorded in Bergmann glial processes as well as the processes and somata of velate protoplasmic astrocytes. To obtain structural information, G-CaMP2 fused with the brighter chromophore DsRed allows three-dimensional (3D) reconstruction of cells. G-CaMP2 expression lasts for at least 3 wk, enabling long-term functional imaging in both anesthetized and awake animals.


Evidence of splinting in low back pain? A systematic review of perturbation studies.
The purpose of this systematic review was to assess whether LBP patients demonstrate signs of splinting by evaluating the reactions to unexpected mechanical perturbations in terms of (1) trunk muscle activity, (2) kinetic and (3) kinematic trunk responses and (4) estimated mechanical properties of the trunk. The literature was systematically reviewed to identify studies that compared responses to mechanical trunk perturbations between LBP patients and healthy controls in terms of muscle activation, kinematics, kinetics, and/or mechanical properties. If more than four studies reported an outcome, the results of these studies were pooled. Nineteen studies were included, of which sixteen reported muscle activation, five kinematic responses, two kinetic responses, and two estimated mechanical trunk properties. We found evidence of a longer response time of muscle activation, which would be in line with splinting behaviour in LBP. No signs of splinting behaviour were found in any of the other outcome measures. We conclude that there is currently no convincing evidence for the presence of splinting behaviour in LBP patients, because we found no indications for splinting in terms of kinetic and kinematic responses to perturbation and derived mechanical properties of the trunk. Consistent evidence on delayed onsets of muscle activation in response to perturbations was found, but this may have other causes than splinting behaviour.


Factors associated with health-related quality of life among Chinese caregivers of the older adults living in the community: a cross-sectional study.
Under the culture of filial piety and due to the Confucianism spirit in China, family caregivers usually undertake the responsibilities of caring for the older adults. They usually suffer from a heavy burden which is believed to impair their mental and physical health. Thus this study aims to describe the health-related quality of life (HRQOL) among Chinese caregivers of the older adults living in the community and explore the predictors of caregivers' HRQOL. A cross-sectional study was conducted through convenience sampling. The study population was composed of 1,144 caregivers of older adults who suffered from one or more types of chronic diseases in 15 communities in 3 eastern cities of China. Family caregivers were interviewed face-to-face using the 36-item Short-Form Health Survey (SF-36) and the ZARIT Caregiver Burden interview (ZBI) scales. The Antonovsky's Sense of coherence (SOC) scale was also used to measure personal coping capability of the caregivers. Hierarchical multiple regression analysis (HMR) was performed to explore the predictors of caregivers' HRQOL. The majority of the caregivers were females (60.0%) or adult children (66.5%). Mental QOL was significantly lower than physical QOL. Hierarchical multiple regression analysis showed that Demographic Characteristics of Caregivers, Patients' Characteristics, and Subjective Caregiver Burden explained most of the total variance of all aspects of HRQOL. While, Objective Caregiving Tasks was only associated with physical QOL. Subjective Caregiver Burden was the strongest predictor of both physical and mental QOL. SOC was also a strong predictor of physical and mental QOL. The mental QOL of the caregivers of older adults was disrupted more seriously than physical QOL. Additionally, Subjective Caregiver Burden might decrease caregiver' health. A decrease in caregiver burden could promote better management of caregiving tasks, and improve HRQOL. Also, coping capabilities, like SOC, are needed to decrease the impact of caregiving on HRQOL of Chinese caregivers of the older adults.


Structural basis for the recognition of a nucleoporin FG repeat by the NTF2-like domain of the TAP/p15 mRNA nuclear export factor.
TAP-p15 heterodimers have been implicated in the export of mRNAs through nuclear pore complexes (NPCs). We report a structural analysis of the interaction domains of TAP and p15 in a ternary complex with a Phe-Gly (FG) repeat of an NPC component. The TAP-p15 heterodimer is structurally similar to the homodimeric transport factor NTF2, but unlike NTF2, it is incompatible with either homodimerization or Ran binding. The NTF2-like heterodimer functions as a single structural unit in recognizing an FG repeat at a hydrophobic pocket present only on TAP and not on p15. This FG binding site interacts synergistically with a second site at the C terminus of TAP to mediate mRNA transport through the pore. In general, our findings suggest that FG repeats bind with a similar conformation to different classes of transport factors.


Homozygous single base deletion in TUSC3 causes intellectual disability with developmental delay in an Omani family.
Intellectual disability (ID) is the term used to describe a diverse group of neurological conditions with congenital or juvenile onset, characterized by an IQ score of less than 70 and difficulties associated with limitations in cognitive function and adaptive behavior. The condition can be inherited or caused by environmental factors. The genetic forms are heterogeneous, with mutations in over 500 known genes shown to cause the disorder. We report a consanguineous Omani family in which multiple individuals have ID and developmental delay together with some variably present features including short stature, microcephaly, moderate facial dysmorphism, and congenital malformations of the toes or hands. Homozygosity mapping combined with whole exome next generation sequencing identified a novel homozygous single base pair deletion in TUSC3, c.222delA, p.R74 fs. The mutation segregates with the disease phenotype in a recessive manner and is absent in 60,706 unrelated individuals from various disease-specific and population genetic studies. TUSC3 mutations have been previously identified as causing either syndromic or non-syndromic ID in patients from France, Italy, Iran and Pakistan. This paper supports the previous clinical descriptions of the condition caused by TUSC3 mutations and describes the seventh family with mutations in this gene, thus contributing to the genetic spectrum of mutations. This is the first report of a family from the Arabian peninsula with this form of ID. © 2016 Wiley Periodicals, Inc.


Prognosis and course of work-participation in patients with chronic non-specific low back pain: a 12-month follow-up cohort study.
To investigate the clinical course of, and prognostic factors for, work-participation in patients with chronic non-specific low back pain. A total of 1,608 patients with chronic non-specific low back pain received a multidisciplinary therapy and were evaluated at baseline and 2-, 5- and 12-month follow-ups. Recovery was defined as absolute recovery if the patient worked 90% of his contract hours at follow-up. Potential factors were identified using multivariable logistic regression analysis. Patients reported a mean increase in work-participation from 38% at baseline to 82% after 12 months. Prognostic factors for ≥ 90% work-participation at 5 months were being married (odds ratio (OR) 1.72 (95% confidence interval (95% CI) 1.12-2.65)), male (OR 1.99 (95% CI 1.24-3.20)), a higher score on disability (OR 1.00 (95% CI 0.997-1.02)) and physical component scale (Short-Form 36 (SF-36)) (OR 1.05 (95% CI 1.02-1.07)), previous rehabilitation (OR 1.85 (95% CI 1.14-2.98)), not receiving sickness benefits (OR 0.52 (95% CI 0.24-1.10)) and more work-participation (OR 4.86 (95% CI 2.35-10.04)). More work-participation (OR 5.22 (95% CI 3.47-7.85)) and male sex (OR 1.79 (95% CI 1.25-2.55)) were also prognostic factors at 12-month follow-up. At 12 months 52% of patients reported ≥ 90% work-participation. The strongest prognostic factor was more work-participation at baseline for the recovery of chronic non-specific low back pain.


Structural differences between the Streptococcus agalactiae housekeeping and pilus-specific sortases: SrtA and SrtC1.
The assembly of pili on the cell wall of Gram-positive bacteria requires transpeptidase enzymes called sortases. In Streptococcus agalactiae, the PI-1 pilus island of strain 2603V/R encodes two pilus-specific sortases (SrtC1 and SrtC2) and three pilins (GBS80, GBS52 and GBS104). Although either pilus-specific sortase is sufficient for the polymerization of the major pilin, GBS80, incorporation of the minor pilins GBS52 and GBS104 into the pilus structure requires SrtC1 and SrtC2, respectively. The S. agalactiae housekeeping sortase, SrtA, whose gene is present at a different location and does not catalyze pilus polymerization, was shown to be involved in cell wall anchoring of pilus polymers. To understand the structural basis of sortases involved in such diverse functions, we determined the crystal structures of S. agalactiae SrtC1 and SrtA. Both enzymes are made of an eight-stranded beta-barrel core with variations in their active site architecture. SrtA exhibits a catalytic triad arrangement similar to that in Streptococcus pyogenes SrtA but different from that in Staphylococcus aureus SrtA. In contrast, the SrtC1 enzyme contains an N-terminal helical domain and a 'lid' in its putative active site, which is similar to that seen in Streptococcus pneumoniae pilus-specific sortases, although with subtle differences in positioning and composition. To understand the effect of such differences on substrate recognition, we have also determined the crystal structure of a SrtC1 mutant, in which the conserved DP(W/F/Y) motif was replaced with the sorting signal motif of GBS80, IPNTG. By comparing the structures of WT wild type SrtA and SrtC1 and the 'lid' mutant of SrtC1, we propose that structural elements within the active site and the lid may be important for defining the role of specific sortase in pili biogenesis.


Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment.
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition in which susceptible individuals are at risk for the development of cutaneous leiomyomas, early onset multiple uterine leiomyomas and an aggressive form of type 2 papillary renal cell cancer. HLRCC is caused by germline mutations in the fumarate hydratase (FH) gene which inactivate the enzyme and alters the function of the tricarboxylic acid (Krebs) cycle. Issues surrounding surveillance and treatment for HLRCC-associated renal cell cancer were considered as part of a recent international symposium on HLRCC. The management protocol proposed in this article is based on a literature review and a consensus meeting. The lifetime renal cancer risk for FH mutation carriers is estimated to be 15 %. In view of the potential for early onset of RCC in HLRCC, periodic renal imaging and, when available, predictive testing for a FH mutation is recommended from 8 to 10 years of age. However, the small risk of renal cell cancer in the 10-20 years age range and the potential drawbacks of screening should be carefully discussed on an individual basis. Surveillance preferably consists of annual abdominal MRI. Treatment of renal tumours should be prompt and generally consist of wide-margin surgical excision and consideration of retroperitoneal lymph node dissection. The choice for systemic treatment in metastatic disease should, if possible, be part of a clinical trial. Screening procedures in HLRCC families should preferably be evaluated in large cohorts of families.


Successful sons or superior daughters: sex-ratio variation in springbok.
Mothers would often benefit from producing more offspring of one sex than the other. Although some species show an astonishing ability to skew their sex ratio adaptively, the trends found in many studies on vertebrates have proved inconsistent. Furthermore, evidence for a mechanism by which such a bias is achieved is equivocal at best. Here, we examine sex-ratio variation over 30 years, both at an individual and a population level, in the highly polygynous, size-dimorphic springbok (Antidorcas marsupialis). Many previous studies of similar species have shown that mothers in superior condition preferentially produce sons, whereas those in poorer condition produce more daughters. We found the opposite to be true in springbok, perhaps because daughters provide mothers in superior condition with a more rapid and secure fitness return. This theory was supported by the findings that earlier-conceived offspring tended to be female and that an increased proportion of daughters were produced with increasing rainfall (which was likely to reduce nutritional stress). We also show that selective reabsorption of embryos is unlikely to be the main mechanism by which deviations from an equal sex ratio are achieved. Hence, either differential implantation occurs or females are able to influence the sex of the sperm fertilizing an egg.


Missed opportunities for participation in prevention of mother to child transmission programmes: simplicity of nevirapine does not necessarily lead to optimal uptake, a qualitative study.
The objective of this study was to examine missed opportunities for participation in a prevention of mother-to-child transmission (PMTCT) programme in three sites in South Africa. A rapid anthropological assessment was used to collect in-depth data from 58 HIV-positive women who were enrolled in a larger cohort study to assess mother-to-child HIV transmission. Semi-structured interviews were conducted with the women in order to gain an understanding of their experiences of antenatal care and to identify missed opportunities for participation in PMTCT. 15 women actually missed their nevirapine not because of stigma and ignorance but because of health systems failures. Six were not tested for HIV during antenatal care. Two were tested but did not receive their results. Seven were tested and received their results, but did not receive nevirapine. Health Systems failure for these programme leakages ranged from non-availability of counselors, supplies such as HIV test kits, consent forms, health staff giving the women incorrect instructions about when to take the tablet and health staff not supplying the women with the tablet to take. HIV testing enables access to PMTCT interventions and should therefore be strengthened. The single dose nevirapine regimen is simple to implement but the all or nothing nature of the regimen may result in many missed opportunities. A short course dual or triple drug regimen could increase the effectiveness of PMTCT programmes.


Vietnamese-born health professionals: negotiating work and life in rural Australia.
Australia is a culturally diverse nation due to migrants from a wide variety of countries creating a multicultural society. The health professions are highly valued by the younger generation of overseas-born migrants who have acculturated into Australian society; many have chosen health care as their profession in Australia. However, most migrants settle in metropolitan areas and young health professionals may find working in rural or remote Australia culturally and professionally highly challenging. The present study of migrant health professionals examined the life experiences and acculturation strategies of Vietnamese-born health professionals working and living in rural Australia. The two main study objectives were to: (1) examine aspects of the acculturation of overseas-born and Australian-trained health professionals in the Australian health discourse; and (2) identify key coping strategies used by them when in working in the rural context. Six overseas-born, Australian-trained health professionals were invited to participate in this qualitative study using a snowball sampling technique. The participants were all born in Vietnam and had experienced working in rural Australia. They included three medical doctors, a dentist, a physiotherapist and a nurse. The interviews were recorded and four participants also provided additional written responses to some of the open-ended interview questions. The interview data were transcribed and later coded for thematic analysis. Topics and themes that emerged focused on the issues and strategies of acculturation to the rural health context. The study showed that the acculturation process was affected by the participants' views about and attitudes towards working in an Australian rural context. The study identified these essential strategies used by the participants in adapting to a new workplace: collaborating, distancing, adjusting, repairing, and accommodating. The study provides insights into the lives of these health professionals in a rural context, and particularly their experience of cultural shock and the coping strategies they may use. A need is identified for a larger study to inform recruitment and retention of these health professionals to rural Australia, and to assist universities to prepare such students and their clinical supervisors for rural placements.


Long-term in vivo transduction of neurons throughout the rat CNS using novel helper-dependent CAV-2 vectors.
Numerous genetic and environmental causes, variable pathophysiologies, and the blood-brain barrier create a formidable challenge for the study and treatment of neurodegenerative diseases affecting the central nervous system. Although there are many intracellular strategies to address neurodegeneration, for example, which transgene to use, one fundamental criterion for the long-term survival of neurons may be their genetic modification. Here, we describe the generation and in vivo efficacy of helper-dependent canine adenovirus (CAV-2) vectors that preferentially transduced neurons and efficiently trafficked via axonal retrograde transport. We used a flexible strategy and the synergy between Cre/loxP and nonlethal packaging-defective helper vectors to generate high titer helper-dependent vector stocks. One year after striatal injections in the rat brain, we found stable, high-level expression in striatal neurons, ~50% of the dopaminergic neurons of the substantia nigra, and the cholinergic neurons in the basal nuclei of Meynert. Due to the intrinsic properties of helper-dependent CAV-2 vectors (27-kb cloning capacity; low preexisting, innate, and induced immunogenicity; retrograde transport; and long-term transgene expression), they will aid fundamental and applied studies in neurobiology. Moreover, helper-dependent CAV-2 vectors may be clinically relevant for the treatment of many neurodegenerative diseases.


Ubiquitin-proteasome-dependent degradation of mammalian ER stearoyl-CoA desaturase.
Mammalian Delta9 stearoyl-CoA desaturase 1 (SCD1) is a key enzyme in the biosynthesis of mono-unsaturated fatty acids in the endoplasmic reticulum (ER). It is a short-lived multispanning ER membrane protein, reported to be degraded by the ubiquitin-proteasome-independent pathway. We have examined SCD1 protein degradation using cultured mammalian cells. Exogenously expressed SCD1 in CHO-K1 cells was localized to the ER and turned over with a half-life of approximately 3 hours. Unexpectedly, proteasome inhibitors increased the half-life of SCD1 to approximately 6 hours. Endogenously expressed SCD1 in adipocyte-differentiated NIH 3T3-L1 cells was also rapidly degraded in a proteasome inhibitor-sensitive manner. In the presence of proteasome inhibitors, polyubiquitylated SCD1 accumulated in the ER and interacted with AAA-ATPase p97, which is involved in ER-associated degradation (ERAD). The 66-residue N-terminal segment carrying the PEST sequence is mainly responsible for SCD1 degradation and this segment induced instability in an otherwise stable ER membrane protein. Furthermore, SCD1 was degraded constitutively irrespective of the cellular levels of unsaturated fatty acids, which strictly regulate SCD1 gene expression. These findings indicate that the ubiquitin-proteasome-dependent ERAD system is also involved in constitutive SCD1 degradation.


Structural basis of hAT transposon end recognition by Hermes, an octameric DNA transposase from Musca domestica.
Hermes is a member of the hAT transposon superfamily that has active representatives, including McClintock's archetypal Ac mobile genetic element, in many eukaryotic species. The crystal structure of the Hermes transposase-DNA complex reveals that Hermes forms an octameric ring organized as a tetramer of dimers. Although isolated dimers are active in vitro for all the chemical steps of transposition, only octamers are active in vivo. The octamer can provide not only multiple specific DNA-binding domains to recognize repeated subterminal sequences within the transposon ends, which are important for activity, but also multiple nonspecific DNA binding surfaces for target capture. The unusual assembly explains the basis of bipartite DNA recognition at hAT transposon ends, provides a rationale for transposon end asymmetry, and suggests how the avidity provided by multiple sites of interaction could allow a transposase to locate its transposon ends amidst a sea of chromosomal DNA.


Methods and implications of limiting resident duty hours.
Current limitations on residency duty hours came about after the death of a patient in 1984 in a New York City hospital. This tragedy served as the catalyst for a new public awareness and subsequent change in philosophy regarding resident duty hours, fatigue factors, and risks to patients from the long and tedious shifts of residency. However, it has proven difficult to limit resident physician duty hours. To analyze the impact of resident duty hour limitation (RDHL) implementation on residents, faculty, and patients. The authors conducted a survey of faculty and resident attitudes and experiences regarding RDHLs in the graduate medical education department at Arrowhead Regional Medical Center (ARMC) in Colton, California. They also conducted a review of the literature on faculty and resident attitudes and experiences before and after implementation of RDHLs. Of 60 surveys sent to ARMC faculty members in 2009, 12 (20.0%) were returned. Of 140 surveys sent to ARMC residents, 96 (68.6%) were returned. The survey results and literature review indicated that most faculty physicians initially believed that decreasing resident duty hours would limit the time available to residents for educational experiences and participation in treatment procedures, operations, and consultations. In addition, faculty initially believed that fewer training hours would diminish the quality of residents' educational experiences. Residents also expected negative outcomes from RDHLs. However, statistical data on actual outcomes revealed that residency programs are not adversely affected by limiting resident work hours to 80 hours per week. Furthermore, benefits of RDHLs appear to include improved patient care and well-rounded and psychologically balanced residents. A survey and literature review revealed a number of benefits of RDHLs. It is unclear, however, whether additional limitations of resident work hours are necessary or could accommodate the growing amount of information and skills that are required to become a competent physician.


Dynamic causal models and autopoietic systems.
Dynamic Causal Modelling (DCM) and the theory of autopoietic systems are two important conceptual frameworks. In this review, we suggest that they can be combined to answer important questions about self-organising systems like the brain. DCM has been developed recently by the neuroimaging community to explain, using biophysical models, the non-invasive brain imaging data are caused by neural processes. It allows one to ask mechanistic questions about the implementation of cerebral processes. In DCM the parameters of biophysical models are estimated from measured data and the evidence for each model is evaluated. This enables one to test different functional hypotheses (i.e., models) for a given data set. Autopoiesis and related formal theories of biological systems as autonomous machines represent a body of concepts with many successful applications. However, autopoiesis has remained largely theoretical and has not penetrated the empiricism of cognitive neuroscience. In this review, we try to show the connections that exist between DCM and autopoiesis. In particular, we propose a simple modification to standard formulations of DCM that includes autonomous processes. The idea is to exploit the machinery of the system identification of DCMs in neuroimaging to test the face validity of the autopoietic theory applied to neural subsystems. We illustrate the theoretical concepts and their implications for interpreting electroencephalographic signals acquired during amygdala stimulation in an epileptic patient. The results suggest that DCM represents a relevant biophysical approach to brain functional organisation, with a potential that is yet to be fully evaluated.


Hepatitis B virus infection is associated with impaired immunological recovery during antiretroviral therapy in the Swiss HIV cohort study.
Hepatitis B virus (HBV) infection is a major cause of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients worldwide. It is unclear whether HIV-related outcomes are affected by HBV coinfection. We compared virological suppression and immunological recovery during antiretroviral therapy (ART) of patients of different HBV serological status in the Swiss HIV Cohort Study. CD4 cell recovery during ART was significantly impaired in hepatitis B surface antigen-positive patients and in those with anti-hepatitis B core antigen alone compared with HBV-uninfected patients, despite similar virological efficacy of ART. CD4 increase in patients with resolved HBV infection was similar to that in HBV-uninfected individuals.


Impact of coronary bifurcation angle on clinical outcomes after percutaneous coronary intervention in real-world practice: results from the COBIS registry.
Bifurcation angle has emerged as a predictor of outcome after percutaneous coronary intervention (PCI) for bifurcation lesions. We investigated the impact of bifurcation angle on clinical outcomes in patients undergoing bifurcation lesion PCI. Consecutive patients who received PCI for bifurcation lesions were enrolled from 16 centers in Korea between January 2004 and June 2006. Patients were divided into low-angle and high-angle groups using the median bifurcation angle (50°). We compared major adverse cardiac events, including cardiac death, myocardial infarction and target lesion revascularization as well as periprocedural outcomes between the 2 groups. We evaluated 1,432 patients with bifurcation lesions with a median follow-up duration of 21 months. The rates of interventional side branch procedures such as guide-wiring of side branches, side-branch ballooning, final kissing ballooning and side-branch stenting were higher in the low-angle group. However, the incidences of major adverse cardiac events and target lesion revascularization were not significantly different between the 2 groups (6.6 vs. 6.9%, p = 0.856 and 4.6 vs. 5.7%, p = 0.375, respectively). Bifurcation angle may not influence long-term clinical outcome in patients with non-left main bifurcation lesion undergoing PCI despite its association with more interventional side-branch procedures.


Variations in torsion of the lower limb in Japanese and Caucasians with and without knee osteoarthritis.
Associations between torsion of the lower limb and knee osteoarthritis (OA) appear to be inconsistent across populations. We examined whether femoral and tibiofibular torsion differed between people with and without knee OA (main effect), and whether the differences were consistent across Japanese and Australian Caucasian persons, and between women and men (interaction effect). Data collection was conducted in Japan and Australia. Subjects with knee OA included 100 Japanese and 102 Australian Caucasians, and healthy subjects included 52 Japanese and 34 Australian Caucasians. Femoral and tibiofibular torsion were measured using reliable clinical techniques. Three-way analysis of variance was conducted to examine the main and interaction effects. While there were no significant differences in femoral and tibiofibular torsion between the subjects with and without knee OA as a whole (main effect), there were significant interactions (p < 0.05). Femoral antetorsion was lower only in the female subjects with knee OA compared with their healthy counterparts (p < 0.05). Tibiofibular torsion was lower only in the Japanese subjects with knee OA compared with their healthy counterparts (p < 0.01). There may be ethnic and sex variations in the relationship between torsion of the lower limb and knee OA; and lower tibiofibular torsion can be a characteristic in a Japanese population with the disease. Longitudinal study is warranted to examine relationships between these variables and knee OA in a population-specific manner to determine whether the observed relationships express cause or effect.


Exposure to herpes simplex virus, type 1 and reduced cognitive function.
Herpes simplex virus, type 1 (HSV-1) causes cold sores, keratitis and rarely, fatal encephalitis. The infection is lifelong, with sensory ganglia serving as reservoirs of latent infection. Recently, exposure to HSV-1 has also been repeatedly associated with reduced cognitive function among healthy individuals without prior encephalitis. Though HSV-1 does not elevate risk for schizophrenia (SZ) per se, exposure is likewise associated with impaired cognitive functions among SZ patients. The range of cognitive changes observed in HSV-1 exposed persons has not been investigated systematically, nor is it known whether interaction between HSV-1 exposure and SZ related factors contributes to the impairment among SZ patients. Persons with or without schizophrenia/schizophreniform disorder (N = 298 total, DSM IV criteria) were assessed for HSV-1 exposure using serum HSV-1 antibody titers. The Penn Computerized Neurocognitive battery was used to assess eight cognitive domains with respect to accuracy and speed. There were no significant case-control differences in HSV-1 exposure. The SZ/schizophreniform disorder cases were significantly impaired in all cognitive domains compared with the controls. HSV-1 exposure was also associated with reduced cognitive function in the entire sample, but the magnitude of the effects and their patterns differed from the SZ related changes. Further, statistically significant interactions between HSV-1 exposure and SZ case status were not detected. HSV-1 exposure does not elevate risk for SZ, but it is associated with reduced function in specific cognitive domains regardless of SZ diagnostic status. An 'epidiagnostic' model for the association is proposed to explain the results.


The Effects of High-Fat Diet Exposure In Utero on the Obesogenic and Diabetogenic Traits Through Epigenetic Changes in Adiponectin and Leptin Gene Expression for Multiple Generations in Female Mice.
Recent studies demonstrate that epigenetic changes under malnutrition in utero might play important roles in transgenerational links with metabolic diseases. We have previously shown that exposure to a high-fat diet (HFD) in utero may cause a metabolic syndrome-like phenomenon through epigenetic modifications of Adiponectin and Leptin genes. Because an association of obesity between mother and offspring endured in multiple generations, we examined whether HFD exposure in utero might affect the metabolic status of female offspring through multigenerational epigenetic changes of Adiponectin and Leptin genes and whether a normal diet in utero for multiple generations might abolish such epigenetic changes after exposure to a HFD in utero using ICR mice. We observed that the effect of maternal HFD on offspring over multiple generations in metabolic syndrome-like phenomenon such as weight and fat mass gain, glucose intolerance, hypertriglyceridemia, abnormal adiponectin and leptin levels, and hypertension, were accumulated with expression and epigenetic changes in Adiponectin and Leptin genes. A normal diet in utero in the subsequent generations after HFD exposure in utero diminished, and a normal diet in utero for 3 generations completely abolished, the effect of HFD in utero on weight and fat mass gain, insulin resistance, serum triglyceride, adiponectin, and leptin levels, with epigenetic changes of Adiponectin and Leptin genes. Exposure to a HFD in utero might affect glucose and lipid metabolism of female offspring through epigenetic modifications to Adiponectin and Leptin genes for multiple generations. Obesogenic and diabetogenic traits were abolished after a maternal normal diet for 3 generations.


Staphylococcal enterotoxin B activates purified NK cells to secrete IFN-gamma but requires T lymphocytes to augment NK cytotoxicity.
Staphylococcal enterotoxin B (SEB) is known for its effects on T lymphocytes; the mechanism of this activation is well studied. Although it is anticipated that there would be effects on other cells in the milieu, the mechanisms of activation of non-T immune cells are not well understood. This report examines the effects of SEB on human NK cells. Incubation of PBMC with SEB augmented NK cytotoxicity against the NK-sensitive targets K562 and Molt-4 and induced activity against the NK-resistant targets, Mel-30 and Raji. The degree of superantigen-augmented killer (SAK) activity induced by the SEB treatment correlated with the concentration of the superantigen in the mixture. Specific neutralizing Abs for lymphokines or monokines added to cultures showed that IL-2, IFN-gamma, or IL-12 each participated in the phenomenon; addition of all Abs together blocked most, but not all, SAK activity. Highly purified T lymphocytes (but not monocytes) supported the development of SAK activity in enriched cultures of CD56+ cells. The SAK activity was blocked by specific Abs to IL-2 and IFN-gamma in cocultures of T cells and CD56+ cells. In addition, SEB induced IFN-gamma secretion from sorted CD56+ cells. These data show for the first time that superantigen directly initiated cytokine synthesis in NK cells, and that SAK activity was induced as a consequence of products secreted from activated T lymphocytes. Such a superantigen effect on NK cells would place the NK lymphocyte in a pivotal role in determining the outcome of infection or immunopathology caused by superantigen exposure.


Systematic review and economic modelling of the clinical effectiveness and cost-effectiveness of art therapy among people with non-psychotic mental health disorders.
Mental health problems account for almost half of all ill health in people under 65 years. The majority are non-psychotic (e.g. depression, anxiety and phobias). For some people, art therapy may provide more profound and long-lasting healing than more standard forms of treatment, perhaps because it can provide an alternative means of expression and release from trauma. As yet, no formal evaluation of art therapy for non-psychotic mental health disorders has been conducted. This review aimed to evaluate evidence for the clinical effectiveness and cost-effectiveness of art therapy for non-psychotic mental health disorders. Comprehensive literature searches for studies examining art therapy in populations with non-psychotic mental health disorders were performed in major health-related and social science bibliographic databases including MEDLINE, EMBASE, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, Allied and Complementary Medicine Database (AMED) and Applied Social Sciences Index and Abstracts (ASSIA) from inception up to May 2013. A quantitative systematic review of clinical effectiveness, a qualitative review to explore the acceptability, relative benefits and potential harms, and a cost-utility analysis of studies evaluating cost-effectiveness of art therapy were conducted. In the quantitative review, 15 randomised controlled trials (RCTs) were included (n = 777). Meta-analysis was not possible because of clinical heterogeneity and insufficient comparable data on outcome measures across studies. A narrative synthesis reports that art therapy was associated with significant positive changes relative to the control group in mental health symptoms in 10 out of the 15 studies. The control groups varied between studies but included wait-list/no treatment, attention placebo controls and psychological therapy comparators. Four studies reported improvement from baseline but no significant difference between groups. One study reported that outcomes were more favourable in the control group. The quality of included RCTs was generally low. In the qualitative review, 12 cohort studies were included (n = 188 service users; n = 16 service providers). Themes relating to benefits of art therapy for service users included the relationship with the therapist, personal achievement and distraction. Areas of potential harms were related to the activation of emotions that were then unresolved, lack of skill of the art therapist and sudden termination of art therapy. The quality of included qualitative studies was generally low to moderate. In the cost-effectiveness review, a de novo model was constructed and populated with data identified from the clinical review. Scenario analyses were conducted allowing comparisons of group art therapy with wait-list control, group art therapy with group verbal therapy, and individual art therapy versus control. Art therapy appeared cost-effective compared with wait-list control with high certainty, although generalisability to the target population was unclear. Verbal therapy appeared more cost-effective than art therapy but there was considerable uncertainty and a sizeable probability that art therapy was more clinically effective. The cost-effectiveness of individual art therapy was uncertain and dependent on assumptions regarding clinical benefit and duration of benefit. From the limited available evidence, art therapy was associated with positive effects when compared with a control in a number of studies in patients with different clinical profiles, and it was reported to be an acceptable treatment and was associated with a number of benefits. Art therapy appeared to be cost-effective compared with wait-list but further studies are needed to confirm this finding as well as evidence to inform future cost-effective analyses of art therapy versus other treatments. The study is registered as PROSPERO CRD42013003957. The National Institute for Health Research Health Technology Assessment programme.


5-Carboxy-8-hydroxyquinoline is a Broad Spectrum 2-Oxoglutarate Oxygenase Inhibitor which Causes Iron Translocation.
2-Oxoglutarate and iron dependent oxygenases are therapeutic targets for human diseases. Using a representative 2OG oxygenase panel, we compare the inhibitory activities of 5-carboxy-8-hydroxyquinoline (IOX1) and 4-carboxy-8-hydroxyquinoline (4C8HQ) with that of two other commonly used 2OG oxygenase inhibitors, N-oxalylglycine (NOG) and 2,4-pyridinedicarboxylic acid (2,4-PDCA). The results reveal that IOX1 has a broad spectrum of activity, as demonstrated by the inhibition of transcription factor hydroxylases, representatives of all 2OG dependent histone demethylase subfamilies, nucleic acid demethylases and γ-butyrobetaine hydroxylase. Cellular assays show that, unlike NOG and 2,4-PDCA, IOX1 is active against both cytosolic and nuclear 2OG oxygenases without ester derivatisation. Unexpectedly, crystallographic studies on these oxygenases demonstrate that IOX1, but not 4C8HQ, can cause translocation of the active site metal, revealing a rare example of protein ligand-induced metal movement.


Fetal erythropoiesis and hemoglobin ontogeny in tail-short (Ts/+) mutant mice.
Mutant Ts/+ fetuses are developmentally retarded as compared to normal +/+ littermates. Mutant fetuses have less total hemoglobin than do normal fetuses of the same gestational age. However, when compared to +/+ fetuses of similar body weight, Ts/+ fetuses have the appropriate amount of total hemoglobin, suggesting that the apparent anemia observed in mutant fetuses is most likely the result of delay in growth and development. Changes in proportions of embryonic hemoglobins during fetal development are similar in Ts/+ and +/+ fetuses at day 12 and later of gestation. Moreover, adult hemoglobin is detected in circulating primitive nucleated erythrocytes in the developmentally retarded Ts/+ mutant fetuses at about the same chronologic age as their +/+ normal littermates.


Nucleoside reverse transcriptase inhibitors prevent HIV protease inhibitor-induced atherosclerosis by ubiquitination and degradation of protein kinase C.
HIV protease inhibitors are important pharmacological agents used in the treatment of HIV-infected patients. One of the major disadvantages of HIV protease inhibitors is that they increase several cardiovascular risk factors, including the expression of CD36 in macrophages. The expression of CD36 in macrophages promotes the accumulation of cholesterol, the development of foam cells, and ultimately atherosclerosis. Recent studies have suggested that alpha-tocopherol can prevent HIV protease inhibitor-induced increases in macrophage CD36 levels. Because of the potential clinical utility of using alpha-tocopherol to limit some of the side effects of HIV protease inhibitors, we tested the ability of alpha-tocopherol to prevent ritonavir, a common HIV protease inhibitor, from inducing atherosclerosis in the LDL receptor (LDLR) null mouse model. Surprisingly, alpha-tocopherol did not prevent ritonavir-induced atherosclerosis. However, cotreatment with the nucleoside reverse transcriptase inhibitors (NRTIs), didanosine or D4T, did prevent ritonavir-induced atherosclerosis. Using macrophages isolated from LDLR null mice, we demonstrated that the NRTIs prevented the upregulation of CD36 and cholesterol accumulation in macrophages. Treatment of LDLR null mice with NRTIs promoted the ubiquitination and downregulation of protein kinase Calpha (PKC). Previous studies demonstrated that HIV protease inhibitor activation of PKC was necessary for the upregulation of CD36. Importantly, the in vivo inhibition of PKC with chelerythrine prevented ritonavir-induced upregulation of CD36, accumulation of cholesterol, and the formation of atherosclerotic lesions. These novel mechanistic studies suggest that NRTIs may provide protection from one of the negative side effects associated with HIV protease inhibitors, namely the increase in CD36 levels and subsequent cholesterol accumulation and atherogenesis.


Using the EngagedMD multimedia platform to improve informed consent for ovulation induction, intrauterine insemination, and in vitro fertilization.
To study patient and provider feedback on how a multimedia platform (EngagedMD) helps patients to understand the risks and consequences of in vitro fertilization (IVF), ovulation induction (OI), and intrauterine insemination (IUI) treatments and the impact of the informed consent process. Prospective survey study. IVF units in the United States. Six-thousand three-hundred and thirty-three patients who viewed the multimedia platform before IVF or OI-IUI treatment at 13 U.S. IVF centers and 128 providers. Quantitative survey with 17 questions. Assessment of the impact of a multimedia platform on patient anxiety, comprehension, and satisfaction and provider/nurse feedback related to the informed consent process. The survey was completed by 3,097 respondents (66% IVF treatment; 34% OI-IUI treatment) and 44 providers. Overall, 93% felt the media platform was intuitive, and 90% and 95% felt it had appropriate duration and detail, respectively. Most agreed/strongly agreed it better prepared them to consent (88%), increased their comfort in pursuing treatment (77%) and increased their satisfaction with their care (83%). Compared with the OI-IUI group, statistically significantly more participants who viewed the IVF media platform strongly agreed that the comprehension questions reinforced key concepts (47% vs. 40%), educated them about treatment risks (55% vs. 44%), helped them ask providers informed questions (45% vs. 36%), and better prepared them to sign consent forms (46% vs. 37%). Overall, 63% of providers felt that the media platform improved patient learning, made patients more accountable, and standardized information dissemination. The EngagedMD media platform improves patient knowledge, satisfaction, and control over medical decision making and better prepares patients to give informed consent. Furthermore, it is well-liked by providers and is easily implemented.


Acceptance of Tinnitus As an Independent Correlate of Tinnitus Severity.
Tinnitus is the experience of sounds without an identified external source, and for some the experience is associated with significant severity (i.e., perceived negative affect, activity limitation, and participation restriction due to tinnitus). Acceptance of tinnitus has recently been proposed to play an important role in explaining heterogeneity in tinnitus severity. The purpose of the present study was to extend previous investigations of acceptance in relation to tinnitus by examining the unique contribution of acceptance in accounting for tinnitus severity, beyond anxiety and depression symptoms. In a cross-sectional study, 362 participants with tinnitus attending an ENT clinic in Sweden completed a standard set of psychometrically examined measures of acceptance of tinnitus, tinnitus severity, and anxiety and depression symptoms. Participants also completed a background form on which they provided information about the experience of tinnitus (loudness, localization, sound characteristics), other auditory-related problems (hearing problems and sound sensitivity), and personal characteristics. Correlational analyses showed that acceptance was strongly and inversely related to tinnitus severity and anxiety and depression symptoms. Multivariate regression analysis, in which relevant patient characteristics were controlled, revealed that acceptance accounted for unique variance beyond anxiety and depression symptoms. Acceptance accounted for more of the variance than anxiety and depression symptoms combined. In addition, mediation analysis revealed that acceptance of tinnitus mediated the direct association between self-rated loudness and tinnitus severity, even after anxiety and depression symptoms were taken into account. Findings add to the growing body of work, supporting the unique and important role of acceptance in tinnitus severity. The utility of the concept is discussed in relation to the development of new psychological models and interventions for tinnitus severity.


Design of a small centrifugal blood pump with magnetic bearings.
Design of a blood pump with a magnetically levitated rotor requires rigorous evaluation of the magnetic bearing and motor requirements and analysis of rotor dynamics and hydraulic performance with attention to hemolysis and thrombosis potential. Given the desired geometric dimensions, the required operating speed, flow in both the main and wash flow regions, and magnetic bearing performance, one of several design approaches was selected for a new prototype. Based on the estimated operating speed and clearance between the rotor and stator, the motor characteristics and dimensions were estimated. The motor stiffness values were calculated and used along with the hydraulic loading due to the fluid motion to determine the best design for the axial and radial magnetic bearings. Radial and axial stability of the left ventricular assist device prototype was verified using finite element rotor dynamic analysis. The analysis indicated that the rotor could be completely levitated and spun to the desired operating speed with low power loss and no mechanical contact. In vitro experiments with a mock loop test setup were performed to evaluate the performance of the new blood pump prototype.


Recent developments in the surgical management of paediatric epilepsy.
Among the 1% of children affected by epilepsy, failure of pharmacological therapy and early age of seizure onset can lead to worse long-term cognitive outcomes, mental health disorders and impaired functional status. Surgical management often improves functional and cognitive outcomes in children with medically refractory epilepsy, especially when seizure remission is achieved. However, surgery remains underused in children with drug-resistant epilepsy, creating a large treatment gap. Several recent innovations have led to considerable improvement in surgical technique, including the recent development of minimally invasive diagnostic and therapeutic techniques such as stereotactic EEG, transcranial magnetic stimulation, MRI-guided laser ablation, as well as novel paradigms of neurostimulation. This article discusses the current landscape of surgical innovation in the management of paediatric epilepsy, leading to a paradigm shift towards minimally invasive therapy and closing the treatment gap in children suffering from drug-resistant seizures.


Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis.
Cholecystokinin (CCK) modulates contractility of the gallbladder, the sphincter of Oddi, and the stomach. These effects are mediated through activation of gastrointestinal smooth muscle as well as enteric neuron CCK-1 receptors (CCK-1Rs). To investigate the potential physiological and pathophysiological functions linked to CCK-1R-mediated signaling, we compared male WT and CCK-1R-deficient mice (129/SvEv). After 12 weeks on either a standard mouse chow or a lithogenic diet (containing 1% cholesterol, 0.5% cholic acid, and 15% dairy fat), small-intestinal transit time, intestinal cholesterol absorption, biliary cholesterol secretion, and cholesterol gallstone prevalence were compared in knockout versus WT animals. Analysis of mice on either the chow or the lithogenic diet revealed that CCK-1R(-/-) animals had larger gallbladder volumes (predisposing to bile stasis), significant retardation of small-intestinal transit times (resulting in increased cholesterol absorption), and increased biliary cholesterol secretion rates. The elevation in bile cholesterol, coupled with a tendency toward gallbladder stasis (due to the absence of CCK-induced contraction), facilitates nucleation, growth, and agglomeration of cholesterol monohydrate crystals; this sequence of events in turn results in a significantly higher prevalence of cholesterol gallstones in the CCK-1R-null mice.


Hedgehog-GLI signaling inhibition suppresses tumor growth in squamous lung cancer.
Lung squamous cell carcinoma (LSCC) currently lacks effective targeted therapies. Previous studies reported overexpression of Hedgehog (HH)-GLI signaling components in LSCC. However, they addressed neither the tumor heterogeneity nor the requirement for HH-GLI signaling. Here, we investigated the role of HH-GLI signaling in LSCC, and studied the therapeutic potential of HH-GLI suppression. Gene expression datasets of two independent LSCC patient cohorts were analyzed to study the activation of HH-GLI signaling. Four human LSCC cell lines were examined for HH-GLI signaling components. Cell proliferation and apoptosis were assayed in these cells after blocking the HH-GLI pathway by lentiviral-shRNA knockdown or small-molecule inhibitors. Xenografts in immunodeficient mice were used to determine the in vivo efficacy of GLI inhibitor GANT61. In both cohorts, activation of HH-GLI signaling was significantly associated with the classical subtype of LSCC. In cell lines, genetic knockdown of Smoothened (SMO) produced minor effects on cell survival, whereas GLI2 knockdown significantly reduced proliferation and induced extensive apoptosis. Consistently, the SMO inhibitor GDC-0449 resulted in limited cytotoxicity in LSCC cells, whereas the GLI inhibitor GANT61 was very effective. Importantly, GANT61 demonstrated specific in vivo antitumor activity in xenograft models of GLI(+) cell lines. Our studies demonstrate an important role for GLI2 in LSCC, and suggest GLI inhibition as a novel and potent strategy to treat a subset of patients with LSCC.


The Effect of Horsfall-Barratt Category Size on the Accuracy and Reliability of Estimates of Pecan Scab Severity.
Pecan scab (Fusicladium effusum) is a destructive pecan disease. Disease assessments may be made using interval-scale-based methods or estimates of severity to the nearest percent area diseased. To explore the effects of rating method-Horsfall-Barratt (H-B) scale estimates versus nearest percent estimates (NPEs)-on the accuracy and reliability of severity estimates over different actual pecan scab severity ranges on fruit valves, raters assessed two cohorts of images with actual area (0 to 6, 6+ to 25%, and 25+ to 75%) diseased. Mean estimated disease within each actual disease severity range varied substantially. Means estimated by NPE within each actual disease severity range were not necessarily good predictors of the H-B scale estimate at <25% severity. H-B estimates by raters most often placed severity in the wrong category compared with actual disease. Measures of bias, accuracy, precision, and agreement using Lin's concordance correlation depended on the range of actual severity, with improvements increasing with actual disease severity category (from 0 to 6 through 25+ to 75%); however, the improvement was unaffected by the H-B assessments. Bootstrap analysis indicated that NPEs provided either equally good or more accurate and precise estimate of disease compared with the H-B scale at severities of 25+ to 75%. Inter-rater reliability using NPEs was greater at 25+ to 75% actual disease severity compared with using the H-B scale. Using NPEs compared with the H-B scale will more often result in more precise and accurate estimates of pecan scab severity, particularly when estimating actual disease severities of 25+ to 75%.


Comparison of SPECT aerosol deposition data with a human respiratory tract model.
Three-dimensional (3D) radionuclide imaging provides detailed information on the distribution of inhaled aerosol material within the body. Analysis of the data can provide estimates of the deposition per airway generation. In this study, two different nebulizers have been used to deliver radiolabeled aerosols of different particle size to 12 human subjects. Medical imaging has been used to assess the deposition in the body. The deposition pattern has also been estimated using the International Commission on Radiological Protection (ICRP) empirical model and compared to values obtained by experiment. The results showed generally good agreement between model and experiment for both aerosols for the deposition in the extrathoracic and conducting airways. However, there were significant differences in the fate of the remainder of the aerosol between the amount deposited in the alveolar region and that exhaled. The inter-subject variability of deposition predicted by the model was significantly less than that measured, for all regions of the body. The model predicted quite well the differences in deposition distribution pattern between the two aerosols. In conclusion, this study has shown that the ICPR model of inhaled aerosol deposition shows areas of good agreement with results from experiment. However, there are also areas of disagreement, which may be explained by hygroscopic particle growth and individual variation in airway anatomy.


Occupational inhalational accidents: analysis of cases from the UK SWORD reporting scheme from 1999 to 2018.
To estimate the reported UK incidence of occupational inhalation accidents, and to consider changes of incidence and potential causes over time. Cases of occupational inhalation accident reported to Surveillance of Work Related Occupational Respiratory Diseases (SWORD) over 20 years were grouped into four 5-year time periods. Cases were characterised by causative exposure, occupation and industrial sector. Incidence rates were calculated using Office of National Statistics employment data. The 172 actual cases reported to SWORD equated to an estimated 502 cases after adjusting for reporting frequency. Their mean age was 41.3 years (SD 12.3); 77% were male. The annual incidence fell from 1.7 per million employed in the first 5-year period, to 0.5 in the most recent. The most common occupations, responsible for 35% of all cases, were in descending order (number, % of total cases): Labourers in process and plant operations (8, 4.7), welding trades (8, 4.7), fire service officers (8, 4.7), heavy goods vehicle drivers (7, 4.1), metal working production and maintenance fitters (7, 4.1), civil service administrative officers and assistants (7, 4.1), food, drink and tobacco process operatives (6, 3.5), and three summated categories of elementary and service occupations including cleaners and domestics (10, 5.8).Three of 40 exposure categories were common to all time periods; acids (19.6% of all cases 1999-2004, 2.3% 2005-2009, 6.3% 2010-2013, 6.3% 2014-2018), chlorine/hypochlorites (7.2%, 7.0%, 2.5%, 6.3%, respectively) and solvents (14.4%, 11.6%, 12.5%, 6.3%, respectively). The incidence of inhalation accidents appears to have fallen, although certain exposures appear to be persistently linked to cases.


Smoking is a predictor of worse trabecular mechanical performance in hip fragility fracture patients.
Clinical risk factors (CRFs) are established predictors of fracture events. However, the influence of individual CRFs on trabecular mechanical fragility is still a subject of debate. In this study, we aimed to assess differences, adjusted for CRFs, between bone macrostructural parameters measured in ex-vivo specimens from hip fragility fracture patients and osteoarthritis patients, and to determine whether individual CRFs could predict trabecular bone mechanical behavior in hip fragility fractures. Additionally, we also looked for associations between the 10-year risk of major and hip fracture calculated by FRAX and trabecular bone mechanical performance. In this case-control study, a group of fragility fracture patients were compared with a group of osteoarthritis patients, both having undergone hip replacement surgery. A clinical protocol was applied in order to collect CRFs [body mass index (BMI), prior fragility fracture, parental history of hip fracture, long-term use of oral glucocorticoids, rheumatoid arthritis, current smoking, alcohol consumption, age and gender]. The 10-year probability of fracture was calculated. Serum bone turnover markers were determined and dual X-ray absorptiometry performed. Femoral head diameter was evaluated and trabecular bone cylinders were drilled for mechanical testing to determine bone strength, stiffness and toughness. We evaluated 40 hip fragility fracture and 52 osteoarthritis patients. Trabecular bone stiffness was significantly lower (p = 0.042) in hip fragility fracture patients when compared to osteoarthritic individuals, adjusted for age, gender and BMI. No other macrostructural parameter was statistically different between the groups. In hip fragility fracture patients, smoking habits (β = -0.403; p = 0.018) and female gender (β = -0.416; p = 0.008) were independently associated with lower stiffness. In addition, smoking was also independently associated with worse trabecular strength (β = -0.323; p = 0.045), and toughness (β = -0.403; p = 0.018). In these patients, the 10-year risk of major (r = -0.550; p = 0.012) and hip fracture (r = -0.513; p = 0.021) calculated using only CRFs was strongly correlated with femoral neck bone mineral density but not with mechanical performance. Our data showed that among fragility fracture patients active smoking is a predictor of worse intrinsic trabecular mechanical performance, and female gender is also independently associated with lower stiffness. In this population, the 10-year risk of fracture using CRFs with different weights only reflects bone mass loss but not trabecular mechanical properties.


Interactions between bottle-brush polyelectrolyte layers: effects of ionic strength and oppositely charged surfactant.
Interactions between cationic bottle-brush polyelectrolyte layers adsorbed on mica across salt and oppositely charged surfactant solutions were investigated with the interferometric surface force apparatus, and the results were compared with what is known for similarly charged linear polyelectrolytes. Ellipsometric measurements demonstrated that the bottle-brush polyelectrolytes, which contain 45 units long poly(ethylene oxide) side chains, are more readily desorbed than linear equivalents when the ionic strength of the solution is increased. It is argued that this is due to the steric repulsion between the poly(ethylene oxide) side chains that reduces the surface affinity. The preadsorbed bottle-brush polyelectrolyte layers were also exposed to sodium dodecyl sulfate (SDS) solutions. It was found that the presence of SDS affected the force profiles less than observed for similarly charged linear polyelectrolytes. This observation was attributed to excluded volume constraints imposed by the poly(ethylene oxide) side chains that reduces the accessibility of the charged polyelectrolyte segments and counteracts formation of large aggregates within the layer.


Power and promise of narrative for advancing physical therapist education and practice.
This perspective article provides a justification for and an overview of the use of narrative as a pedagogical tool for educators to help physical therapist students, residents, and clinicians develop skills of reflection and reflexivity in clinical practice. The use of narratives is a pedagogical approach that provides a reflective and interpretive framework for analyzing and making sense of texts, stories, and other experiences within learning environments. This article describes reflection as a well-established method to support critical analysis of clinical experiences; to assist in uncovering different perspectives of patients, families, and health care professionals involved in patient care; and to broaden the epistemological basis (ie, sources of knowledge) for clinical practice. The article begins by examining how phronetic (ie, practical and contextual) knowledge and ethical knowledge are used in physical therapy to contribute to evidence-based practice. Narrative is explored as a source of phronetic and ethical knowledge that is complementary but irreducible to traditional objective and empirical knowledge-the type of clinical knowledge that forms the basis of scientific training. The central premise is that writing narratives is a cognitive skill that should be learned and practiced to develop critical reflection for expert practice. The article weaves theory with practical application and strategies to foster narrative in education and practice. The final section of the article describes the authors' experiences with examples of integrating the tools of narrative into an educational program, into physical therapist residency programs, and into a clinical practice.


Coumarin-induced intramural hematoma of the duodenum: case report and review of the literature.
Intramural hematoma of the small intestine is a complication of anticoagulant treatment with an estimated incidence of 1 case per 2500 anticoagulated patients per year. Patients may present with signs of small bowel obstruction or, in case of a ruptured hematoma, with upper gastrointestinal tract hemorrhage and hypovolemic shock. Case report and review of the literature. We present a case of a 73-year-old male who was referred for a protruding mass in the duodenum and subsequently developed hematemesis and melena caused by a ruptured hematoma of the duodenal wall. Although intramural hematoma of the duodenum is a rare complication of anticoagulant therapy, early diagnosis with subsequent correction of coagulation parameters is of vital importance.


Dimensions of Peer Sexual Harassment Victimization and Depressive Symptoms in Adolescence: A Longitudinal Cross-Lagged Study in a Swedish Sample.
Sexual harassment is commonly considered unwanted sexual attention and a form of gender-based violence that can take physical, verbal and visual forms and it is assumed to cause later depression in adolescents. There is a dearth of research explicitly testing this assumption and the directional pathway remains unclear. The purpose of this study was to use a feminist theoretical framework to test competing models in respect of the direction of the relationships between dimensions of peer sexual harassment victimization and dimensions of depressive symptoms from ages 14 to 16 in adolescents. The study also aimed to investigate gender differences in these pathways. Cross-lagged models were conducted using a three-wave (2010, 2011 and 2012) longitudinal study of 2330 students (51 % females) from Sweden, adjusted for social background. Girls subjected to sexual harassment in grade seven continued to experience sexual harassment the following 2 years. There was weaker evidence of repeated experience of sexual harassment among boys. Depressive symptoms were stable over time in both genders. Sexual name-calling was the dimension that had the strongest associations to all dimensions of depressive symptoms irrespective of gender. In girls, name-calling was associated with later somatic symptoms and negative affect, while anhedonia (reduced ability to experience pleasure) preceded later name-calling. Physical sexual harassment had a reciprocal relationship to somatic symptoms in girls. In boys, name-calling was preceded by all dimensions of depressive symptoms. It is an urgent matter to prevent sexual harassment victimization, as it is most likely to both cause depressive symptoms or a reciprocal cycle of victimization and depression symptoms in girls as well as boys.


Extracranial-intracranial bypass and vessel occlusion for the treatment of unclippable giant middle cerebral artery aneurysms.
Giant middle cerebral artery (MCA) aneurysms pose management challenges. To review the outcomes of patients with giant MCA aneurysms not amenable to clipping or vessel reconstruction treated with extracranial-intracranial (EC-IC) bypass and vessel sacrifice. We retrospectively reviewed a database of aneurysms treated at our institution between 1983 and 2011. Sixteen patients (11 males, 5 females) were identified. There were 10 saccular, 4 fusiform, and 2 serpentine aneurysms. The aneurysms predominantly involved the M1 segment in 5 cases, M2 in 9 cases, and both M1 and M2 in 2 cases. The EC-IC bypasses performed included 13 superficial temporal artery-MCA, 1 saphenous vein graft-MCA, and 2 radial artery grafts-MCA. The postoperative bypass patency rate was 93.8% (15/16). There were 3 cerebrovascular accidents (18.8%), but no perioperative deaths (0% mortality). The mean follow-up was 58.4 months (range, 1-265; median, 23.5 months). In 75% (12/16) of cases the aneurysms were occluded successfully. A small residual was noted in 3 cases with the use of this treatment strategy, and they were re-treated. In a fourth case treated with partial distal occlusion, reduced flow through the aneurysm was noted postoperatively, but the patient did not undergo further treatment. The mean modified Rankin scale and mean Glasgow Outcome Scale scores at last follow-up were 1.6 (range, 1-4; median, 1) and 4.8 (range, 3-5; median, 5), respectively. Giant MCA aneurysms are challenging lesions. EC-IC bypass with parent vessel occlusion can provide a durable form of treatment with acceptable rates of morbidity and mortality.


Determination of mosaicity in oriented stacks of lipid bilayers.
Two methods of measuring the misorientation of domains in oriented multilamellar stacks of lipid bilayers superficially appeared to give different values for the mosaic spread. It is first shown that the traditional rocking method and a newer ring method give the same value of the mosaic spread when the two types of data are similarly analyzed. Both indicate a long-tailed, nearly Lorentzian, mosaic distribution function. Our primary innovation is the analysis of ring data as a function of the rocking angle. For our best oriented DOPC sample, this analysis is consistent with a single Lorentzian mosaic distribution function with width 0.05°. In contrast, samples of DMPC indicate a more complex mosaic distribution and larger widths.


Taking a hard line with biotemplating: cobalt-doped magnetite magnetic nanoparticle arrays.
Rapid advancements made in technology, and the drive towards miniaturisation, means that we require reliable, sustainable and cost effective methods of manufacturing a wide range of nanomaterials. In this bioinspired study, we take advantage of millions of years of evolution, and adapt a biomineralisation protein for surface patterning of biotemplated magnetic nanoparticles (MNPs). We employ soft-lithographic micro-contact printing to pattern a recombinant version of the biomineralisation protein Mms6 (derived from the magnetotactic bacterium Magnetospirillum magneticum AMB-1). The Mms6 attaches to gold surfaces via a cysteine residue introduced into the N-terminal region. The surface bound protein biotemplates highly uniform MNPs of magnetite onto patterned surfaces during an aqueous mineralisation reaction (with a mean diameter of 90 ± 15 nm). The simple addition of 6% cobalt to the mineralisation reaction maintains the uniformity in grain size (with a mean diameter of 84 ± 14 nm), and results in the production of MNPs with a much higher coercivity (increased from ≈ 156 Oe to ≈ 377 Oe). Biotemplating magnetic nanoparticles on patterned surfaces could form a novel, environmentally friendly route for the production of bit-patterned media, potentially the next generation of ultra-high density magnetic data storage devices. This is a simple method to fine-tune the magnetic hardness of the surface biotemplated MNPs, and could easily be adapted to biotemplate a wide range of different nanomaterials on surfaces to create a range of biologically templated devices.


[Chemotherapy at the end of life for patients with lung cancer. A practice analysis].
Few studies have analyzed the aggressiveness of the care (continuation of active treatments) at the end of life in patients with lung cancer. The objective of this study was to assess practices in this setting in a university department of respiratory medicine. This retrospective study has consecutively included all patients who were managed for lung cancer and died over a period of 18 months. The analysis focused on the characteristics of the patients, the modalities of cancer treatment and the delays between the last active treatment and death. The overall median survival of the 94 patients included was 9.6 months; 92% of patients having received at least one active treatment. During the 4 and 2 weeks periods preceding death, respectively 55% and 22% of the patients received active treatments. The median time between the last day of active treatment and death was 27 days. These results, in concordance with the published data, showed that end of life active treatment in patients with lung cancer is a complex problem. We need prospective multicentric studies, with testing tools allowing better sharing of the decisions on active treatment between the medical team, the patient and his family.


FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice.
Breast cancers commonly become resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs); however, the mechanisms of this resistance remain largely unknown. We hypothesized that resistance may originate, at least in part, from molecular alterations that activate signaling downstream of EGFR. Using a screen to measure reversion of malignant cells into phenotypically nonmalignant cells in 3D gels, we identified FAM83A as a candidate cancer-associated gene capable of conferring resistance to EGFR-TKIs. FAM83A overexpression in cancer cells increased proliferation and invasion and imparted EGFR-TKI resistance both in cultured cells and in animals. Tumor cells that survived EGFR-TKI treatment in vivo had upregulated FAM83A levels. Additionally, FAM83A overexpression dramatically increased the number and size of transformed foci in cultured cells and anchorage-independent growth in soft agar. Conversely, FAM83A depletion in cancer cells caused reversion of the malignant phenotype, delayed tumor growth in mice, and rendered cells more sensitive to EGFR-TKI. Analyses of published clinical data revealed a correlation between high FAM83A expression and breast cancer patients' poor prognosis. We found that FAM83A interacted with and caused phosphorylation of c-RAF and PI3K p85, upstream of MAPK and downstream of EGFR. These data provide an additional mechanism by which tumor cells can become EGFR-TKI resistant.


Epidemiological trends in patients living with human immunodeficiency virus: a 13-year experience from a tertiary care center in India.
With significant advancement in the tools and strategies available for diagnosis and management, there is an expected change in the epidemiological profile of patients living with HIV/AIDS (Human immunodeficiency syndrome/Acquired immunedeficiency syndrome). We retrospectively analyzed the changing epidemiological pattern of HIV infection over a period of 13 years in the anti-retroviral (ART) center of a tertiary care hospital in India. The study included a total of 9419 patients (8811 adults and 608 children) who were registered at our ART center between 2005 and 2017. Among adult patients, 68.9% patients were males and the mean age of presentation was 35.6±9.9 years. Heterosexual route was the most common route of transmission (95.5%). A total of 97.4% of pediatric patients acquired HIV infection via vertical transmission from their mothers. Most of the adult patients (77.1%) were educated only to primary level. Despite the economic growth in the country over the years, the monthly income of these patients has not significantly changed. The median CD4 count at the time of eligibility for starting ART was 244/μl of blood. An increasing trend in the baseline CD4 count was noticed from 2005 to 2017. Also, improved outcomes with less loss to follow up were noticed in the latter years. However, an increasing trend was also noted in the time gap between registration at the ART center and initiation of ART. Improvement in the baseline CD4 count and better treatment outcomes are indicators of a well-functioning national program. However, continued programmatic interventions are needed to further tackle the menace of HIV/AIDS in India.