Blood pressure in a national birth cohort at the age of 36 related to social and familial factors, smoking, and body mass.
Blood pressure was measured in a birth cohort of 5362 subjects at the age of 36. The prevalence of hypertension in men (blood pressure greater than 140/90 mm Hg) was almost twice that in women, although women received treatment more often. Deaths of fathers of subjects from hypertensive and ischaemic heart disease were associated with significantly higher mean systolic and diastolic pressures in both sexes. Cigarette smoking was not strongly associated with blood pressure in men and not associated at all in women. Of the social factors, low social class of family of origin was associated with high blood pressure in both sexes; but the strongest association was with current body mass, and birth weight also contributed. Differences in blood pressures between the sexes may have been related to protective biological factors, such as endogenous sex hormones, in women and also to differences in types of employment, smoking habits, and body mass. Differences in blood pressures related to the social class of family of origin may reflect long term influences of class differences on diet, exercise, and educational achievement. The importance of measuring secular trends in obesity and blood pressures is emphasised.


Obesity and recurrent intervertebral disc prolapse after lumbar microdiscectomy.
The primary aim of this study was to investigate the relationship between obesity and recurrent intervertebral disc prolapse (IDP) following lumbar microdiscectomy. A retrospective review of case notes from 2008 to 2012 was conducted for all patients who underwent single level lumbar microdiscectomy performed by a single surgeon. All patients were followed up at two weeks and six weeks following surgery, and given an open appointment for a further six months. A total of 283 patients were available for analysis: 190 (67%) were in the non-obese group and 93 (32.9%) in the obese group. There was no statistical difference in postoperative infection, dural tear or length of stay between the non-obese and obese groups. Recurrent symptomatic IDP was seen in 27 patients (9.5%) confirmed by magnetic resonance imaging. Nineteen (10.0%) were in the non-obese group and eight (8.6%) in the obese group (p>0.8). In our study, obesity was not a predictor of recurrent IDP following lumbar microdiscectomy. Our literature review confirmed that this study reports the largest series to date analysing the relationship between obesity and recurrent IDP following lumbar microdiscectomy in the British population.


Serum TIMP-1 and response to the aromatase inhibitor letrozole versus tamoxifen in metastatic breast cancer.
To determine the effect of elevated serum TIMP-1 on the response of patients with metastatic breast cancer to an aromatase inhibitor versus tamoxifen. Five hundred twenty-two patients estrogen receptor-positive metastatic breast cancer were randomly assigned to receive first-line hormone therapy with letrozole or tamoxifen. Serum tissue inhibitor of metalloproteinases-1 (TIMP-1) levels were measured using an enzyme-linked immunosorbent assay. Pretreatment serum TIMP-1 was elevated in 120 (23%) of 522 patients. Patients with elevated serum TIMP-1 had a significantly reduced objective response rate (19.2% v 30.6%; odds ratio, 0.54; P = .01), duration of response (median, 15.5 v 26.2 months; P = .001), time to treatment progression (TTP; median, 4.5 v 9.2 months; HR, 1.78; P = .0001), time to treatment failure (median, 3.5 v 9.0 months; HR, 1.77; P = .0001), and overall survival (median, 20.3 v 35.8 months; HR, 1.77; P = .0001) compared with patients with normal pretreatment TIMP-1 levels. Letrozole was superior to tamoxifen in both the normal serum TIMP-1 group (median TTP, 11.8 v 8.6 months; P = .003) and in the elevated serum TIMP-1 group (median, 6.1 v 3.2 months; P = .03) In multivariate analysis, elevated serum TIMP-1 remained an independent predictor of both shorter TTP (HR, 1.46; P = .002) and survival (HR, 1.44; P = .002), as did serum HER-2. Combined analysis of both serum TIMP-1 and HER-2/neu conferred additional ability to predict significantly different clinical outcomes compared to using either biomarker alone. Patients with elevated pretreatment serum TIMP-1 had a significantly reduced response and survival. Serum TIMP-1 was an independent predictive and prognostic factor. Blockade of TIMP-1 and HER-2/neu activity may be beneficial in a subset of patients with breast cancer.


Investigations into Chemical Components from Monascus purpureus with Photoprotective and Anti-Melanogenic Activities.
Monascus species are asexually or sexually reproduced homothallic fungi that can produce a red colorant, specifically the so-called red yeast rice or Anka, which is used as a food ingredient in Asia. Traditional experiences of using Monascus for treating indigestion, enhancing blood circulation, and health remedies motivate us to investigate and repurpose Monascus-fermented products. Here, two new 5H-cyclopenta[c]pyridine type azaphilones, 5S,6S-monaspurpyridine A (1) and 5R,6R-monaspurpyridine A (2), two new xanthonoids, monasxanthones A and B (3 and 4), one new naphthalenone, monasnaphthalenone (5), and one new azaphilone, monapurpurin (6), along with two known compounds were isolated from the 70% EtOH extract of a citrinin-free domesticated strain M. purpureus BCRC 38110. The phytochemical properties of the xanthonoid and naphthalenone components were first identified from Monascus sp. differently from the representative ingredients of polyketide-derived azaphilones. UVB-induced cell viability loss and reactive oxygen species (ROS) overproduction in human keratinocytes were attenuated by monascuspirolide B (7) and ergosterol peroxide (8), indicating their photoprotective potentials. Ergosterol peroxide (8) decreased the melanin contents and tyrosinase activities of mouse melanocytes, depending on the concentration, suggesting their anti-melanogenic effects. In conclusion, six new and two known compounds were isolated from M. purpureus BCRC 38110, and two of them exhibited dermal protective activities. The results revealed the novel potential of M. purpureus for developing natural cosmeceutics against skin photoaging.


Chronic myeloid leukemia: In pursuit of perfection.
The resounding success of imatinib (IM) as front line treatment in patients with chronic myeloid leukemia (CML) has certainly made a paradigm shift in the therapeutic algorithm of this disorder. The precise targeting of the BCR-ABL oncogene in CML has entitled it to be the poster child of translational medicine with a well-deserved Oscar ovation from the oncology community. Clinicians are now empowered with first-, second- and third-generation tyrosine kinases, as well as advanced molecular tools to monitor disease and characterize resistance. We have come a long way in successfully managing these patients, but there are still a significant few unmet clinical needs which need addressing and targeting to optimize clinical outcomes. This review focuses on 4 such pertinent and relevant clinical issues, which still need ironing out to fulfill our ambition of achieving 'perfection' in this patient cohort.


Genetic variants analysis of three dromedary camels using whole genome sequencing data.
Whole genome wide identification and annotation of genetic variations in camels is in its first steps. The aim of this study was the identification of genome wide variants, functional annotations of them and enrichment analysis of affected genes using whole genome sequencing data of three dromedary camels. The genomes of two Iranian female dromedary camels that mostly used to produce meat and milk were sequenced to 41.9-fold and 38.6-fold coverage. A total of 4,727,238 single-nucleotide polymorphisms (SNPs) and 692,908 indels (insertions and deletions) were found by mapping raw reads to the dromedary reference assembly (GenBank Accession: GCA_000767585.1). In-silico functional annotation of the discovered variants in under study samples revealed that most SNPs (2,305,738; 48.78%) and indels (339,756; 49.03%) were located in intergenic regions. A comparison of the identified SNPs with those of the African camel (BioProject Accession: PRJNA269274) indicated that they had 993,474 SNPs in common. We found 15,168 non-synonymous SNPs in the shared variants of the three camels that could affect gene function and protein structure. Obtained results revealed that there were 7085, 6271 and 4688 non-synonymous SNPs among the 3436, 3058 and 2882 genes in the specific gene sets of Yazd dromedary, Trod dromedary and African dromedary, respectively. The list of genes predicted to be affected by non-synonymous variants in different individuals was subjected to gene ontology (GO) enrichment analysis.


Energy drink and ginseng consumption by Italian university students: a cross-sectional study.
The consumption of energy drinks (ED) and ginseng by young people to enhance their mental and physical performance has become widespread. Reported side-effects of ED have raised doubts regarding their safety. This cross-sectional study investigates the phenomenon. An anonymous questionnaire was administered to a representative sample of Verona university students. The resulting data were analyzed with Excel 2013, STATA 13 software. ED and ginseng consumption was reported by 38.6% and 37.4% of the students, respectively. More than 70% of ED and ginseng users were 18 to 22 years old. Excluding non-responders, ED consumers were mostly males (51.8% vs 33.0%), contrary to ginseng consumers (females 40.4% vs 30.9%). Being a working student was significantly positively associated both to EDs (OR 1.5) and ginseng use (OR 1.4). The most frequently reported academic and other reasons for ED use were: "to study longer" (47.5%), and "to socialize" (29.1%). The most often used combinations were ED containing alcohol (65.6%) and ginseng-coffee beverages (71.8%). The diffusion of ED and ginseng consumption warrants prevention and monitoring measures, and deserves further analysis.


Evidence-Based Study Design for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia.
The US Food and Drug Administration solicited evidence-based recommendations to improve guidance for studies of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). We analyzed 7 HABP/VABP datasets to explore novel noninferiority study endpoints and designs, focusing on alternatives to all-cause mortality (ACM). ACM at day 28 differed for ventilated HABP (27.8%), VABP (18.0%), and nonventilated HABP (14.5%). A "mortality-plus" (ACM+) composite endpoint was constructed by combining ACM with patient-relevant, infection-related adverse events from the Medical Dictionary for Regulatory Activities toxic/septic shock standardized query. The ACM+ rate was 3-10 percentage points above that of ACM across the studies and treatment groups. Predictors of higher ACM/ACM+ rates included older age and elevated acute physiology and chronic health evaluation (APACHE) II score. Only patients in the nonventilated HABP group were able to report pneumonia symptom changes. If disease groups and patient characteristics in future studies produce an ACM rate so low (<10%-15%) that a fixed noninferiority margin of 10% cannot be justified (requiring an odds ratio analysis), an ACM+ endpoint could lower sample size. Enrichment of studies with patients with a higher severity of illness would increase ACM. Data on symptom resolution in nonventilated HABP support development of a patient-reported outcome instrument.


Human Tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint.
All eukaryotes respond to DNA damage by modulation of diverse cellular processes to preserve genomic integrity and ensure survival. Here we identify mammalian Tousled like kinases (Tlks) as a novel target of the DNA damage checkpoint. During S-phase progression, when Tlks are maximally active, generation of DNA double-strand breaks (DSBs) leads to rapid and transient inhibition of Tlk activity. Experiments with chemical inhibitors, genetic models and gene targeting through RNA interference demonstrate that this response to DSBs requires ATM and Chk1 function. Chk1 phosphorylates Tlk1 on serine 695 (S695) in vitro, and this UCN-01- and caffeine-sensitive site is phosphorylated in vivo in response to DNA damage. Substitution of S695 to alanine impaired efficient downregulation of Tlk1 after DNA damage. These findings identify an unprecedented functional co- operation between ATM and Chk1 in propagation of a checkpoint response during S phase and suggest that, through transient inhibition of Tlk kinases, the ATM-Chk1-Tlk pathway may regulate processes involved in chromatin assembly.


[A comparison of the value of magnetic resonance tomography and computed tomography in Nelson syndrome patients].
The hypophyses of 13 patients with Nelson syndrome following bilateral adrenalectomy were examined by MRI and CT. Diffuse enlargement of the hypophysis was demonstrated in 8 patients by CT and in 9 by MRI. Compared with CT, MRI provides better demonstration of tumour development, such as abnormal convexity of the cranial margin of the hypophysis (MRI 4/13, CT 1/13), displacement of the infundibulum (MRI 4/13, CT 0/13) or optic chiasm (MRI 2/13, CT 0/13). MRI also provides diagnostically important differentiation between scar tissue and recurrence of tumour following hypophysectomy (MRI 1/3, CT 0/3) and more accurate demonstration of infiltration of the cavernous sinus (MRI 4/13, CT 2/13). CT is superior only in showing the floor of the sella. MRI is the method of choice for imaging in cases of Nelson syndrome.


Drug-induced liver injury due to antimicrobials, central nervous system agents, and nonsteroidal anti-inflammatory drugs.
Antimicrobial agents including antituberculosis (anti-TB) agents are the most common cause of idiosyncratic drug-induced liver injury (DILI) and drug-induced liver failure across the world. Better molecular and genetic biomarkers are acutely needed to help identify those at risk of liver injury particularly for those needing antituberculosis therapy. Some antibiotics such as amoxicillin-clavulanate and isoniazid consistently top the lists of agents in retrospective and prospective DILI databases. Central nervous system agents, particularly antiepileptics, account for the second most common class of agents implicated in DILI registries. Hepatotoxicity from older antiepileptics such as carbamazepine, phenytoin, and phenobarbital are often associated with hypersensitivity features, whereas newer antiepileptic drugs have a more favorable safety profile. Antidepressants and nonsteroidal anti-inflammatory drugs carry very low risk of significant liver injury, but their prolific use make them important causes of DILI. Early diagnosis and withdrawal of the offending agent remain the mainstays of minimizing hepatotoxicity.


A process evaluation of a "physical activity pathway" in the primary care setting.
Let's Get Moving (LGM) is a systematic approach to integrating physical activity promotion into the primary care setting. LGM combines a number of recommended strategies to support behavior change including brief interventions, goal-setting, written resources, and follow-up support. This study involved a process evaluation of implementing LGM in UK general practice. The LGM intervention was implemented in six general practices in London. Practices recruited patients either 'opportunistically' in routine consultations or by letter of invitation sent to patients on the hypertension disease register. A key component of the intervention was the delivery of a brief counselling session aimed at facilitating physical activity behaviour change. Data collection methods included electronic patient records, a practice survey and focus groups and interviews with practitioners. A total of 526 patients were considered for LGM, 378 via the 'opportunistic' recruitment method and 148 using the disease register approach. Patient interest in the brief counselling session was high although the actual delivery style and content varied between practitioners. Patients were directed towards a variety of physical activity opportunities including local leisure services and walking schemes. The learning from this pilot should inform a revised update of the LGM protocols before the planned dissemination of the intervention which is outlined in the Governments 'Be Active, Be Healthy' physical activity strategy. A robust assessment of effectiveness involving an experimental design and behaviour change measures is also warranted prior to wider dissemination.


Galactose neuropathy. Structural changes evaluated by nuclear magnetic resonance spectroscopy.
We examined the hypothesis that the polyol accumulation resulting from chronic galactose supplementation in the diet produces endoneurial edema that can be prevented by inhibition of aldose reductase. We explored the potential of nuclear magnetic resonance (NMR) spectroscopy to quantitate and characterize the water accumulation in the sciatic nerve in this "galactose neuropathy." The data demonstrate a 16% increase in gravimetrically determined total water content of nerve in the galactose-fed rat after 8 mo of this diet and a 50% increase in the T1 relaxation time for nerve water as determined by NMR spectroscopy. Prolongation of the T1 relaxation time reflects increased rotation of water in a magnetic field, consistent with an extracellular site of the additional water. Simultaneous feeding of sorbinil to inhibit aldose reductase resulted in normalization of both total nerve water and of the prolongation of T1 relaxation time. These data define the NMR-spectroscopic state of endoneurial edema in the galactose-fed rat and suggest specific application to the investigation of the role of aldose reductase in human diabetic neuropathy.


The chronography of interactions with autistic speakers: an initial report.
The aims of this study were to (a) describe the conversational time patterns of autistic persons capable of talking, and (b) examine the degree to which the autistic speakers synchronize the time patterns of their speech with those of the persons with whom they interact. Each of twelve autistic youths participated in two interactions, one with an experimenter and one with his or her parent. In addition, each parent engaged in a conversation with the experimenter. The results indicate that: (a) compared with those interactions involving the parents and experimenter, those involving the youths and parents exhibited longer switching pauses whereas those involving the youths and experimenter exhibited longer switching pauses and pauses; and (b) although the parents and experimenter achieved temporal synchrony in their interactions, there was no evidence that the youths achieved it with either the experimenter or their parents.


Amnesia in acute herpetic and nonherpetic encephalitis.
To evaluate how often global amnesia syndrome is encountered as a sequel of herpes simplex virus type 1 encephalitis (HSVE) and in other types of acute encephalitides, and to evaluate whether there are qualitative differences in amnesia caused by different encephalitides. Forty-five consecutive patients with encephalitis (mean age, 40.8 years) studied prospectively within a 5-year period, 8 of whom had HSVE. There were 24 normal controls. Neuropsychological assessment and memory evaluation after the acute stage of encephalitis, as well as at follow-up after 27.7 +/- 18.6 months. Three patients (6%), including 1 with HSVE, had persistent anterc grade and retrograde memory defects, typical features of global amnesia. Twelve patients had anterograde amnesia in the first assessment. No statistically significant differences in the memory measures were found between the HSVE (n = 4) and the non-HSVE (n = 8) groups. Some patients had predominantly semantic difficulty, some had a "frontal-type" memory disorder, and in some patients rapid forgetting was the prominent feature. The frequency of amnesia can reliably be evaluated only in consecutive series of patients. Previous literature, mainly case reports, may give the impression that global amnesia is a common consequence of encephalitis. Our findings do not support that view. Furthermore, there are clear differences in the quality of the memory impairment between cases of acute encephalitides. Our findings suggest that amnesia as a consequence of encephalitis, even HSVE, should not be considered a uniform phenomenon.


A Multicentre Italian Validation Study in Aging Adults with Down Syndrome and Other Forms of Intellectual Disabilities: Dementia Screening Questionnaire for Individuals with Intellectual Disabilities.
The USA National Task Group (NTG) guidelines advocate the use of an adapted version of Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID) for dementia screening of individuals with Down syndrome (DS) and with other forms of ID (non-DS). In order to meet these guidelines, this study verifies the psychometric properties of an Italian version of the original DSQIID in a population composed of adults aged 40 years and over with DS and non-DS ID. Internal consistency, inter-rater and intra-rater reliabilities, structural validity, convergent validity and known group differences of DSQIID-I were assessed with 200 individuals with ID (mean of 55.2 years; range: 40-80 years) recruited from 15 different centers in Italy. Diagnosis of dementia was done according to IASSID diagnostic criteria and its degree of clinical certainty was defined according to Silverman et al.'s classification (2004). Cronbach's alpha for the DSQIID-I was 0.94. The ICCs for inter-rater and test-retest reliability were both 0.89. A Principal Component analysis revealed three domains, namely memory and confusion- related items, motor and functional disabilities, depression and apathy, which explained almost 40% of the overall variance. The total DSQIID-I score correlated significantly with DMR and differed significantly among those individuals (n = 34) with cognitive decline from those without (n = 166). Age, gender and severity of ID were unrelated to the DSQIID-I. The present study confirms the cross-cultural value of DSQIID which was proved to be a psychometrically valid and user-friendly observer-rated scale for dementia screening in adults with both DS and non-DS ID.


IL-7 expands lymphocyte populations and enhances immune responses to sipuleucel-T in patients with metastatic castration-resistant prostate cancer (mCRPC).
Sipuleucel-T (sip-T) is a Food and Drug Administration (FDA)-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). We hypothesized that combining sip-T with interleukin (IL)-7, a homeostatic cytokine that enhances both B and T cell development and proliferation, would augment and prolong antigen-specific immune responses against both PA2024 (the immunogen for sip-T) and prostatic acid phosphatase (PAP). Fifty-four patients with mCRPC treated with sip-T were subsequently enrolled and randomized 1:1 into observation (n=26) or IL-7 (n=28) arms of a phase II clinical trial (NCT01881867). Recombinant human (rh) IL-7 (CYT107) was given weekly×4. Immune responses were evaluated using flow cytometry, mass cytometry (CyTOF), interferon (IFN)-γ ELISpot, 3H-thymidine incorporation, and ELISA. Treatment with rhIL-7 was well tolerated. For the rhIL-7-treated, but not observation group, statistically significant lymphocyte subset expansion was found, with 2.3-2.6-fold increases in CD4+T, CD8+T, and CD56bright NK cells at week 6 compared with baseline. No significant differences in PA2024 or PAP-specific T cell responses measured by IFN-γ ELISpot assay were found between rhIL-7 and observation groups. However, antigen-specific T cell proliferative responses and humoral IgG and IgG/IgM responses significantly increased over time in the rhIL-7-treated group only. CyTOF analyses revealed pleiotropic effects of rhIL-7 on lymphocyte subsets, including increases in CD137 and intracellular IL-2 and IFN-γ expression. While not powered to detect clinical outcomes, we found that 31% of patients in the rhIL-7 group had prostate specific antigen (PSA) doubling times of >6 months, compared with 14% in the observation group. Treatment with rhIL-7 led to a significant expansion of CD4+ and CD8+ T cells, and CD56bright natural killer (NK) cells compared with observation after treatment with sip-T. The rhIL-7 treatment also led to improved antigen-specific humoral and T cell proliferative responses over time as well as to increased expression of activation markers and beneficial cytokines. This is the first study to evaluate the use of rhIL-7 after sip-T in patients with mCRPC and demonstrates encouraging results for combination approaches to augment beneficial immune responses.


Incidence and physiological relevance of protein thiol switches.
A few small-molecule oxidants, most notably hydrogen peroxide, can act as messengers in signal transduction. They trigger so-called 'thiol switches', cysteine residues that are reversibly oxidized to transiently change the functional properties of their host proteins. The proteome-wide identification of functionally relevant 'thiol switches' is of significant interest. Unfortunately, prediction of redox-active cysteine residues on the basis of surface accessibility and other computational parameters appears to be of limited use. Proteomic thiol labeling approaches remain the most reliable strategy to discover new thiol switches in a hypothesis-free manner. We discuss if and how genomic knock-in strategies can help establish the physiological relevance of a 'thiol switch' on the organismal level. We conclude that surprisingly few attempts have been made to thoroughly verify the physiological relevance of thiol-based redox switches in mammalian model organisms.


Advantages of pressurized canister metered dose inhalers.
Metered dose inhalers (MDI) have provided a versatile, reliable, instantly available, self-contained, portable, low cost medical aerosol delivery system for more than 35 years. Currently, most of the drugs commonly used for treating reversible airflow obstruction due to asthma and chronic obstructive pulmonary disease (COPD) are available as MDI and consideration is being given to formulating other potentially useful drugs such as antibiotics, amiloride, and pentamidine in MDI. By means of particle size selective accessory devices, MDI can be used for pulmonary drug targeting which, by further improving the therapeutic ratio inherent to aerosol therapy, reduces local and systemic side effects and should allow application to the pulmonary airways of significantly larger doses of medication than could otherwise be administered safely. Appropriate masks and a variety of adapters have been developed to allow the MDI to be used in infants and children, as well as patients of all ages requiring assisted ventilation. While nebulizers and powder inhalers both have an important role to play in the management of airway and parenchymal disease, there is, as yet, no all-purpose aerosol generation and delivery system to replace the MDI. While the ideal is obviously to develop new environmentally friendly pressurizing liquid/gaseous systems that are chlorofluorocarbon free, this will take a minimum of a decade if, in the final analysis, it can be done at all. In the meantime, patients should be provided with the current formulations until appropriate substitutes become available.


The good engineer: giving virtue its due in engineering ethics.
During the past few decades, engineering ethics has been oriented towards protecting the public from professional misconduct by engineers and from the harmful effects of technology. This "preventive ethics" project has been accomplished primarily by means of the promulgation of negative rules. However, some aspects of engineering professionalism, such as (1) sensitivity to risk (2) awareness of the social context of technology, (3) respect for nature, and (4) commitment to the public good, cannot be adequately accounted for in terms of rules, certainly not negative rules. Virtue ethics is a more appropriate vehicle for expressing these aspects of engineering professionalism. Some of the unique features of virtue ethics are the greater place it gives for discretion and judgment and also for inner motivation and commitment. Four of the many professional virtues that are important for engineers correspond to the four aspects of engineering professionalism listed above. Finally, the importance of the humanities and social sciences in promoting these virtues suggests that these disciplines are crucial in the professional education of engineers.


Development of a Remodeled Caspar Retractor and Its Application in the Measurement of Distractive Resistance in an In Vitro Anterior Cervical Distraction Model.
In vitro biomechanical study of the cervical intervertebral distraction using a remodeled Caspar retractor. To investigate the torques required for distraction to different heights in an in vitro C3-C4 anterior cervical distraction model using a remodeled Caspar retractor, focusing on the influence of the intervertebral disk, posterior longitudinal ligament (PLL), and ligamentum flavum (LF). No previous studies have reported on the torques required for distraction to various heights or the factors resisting distraction in anterior cervical discectomy and fusion. Anterior cervical distractions at C3-C4 was performed in 6 cadaveric specimens using a remodeled Caspar retractor, under 4 conditions: A, before disk removal; B, after disk removal; C, after disk and PLL removal; and D, after disk and PLL removal and cutting of the LF. Distraction was performed for 5 teeth, and distractive torque of each tooth was recorded. The torque increased with distraction height under all conditions. There was a sudden increase in torque at the fourth tooth under conditions B and C, but not D. Under condition A, distraction to the third tooth required 84.8±13.3 cN m. Under conditions B and C, distraction to the third tooth required <13 cN m, and further distraction required dramatically increased torque. Under condition D, no marked increase in torque was recorded. Distraction of the intervertebral space was much easier after disk removal. An intact LF caused a sudden marked increase in the force required for distraction, possibly indicating the point at which the LF was fully stretched. This increase in resistance may help to determine the optimal distraction height to avoid excessive stress to the endplate spacer. The remodeled Caspar retractor in the present study may provide a feasible and convenient method for intraoperative measurement of distractive resistance.


Polyamines serum levels in episodic and chronic migraine.
Background: Previous studies focused on food as the trigger of a migraine attack did not consider polyamines as possible activators and sensitizers of the trigeminal-vascular system through their interaction with NMDA glutamate receptors. Therefore, this study aimed to assess serum levels of nine polyamines and to evaluate their role as possible triggers and crisis maintainers in episodic and chronic migraine patients. Materials and methods: The study included 50 patients with episodic migraine (EM), 50 patients with chronic migraine (CM) and 50 healthy controls (HC). Serum levels of nine polyamines have been determined by Liquid Chromatography tandem Mass Spectrometry. Specifically, agmatine, spermidine, spermine, putrescine, cadaverine, arginine, ornithine, citrulline and lysine levels were studied. Results: Agmatine serum levels resulted reduced in EC patients with respect to CM and HC. Compared to HC subjects, serum levels of spermine and spermidine were statistically significantly increased both in CM and EM patients. Conclusions: The authors suggest that alterations of polyamines levels might contribute to the understanding of migraine external activation and help to clarify the potential role of NMDA receptor polyamines site antagonists in migraine treatment.


Ischemic stroke subtype incidence among whites, blacks, and Hispanics: the Northern Manhattan Study.
Stroke incidence is greater in blacks than in whites; data on Hispanics are limited. Comparing subtype-specific ischemic stroke incidence rates may help to explain race-ethnic differences in stroke risk. The aim of this population-based study was to determine ischemic stroke subtype incidence rates for whites, blacks, and Hispanics living in one community. A comprehensive stroke surveillance system incorporating multiple overlapping strategies was used to identify all cases of first ischemic stroke occurring between July 1, 1993, and June 30, 1997, in northern Manhattan. Ischemic stroke subtypes were determined according to a modified NINDS scheme, and age-adjusted, race-specific incidence rates calculated. The annual age-adjusted incidence of first ischemic stroke per 100,000 was 88 (95% CI, 75 to 101) in whites, 149 (95% CI, 132 to 165) in Hispanics, and 191 (95% CI, 160 to 221) in blacks. Among blacks compared with whites, the relative rate of intracranial atherosclerotic stroke was 5.85 (95% CI, 1.82 to 18.73); extracranial atherosclerotic stroke, 3.18 (95% CI, 1.42 to 7.13); lacunar stroke, 3.09 (95% CI, 1.86 to 5.11); and cardioembolic stroke, 1.58 (95% CI, 0.99 to 2.52). Among Hispanics compared with whites, the relative rate of intracranial atherosclerotic stroke was 5.00 (95% CI, 1.69 to 14.76); extracranial atherosclerotic stroke, 1.71 (95% CI, 0.80 to 3.63); lacunar stroke, 2.32 (95% CI, 1.48 to 3.63); and cardioembolic stroke, 1.42 (95% CI, 0.97 to 2.09). The high ischemic stroke incidence among blacks and Hispanics compared with whites is due to higher rates of all ischemic stroke subtypes.


Sexual difference in kininase activity in the mouse submandibular gland.
A marked sexual difference in kininase activity was found in the adult mouse submandibular gland. The activity was over 3-fold higher in females than in males between 10 and 12 weeks of age. Castration of male mice increased kininase activity up to the level of females. Testosterone administration to castrated males restored enzyme activity to about the normal level. Moreover, testosterone administration to normal females decreased enzyme activity to about the level of normal male mice, while ovariectomy had no effect. These results suggest that kininase activity in the mouse submandibular gland is suppressively regulated by endogenous androgen.


Assembly of functional alpha6beta3gamma2delta GABA(A) receptors in vitro.
Transgenic mice deficient in the alpha6 subunit of the GABA(A) receptor show reduced levels of the delta subunit protein and an altered GABA(A) receptor pharmacology, suggesting selective assembly mechanisms. Delta reduced the binding of [3H]Ro15-4513 or t-butylbicyclophosphoro[35S]thionate and, to a lesser extent, [3H]muscimol to recombinant alpha1beta1gamma2(delta), alpha4beta1gamma2(delta) and alpha6beta1gamma2(delta) receptors, paralleled by diminished GABA-evoked maximal currents in electrophysiological recordings for the latter one. The delta subunit gave rise to a lower EC50 for GABA and a slowed desensitization indicating its assembly in alpha6beta2delta, alpha6beta1gamma2delta and alpha6beta2gamma2delta receptors. The data show that the delta subunits assemble in various functional GABA(A) receptor subtypes in vitro to reduce GABA-evoked maximal currents and ligand binding, but increase the potency for GABA.


An HIV-1 gp120 envelope human monoclonal antibody that recognizes a C1 conformational epitope mediates potent antibody-dependent cellular cytotoxicity (ADCC) activity and defines a common ADCC epitope in human HIV-1 serum.
Among nonneutralizing HIV-1 envelope antibodies (Abs), those capable of mediating antibody-dependent cellular cytotoxicity (ADCC) activity have been postulated to be important for control of HIV-1 infection. ADCC-mediating Ab must recognize HIV-1 antigens expressed on the membrane of infected cells and bind the Fcγ receptor (FcR) of the effector cell population. However, the precise targets of serum ADCC antibody are poorly characterized. The human monoclonal antibody (MAb) A32 is a nonneutralizing antibody isolated from an HIV-1 chronically infected person. We investigated the ability of MAb A32 to recognize HIV-1 envelope expressed on the surface of CD4(+) T cells infected with primary and laboratory-adapted strains of HIV-1, as well as its ability to mediate ADCC activity. The MAb A32 epitope was expressed on the surface of HIV-1-infected CD4(+) T cells earlier than the CD4-inducible (CD4i) epitope bound by MAb 17b and the gp120 carbohydrate epitope bound by MAb 2G12. Importantly, MAb A32 was a potent mediator of ADCC activity. Finally, an A32 Fab fragment blocked the majority of ADCC-mediating Ab activity in plasma of subjects chronically infected with HIV-1. These data demonstrate that the epitope defined by MAb A32 is a major target on gp120 for plasma ADCC activity.


The significance of measuring body fat percentage determined by bioelectrical impedance analysis for detecting subjects with cardiovascular disease risk factors.
Body fat percentage (BF%) determined by bioelectrical impedance analysis is widely used at home and in medical check-ups. However, the clinical significance of measuring BF% has not been studied in detail. A cross-sectional study was carried out on a cohort of 10,774 middle-aged Japanese men who had undergone an annual check-up in 2008. Cut-off points were evaluated for body mass index (BMI), waist circumference (WC), and BF% for detecting participants with cardiovascular disease (CVD) risk factors (diabetes mellitus, hypertension, dyslipidemia), and effectiveness compared for each marker's cut-off point. Additionally, the effects of smoking on cut-off points were evaluated. The cut-off points of BMI, WC, and BF% for detecting participants with 1 or more CVD risk factors were 22.7kg/m(2), 81.4cm, and 20.3%, respectively. The cut-off points of BF% for 1 or more CVD risk factors classified 3.43% more subjects into correct categories than those of BMI (P<0.001). The cut-off points of BMI, WC, and BF% for detecting individuals with 3 CVD risk factors in current smokers were 24.9kg/m(2), 87.8cm, and 23.7%, while those in non-smokers were 23.3kg/m(2), 83.9cm, and 22.3%, respectively. BF% could be more effective in detecting individuals with early stage CVD risk accumulation than BMI. The cut-off points for current smokers were lower than those for non-smokers in all markers.


Early Liver Transplantation for Neonatal-Onset Methylmalonic Acidemia.
With conventional dietary treatment, the clinical course of methylmalonic acidemia due to cobalamin-unresponsive methylmalonyl-CoA mutase (MCM) deficiency is characterized by the persistent risk of recurrent life-threatening decompensation episodes with metabolic acidosis, hyperammonemia, and coma. Liver transplant has been proposed as an alternative treatment and anecdotally attempted in the last 2 decades with inconsistent results. Most criticisms of this approach have been directed at the continuing risk of neurologic and renal damage after transplant. Here, we report the perioperative and postoperative clinical and biochemical outcomes of 2 patients with severe MCM deficiency who underwent early liver transplant. In both cases, liver transplant allowed prevention of decompensation episodes, normalization of dietary protein intake, and a marked improvement of quality of life. No serious complications have been observed at 12 years' and 2 years' follow-up, respectively, except for mild kidney function impairment in the older patient. On the basis of our experience, we strongly suggest that liver transplant should be offered as a therapeutic option for children with cobalamin-unresponsive MCM deficiency at an early stage of the disease.


Gastric adenocarcinoma of the fundic gland type shares common genetic and phenotypic features with pyloric gland adenoma.
Gastric adenocarcinoma of the fundic gland type (GAFG) and pyloric gland adenoma (PGA) have recently been recognized as rare types of neoplasia. We performed comparative immunohistochemical and genetic analyses of 3 GAFGs and 12 PGAs. All of the 3 GAFGs were diffusely positive for pepsinogen-I, MIST1 and MUC6, indicating the predominantly chief cell/mucous neck cell differentiation of these tumors. A small number of H.K-ATPase-positive parietal cells were also scattered. PGAs invariably exhibited diffuse MUC6 and TFF2 expression, consistent with the pyloric gland differentiation of these tumors. Ten of the 12 PGAs also unexpectedly exhibited focal expression of pepsinogen-I and MIST1, suggesting that PGAs often show focal chief cell differentiation and phenotypically resemble mucous neck cells rather than pyloric glands. The mutation analyses revealed activating GNAS mutations, which have been reported to be frequently detected in PGAs, in two of the GAFGs. While GAFGs and PGAs are morphologically distinct lesions, our observations showed their partially overlapping immunohistochemical profiles and shared presence of GNAS mutations, in addition to their common occurrence in the fundic gland mucosa. Based on these observations, we suggest that both GAFGs and PGAs are closely related lesions characterized by a mucous neck cell/chief cell lineage phenotype.


Influence of pharmacological experiments of chemicals and other factors in diets of laboratory animals.
Results derived from animal experimentation depend to a considerable degree on the health and welfare of the animal from which the results are obtained. This, in turn, reflects the quality of housing, care, and nutrition provided the animal. Most diets designed for a particular species provide a reasonable balance of nutrients in quantities sufficient for normal growth and maintenance and reproduction of that species. Under usual conditions of animal feed manufacture, however, concentrations of essential ingredients may vary appreciably in different batches of a formulation made with different lots of natural ingredients, even though the guaranteed analysis shown on the label remains correct. A feed may also contain intentional or unintentional additives and other biologically active components. Variations in the concentrations of essential dietary components, as well as the presence of extraneous materials, can significantly influence the performance of an experimental animal consuming the diet and can thus lead to a biased interpretation of esperimental results. Investigators must consider factors which can result in efficient or inefficient utilization of energy, the variation in prepared diets whether from natural or purified products, and how these can modify the animal and change the response to a given experimental regimen. Proteins, fat, carbohydrates, vitamins, and minerals can all have pharmacological as well as physiological effects on a biological system. The control of vitamin D metabolism and calcium, parathormone, calcitonin among others are important factors subject to dietary modification. A conditioned marginal or frank deficiency of folic acid can result from oral contraceptives and administration of anticonvulsants; if studies are done in animals using these types of chemicals, dietary folate will be highly significant. Newer information about the role of ascorbic acid in activation of lipase and lipid mobilization is of direct concern to those using research animals requiring a source of dietary ascorbic acid. Trace elements, some amino acids, natural enzyme inducers, and toxic contaminants, all of which can affect the response of experimental animals, are highly important to the quality of animal research in pharmacologic investigations.


Choosing dentistry as a career--Part II--The meaning of motives.
This part of the study points out that concepts such as service to others, the need for regular working hours, financial security and independence have different meanings for different people. What is ultimately shown however, is that despite group and meaning differences, motives for a career choice in dentistry appear to operate on two levels. The first is on the level of the rational and the conscious and the second on the level of the irrational and the subconscious. Knowledge of this process has important implications for the selection and training of students.


Short-term results of quality of life for curatively treated colorectal cancer patients in Lithuania.
Treatment options for colorectal cancer patients create the need to assess the quality of life (QoL) of colorectal cancer patients in the early postoperative period when changes are potentially greatest. The aim of the current study was to assess the QoL of colorectal cancer patients following open and laparoscopic colorectal surgery. A total of 82 consecutive patients requiring elective open or laparoscopic colorectal surgery were recruited to the study for 3 months in the three colorectal surgery centers of Lithuania. Patients completed the EORTC QLQ-C30 (version 3.0) questionnaire before surgery, 2 and 5 days, 1 and 3 months after operation. The EORTC QLQ-CR29 questionnaire was completed before surgery and at 1 and 3 months after operation. Analysis was done according to the manual for each instrument. EORTC QLQ-C30 reflected the postoperative recovery of QoL. The global health status, cognitive and emotional functioning came back to the preoperative level in one month after operation. Physical and role functioning for laparoscopic group was significantly improved in 1 month after operation and in 3 months for open surgery group respectively. Colorectal module EORTC-QLQ-CR29 found that future perspective increased significantly in laparoscopic group 1 month after operation. The present study showed that majority of functional scale scores came back to the preoperative level during the first 3 months after colorectal cancer surgery. Differences in QoL according to surgical approach are mostly expressed on this period.


Cross-protection against bean yellow mosaic virus (BYMV) and clover yellow vein virus by Attenuated BYMV isolate M11.
Attenuated isolate M11 of Bean yellow mosaic virus (BYMV), obtained after exposing BYMV-infected plants to low temperature, and its efficacy in cross-protecting against infection by BYMV isolates from gladiolus, broad bean (Vicia faba) and white clover (Trifolium repens) was assessed with western blotting and reverse transcription-polymerase chain reaction. The level of cross-protection varied depending on the challenge virus isolates. Cross-protection was complete against BYMV isolates from gladiolus, but incomplete against BYMV isolates from other hosts. M11 also partially cross-protected against an isolate of Clover yellow vein virus. A comparison of the nucleotide sequence of M11 and those of BYMV isolates from gladiolus and from other hosts showed higher homology among gladiolus isolates than the homology between gladiolus isolates and nongladiolus isolates. In the phylogenetic trees, constructed using the nucleotide sequences of an overall polyprotein of the genomes, five gladiolus isolates clustered together, completely separated from the three BYMV isolates from other hosts. A comparison of the amino acid sequences between M11 and its parental isolate IbG, and analysis of recombinant infectious clones between M11 and IbG revealed that an amino acid at position 314 was involved in the attenuation of BYMV.


Beyond traditional methods: Unveiling the skin whitening properties of Rhein-Embedded PROTACs.
Proteolysis Targeting Chimeras (PROTAC) technology has emerged as a promising approach for targeted protein degradation. In this study, we focused on tyrosinase (TYR), a key enzyme involved in melanin synthesis and pigmentation. For this target, we designed and synthesized a series of PROTACs (D3-D9), employing Rhein as the target protein-ligand. Through some experimental tests, we made a significant discovery. Preliminary experimental results show that the most promising compound (D6) demonstrated the ability to degrade MITF and inhibit the expression and TYR in B16-F10 cells, effectively suppressing melanogenesis in zebrafish. Notably, at equivalent concentrations, the whitening effect of D6 surpassed that of its precursor Rhein and was even comparable to that of the well-established whitening agent, β-arbutin. Validating experiments further revealed that the action of D6 was reliant on the E3 ligand, indicating its capacity to degrade TYR and MITF through the ubiquitination pathway. Whether D6 acts directly on TYR or MITF needs to be further explored. These compelling results underscore the tremendous whitening potential of D6, suggesting its suitability as a valuable lead for whitening agents and its potential to expand the range of whitening cosmetic products.


BERT-GT: cross-sentence n-ary relation extraction with BERT and Graph Transformer.
A biomedical relation statement is commonly expressed in multiple sentences and consists of many concepts, including gene, disease, chemical and mutation. To automatically extract information from biomedical literature, existing biomedical text-mining approaches typically formulate the problem as a cross-sentence n-ary relation-extraction task that detects relations among n entities across multiple sentences, and use either a graph neural network (GNN) with long short-term memory (LSTM) or an attention mechanism. Recently, Transformer has been shown to outperform LSTM on many natural language processing (NLP) tasks. In this work, we propose a novel architecture that combines Bidirectional Encoder Representations from Transformers with Graph Transformer (BERT-GT), through integrating a neighbor-attention mechanism into the BERT architecture. Unlike the original Transformer architecture, which utilizes the whole sentence(s) to calculate the attention of the current token, the neighbor-attention mechanism in our method calculates its attention utilizing only its neighbor tokens. Thus, each token can pay attention to its neighbor information with little noise. We show that this is critically important when the text is very long, as in cross-sentence or abstract-level relation-extraction tasks. Our benchmarking results show improvements of 5.44% and 3.89% in accuracy and F1-measure over the state-of-the-art on n-ary and chemical-protein relation datasets, suggesting BERT-GT is a robust approach that is applicable to other biomedical relation extraction tasks or datasets. the source code of BERT-GT will be made freely available at https://github.com/ncbi/bert_gt upon publication. Supplementary data are available at Bioinformatics online.


VoluDerm microneedle technology for skin treatments-in vivo histological evidence.
The growing demand for skin rejuvenation procedures with minimal down time and low risk has led to the development of fractional radiofrequency (RF) systems. The new VoluDerm™ RF microneedle technology creates minute columns of tissue thermal microablation. Treatment triggers natural fractional healing, resulting in dermal volumizing and skin renewal. This preclinical research assessed the safety and efficacy of the VoluDerm through histological evaluation of morphological changes in the target tissue. Following approval of protocol by ethical committee, treatments were conducted on two domestic pigs using VoluDerm disposable tips. Histological samples of 14, 7, 4 days and immediately after treatment with various energy settings were analyzed. Immediate VoluDerm epidermal and dermal effects, and progress of healing process, as function of time following treatment (days 4 and 7), were demonstrated. Histology analysis of samples of 14 days demonstrated complete healing for all energy levels. This in vivo histology confirmed the safe and effective performance of the VoluDerm treatment. A fractional pattern of affected areas, surrounded by healthy tissue, was demonstrated. Healing process proved natural dermal renewal and epidermal complete regeneration. Histology supports clinical advantages of the VoluDerm natural-looking skin enhancement, with none to minimal pain and no downtime.


Restoration of a tumorigenic phenotype by beta 2-microglobulin transfection to EL-4 mutant cells.
It has frequently been suggested that loss of beta 2-microglobulin (beta 2m) in tumor cells may lead to malignant progression due to escape from immunological recognition. Here, we directly tested the role of beta 2m expression in tumorigenicity. A beta 2 m loss mutant (C4.4-25-), selected from the murine lymphoma EL-4, showed a marked reduction in tumorigenicity as compared with EL-4 in normal C57B1/6 (B6) mice. The reduced tumorigenicity was directly related to beta 2 m expression. Transfection of an intact murine beta 2m gene markedly increased the tumorigenic potential. The reduced tumorigenicity of C4.4-25- compared with beta 2m transfected cells was observed also in athymic B6 nu/nu mice, but was abolished in B6 mice depleted of natural killer (NK) 1.1-positive cells. These results show that restoration of beta 2m expression can promote tumorigenicity and demonstrate for the first time that induction of major histocompatibility complex class I expression by transfection can lead to escape from NK cells in vivo.


Increased activity of carotid sinus baroreceptors by sympathetic stimulation and norepinephrine.
Effects of electrical stimulation of sympathetic nerves to the carotid sinus on the discharge of single active baroreceptor fibers of the rabbit were examined in situ and in functionally isolated carotid sinus preparations with an intact sympathetic innervation under controlled conditions of pressure and temperature. Among 30 single units, 18 units responded to sympathetic stimulation of increasing discharge frequency. The excitatory effect of sympathetic stimulation on baroreceptor activity was not abolished by phentolamine (1 mg/kg iv or 10(-6) g/ml in perfusate). In isolated carotid sinus preparations perfused with Krebs-Henseleit solution, various pressure steps were applied to the sinus, and effects of norepinephrine (NE; 10(-9) and 10(-6) g/ml) on activity of nine single baroreceptor units were examined. In the presence of 10(-9) g/ml NE, discharge frequency of all units significantly increased at a given pressure step when compared with the control, whereas NE at a high concentration (10(-6) g/ml) did not produce significant changes in the discharge frequency. It is concluded that NE released by sympathetic nerve endings most likely acts directly on the baroreceptor nerve endings and sensitizes them.


Co-debriefing for simulation-based education: a primer for facilitators.
As part of simulation-based education, postevent debriefing provides an opportunity for learners to critically reflect on the simulated experience, with the goal of identifying areas in need of reinforcement and correcting areas in need of improvement. The art of debriefing is made more challenging when 2 or more educators must facilitate a debriefing together (ie, co-debriefing) in an organized and coordinated fashion that ultimately enhances learning. As the momentum for incorporating simulation-based health care education continues to grow, the need for faculty development in the area of co-debriefing has become essential. In this article, we provide a practical toolbox for co-facilitators by discussing the advantages of co-debriefing, describing some of the challenges associated with co-debriefing, and offering practical approaches and strategies to overcome the most common challenges associated with co-debriefing in the context of simulation-based health care education.


Indoleamine 2,3-dioxygenase as a new target for malignant glioma therapy. Laboratory investigation.
Indoleamine 2,3-dioxygenase (IDO), a kynurenine pathway (KP) enzyme catalyzing oxidation of the essential amino acid tryptophan (Trp), is thought to be involved in the immune resistance of malignant tumors through T-cell inactivation caused by Trp depletion and metabolite accumulation. Human malignant gliomas may use this strategy to escape immune attack. The object of this study was to investigate the possibility of IDO-dependent Trp depletion by malignant gliomas and the practicability of using an IDO inhibitor together with anticancer drugs to reserve Trp without decreasing the cytotoxicity of the drugs. The authors studied expression of IDO and other KP enzymes and the effects of an IDO inhibitor, 1-methyl L-tryptophan (1MT), on Trp metabolism and cytotoxicity of anticancer drugs, together with direct measurement of KP metabolites, in cultured human malignant glioma cells. Upon interferon-gamma (IFN-gamma) stimulation, the glioma cells greatly increased their IDO mRNA expression concomitant with depletion of Trp. The IDO inhibitor 1MT successfully prevented Trp consumption by the stimulated glioma cells. Combining 1MT with anticancer drugs (temozolomide, bischloroethylnitrosourea [BCNU], etoposide and cisplatin) did not interfere with the drugs' suppression of growth of LN229 glioma cells but rather increased their inhibitory effects on IDO activity. These findings suggest that the robust IDO expression with rapid consumption of Trp in human glioma cells induced by IFN-gamma could lead to immune resistance in glioma cells. Indoleamine 2,3-dioxygenase inhibitors that prevent Trp depletion could be used with anticancer drugs to improve therapeutic effects.


Luminal and cellular mechanisms for the mediation of tubuloglomerular feedback responses.
The results of our studies indicate that feedback-mediated changes in SFP are most likely the result of receptor cell detection of luminal fluid solute concentration. No specificity for any particular ion in mediating feedback responses could be identified. The detection of luminal fluid solute concentration may involve an intracellular cytoplasmic calcium system. The existence of a receptor cell intracellular calcium messenger system could serve as the link between changes in distal tubular fluid concentration and the alteration in glomerular vascular resistance.


Low Dose Radiation Therapy, Particularly with 0.5 Gy, Improves Pain in Degenerative Joint Disease of the Fingers: Results of a Retrospective Analysis.
Low-dose radiation therapy (LDRT) has been successfully established for decades as an alternative analgesic treatment option for patients suffering from chronic degenerative and inflammatory diseases. In this study, 483 patients were undergoing LDRT for degenerative joint disease of the fingers and thumb at the University Hospital Erlangen between 2004 and 2019. Radiotherapy was applied according to the German guidelines for LDRT. Several impact factors on therapeutic success, such as the age and gender, the number of affected fingers, the single and cumulative dose, as well as the number of series, were investigated. In summary, 70% of the patients showed an improvement of their pain following LDRT. No significant impact was found for the factors age, gender, the number of series or the cumulative dosage. Patients with an involvement of the thumb showed a significantly worse outcome compared to patients with an isolated affection of the fingers. In this cohort, patients receiving a single dose of 0.5 Gy reported a significantly better outcome than patients receiving 1.0 Gy, strongly suggesting a reduction in the total dose. In summary, LDRT is a good alternative treatment option for patients suffering from degenerative and inflammatory joint disease of the fingers.


Influence of subject discontinuation on long-term nonvertebral fracture rate in the denosumab FREEDOM Extension study.
Denosumab treatment for up to 8 years in the FREEDOM study and Extension was associated with low fracture incidence. It was not clear whether subjects who discontinued during the study conduct had a higher risk of fracture than those who remained enrolled, thereby underestimating the true fracture risk for the entire trial cohort. Thus, we explored the influence of early withdrawals on nonvertebral fracture incidence during the Extension study. To understand the potential effect of depletion of susceptible subjects on fracture incidence, we first evaluated subject characteristics in patients who were enrolled in the Extension vs those who were not. We subsequently employed a Kaplan-Meier multiple imputation (KMMI) approach to consider subjects who discontinued as if they remained enrolled with a 0%, 20%, 50%, and 100% increase in fracture risk compared with participants remaining on study. Extension enrollees were generally similar to nonparticipants in median age (71.9 and 73.1 years, respectively), mean total hip bone mineral density T-score (-1.9 and -2.0, respectively), and probability of fracture risk by Fracture Risk Assessment Tool (FRAX®) at FREEDOM baseline (16.9% and 17.7% for major osteoporotic fracture and 6.7% and 7.4% for hip fracture, respectively). When we assumed a doubled fracture risk (100% increase) after discontinuation in KMMI analyses, nonvertebral fracture rate estimates were only marginally higher than the observed rates for both the crossover group (10.32% vs 9.16%, respectively) and the long-term group (7.63% vs 6.63%, respectively). The observation of continued denosumab efficacy over 8 years of treatment was robust and does not seem to be explained by depletion of susceptible subjects. ClincalTrials.gov registration number NCT00523341 ; registered August 30, 2007.


History of mathematics and history of science reunited?
For some years now, the history of modern mathematics and the history of modern science have developed independently. A step toward a reunification that would benefit both disciplines could come about through a revived appreciation of mathematical practice. Detailed studies of what mathematicians actually do, whether local or broadly based, have often led in recent work to examinations of the social, cultural, and national contexts, and more can be done. Another recent approach toward a historical understanding of the abstractness of modern mathematics has been to see it as a species of modernism, and this thesis will be tested by the raft of works on the history of modern applied mathematics currently under way.


Differential gene expression of ewes varying in tolerance to dietary nitrate.
Ruminants consuming diets with increased concentrations of nitrate (NO(3)(-)) can accumulate nitrite (NO(2)(-)) in the blood, resulting in toxicity. In a previous experiment, ewes identified as highly tolerant to subacute dietary NO(3)(-) were able to consume greater amounts of NO(3)(-) than lowly tolerant ewes without exhibiting signs of toxicity. We hypothesized that highly tolerant and lowly tolerant ewes differ in their ability to metabolize NO(3)(-) and thereby differ in the expression of hepatic genes involved in NO(3)(-) metabolism. Therefore, our objective was to identify hepatic genes differentially expressed between ewes classified as lowly tolerant and highly tolerant after administration of a subacute quantity of dietary NO(3)(-). Analysis of the Bovine Oligonucleotide Microarray data identified 100 oligonucleotides as differentially expressed (P < 0.05) between lowly tolerant and highly tolerant ewes. Functional analysis of the genes associated with these oligonucleotides revealed 2 response clusters of interest: metabolic and stress. Genes of interest within these 2 clusters (n = 17) and nonclustered genes with the greatest fold changes (FC; n = 5) were selected for validation by real-time reverse-transcription PCR. Relative expression, genomic regulation, and FC agreed between microarray and real-time reverse-transcription-PCR analyses, and FC differences (P < 0.05) between lowly tolerant and highly tolerant ewes were confirmed for 12 genes. Metabolic genes that were downregulated (P ≤ 0.032) in lowly tolerant ewes vs. highly tolerant ewes included aldehyde oxidase 1, argininosuccinate lyase, putative steroid dehydrogenase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase1, and sterol carrier protein 2. In contrast, the metabolic gene homeobox was upregulated (P = 0.037) in lowly tolerant ewes. The glutathione peroxidase 3 and inter-α (globulin) inhibitor H4 genes in the stress response cluster were upregulated (P ≤ 0.045) in lowly tolerant ewes. Genes with the greatest FC, but did not cluster within the functional analysis included haptoglobin, which was upregulated (P = 0.024) in lowly tolerant ewes, and fatty acid desaturase 2 and thyroid hormone responsive, both of which were downregulated (P ≤ 0.019) in lowly tolerant ewes. Results from this study indicate that hepatic gene expression differs in ewes identified as lowly tolerant and highly tolerant to increased dietary NO(3)(-).


Chronic exertional compartment syndrome of the leg in athletes: evaluation and management.
Chronic exertional compartment syndrome (CECS) is a well-known cause of activity-related lower leg pain in both athletes and nonathletes. In contrast to acute compartment syndrome, CECS is generally not related to trauma, and is often suspected in the outpatient setting by primary care physicians, podiatrists, sports medicine clinicians, and orthopedic surgeons. The diagnosis of CECS is often overlooked because patients avoid or withdraw from exacerbating physical activities instead of seeking treatment for their symptoms from a health care professional. A thorough history and physical examination of an individual with activity-related lower leg pain is necessary for correct diagnosis to occur. Appropriate diagnostic testing with measurement of intracompartmental pressures reliably confirms the diagnosis of CECS. Nonoperative treatments of CECS rarely leads to complete resolution of symptoms or an individual's ability to return to previous levels of recreational or athletic activity. Fasciotomy of the involved compartments can reliably lead to resolution of pain and the ability to return to previous activities within 6 weeks.


Understanding Hearing Loss and Barriers to Hearing Health Care Among Korean American Older Adults: A Focus Group Study.
Hearing loss is associated with an accelerated decline in social, cognitive, and physical functioning among older adults. However, little is known about its impact and barriers to hearing health care in any ethnic minorities. The aim of this study was to explore experiences related to hearing loss and barriers to hearing health care among older Korean Americans (KAs). We conducted four focus groups with 19 older KAs with hearing loss and four communication partners. Qualitative content analysis revealed four themes: (a) impact of hearing loss, (b) self-perception of hearing loss, (c) coping strategies for hearing loss, and (d) barriers to hearing health care (price, language, lack of collaborative communications, perceptions about hearing aids, and lack of knowledge). Older KAs were significantly impacted by hearing loss but tended not to seek care due to multiple factors. Culturally tailored hearing interventions are urgently needed to promote hearing health in the KA community.


SP1-mediated downregulation of ADAMTS3 gene expression in osteosarcoma models.
ADAMTS3 is a member of procollagen N-proteinase subfamily of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family. It has an important function in the procollagen maturation process. The removal of N-peptidases is required for the accurate processing of fibrillar collagens. Otherwise, several disorders can occur that is related with the collagenous tissues. ADAMTS3 mainly maturates type II collagen molecule which is the main component of the bone and cartilage. There are several expression studies about ADAMTS3 gene however its transcriptional regulation has not been lightened up, yet. Here we first time cloned and functionally analyzed the promoter region of ADAMTS3 gene, approximately 1380 bp upstream of the transcription start site. Transient transfection experiments showed that all truncated promoter constructs are active and 171 bp fragment is sufficient to activate gene expression in both Saos-2 and MG63 cells. In silico analysis showed that ADAMTS3 has a TATA-less promoter and contains several SP1/GC box binding motifs and a CpG island. Therefore we mainly investigated the SP1 dependent regulation of ADAMTS3 promoter. SP1 downregulated ADAMTS3 transcriptional activity. As consistent with the transcriptional activity, mRNA, and protein expression levels were also decreased by SP1. On the other hand, functional binding of the SP1 on multiple regions of ADAMTS3 promoter was confirmed by EMSA studies. As ADAMTS3 is responsible for the collagen maturation and biosynthesis, further we investigated the effect of SP1 on type I-II and III collagen gene expressions. We point out that SP1 increased type II and III collagen expression and in contrast decreased type I collagen expression levels in Saos-2 cells. mRNA expression level was decreased for all collagen types in MG63 model. Decrease in the type II collagen expression was also demonstrated at the protein level by SP1. Collectively these results provide first findings for the SP1-related transcriptional regulation of ADAMTS3 and collagen genes in osteosarcoma cell lines.


Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat.
Acute administration of the psychotomimetic phencyclidine (PCP) can mimic some features of schizophrenia, while a repeated treatment regimen of PCP may provide a more effective way to model in animals the enduring cognitive dysfunction observed in many schizophrenic patients. The present study aims to investigate behavioural and neuropathological effects of sub-chronic PCP administration. The cognitive deficit induced by sub-chronic PCP was examined using a previously established operant reversal-learning paradigm. Subsequently, the effect of sub-chronic PCP on parvalbumin-immunoreactive (parvalbumin-IR) neurons was assessed using immunohistochemical techniques. Rats were trained to respond for food in an operant reversal-learning paradigm for approximately 6 weeks, followed by sub-chronic administration of PCP (2mg/kg) or vehicle twice daily for 7 days followed 7 days later by behavioural testing. Six weeks post PCP, brains were analysed using immunohistochemical techniques to determine the size and density of parvalbumin-IR in the frontal cortex and hippocampus. Sub-chronic PCP significantly reduced (p <0.001) percentage correct responding in the reversal phase relative to the initial phase, an effect that persisted throughout the experimental period (4 weeks). The density of parvalbumin-IR neurons was reduced in the hippocampus, with significant reductions in the dentate gyrus and CA2/3 regions (p <0.001). There were significant changes in the frontal cortex, with a reduction (p <0.01) in the M1 (motor area 1) region and increases in the M2 (motor area 2) region and cingulate cortex (p <0.01-p <0.001). These results parallel findings of profound hippocampal and more subtle cortical deficits of parvalbumin-IR neurons in schizophrenia, and provide evidence to suggest that sub-chronic PCP can induce a lasting cognitive deficit, an effect that may be related to the observed neuronal deficits.


Prevalence of hepatitis C virus infection and the IL28B genotype polymorphism among blood donors and high-risk populations.
To study the prevalence of hepatitis C virus (HCV) infection in blood donor (BD), haemodialysis (HD) and intravenous drug user (IVDU) populations in Singapore and assess the IL28B polymorphism if HCV positive. The BD population were healthy volunteers, the HD population were patients who were on haemodialysis for at least six months of follow-up between January 2009 and December 2014. IVDU population was from inmates at halfway houses who consented. Between 2011 and 2014, of 161,658 individuals who underwent screening prior to blood donation, 95 (0.059%) were positive for HCV. Of the 42 sera available, common genotypes (GTs) were GT-3 (47.6%) and GT-1 (31.0%). Of 1,575 HD patients, 2.2% were anti-HCV positive. The HCV GT distribution was HCV GT-1 (32.4%), HCV GT-3 (20.5%) and GT-6 (8.8%). 83 halfway house inmates were screened. Of the 47 IVDUs, 36.2% were anti-HCV positive with predominant GT-3 (%). IL28B polymorphism was noted to be CC predominantly 85.3%. Prevalence of HCV infection has decreased in both the BD and HD populations. However, it remains high in the IVDU population. GT-1 remains the most common in the HD population; however, GT-3 infection is now more common among the BD population in Singapore. IL28B - CC is the predominant variant among the HCV-infected individuals in Singapore.


Impact of cognitive behavior therapy on health-related quality of life among adult hypnotic users with chronic insomnia.
Results were combined from representative surveys of health related quality of life (HRQoL; n=11,877; age range=16-104) with data from a randomized controlled trial of cognitive behavior therapy for chronic insomnia (n=209; age range=31-92). Secondary analyses of scores from the SF-36 measure of HRQoL were conducted in order: (a) to compare the health related quality of life profiles of adult hypnotic users with chronic insomnia with those of population norms, and (b) to assess the impact of cognitive behavior therapy (CBT) for insomnia on HRQoL outcomes over 6 months. Compared with the primary care reference values, HRQoL among the trial participants at baseline was generally poorer. The magnitude of these decrements reduced markedly with advancing age. In the evaluation of the CBT intervention, statistically significant differences in SF-36 scores in favor of the intervention were present for physical functioning, emotional role limitation, and mental health over 6 months. Overall, this study shows that the SF-36 can play an important role in describing HRQoL in this patient group, and in the evaluation of interventions within this group.


Lack of time-dependent augmentation of carotid sinus baroreflex system after vagotomy.
The purpose of this experiment was to study whether the carotid sinus baroreflex system (CS system) increases its gain with time after vagotomy in compensation for the loss of the vagally mediated arterial pressure control system (V system). In 7 dogs anesthetized with pentobarbital sodium we determined the responsiveness of the V system by repeatedly measuring the overall open-loop gain (G) of the negative feedback control system. G was assessed as (delta API/delta APS) -- 1, where delta API and delta APS are, respectively, the immediate and steady-state falls in arterial pressure at the aortic arch following a stepwise reduction in blood volume. delta API, delta APS, and G in intact condition were -12.0 +/- 1.8 mmHg, -1.1 +/- 0.2 mmHg, and 10.1 +/- 0.7 (SD), respectively. delta API, delta APS, and G after vagotomy, i.e., G of the CS system (GCS), were -15.6 +/- 3.6 mmHg, -6.4 +/- 1.9 mmHg, and 1.6 +/- 0.4 GCS did not change with time over 4 h after vagotomy. We conclude that the CS system cannot augment its ability to restore arterial pressure in compensation for the lost function of the V system within 4 h after vagotomy in the anesthetized dog.


fMRI BOLD Correlates of EEG Independent Components: Spatial Correspondence With the Default Mode Network.
Goal: We aimed to identify electroencephalographic (EEG) signal fluctuations within independent components (ICs) that correlate to spontaneous blood oxygenation level dependent (BOLD) activity in regions of the default mode network (DMN) during eyes-closed resting state. Methods: We analyzed simultaneously acquired EEG and functional magnetic resonance imaging (fMRI) eyes-closed resting state data in a convenience sample of 30 participants. IC analysis (ICA) was used to decompose the EEG time-series and common ICs were identified using data-driven IC clustering across subjects. The IC time courses were filtered into seven frequency bands, convolved with a hemeodynamic response function (HRF) and used to model spontaneous fMRI signal fluctuations across the brain. In parallel, group ICA analysis was used to decompose the fMRI signal into ICs from which the DMN was identified. Frequency and IC cluster associated hemeodynamic correlation maps obtained from the regression analysis were spatially correlated with the DMN. To investigate the reliability of our findings, the analyses were repeated with data collected from the same subjects 1 year later. Results: Our results indicate a relationship between power fluctuations in the delta, theta, beta and gamma frequency range and the DMN in different EEG ICs in our sample as shown by small to moderate spatial correlations at the first measurement (0.234 < |r| < 0.346, p < 0.0001). Furthermore, activity within an EEG component commonly identified as eye movements correlates with BOLD activity within regions of the DMN. In addition, we demonstrate that correlations between EEG ICs and the BOLD signal during rest are in part stable across time. Discussion: We show that ICA source separated EEG signals can be used to investigate electrophysiological correlates of the DMN. The relationship between the eye movement component and the DMN points to a behavioral association between DMN activity and the level of eye movement or the presence of neuronal activity in this component. Previous findings of an association between frontal midline theta activity and the DMN were replicated.


Post-embryonic pericardial cells of Drosophila are required for overcoming toxic stress but not for cardiac function or adult development.
The Drosophila heart is composed of two cell types: cardioblasts (CB) and pericardial cells (PC). Whereas CBs act to maintain rhythmic contractions, the functions of accessory PCs are not clear. The close association between these two cell types has led to speculation of a cardio-regulatory role for PCs. However, we find that viability and cardiac function are normal in larvae following post-embryonic ablation of PCs by induced cell death. Removal of PCs during the larval instars or before metamorphosis results in viable and fertile adults. Interestingly, such animals have a reduced lifespan and increased sensitivity to toxic chemicals. Thus, although PCs may have an embryonic role in cardiogenesis, they do not appear to play a part later in cardiac function as suggested. However, the role of PCs in the uptake and sequestering of toxins, their sensitivity to toxic stress and the decreased lifespan of animals without PCs indicate the importance of PCs in organismal homeostasis.


Multiple determinants within iron-responsive elements dictate iron regulatory protein binding and regulatory hierarchy.
Iron regulatory proteins (IRPs) are iron-regulated RNA binding proteins that, along with iron-responsive elements (IREs), control the translation of a diverse set of mRNA with 5' IRE. Dysregulation of IRP action causes disease with etiology that may reflect differential control of IRE-containing mRNA. IREs are defined by a conserved stem-loop structure including a midstem bulge at C8 and a terminal CAGUGH sequence that forms an AGU pseudo-triloop and N19 bulge. C8 and the pseudo-triloop nucleotides make the majority of the 22 identified bonds with IRP1. We show that IRP1 binds 5' IREs in a hierarchy extending over a ninefold range of affinities that encompasses changes in IRE binding affinity observed with human L-ferritin IRE mutants. The limits of this IRE binding hierarchy are predicted to arise due to small differences in binding energy (e.g., equivalent to one H-bond). We demonstrate that multiple regions of the IRE stem not predicted to contact IRP1 help establish the binding hierarchy with the sequence and structure of the C8 region displaying a major role. In contrast, base-pairing and stacking in the upper stem region proximal to the terminal loop had a minor role. Unexpectedly, an N20 bulge compensated for the lack of an N19 bulge, suggesting the existence of novel IREs. Taken together, we suggest that a regulatory binding hierarchy is established through the impact of the IRE stem on the strength, not the number, of bonds between C8 or pseudo-triloop nucleotides and IRP1 or through their impact on an induced fit mechanism of binding.


H2S induced hypometabolism in mice is missing in sedated sheep.
On the basis of studies performed in mice that showed H(2)S inhalation decreasing dramatically the metabolic rate, H(2)S was proposed as a means of protecting vital organs from traumatic or ischemic episodes in humans. Hypoxia has in fact also long been shown to induce hypometabolism. However, this effect is observed solely in small-sized animals with high VO2 kg(-1), and not in large mammals. Thus, extrapolating the hypometabolic effect of H(2)S to large mammals is questionable and could be potentially dangerous. We measured metabolism in conscious mice (24 g) exposed to H(2)S (60 ppm) at an ambient temperature of 23-24 degrees C. H(2)S caused a rapid and large (50%) drop in gas exchange rate, which occurred independently of the change in body temperature. The metabolic response occurred within less than 3 min. In contrast, sheep, sedated with ketamine and weighing 74 kg did not exhibit any decrease in metabolic rate during a similar challenge at an ambient temperature of 22 degrees C. While a part of H(2)S induced hypometabolism in the mice is related to the reduction in activity, we speculate that the difference between sheep and mice may rely on the nature and the characteristics of the relationship between basal metabolic rate and body weight thus on the different mechanisms controlling resting metabolic rate according to body mass. Therefore, the proposed use of H(2)S administration as a way of protecting vital organs should be reconsidered in view of the lack of hypometabolic effect in a large sedated mammal and of H(2)S established toxicity.


Career orientations of medical and pediatric residents.
Educators have expressed concern about the declining percentage of graduating residents who choose an academic career. This study identifies characteristics of postgraduate physicians that are associated with intentions to pursue an academic career or a full-time private practice. Data were obtained from 299 residents in pediatrics and internal medicine at five academic medical centers in Southern California, using self-report questionnaires. Preference for an academic career was strongest among residents who were most satisfied with their work, were frequently sponsored by faculty, had published, or who either lived alone or were married to another professional. The likelihood of full-time private practice was strongest among residents who were less frequently sponsored by faculty, had not published, lived with others, were from certain medical schools, or were females. Training programs may wish to consider some of these factors in the selection of residents and in program development.


Age-dependent increases in tau phosphorylation in the brains of type 2 diabetic rats correlate with a reduced expression of p62.
Aging increases the co-incidence of Alzheimer's disease (AD) and type 2 diabetes (T2DM). However, the critical factors that contribute to the age-related increase in AD-T2DM comorbidity have yet to be clarified. In this study, aging effects and their relationship to AD-related pathology and T2DM as well as the underlying mechanisms of this process were investigated using obese rats with chronic T2DM. Tau pathology and its associated signaling pathways in the brain were compared between Otsuka Long-Evans Tokushima Fatty (OLETF) rats and corresponding non-diabetic controls at various ages. Tau phosphorylation at AD-related epitopes, including Thr212, Thr231, Ser262, and Ser396, increased with age in the soluble brain extracts of chronic OLETF rats and were accompanied by synaptic protein loss. There was also a marked age-dependent accumulation of polyubiquitinated substances in diabetic rats. Accordingly, tau proteins were highly polyubiquitinated in aged OLETF rats and a strong degree of co-localization existed between p-tau and ubiquitin in these neurons. In addition, the mRNA and protein levels of p62, a known cargo molecule that transports polyubiquitinated tau to proteasomal and autophagic degradation systems, decreased robustly with age in OLETF rats and there was an inverse correlation between protein levels of p62 and p-tau. The impaired degradation of polyubiquitinated p-tau due to age- and T2DM-dependent decreases in p62 transcription is a primary mechanism underlying increased AD-like pathology in a T2DM rat model as age increases. These results provide novel insight into the mechanisms supporting the age-related increase in AD-T2DM comorbidity.


What do qualitative rapid assessment collections of macroinvertebrates represent? A comparison with extensive quantitative sampling.
It is a fundamental tenet of Rapid Biological Assessments (RBA) that the samples collected reflect the community from which they are drawn. As with any biological sampling, RBA collections are subject to sampling error resulting in the omission of some taxa. The aim of this study is to compare the composition of RBA samples with an estimate of community structure based on extensive quantitative sampling. We used logistic regression to explore the relationships between the frequency of a taxon being collected in an RBA sample and its biological and ecological traits, namely its abundance, distribution, body size and habit. RBA samples and quantitative estimates of community structure were made in riffles in the Kangaroo and Nepean Rivers, New South Wales, Australia. Single RBA samples may collect up to 63% of the taxa that are collected by extensive quantitative sampling at a site. The frequency of a taxon being recorded in an RBA sample was significantly and positively related to all traits tested indicating a bias in the collection methods towards large, abundant and widely distributed taxa. Accordingly, taxa missed by RBA sampling were generally small, narrowly distributed or rare. These findings enhance our understanding of what RBA samples represent, and the bias and source of errors associated with RBA sampling. This study also quantifies the utility of RBA methods for biodiversity assessment.


A noncanonical function of cGAMP in inflammasome priming and activation.
Recognition of pathogen-associated molecular patterns and danger-associated molecular patterns by host cells is an important step in innate immune activation. The DNA sensor cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) binds to DNA and produces cGAMP, which in turn binds to stimulator of interferon genes (STING) to activate IFN-I. Here we show that cGAMP has a noncanonical function in inflammasome activation in human and mouse cells. Inflammasome activation requires two signals, both of which are activated by cGAMP. cGAMP alone enhances expression of inflammasome components through IFN-I, providing the priming signal. Additionally, when combined with a priming signal, cGAMP activates the inflammasome through an AIM2, NLRP3, ASC, and caspase-1 dependent process. These two cGAMP-mediated functions, priming and activation, have differential requirements for STING. Temporally, cGAMP induction of IFN-I precedes inflammasome activation, which then occurs when IFN-I is waning. In mice, cGAS/cGAMP amplify both inflammasome and IFN-I to control murine cytomegalovirus. Thus, cGAMP activates the inflammasome in addition to IFN-I, and activation of both is needed to control infection by a DNA virus.


New population and life expectancy estimates for the Indigenous population of Australia's Northern Territory, 1966-2011.
The Indigenous population of Australia suffers considerable disadvantage across a wide range of socio-economic indicators, and is therefore the focus of many policy initiatives attempting to 'close the gap' between Indigenous and non-Indigenous Australians. Unfortunately, past population estimates have proved unreliable as denominators for these indicators. The aim of the paper is to contribute more robust estimates for the Northern Territory Indigenous population for the period 1966-2011, and hence estimate one of the most important of socio-economic indicators, life expectancy at birth. A consistent time series of population estimates from 1966 to 2011, based off the more reliable 2011 official population estimates, was created by a mix of reverse and forward cohort survival. Adjustments were made to ensure sensible sex ratios and consistency with recent birth registrations. Standard life table methods were employed to estimate life expectancy. Drawing on an approach from probabilistic forecasting, confidence intervals surrounding population numbers and life expectancies were estimated. The Northern Territory Indigenous population in 1966 numbered between 23,800 and 26,100, compared to between 66,100 and 73,200 in 2011. In 1966-71 Indigenous life expectancy at birth lay between 49.1 and 56.9 years for males and between 49.7 and 57.9 years for females, whilst by 2006-11 it had increased to between 60.5 and 66.2 years for males and between 65.4 and 70.8 for females. Over the last 40 years the gap with all-Australian life expectancy has not narrowed, fluctuating at about 17 years for both males and females. Whilst considerable progress has been made in closing the gap in under-five mortality, at most other ages the mortality rate differential has increased. A huge public health challenge remains. Efforts need to be redoubled to reduce the large gap in life expectancy between Indigenous and non-Indigenous Australians.


Tracking nonparameterized object contours in video.
We propose a new method for contour tracking in video. The inverted distance transform of the edge map is used as an edge indicator function for contour detection. Using the concept of topographical distance, the watershed segmentation can be formulated as a minimization. This new viewpoint gives a way to combine the results of the watershed algorithm on different surfaces. In particular, our algorithm determines the contour as a combination of the current edge map and the contour, predicted from the tracking result in the previous frame. We also show that the problem of background clutter can be relaxed by taking the object motion into account. The compensation with object motion allows to detect and remove spurious edges in background. The experimental results confirm the expected advantages of the proposed method over the existing approaches.


The Psychopathy Q-sort: construct validity evidence in a nonclinical sample.
Scant research has examined the validity of instruments that permit observer ratings of psychopathy. Using a nonclinical (undergraduate) sample, the authors examined the associations between both self-and observer ratings on a psychopathy prototype (Psychopathy Q-Sort, PQS) and widely used measures of psychopathy, antisocial behavior, and negative emotionality. Self- and observer prototype correlations generally displayed predicted patterns of convergent and discriminant validity for the PQS. Future research using the PQS should focus on potential domains of incremental validity of peer-rated psychopathy beyond self-reported psychopathy.


Eribulin is an immune potentiator in breast cancer that upregulates human leukocyte antigen class I expression via the induction of NOD-like receptor family CARD domain-containing 5.
Eribulin inhibits microtubule polymerization and improves the overall survival of patients with recurrent metastatic breast cancer. A subgroup analysis revealed a low neutrophil to lymphocyte ratio (NLR) (<3) to be a prognostic factor of eribulin treatment. We thus hypothesized that eribulin might be related to the immune response for breast cancer cells and we analyzed the effects of eribulin on the immune system. Immunohistochemical staining revealed that human leukocyte antigen (HLA) class I expression was increased in clinical samples after eribulin treatment. In vitro assays revealed that eribulin treatment increased HLA class I expression in breast cancer line cells. RNA-sequencing demonstrated that eribulin treatment increased the expression of the NOD-like family CARD domain-containing 5 (NLRC5), a master regulator of HLA class I expression. Eribulin treatment increased the NY-ESO-1-specific T-cell receptor (TCR) transduced T (TCR-T) cell response for New York oesophageal squamous cell carcinoma 1 (NY-ESO-1) overexpressed breast cancer cells. The eribulin and TCR-T combined therapy model revealed that eribulin and immunotherapy using TCR-T cells has a synergistic effect. In summary, eribulin increases the expression of HLA class 1 via HLA class 1 transactivatior NLRC5 and eribulin combination with immunotherapy can be effective for the treatment of breast cancer.


Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score.
The outcome of chronic myeloid leukemia (CML) has been profoundly changed by the introduction of tyrosine kinase inhibitors into therapy, but the prognosis of patients with CML is still evaluated using prognostic scores developed in the chemotherapy and interferon era. The present work describes a new prognostic score that is superior to the Sokal and Euro scores both in its prognostic ability and in its simplicity. The predictive power of the score was developed and tested on a group of patients selected from a registry of 2060 patients enrolled in studies of first-line treatment with imatinib-based regimes. The EUTOS score using the percentage of basophils and spleen size best discriminated between high-risk and low-risk groups of patients, with a positive predictive value of not reaching a CCgR of 34%. Five-year progression-free survival was significantly better in the low- than in the high-risk group (90% vs 82%, P = .006). These results were confirmed in the validation sample. The score can be used to identify CML patients with significantly lower probabilities of responding to therapy and survival, thus alerting physicians to those patients who require closer observation and early intervention.


Absence of lutropin (LH) receptor mRNA in the rat thyroid: further evidence for specificity cross-over at the thyroid-stimulating hormone receptor level.
Chorionic gonadotropin (CG) and purified lutropin (LH) activate intact thyroid tissue and isolated thyroid cells. A recent report has suggested that the presence of aberrant LH/CG receptors in human and rat thyroid tissue may interact with gonadotropin thus explaining the mechanisms of thyroid cell stimulation. To detect putative thyroidal LH receptor mRNA, a segment of the transmembrane region containing domains 3 through 6 of the rat (r) LH receptor was targeted for amplification using the polymerase chain reaction (PCR). cDNA prepared from a rLH receptor-positive control tissue (testis) was efficiently amplified under stringent annealing conditions giving a 486 bp product as predicted. However, cDNAs from thyroidal tissue and from the thyroid-stimulating hormone (TSH)- and hCG-responsive 1B-6 subclone of Fisher rat thyroid cells (FRTL-5) yielded no detectable 486 bp product. A smaller (non-LH) fragment amplified to similar extents from both testis and thyroidal cDNAs provided a useful internal control for amplification. This allowed the conclusion that specificity cross-over between LH/CG and TSH occurs at the TSH receptor and that the LH/CG receptor gene is transcriptionally silent in rat thyroidal cells.


A Novel Saliency Detection Algorithm Based On Adversarial Learning Model.
The traditional salient object detection models can be divided into several classes based on the low-level features of images and contrast between the pixels. This paper proposes an adversarial learning model (ALM) that includes the generative model and discriminative model. The ALM uses the original image as an input of the generative model to extract the high-level features and forms an initial salient map. Then, the discriminative model is utilized to compare differences in the features between the initial salient map and the ground truth, and the obtained differences are sent to the convolutional layers of the generative model to adjust the parameters for the generative model updating. Due to the serial-iterative adjustment, the salient map of the generative model becomes more similar to the ground truth. Lastly, the ALM forms the salient map fused with the super-pixels by enhancing the color and texture features, so the final salient map is obtained. The ALM is not limited to the color and texture features; on the contrary, it fuses multiple features and achieves good results in the salient target extraction. The experimental results show that ALM performs better than the other ten state-of-the-art models on three different datasets. Thus, the proposed ALM is widely applicable to the salient target extraction.


Scaling and maintenance of corneal thickness during aging.
Corneal thickness is tightly regulated by its boundary endothelial and epithelial layers. The regulated set-point of corneal thickness likely shows inter-individual variations, changes by age, and response to stress. Using anterior segment-optical coherence tomography, we measure murine central corneal thickness and report on body size scaling of murine central corneal thickness during aging. For aged-matched mice, we find that corneal thickness depends on sex and strain. To shed mechanistic insights into these anatomical changes, we measure epithelial layer integrity and endothelial cell density during the life span of the mice using corneal fluorescein staining and in vivo confocal microscopy, respectively and compare their trends with that of the corneal thickness. Cornea thickness increases initially (1 month: 114.7 ± 3.0 μm, 6 months: 126.3 ± 1.6 μm), reaches a maximum (9 months: 129.3 ± 4.4 μm) and then reduces (12 months: 127 ± 2.9 μm, 13 months: 119.5 ± 7.6 μm, 14 months: 110.6 ± 10.6 μm), while the body size (weight) increases with age. We find that endothelial cell density reduces from 2 months old to 8 months old as the mice age and epithelial layer accumulates damages within this time frame. Finally, we compare murine corneal thickness with those of several other mammals including humans and show that corneal thickness has an allometric scaling with body size. Our results have relevance for organ size regulation, translational pharmacology, and veterinary medicine.