LysPBC2, a Novel Endolysin Harboring a Bacillus cereus Spore Binding Domain.
To control the spore-forming human pathogen Bacillus cereus, we isolated and characterized a novel endolysin, LysPBC2, from a newly isolated B. cereus phage, PBC2. Compared to the narrow host range of phage PBC2, LysPBC2 showed very broad lytic activity against all Bacillus, Listeria, and Clostridium species tested. In addition to a catalytic domain and a cell wall binding domain, LysPBC2 has a spore binding domain (SBD) partially overlapping its catalytic domain, which specifically binds to B. cereus spores but not to vegetative cells of B. cereus Both immunogold electron microscopy and a binding assay indicated that the SBD binds the external region of the spore cortex layer. Several amino acid residues required for catalytic or spore binding activity of LysPBC2 were determined by mutagenesis studies. Interestingly, LysPBC2 derivatives with impaired spore binding activity showed an increased lytic activity against vegetative cells of B. cereus compared with that of wild-type LysPBC2. Further biochemical studies revealed that these LysPBC2 derivatives have lower thermal stability, suggesting a stabilizing role of SBD in LysPBC2 structure.IMPORTANCE Bacteriophages produce highly evolved lytic enzymes, called endolysins, to lyse peptidoglycan and release their progeny from bacterial cells. Due to their potent lytic activity and specificity, the use of endolysins has gained increasing attention as a natural alternative to antibiotics. Since most endolysins from Gram-positive-bacterium-infecting phages have a modular structure, understanding the function of each domain is crucial to make effective endolysin-based therapeutics. Here, we report the functional and biochemical characterization of a Bacillus cereus phage endolysin, LysPBC2, which has an unusual spore binding domain and a cell wall binding domain. A single point mutation in the spore binding domain greatly enhanced the lytic activity of endolysin at the cost of reduced thermostability. This work contributes to the understanding of the role of each domain in LysPBC2 and will provide insight for the rational design of efficient antimicrobials or diagnostic tools for controlling B. cereus.


Liver resection for colorectal metastases.
Colorectal cancer is the second commonest malignancy in the UK. Metastases to the liver occur in greater than 50% of patients and remain the biggest determinant of outcome in these patients. Liver resection is a safe procedure that achieves good long-term survival, but surgery has traditionally been limited to select groups of patients. The improved outcome suggests that more patients could benefit from resection if more was known of what criteria are predictive of a good outcome. A retrospective analysis was performed on all patients undergoing surgical resection of the liver for colorectal metastases between March 1989 and March 2001 in the Birmingham Liver Unit. During this period, 212 liver resections for colorectal cancer metastases were performed in 82 females and 130 males. The median follow-up was 16 months with an overall actuarial survival of 86% at 1 year, 54% at 3 years, and 28% at 5 years. The peri-operative mortality was 2.8%. The number and timing (metachronous or synchronous) of metastatic lesions, the gender of the patient, pathological staging of the primary lesion or surgical resection margins had no significant influence on survival. Patients with lesions less than 5 cm in size had a significantly prolonged survival compared with patients with lesions greater than 5 cm in size (P < 0.004). Liver resection is the only curative treatment for patients with colorectal metastases. The long-term survival reported in patients with resected colorectal metastases confined to the liver is comparable to primary surgery for solid gastrointestinal tumours. Every attempt must be made to increase the availability of liver resection to patients with hepatic metastases from colorectal cancer.


The effects of post-mortem changes and calcium depletion on the ultrastructure of myocardial cells in a teleost.
The effects of post-mortem changes and calcium depletion on the ultrastructure of myocardial cells in a teleost, Gadus virens L., are described. When incubated at 4 degrees C in cacodylate buffer/Ringer's solution for 8 h some few myocardial cells appear swollen and their mitochondria contain several small (50-250 nm) flocculent densities. In tissue incubated for at least 80 h the mitochondria in all myocardial cells contain a number of such densities. Also, the size of these structures seems to increase with incubation time. Further, after being incubated for at least 150 h the myofibrils appear often twisted and broken, and the electron density of the Z and I bands gradually declines. At prolonged incubation times (about 1,000-1,300 h) the actin filaments and Z band material seem gradually to dissolve, whereas the myosin filaments still make up a distinct A band. Intercalated discs in tissue incubated in calcium-free medium for 4-28 h appear to display a nearly normal structure. The results of the present study are compared with those previously reported for mammals. The observed differences in decomposition rates within teleostean myocardial tissue are discussed.


The mortality of hospitalized patients with COVID-19 and non-cirrhotic chronic liver disease: a retrospective multi-center study.
Patients with chronic liver disease (CLD) have a higher risk of mortality when infected with severe acute respiratory syndrome coronavirus 2. Although the fibrosis-4 (FIB-4) index, aspartate aminotransferase-to-platelet ratio index (APRI), and albumin-bilirubin grade (ALBI) score can predict mortality in CLD, their correlation with the clinical outcomes of CLD patients with coronavirus disease 2019 (COVID-19) is unclear. This study aimed to investigate the association between the liver severity and the mortality in hospitalized patients with non-cirrhotic CLD and COVID-19. This retrospective study analyzed 231 patients with non-cirrhotic CLD and COVID-19. Clinical characteristics, laboratory data, including liver status indices, and clinical outcomes were assessed to determine the correlation between liver status indices and the mortality among patients with non-cirrhotic CLD and COVID-19. Non-survivors had higher levels of prothrombin time-international normalized ratio (PT-INR), alanine aminotransferase, aspartate aminotransferase, and high-sensitivity C-reactive protein (hs-CRP) and lower albumin levels. Multivariable analysis showed that ALBI grade 3 (odds ratio (OR): 22.80, 95% confidence interval (CI) [1.70-305.38], p = 0.018), FIB-4 index ≥ 3.25 (OR: 10.62, 95% CI [1.12-100.31], p = 0.039), PT-INR (OR: 19.81, 95% CI [1.31-299.49], p = 0.031), hs-CRP (OR: 1.02, 95% CI [1.01-1.02], p = 0.001), albumin level (OR: 0.08, 95% CI [0.02-0.39], p = 0.002), and use of vasopressors (OR: 4.98, 95% CI [1.27-19.46], p = 0.021) were associated with the mortality. The ALBI grade 3 and FIB-4 index ≥ 3.25, higher PT-INR, hsCRP levels and lower albumin levels could be associated with mortality in non-cirrhotic CLD patients with COVID-19. Clinicians could assess the ALBI grade, FIB-4 index, PT-INR, hs-CRP, and albumin levels of patients with non-cirrhotic CLD upon admission.


Screening for cognitive functioning in psychiatric outpatients with schizophrenia, alcohol dependence, and dual diagnosis.
Cognitive impairment is common to both schizophrenia and alcoholism. Despite increasing recognition that people with both disorders represent a problematic client group, little is known about the possible additive effect of a dual diagnosis upon impaired cognitive function. This study investigates impairment of cognitive functioning in patients with schizophrenia, alcohol dependence, or a dual diagnosis of schizophrenia and alcohol use disorder. It was hypothesised that patients with dual diagnosis would show greater cognitive impairment than those with a single diagnosis. The Mini-Mental State Examination (MMSE) and standardised measures of psychiatric health and substance use were administered to 120 community psychiatric patients with a diagnosis of schizophrenia, alcohol dependence and both conditions (dual diagnosis). Higher rates of cognitive impairment were found among dual diagnosis patients compared to the schizophrenia or alcohol patients. This was shown in age-adjusted measures of global functioning, and on the tests of language, reading and writing, and visuospatial construction. Despite its common usage, global MMSE scores were insensitive to the cognitive impairments typically found in these clinical groups. Where the MMSE is used as a screening tool, it is recommended that scores are adjusted for the effects of age.


Digital inclusion to enhance energy sustainability: public participation and environmental governance in the new media era to achieve energy sustainable goals.
Renewable energy not only helps to safeguard the environment and slow down climate change but also supports economic growth and energy security. The significance of renewable energy sources is expanding as more people throughout the globe understand how important it is to switch to clean energy sources. Therefore, empirics are in search of the factors that can promote renewable energy production. This analysis investigates some of the novel determinants of renewable energy production, such as digital inclusion, public participation, and environmental governance, which have not been examined previously in any study. For empirical analysis, the study employs the ARDL and QARDL estimation techniques using Chinese data from 1998Q1 to 2021Q4. The analysis findings confirm that digital financial inclusion, ICT, and GDP are vital in boosting both short and long-run renewable production. Green investment, environmental governance, and carbon emissions also significantly and favourably impact long-run renewable energy production. In the Quantile ARDL model, digital financial inclusion is positively linked to renewable energy production at most of its quantiles in the short and long run, while the ICT, GDP, environmental governance, and carbon emissions are positively linked to renewable energy in most quantiles in the long-run only. The Wald test confirms the asymmetric impact for all variables in the long run, which implies that policymakers should consider the positive and negative changes in these factors while devising policies for enhancing renewable energy production.


Stereospecific formation of the (R)-gamma-hydroxytrimethylene interstrand N2-dG:N2-dG cross-link arising from the gamma-OH-1,N2-propano-2'-deoxyguanosine adduct in the 5'-CpG-3' DNA sequence.
Acrolein reacts with dG to form hydroxylated 1,N(2)-propanodeoxyguanosine (OH-PdG) adducts. Most abundant are the epimeric 3-(2-deoxy-beta-D-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2a] purin-10(3H)-ones, commonly referred to as the gamma-OH-PdG adducts. When placed complementary to deoxycytosine in duplex DNA, these undergo rearrangement to the N(2)-(3-oxopropyl)-dG aldehyde. The latter forms diastereomeric interstrand N(2)-dG:N(2)-dG cross-links in the 5'-CpG-3' sequence. Here we report the structure of the stereochemically favored (R)-gamma-hydroxytrimethylene N(2)-dG:N(2)-dG interstrand DNA cross-link in 5'-d(G(1)C(2)T(3)A(4)G(5)C(6)X(7)A(8)G(9)T(10)C(11)C(12))-3' x 5'-d(G(13)G(14)A(15)C(16)T(17)C(18)Y(19)C(20)T(21)A(22)G(23)C(24))-3' (X(7) is the dG linked to the alpha-carbon of the carbinolamine linkage, and Y(19) is the dG linked to the gamma-carbon of the carbinolamine linkage; the cross-link is in the 5'-CpG-3' sequence). The structure was characterized using isotope-edited (15)N nuclear Overhauser enhancement spectroscopy heteronuclear single quantum correlation (NOESY-HSQC) NMR, in which the exocyclic amines at X(7) or Y(19) were (15)N-labeled. Analyses of NOE intensities involving Y(19) N(2)H indicated that the (R)-gamma-hydroxytrimethylene linkage was the major cross-link species, constituting 80-90% of the cross-link. The X(7) and Y(19) imino resonances were observed at 65 degrees C. Additionally, for the 5'-neighbor base pair G(5) x C(20), the G(5) imino resonance remained sharp at 55 degrees C but broadened at 65 degrees C. In contrast, for the 3'-neighbor A(8) x T(17) base pair, the T(17) imino resonance was severely broadened at 55 degrees C. Structural refinement using NOE distance restraints obtained from isotope-edited (15)N NOESY-HSQC data indicated that the (R)-gamma-hydroxytrimethylene linkage maintained the C(6) x Y(19) and X(7) x C(18) base pairs with minimal structural perturbations. The (R)-gamma-hydroxytrimethylene linkage was located in the minor groove. The X(7) N(2) and Y(19) N(2) atoms were in the gauche conformation with respect to the linkage, which maintained Watson-Crick hydrogen bonding of the cross-linked base pairs. The anti conformation of the hydroxyl group with respect to C(alpha) of the tether minimized steric interaction and, more importantly, allowed the formation of a hydrogen bond between the hydroxyl group and C(20) O(2) located in the 5'-neighboring base pair G(5) x C(20). The formation of this hydrogen bond may, in part, explain the thermal stability of this carbinolamine interstrand cross-link and the stereochemical preference for the (R) configuration of the cross-link.


[Multimodal therapy for malignant pleural mesothelioma including extrapleural pneumonectomy].
Multimodal therapy including neoadjuvant chemotherapy with subsequent extrapleural pneumonectomy and postoperative radiotherapy has been shown to improve the survival of patients with malignant pleural mesothelioma (MPM) if they are selected carefully. Careful patient selection is required in order to administer aggressive multimodal therapy only to patients who will benefit from such a treatment. To achieve an accurate staging (<or= cT3, < pN2, cM0), mediastinoscopy is recommended in addition to computed tomography of the chest and upper abdomen. Currently, neoadjuvant chemotherapy with pemetrexed and cisplatin followed by extrapleural pneumonectomy and postoperative radiotherapy is claimed to afford the best treatment results. We have treated 17 patients with such a regimen and achieved a 3-year survival rate of 76 % so far. During the follow-up duration of 23 months, 3 patients (18 %) developed distant metastasis and one (6 %) a mediastinal local recurrence. Multimodal therapy of malignant pleural mesothelioma including extrapleural pneumonectomy should only be performed in specialised centres for thoracic surgery where uncomplicated interdisciplinary communication is the rule and which provide the required expertise in patient selection, operative technique and postoperative care.


Protecting Incapacitated Patients' Rights and Best Interests.
Contemporary medical ethics requires providing healthcare services in accordance with the patient's values, preferences and interests based on the rights to self-determination and privacy. Incapacitated patients utilise these rights through substitute decision-makers in light of the substituted judgement and best interest standards. In this context, the article aims to briefly study informed consent and focus on protecting incapacitated patients' rights and best interests. The article underscores the importance of promoting the autonomy of every patient as much as possible. However, in the case of the lack of decisional capacity and advance directives, surrogates should decide for incapacitated patients based on patients' known/documented/expressed wishes/ preferences and best interests. Nevertheless, due to the high possibility of the misinterpretation of patients' values, preferences and interests by surrogates as well as potential financial and social conflicts between patients and their surrogates, in the event of medical procedures with serious consequences, such as life-sustaining support, surrogates should be requested to provide convincing evidence proving that their decisions are in line with the patient's values, preferences and interests.


Treatment of colorectal carcinoids: A new paradigm.
It is often difficult to evaluate the grade of malignancy and choose an appropriate treatment for colorectal carcinoids in clinical settings. Although tumor size and depth of invasion are evidently not enough to stratify the risk of this rare tumor, the present guidelines or staging systems do not mention other clinicopathological variables. Recent studies, however, have shed light on the impact of lymphovascular invasion on the outcome of colorectal carcinoids. It has been revealed that the presence of lymphovascular invasion was among the strongest risk factors for metastasis along with tumor size and depth of invasion. Furthermore, tumors smaller than 1 cm, within submucosal invasion and without lymphovascular invasion, carry minimal risk for metastasis with 100% 5-year survival in the studies from Japan as well as from the USA. This would suggest that these tumors could be curatively treated by endoscopic resection or transanal local excision. On the other hand, colorectal carcinoids with either lymphovascular invasion or tumor size larger than 1 cm carry the risk for metastasis equivalent to adenocarcinomas. Therefore, it should be emphasized that histological examination of lymphovascular invasion is mandatory in the specimens obtained by endoscopic resection or transanal local excision, as this would provide useful information for determining the need for additional radical surgery with regional lymph node dissection. Although the present guidelines or TNM staging system do not mention the impact of lymphovascular invasion, this would be among the next promising targets in order to establish better guidelines and staging systems, particularly in early-stage colorectal carcinoids.


Influence of the rehabilitation outcome on returning to drive after neurological impairment.
In traumatic brain injury (TBI) and stroke rehabilitation, the question of reintegration of the driver into traffic is faced very often. Driving is an important domain and for some patients, return to driving represents a crucial event for community inclusion. The aim of our study was to examine the utility of Glasgow Coma Scale within the first 24 h of injury and the Functional Independence Measure (FIM) at rehabilitation admission for predicting the return to driving. We included 72 patients after TBI or stroke. Driving outcome was assessed in terms of being allowed to drive without restrictions as opposed to failing the test or being allowed to drive with restrictions. We examined two samples: the TBI patients only and the entire sample including patients after stroke. The results indicate that for TBI patients, Glasgow Coma Scale and motor FIM could be predictors of driving outcome; in the entire sample, the unrestricted driving outcome was also associated with a high score on the FIM motor scale. Early prediction of return to driving after TBI and stroke is important for the patients, their families and the rehabilitation teams to set realistic goals that enable the best possible reintegration after rehabilitation.


Neuropsychological Characterization of Aggressive Behavior in Children and Adolescents with CD/ODD and Effects of Single Doses of Medications: The Protocol of the Matrics_WP6-1 Study.
Aggressive behaviors and disruptive/conduct disorders are some of the commonest reasons for referral to youth mental health services; nevertheless, the efficacy of therapeutic interventions in real-world clinical practice remains unclear. In order to define more appropriate targets for innovative pharmacological therapies for disruptive/conduct disorders, the European Commission within the Seventh Framework Programme (FP7) funded the MATRICS project (Multidisciplinary Approaches to Translational Research in Conduct Syndromes) to identify neural, genetic, and molecular factors underpinning the pathogenesis of aggression/antisocial behavior in preclinical models and clinical samples. Within the program, a multicentre case-control study, followed by a single-blind, placebo-controlled, cross-over, randomized acute single-dose medication challenge, was conducted at two Italian sites. Aggressive children and adolescents with conduct disorder (CD) or oppositional defiant disorder (ODD) were compared to the same age (10-17 y) typically developing controls (TDC) on a neuropsychological tasks battery that included both "cold" (e.g., inhibitory control, decision making) and "hot" executive functions (e.g., moral judgment, emotion processing, risk assessment). Selected autonomic measures (heart rate variability, skin conductance, salivary cortisol) were recorded before/during/after neuropsychological testing sessions. The acute response to different drugs (methylphenidate/atomoxetine, risperidone/aripiprazole, or placebo) was also examined in the ODD/CD cohort in order to identify potential neuropsychological/physiological mechanisms underlying aggression. The paper describes the protocol of the clinical MATRICS WP6-1 study, its rationale, the specific outcome measures, and their implications for a precision medicine approach.


Low-dosage ancrod for prevention of thrombotic complications after surgery for fractured neck of femur.
The effect of a low-dosage regimen of ancrod in the prevention of postoperative deep vein thrombosis was assessed in 24 patients having surgical repair of fractured neck femur and compared with 25 control patients who did not receive therapy. The objective of the therapy was to lower the preoperative fibrinogen level and produce a low concentration of fibrin degradation products yet avoid the haemorrhagic complications of total defibrination. Ancrod therapy proved feasible to carry out, was not associated with haemorrhagic complications, and produced sustained, predictable reductions in fibrinogen concentration. There were seven thromboembolic complications in the control patients compared to one such complication in the ancrod-treated patients. Five deaths occurred in the control group and one in the treated group. Though the incidence of deep vein thrombosis was not apparently affected by ancrod it appeared on venography that the thrombi in the treated patients were less extensive than those in the control patients. Finally, some discrepancies in the diagnosis of deep vein thrombosis by the three techniques of clinical examination, (125)I-fibrinogen scanning, and ascending venography were identified.


Modulations of Insular Projections by Prior Belief Mediate the Precision of Prediction Error during Tactile Learning.
Awareness for surprising sensory events is shaped by prior belief inferred from past experience. Here, we combined hierarchical Bayesian modeling with fMRI on an associative learning task in 28 male human participants to characterize the effect of the prior belief of tactile events on connections mediating the outcome of perceptual decisions. Activity in anterior insular cortex (AIC), premotor cortex (PMd), and inferior parietal lobule (IPL) were modulated by prior belief on unexpected targets compared with expected targets. On expected targets, prior belief decreased the connection strength from AIC to IPL, whereas it increased the connection strength from AIC to PMd when targets were unexpected. Individual differences in the modulatory strength of prior belief on insular projections correlated with the precision that increases the influence of prediction errors on belief updating. These results suggest complementary effects of prior belief on insular-frontoparietal projections mediating the precision of prediction during probabilistic tactile learning.SIGNIFICANCE STATEMENT In a probabilistic environment, the prior belief of sensory events can be inferred from past experiences. How this prior belief modulates effective brain connectivity for updating expectations for future decision-making remains unexplored. Combining hierarchical Bayesian modeling with fMRI, we show that during tactile associative learning, prior expectations modulate connections originating in the anterior insula cortex and targeting salience-related and attention-related frontoparietal areas (i.e., parietal and premotor cortex). These connections seem to be involved in updating evidence based on the precision of ascending inputs to guide future decision-making.


Microwave reactions under continuous flow conditions.
Microwave chemistry has already impacted significantly on the everyday synthesis of organic molecules. The adoption and integration of this liberating technology has permitted a resurrection of many synthetic transformations that were previously considered too extreme in their conditions (temperatures, pressures, reaction times) to be synthetically useful. Furthermore, whole arrays of additional chemical transformations have been devised under microwave heating that allow access to more diverse chemical architectures via more expedient routes. Continuous flow processing of chemical intermediates taking advantage of the unique heating mechanism and characteristics of microwave irradiation will certainly be the next evolutionary step forward in this area. The synergistic combination afforded by the simultaneous application of these two core processing tools will enhance still further the synthetic capabilities of tomorrow's chemists. This short review aims to highlight the current developments and future potential offered by continuous flow microwave mediated synthesis.


Evaluation of the 24-Hour Recall as a Reference Instrument for Calibrating Other Self-Report Instruments in Nutritional Cohort Studies: Evidence From the Validation Studies Pooling Project.
Calibrating dietary self-report instruments is recommended as a way to adjust for measurement error when estimating diet-disease associations. Because biomarkers available for calibration are limited, most investigators use self-reports (e.g., 24-hour recalls (24HRs)) as the reference instrument. We evaluated the performance of 24HRs as reference instruments for calibrating food frequency questionnaires (FFQs), using data from the Validation Studies Pooling Project, comprising 5 large validation studies using recovery biomarkers. Using 24HRs as reference instruments, we estimated attenuation factors, correlations with truth, and calibration equations for FFQ-reported intakes of energy and for protein, potassium, and sodium and their densities, and we compared them with values derived using biomarkers. Based on 24HRs, FFQ attenuation factors were substantially overestimated for energy and sodium intakes, less for protein and potassium, and minimally for nutrient densities. FFQ correlations with truth, based on 24HRs, were substantially overestimated for all dietary components. Calibration equations did not capture dependencies on body mass index. We also compared predicted bias in estimated relative risks adjusted using 24HRs as reference instruments with bias when making no adjustment. In disease models with energy and 1 or more nutrient intakes, predicted bias in estimated nutrient relative risks was reduced on average, but bias in the energy risk coefficient was unchanged.


Initial experience of laparoscopic incisional hernia repair.
Laparoscopic repair of ventral and incisional hernia has become increasingly popular as compared to open repair. The procedure has the advantages of minimal access surgery, reduction of post operative pain and the recurrence rate. A prospective study of laparoscopic incisional hernia repair was performed in our center from August 2002 to April 2004. Eighteen cases (n: 18) were performed during the study period. Fifteen cases (n: 15) had open hernia repair previously. Sixteen patients (n: 16) had successful repair of the hernia with the laparoscopic approach and two cases were converted to open repair. The mean hernia defect size was 156cm2. There was no intraoperative or immediate postoperative complication. The mean operating time was 100 +/- 34 minutes (75 - 180 minutes). The postoperative pain was graded as mild to moderate according to visual analogue score. The mean day of discharge after surgery was two days (1 - 3 days). During follow up, three patients (16.7%) developed seroma at the hernia sac which was resolved with conservative management after three weeks. One (5.6%) patient developed recurrence six months after surgery. In conclusion, laparoscopic repair of incisional hernia particularly recurrent hernia has been shown to be safe and effective in our centre. However, careful patient selection and acquiring the necessary advanced laparoscopic surgical skills coupled with the proper use of equipment are mandatory before embarking on this procedure.


Can peripheral DXA measurements be used to predict fractures in elderly women living in the community?
While axial dual energy X-ray absorptiometry (DXA) is the accepted "gold standard" method both for diagnosing osteoporosis and predicting fractures, appropriate equipment is not universally available. Peripheral bone mass measurements may have the potential to identify patients at risk of fracture and to be used to target appropriate treatment. We assessed the effectiveness of peripheral DXA (PIXI, GELunar) in the assessment of risk and targeting treatment to prevent future fracture in 7,604 women aged 60-80 from five centres across Britain. At enrolment women completed a lifestyle and risk factor questionnaire and had a PIXI DXA scan of the heel. Women were categorised by PIXI DXA bone mineral density (BMD) into high, medium or low risk of future osteoporotic fracture. Treatment was recommended to those at highest risk. Follow-up was by simple questionnaire 18-24 months after baseline assessment. Seventy-four percent returned the follow-up questionnaire. The area under the receiver operator characteristic (ROC) curves for any fracture and osteoporotic fracture were comparable to those published using other sites and technologies. A 1-SD decrease in PIXI BMD was associated with an 86% increase in risk of osteoporotic fracture. Of the women identified as high risk, 74% had started treatment following their heel scan and 84.7% continued to take treatment at follow-up. No significant difference was noted in fracture rates in those who started treatment after assessment compared to those who did not. While peripheral DXA is highly effective for predicting older women who are at increased risk of future fracture, it has yet to be established as an effective method for targeting bisphosphonate or other therapy.


Vascular Permeability and Remodelling Coincide with Inflammatory and Reparative Processes after Joint Bleeding in Factor VIII-Deficient Mice.
Vascular remodelling is a prominent feature of haemophilic arthropathy (HA) that may underlie re-bleeding, yet the nature of vascular changes and underlying mechanisms remain largely unknown. Here, we aimed to characterize synovial vascular remodelling and vessel integrity after haemarthrosis, as well as temporal changes in inflammatory and tissue-reparative pathways. Thirty acutely painful joints in patients with haemophilia (PWH) were imaged by musculoskeletal ultrasound with Power Doppler (MSKUS/PD) to detect vascular abnormalities and bloody effusions. Nineteen out of 30 painful joint episodes in PWH were associated with haemarthrosis, and abnormal vascular perfusion was unique to bleeding joints. A model of induced haemarthrosis in factor VIII (FVIII)-deficient mice was used for histological assessment of vascular remodelling (α-smooth muscle actin [αSMA] expression), and monitoring of in vivo vascular perfusion and permeability by MSKUS/PD and albumin extravasation, respectively. Inflammatory (M1) and reparative (M2) macrophage markers were quantified in murine synovium over a 10-week time course by real-time polymerase chain reaction. The abnormal vascular perfusion observed in PWH was recapitulated in FVIII-deficient mice after induced haemarthrosis. Neovascularization and increased vessel permeability were apparent 2 weeks post-bleed in FVIII-deficient mice, after a transient elevation of inflammatory macrophage M1 markers. These vascular changes subsided by week 4, while vascular remodelling, evidenced by architectural changes and pronounced αSMA expression, persisted alongside a reparative macrophage M2 response. In conclusion, haemarthrosis leads to transient inflammation coupled with neovascularization and associated vascular permeability, while subsequent tissue repair mechanisms coincide with vascular remodelling. Together, these vascular changes may promote re-bleeding and HA progression.


[Study on diagnostic and therapeutic behavior in tumors of the medial-lower third of the rectum in 2 Italian regions].
The authors report about a survey on the behaviour of 51 departments of surgery in Lazio and Lombardia as to diagnosis, staging and therapy of carcinoma of the medium-lower one-third of the rectum. A set of 722 patients treated in 1993 was considered. A questionnaire was distributed and answers collected about the staging protocols, the therapeutic choices and some details of surgical technique as the ligation of the lower mesenteric artery or the extent of the lymphadenectomy. The results indicate some stable trends as to preoperative study (digital examination and fibre optic endoscopy in almost all cases) and as to the choice of the technique of anastomosis (43.1% of termino-terminal stapled anastomosis). Intrarectal ultrasound gains consensus but is still not much diffuse (18.6% of cases). Almost all of the participating Institutions agreed in joining further prospective studies.


Meat and poultry nitrogen factors.
The determination of nitrogen as a quantitative marker for meat fat-free protein and the calculation of meat content of compound foods began almost 100 years ago. It is the established official chemical method to enforce labelling declarations of meat content in food products, and also widely used by food producers to check the specification and added water of their meat raw materials. A "nitrogen factor" is the average nitrogen content of a specific cut or whole animal on a fat free basis. The AMC has been overseeing studies to determine nitrogen factors since the 1950's, and more recent government funded studies have been made to accommodate changing rearing regimes and the genetics of the animals.


Natriuretic peptides: degradation, circulating forms, dosages and new therapeutic approaches.
Testing for natriuretic peptides (BNP, NT-proBNP or MR-proANP) is recommended by the European Society of Cardiology (ESC) since 2005 for the exclusion diagnosis of acute and chronic heart failure because of very high predictive values. Natriuretic peptides are produced by the heart in response to high transmural pressure and/or myocardial ischemia. These peptides circulate in blood of both healthy subjects and heart failure patients. Mass spectrometry methods allowed identifying a collection of circulating and degraded forms of BNP, NT-proBNP and proBNP. Glycosylated forms of NT-proBNP and proBNP have also been identified. Current immunoassays are lacking analytical specificity due to high cross-reactivities between circulating forms. Moreover, glycosylation has been found to interfere with the capacity of antibodies to bind correctly to analytes. These elements have been taken into account to propose strategies for the development of new standardized and improved immunoassays. More recently, the better understanding of the degradation pathways of natriuretic peptides allowed the raise of new therapeutic approaches for heart failure patients. All these elements are detailed in this review.


Changes in Point of Maximal Curvature During Collagenase Clostridium Histolyticum Injections for Peyronie's Disease.
To determine change in the point of maximal curvature (POMC) during Collagenase Clostridium histolyticum (CCH) injections for Peyronie's disease (PD). A prospective database has been maintained of all men undergoing CCH injections since March 2014. For the current study, data were abstracted on the POMC with each curve assessment and correlated with demographic and clinical factors. Maximal changes were defined as the largest change in POMC from baseline. 618 men underwent ≥1 series of CCH, with 313 having a baseline and subsequent POMC measurements available. Median baseline curvature was 60.0° and POMC 2.8 cm. Among 189 men who were satisfied or completed 8 CCH injections, the median improvement in penile curvature was -27.5° (40.9%). The median maximal change in POMC during CCH treatment was 1.0 cm (IQR, 0.5, 1.8). Overall, 55.6% had changes in POMC of ≥1 cm, 23.6% ≥2 cm, 8.9% ≥3 cm, and 3.8% ≥4 cm. Multivariate logistic regression identified ventral curvature as a predictor of larger change in POMC, after controlling for other variables. Study limitations included the observational, non-randomized study design and potential for intra- and inter-individual measurement variability. Strengths are the inclusion of an all-comer population, large series, prospective database, and routine objective assessments. Approximately half of PD men undergoing CCH experience ≥1 cm of change in POMC during the treatment course, with nearly 1/4 experiencing ≥2 cm. Pending external validation, findings suggest that patients may benefit from repeat curvature assessments with each CCH series to optimize accuracy of drug administration.


Formation of degradation compounds from lignocellulosic biomass in the biorefinery: sugar reaction mechanisms.
The degradation compounds formed during pretreatment when lignocellulosic biomass is processed to ethanol or other biorefinery products include furans, phenolics, organic acids, as well as mono- and oligomeric pentoses and hexoses. Depending on the reaction conditions glucose can be converted to 5-(hydroxymethyl)-2-furaldehyde (HMF) and/or levulinic acid, formic acid and different phenolics at elevated temperatures. Correspondingly, xylose can follow different reaction mechanisms resulting in the formation of furan-2-carbaldehyde (furfural) and/or various C-1 and C-4 compounds. At least four routes for the formation of HMF from glucose and three routes for furfural formation from xylose are possible. In addition, new findings show that biomass monosaccharides themselves can react further to form pseudo-lignin and humins as well as a wide array of other compounds when exposed to high temperatures. Hence, several aldehydes and ketones and many different organic acids and aromatic compounds may be generated during hydrothermal treatment of lignocellulosic biomass. The reaction mechanisms are of interest because the very same compounds that are possible inhibitors for biomass processing enzymes and microorganisms may be valuable biobased chemicals. Hence a new potential for industrial scale synthesis of chemicals has emerged. A better understanding of the reaction mechanisms and the impact of the reaction conditions on the product formation is thus a prerequisite for designing better biomass processing strategies and forms an important basis for the development of new biorefinery products from lignocellulosic biomass as well.


[Action of chemical and physical mutagenic factors on the tetracycline producer Streptomyces aureofaciens].
The mutagenic effects of N-nitrozomethylbiuret (N-NMB), N-nitrozomethylurea (N-NMU), N-nitrozodimethylurea (N-NDMU), ethylene imine and UV light on Str. aureofacients producing tetracycline was studied comparatively. It was shown that N-NMU and N-NMB had a higher toxicity and mutagenic activity as compared to N-NDMU. The toxicity levels of N-NMU and N-NMB were similar. Still, by the number of the morphological mutations induced by them N-NMU was more effective.


Biomimetic Surface-Enhanced Raman Scattering Nanoparticles with Improved Dispersibility, Signal Brightness, and Tumor Targeting Functions.
The development of biocompatible and nontoxic surface-enhanced Raman scattering (SERS) nanoparticles is of considerable current interest because of their attractive biomedical applications such as ultrasensitive in vitro diagnostics, in vivo tumor imaging, and spectroscopy-guided cancer surgery. However, current SERS nanoparticles are prepared and stored in aqueous solution, have limited stability and dispersibility, and are not suitable for lyophilization and storage by freeze-drying or other means. Here, we report a simple but robust method to coat colloidal SERS nanoparticles by naturally derived biomimetic red blood cell membranes (RBCM), leading to a dramatic improvement in stability and dispersibility under freeze-thawing, lyophilization, heating, and physiological conditions. The results demonstrate that the lyophilized SERS nanoparticles in the solid form can be readily dissolved and dispersed in physiological buffer solutions. A surprising finding is that the RBCM-coated SERS particles are considerably brighter (by as much as 5-fold) than PEGylated SERS particles under similar experimental conditions. This additional enhancement is believed to arise from the hydrophobic nature of RBCM's hydrocarbon chains, which is known to reduce electronic dampening and boost electromagnetic field enhancement. A further advantage in using biomimetic membrane coatings is that the bilayer membrane structure allows nonvalent insertion of molecular ligands for tumor targeting. In particular, we show that cyclic-RGD, a tumor-targeting peptide, can be efficiently inserted into the membrane coatings of SERS nanoparticles for targeting the ανβ3 integrin receptors expressed on cancer cells. Thus, biomimetic RBCMs provide major advantages over traditional polyethylene glycols for preparing SERS nanoparticles with improved dispersibility, higher signal intensity, and more efficient biofunctionalization.


[Hospitalisations for acute myocardial infarction--comparing data from three different sources].
The aim of this study is to compare information on hospitalisations for acute myocardial infarction (AMI) from three different sources. (A) The national hospital discharge statistics, covering all hospitalisations in Germany, is representative for this population. However, the information is limited, as data are collected case-related containing only few characteristics. (B) In contrast, claims data of sickness funds can be analysed longitudinally and contain more characteristics. The data have to be collected from single sickness funds. As for the data from registries (C) these data cannot be assumed to be representative. Data from the included sickness fund showed good consistency when compared to data from the national hospital discharge statistics regarding most, but not all, results. Comparisons with the register in Augsburg lead to divergent results regarding case fatality rates and rates of utilisation of technologies. None of the three sources can be considered ideal. Part of the differences could be explained by methodological and regional effects. More insight could be gained by comparing data at the individual level. According to recent legislation, data from all statutory sickness funds are supposed to be merged. This would simplify such comparisons and most likely would allow for more valid information regarding the incidence and treatment of AMI and many other diseases.


[Antioxidant activity of cytoflavin in experimental diffuse purulent peritonitis].
One of key factors in the development of endogenous intoxication during widespread purulent peritonitis is a disbalance in the free-radical oxidation. A hyperactivation of lipid peroxidation and a decrease in the antioxidant activity cause impairment of the cell mitochondria function. The new metabolic drug cytoflavin possesses pronounced antioxidant properties, provides an effective and fast restoration of the LPO and antioxidant activity balance, and increases the speed of free radical elimination. This investigation confirmed the expediency of including cytoflavin in the complex treatment of widespread purulent peritonitis with the aim of normalizing biological oxidation processes and eliminating endogenous intoxication factors.


New endemic familial parkinsonism in south Moravia, Czech Republic and its genetical background.
An increased prevalence of familial neurodegenerative parkinsonism or cognitive deterioration was recently found in a small region of southeastern Moravia.The aim of the study was to assess the genetic background of this familial disease.Variants in the ADH1C, EIF4G1, FBXO7, GBA + GBAP1, GIGYF2, HTRA2, LRRK2, MAPT, PRKN, DJ-1, PINK1, PLA2G6, SNCA, UCHL1, VPS35 genes were examined in 12 clinically positive probands of the pedigree in which familial atypical neurodegenerative parkinsonism was identified in previous epidemiological studies. Libraries were sequenced by massive parallel sequencing (MPS) on the Personal Genome Machine (PGM; Ion Torrent). Data were analyzed using Torrent Suite and IonReporter software. All variants were then verified and confirmed by Sanger sequencing.We identified 31 rare heterozygous variants: 11 missense variants, 3 synonymous variants, 8 variants in the UTR region, and 9 intronic variants. Six variants (rs1801334, rs33995883, rs35507033, rs781737269, rs779760087, and rs63750072) were evaluated as pathogenic by at least one in-silico predictor.No single "founder" pathogenic variant associated with parkinsonism has been found in any of the probands from researched pedigree. It may rather be assumed that the familial occurrence of this disease is caused by the combined influence of several "small-effect" genetic variants that accumulate in the population with long-lasting inbreeding behavior.


A predictably selective aliphatic C-H oxidation reaction for complex molecule synthesis.
Realizing the extraordinary potential of unactivated sp3 C-H bond oxidation in organic synthesis requires the discovery of catalysts that are both highly reactive and predictably selective. We report an iron (Fe)-based small molecule catalyst that uses hydrogen peroxide (H2O2) to oxidize a broad range of substrates. Predictable selectivity is achieved solely on the basis of the electronic and steric properties of the C-H bonds, without the need for directing groups. Additionally, carboxylate directing groups may be used to furnish five-membered ring lactone products. We demonstrate that these three modes of selectivity enable the predictable oxidation of complex natural products and their derivatives at specific C-H bonds with preparatively useful yields. This type of general and predictable reactivity stands to enable aliphatic C-H oxidation as a method for streamlining complex molecule synthesis.


[Foetal programming of nutrition-related chronic diseases].
Intrauterine growth retardation, which reflects in large part maternal malnutrition in poorer communities, contributes to chronic disease risk through foetal programming, according to the early origins hypothesis of Barker. Foetal programming implies that during critical periods of prenatal growth, permanent changes in metabolism or structures result from adverse intrauterine conditions. Observational studies first showed an association between lower birth weights and higher rates of coronary disease in the 80s, in England and Scandinavia. The link between low birth weights, or other indicators of small birth size, and cardiovascular disease was later confirmed in many epidemiological studies, including in the USA and in India. Similarly, a reverse relationship of birth weight and systolic blood pressure was shown in men and women, in developed as well as developing countries, and in all age groups, although it was less consistent in adolescents. Insulin resistance and type-2 diabetes have also been found to be independently related to small size at birth in several studies around the world. Insulin resistance associated with small size at birth was frequently shown to be present at a young age. The association of small birth size with chronic disease tends to increase with catch-up growth and obesity, and usually persists after adjusting for confounding factors such as age, family history, and socio-economic status. Several, but not all, twin studies lend support to the hypothesis. There is a tendency for lighter members of twin pairs to have a higher blood pressure, and more diabetes. Observations in people exposed to the Dutch famine while in utero also tend to corroborate the hypothesis. Those who were exposed early in their intrauterine life did not have lower birth weights, but they were prone to becoming obese later on. In contrast, those exposed towards the end of gestation had lower birth weights, and showed a higher rate of impaired glucose tolerance, while having a lower risk of obesity. Dietary manipulations in animal models provide further support and mechanistic explanations, in particular protein deficiency in pregnant rats, which elevates blood pressure, impairs glucose tolerance, and increases the likelihood of obesity in the progeny. Although there are still controversial areas, there is at present sufficient scientific evidence for foetal programming to be regarded as an additional risk factor for chronic disease, in interaction with genetic and lifestyle risk factors. The fact that intrauterine growth retardation may predispose to nutrition-related chronic disease has serious implications for developing countries, particularly those undergoing rapid nutritional transition, as it may further increase the rates of obesity, cardiovascular disease and diabetes when diets and lifestyles are in themselves "atherogenic". The challenge is for programmes to simultaneously combat apparently opposite nutrition problems, malnutrition and "over-nutrition". Improving the nutrition of women is even more imperative when considering that it may contribute to preventing chronic diseases in the next generation, in addition to enhancing health and survival of mothers and children.


Measurement of the Psychosocial Work Environment in Spanish: Validation of the Psychosocial Factors Questionnaire 75 (PSF-Q75) to Capture Demands and Resources at Different Levels of Analysis.
The psychological work environment is composed of both stressful and motivational work conditions at different levels of analysis. However, most relevant theory and research lack an integrative conceptualization and appropriate instrumentation to account for this work context structure. These limitations are particularly present in non-mainstream populations, such as the Spanish community of researchers and practitioners. In this study, based on the job demands-resources model, we present an updated conceptualization in which stressful and motivational psychosocial factors are integrated and defined at the job, the group, and the organizational level of analysis into a single conceptualization. Furthermore, derived from this conceptualization, we present a study of the development and validation of a questionnaire to account for the psychosocial work environment in Spanish, labeled Psychosocial Factors Questionnaire 75 (PSF-Q75), which provides measures for 23 different psychosocial factors. The results of this study supported the questionnaire's construct, convergent, divergent, and predictive validity, together with its reliability. Thus, this conceptualization and questionnaire provides researchers and partitioners with a more comprehensive approach to the assessment of the psychosocial work environment and promises benefits for interventions in the workplace.


Healthful Dietary Patterns and the Risk of Hypertension Among Women With a History of Gestational Diabetes Mellitus: A Prospective Cohort Study.
Women who developed gestational diabetes mellitus represent a high-risk population for hypertension later in life. The role of diet in the progression of hypertension among this susceptible population is unknown. We conducted a prospective cohort study of 3818 women with a history of gestational diabetes mellitus in the Nurses' Health Study II as part of the ongoing Diabetes & Women's Health Study. These women were followed-up from 1989 to 2011. Incident hypertension was identified through self-administered questionnaires that were validated previously by medical record review. Adherence scores for the alternative Healthy Eating Index 2010, the alternative Mediterranean diet, and the Dietary Approaches to Stop Hypertension were computed for each participant. Cox proportional hazard models were used to evaluate the associations between dietary scores and hypertension while adjusting for major risk factors for hypertension. We documented 1069 incident hypertension cases during a median of 18.5 years of follow-up. After adjustment for major risk factors for hypertension, including body mass index, alternative Healthy Eating Index 2010, alternative Mediterranean diet, and Dietary Approaches to Stop Hypertension scores were significantly inversely associated with the risk of hypertension; hazard ratio and 95% confidence interval comparing the extreme quartiles (highest versus lowest) were 0.76 (0.61-0.94; P for linear trend =0.03) for AHEI score, 0.72 (0.58-0.90; P for trend =0.01) for Dietary Approach to Stop Hypertension score, and 0.70 (0.56-0.88; P for trend =0.002) for alternative Mediterranean diet score. Adherence to a healthful dietary pattern was related to a lower subsequent risk of developing hypertension among women with a history of gestational diabetes mellitus.


Adrenergic responses of gracilis arteries removed during hemorrhagic hypotension and shock.
Previous studies suggest that the gracilis vasculature responds to hypovolemic hypotension by constriction followed by vasodilation [Circ Shock 4:327, 1977; Circ Shock 6:43, 1979]. The objectives of the present study were to determine if the effective vascular smooth muscle population and/or adrenergic innervation density varies as the dog moves from compensatory into decompensatory shock. Gracilis arteries with adventitia intact were resected during four different stages of shock and compared to nonshocked vessels. All vessels were placed in a tissue chamber filled with warm (37 degrees C) Krebs-Henseleit solution and bubbled with 95% O2 and 5% CO2. Norepinephrine (NE) dose-response and periarterial electrical stimulation (ES) frequency-response studies were conducted. The maximum response to NE was not altered from control during either compensatory or decompensatory shock, but the maximum response to ES fell during compensatory and early decompensatory hypovolemic hypotension. The sensitivity of the innervated alpha receptors, as measured by the ES necessary to obtain a 50% maximal response (ES50), also fell below control during early decompensatory hypotension but returned to control values during early and late normovolemic shock, even though the sensitivity of the alpha receptors to NE (ED50) increased. These data support the suggestion that the skeletal muscle vascular decompensation occurring as a consequence of hemorrhage may be caused by a neuromuscular transmission failure.


Maxillomandibular advancement for the treatment of obstructive sleep apnea: a systematic review and meta-analysis.
The reported efficacy of maxillomandibular advancement (MMA) for the treatment of obstructive sleep apnea (OSA) is uncertain. We performed a meta-analysis and systematic review to estimate the clinical efficacy and safety of MMA in treating OSA. We searched Medline and bibliographies of retrieved articles, with no language restriction. We used meta-analytic methods to pool surgical outcomes. Fifty-three reports describing 22 unique patient populations (627 adults with OSA) met inclusion criteria. Additionally, 27 reports provided individual data on 320 OSA subjects. The mean apnea-hypopnea index (AHI) decreased from 63.9/h to 9.5/h (p<0.001) following surgery. Using a random-effects model, the pooled surgical success and cure (AHI <5) rates were 86.0% and 43.2%, respectively. Younger age, lower preoperative weight and AHI, and greater degree of maxillary advancement were predictive of increased surgical success. The major and minor complication rates were 1.0% and 3.1%, respectively. No postoperative deaths were reported. Most subjects reported satisfaction after MMA with improvements in quality of life measures and most OSA symptomatology. We conclude that MMA is a safe and highly effective treatment for OSA.


Roles of activated astrocyte in neural stem cell proliferation and differentiation.
Recent studies demonstrated that the molecules secreted from astrocytes play important roles in the cell fate determination of neural stem cells (NSCs). However, the exact molecules involved and its possible mechanisms in the process remain largely unknown. In this study, astrocyte-conditioned medium (ACM) obtained from astrocytes unstimulated or stimulated by lipopolysaccharide was prepared to treat NSCs. The results showed that both the proliferation and differentiation of NSCs treated with stimulated ACMs were significantly increased compared with those treated with unstimulated ACM. Interleukin-6 (IL-6) antibody neutralization of the ACMs decreased NSC proliferation and astrogliogenesis, while NSC neurogenesis was increased. In contrast, recombinant IL-6 cytokine increased NSC proliferation and astrogliogenesis, but decreased neurogenesis. Furthermore, the expression of phosphorylated signal transducer and activator of transcription 3 (p-stat3) protein as well as serial of basic helix-loop-helix transcription factors (bHLH) mRNA in NSCs exposed to stimulated ACMs significantly increased, respectively. The expression levels of p-stat3 protein and bHLH mRNA of NSCs were significantly altered after adding anti-IL-6 antibody or recombinant IL-6, respectively. The data suggest that IL-6 secreted from activated astrocytes participates in ACM-induced proliferation and differentiation of NSCs via the phosphorylation of stat3 signals and the expression of bHLH transcription factors.


Kinetics of IgE antibody response to trichosanthin alpha-momorcharin and beta-momorcharin in mice.
Allergenicity of three plant abortifacient proteins, trichosanthin (TCS), alpha-momorcharin (alpha-MMC) and beta-momorcharin (beta-MMC) and the kinetics of IgE antibody response against these proteins were studied in C57BL/6N and BALB/cAn mice. These proteins were purified from Chinese medicinal herbs, characterized by biochemical and immunological procedures and found to be homogeneous by PAGE, SDS-PAGE and immunoelectrophoresis. The results obtained were summarized as follows: 1) different levels of IgE antibody responses against TCS, alpha-MMC and beta-MMC were induced when they were injected i.p. as antigen adsorbed onto AI(OH)3 gel into BALB/cAn or C57BL/6N mice on day 0 and day 28; 2) the allergenicity of the proteins was in the order of beta-MMC greater than alpha-MMC greater than TCS; 3) two injections of 10 micrograms or 50 micrograms of TCS or alpha-MMC given at 4 weeks interval without adjuvant elicited a low or undetectable PCA titer, while the same dose given weekly for 5 weeks resulted in high levels of IgE production; and 4) on the basis of PCA observations, no cross immunological reactivity among these three proteins was found, it seemed to support that TCS, alpha-MMC and beta-MMC may be alternately used for inducing abortion.


An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer.
Recent evidence suggests that blockade of aberrant Hedgehog signaling can be exploited as a therapeutic strategy for pancreatic cancer. Our previous studies using the prototype Hedgehog small-molecule antagonist cyclopamine had shown the striking inhibition of systemic metastases on Hedgehog blockade in spontaneously metastatic orthotopic xenograft models. Cyclopamine is a natural compound with suboptimal pharmacokinetics, which impedes clinical translation. In the present study, a novel, orally bioavailable small-molecule Hedgehog inhibitor, IPI-269609, was tested using in vitro and in vivo model systems. In vitro treatment of pancreatic cancer cell lines with IPI-269609 resembled effects observed using cyclopamine (i.e., Gli-responsive reporter knockdown, down-regulation of the Hedgehog target genes Gli1 and Ptch, as well as abrogation of cell migration and colony formation in soft agar). Single-agent IPI-269609 profoundly inhibited systemic metastases in orthotopic xenografts established from human pancreatic cancer cell lines, although Hedgehog blockade had minimal effect on primary tumor volume. The only discernible phenotype observed within the treated primary tumor was a significant reduction in the population of aldehyde dehydrogenase-bright cells, which we have previously identified as a clonogenic tumor-initiating population in pancreatic cancer. Selective ex vivo depletion of aldehyde dehydrogenase-bright cells with IPI-269609 was accompanied by significant reduction in tumor engraftment rates in athymic mice. Pharmacologic blockade of aberrant Hedgehog signaling might prove to be an effective therapeutic strategy for inhibition of systemic metastases in pancreatic cancer, likely through targeting subsets of cancer cells with tumor-initiating ("cancer stem cell") properties.


Impact of socio-economic inequities on tuberculosis in a Southern European city: what is the effect of the recession?
Economic crises affect a population's health, particularly among the most deprived. The increase in health inequalities in the latest recession may have influenced the incidence of tuberculosis (TB). We analysed the effect of socio-economic inequities and recession on TB incidence in Barcelona, Spain. We conducted a population-based incidence study of TB cases in Barcelona of patients who started treatment between 2003 and 2015. A multilevel interrupted time-series analysis was performed to analyse differences in incidence trends between the pre-recession (until 2008) and recession periods. We found differences in TB incidence according to deprivation and immigration status. TB incidence among the most deprived neighbourhoods was 2.72 times higher than the least deprived neighbourhoods. Compared with native-born persons, incidence was nine times higher among those born in Africa, and six times higher among those born in Asia and Oceania. The previous decreasing trend in incidence (4%) was accentuated during the recession (7%). TB incidence decreased during the recession, probably due to a reduction in the number of new immigrants and the TB programme. However, incidence was highly unequal between districts with different levels of deprivation, and between foreign-born persons from different geographic regions. Social measures are important to reduce inequalities and TB incidence in Barcelona.


P300 component identification using source analysis techniques: reduced latency variability.
P300 latency variability in normal subjects is a complicating factor in clinical event-related potential studies because it limits diagnostic applicability. The current study was conducted to determine whether identification of P300 (P3A and P3B) components using source analysis techniques can reduce variability in P300 parameters. Data were recorded with a 128-channel EEG system in 18 healthy subjects. The authors used a standard, auditory two-tone oddball paradigm with targets of 2000 Hz and standards of 1000 Hz. Two simple source analysis models with one or two rotating dipoles were applied to grand average data and individual data. Dipole time courses were combined with mapping results to extract P3A and P3B component latencies. Latencies obtained with conventional P300 analysis were compared with source analysis results. The source analysis method identified both P3A and P3B components in a substantially larger percentage of subjects (88% vs. 33%) than the conventional method. The source analysis method yielded a later mean P3B latency (357 msec vs. 323 msec, P < 0,001) with a smaller standard deviation (9 msec vs. 23 msec, P = 0,003) than the conventional P300 method. The relative contribution of the temporally separate P3A and P3B components to the P300 complex amplitude is highly variable. This explains the larger latency standard deviation in conventional P300 analysis. The source analysis method was able to identify P300 components in a large percentage of the cases. The result is a considerable reduction of P300 latency variability in normal subjects. This could have important consequences for clinical event-related potential research, because diagnostic sensitivity and specificity of P300 latency may improve with this method.


Vehicle-related injuries in and around a medium sized Swedish City - bicyclist injuries caused the heaviest burden on the medical sector.
A data acquisition from the medical sector may give one important view of the burden on the society caused by vehicle related injuries. The official police-reported statistics may only reflect a part of all vehicle-related injured seeking medical attention. The aim is to provide a comprehensive picture of the burden of vehicle related injuries on the medical sector (2013), and to compare with official police-reported statistics and the development year 2000-2013. The data set includes 1085 injured from the Injury Data Base at Umeå University Hospital's catchment area with 148,500 inhabitants in 2013. Bicyclists were the most frequently injured (54%). One-third had non-minor (MAIS2+) injuries, and bicyclists accounted for 58% of the 1071 hospital bed days for all vehicle-related injuries. Car occupants represented 23% of all injured, and only 9% had MAIS2+ injuries. They accounted for 17% of the hospital bed days. Motorized two wheel vehicle riders represented 11% of the injured and 39% had MAIS2+ injuries and they occupied 11% of the hospital bed days. Of the 1085 medically treated persons, 767 were injured in public traffic areas, and, therefore, should be included in the official police statistics; however, only a third (232) of them were reported by the police. The annual injury rate had not changed during 2000-2013 for bicyclists, motor-cycle riders, pedestrians or snowmobile riders. However, for passenger car occupants a decrease was observed after 2008, and for mopedists the injury rate was halved after 2009 when a licensing regulation was introduced. The Swedish traffic injury reducing strategy Vision Zero, may have contributed to the reduction of injured car occupants and moped riders. The official police-reported statistics was a biased data source for vehicle related injuries and the total number medically treated was in total five times higher. Bicyclists caused the heaviest burden on the medical sector; consequently, they need to be prioritized in future safety work, as recently declared in the Government plan Vision Zero 2.0.


Admission and discharge criteria for adolescents requiring inpatient or residential mental health care: a scoping review.
This scoping review sought to locate and describe criteria relating to admission to and discharge from inpatient mental health care for adolescents aged 11 to 19 years in the literature. In the United Kingdom (UK) and internationally, it is estimated that one in 10 children and adolescents has a diagnosable mental health problem. Children and adolescents with the highest levels of need are cared for in hospital, but there is a high demand for beds and a general lack of agreement regarding the criteria for admission to, and discharge from, such units. We considered research studies that focused on criteria for admission to and discharge from inpatient mental healthcare units for adolescents aged 11 to 19 years. We included all quantitative and qualitative research designs and text and opinion papers. We searched MEDLINE, Embase, PsycINFO, CINAHL, ERIC, British Nursing Index, Applied Social Sciences Index and Abstracts, ProQuest Dissertations and Theses, the Cochrane Central Register of Controlled Trials, OpenGrey, EThOS and websites of professional organizations for English language citations from 2009 to February 2018. Potentially relevant citations were retrieved in full and their citation details imported into the JBI System for the Unified Management, Assessment and Review of Information. Full texts of selected citations were assessed in detail against the inclusion criteria by two independent reviewers. Findings were extracted directly into tables accompanied by a narrative summary relating to the review objectives. Thirty-five citations were included: quantitative research studies (n = 18), qualitative research studies (n = 1), and textual and opinion publications (n = 16). Of the quantitative research studies, 16 used a retrospective cohort design using case note reviews and two were prospective cohort studies. The qualitative study used interviews. The research studies were conducted in nine countries: USA (n = 7), UK (n = 3), New Zealand (n = 2), Israel (n = 2), Canada (n = 1), Norway (n = 1), Ireland (n = 1), Greece (n = 1) and Turkey (n = 1). The 16 textual and opinion publications included book chapters (n = 3), reviews (n = 3), policy and guidance documents (n = 3), reports (n = 3) and service specifications (n = 4). The majority of these were published in the UK (n = 10), with the remainder published in Ireland (n = 2), Australia (n = 2), and USA (n = 2). Research was conducted across a variety of settings including child and adolescent mental health service inpatient and outpatient units, emergency departments and adult psychiatric units. Length of stay, where recorded, ranged from < 1 day to 351 days. Several categories emerged from the data: type of admission process, referral or point of access, reasons for admission to inpatient mental health care, assessment processes, criteria for discharge and reasons for non-admission. There is little evidence identifying which behavioral or symptomatic indicators suggest that admission is required, beyond retrospective identification of diagnoses attributed to adolescents who become inpatients. The threshold of severity of risk or need is not currently articulated. No studies were identified that drew on the perspectives of adolescents and their families or carers regarding criteria warranting admission to inpatient mental health care, which indicates an important area for future investigation.


Confirming Silent Translocation through Nanopores with Simultaneous Single-Molecule Fluorescence and Single-Channel Electrical Recordings.
Most of what is known concerning the luminal passage of materials through nanopores arises from electrical measurements. Whether nanopores are biological, solid-state, synthetic, hybrid, glass-capillary-based, or protein ion channels in cells and tissues, characteristic signatures embedded in the flow of ionic current are foundational to understanding functional behavior. In contrast, this work describes passage through a nanopore that occurs without producing an electrical signature. We refer to the phenomenon as "silent translocation." By definition, silent translocations are invisible to the standard tools of electrophysiology and fundamentally require a simultaneous ancillary measurement technique for positive identification. As a result, this phenomenon has been largely unexplored in the literature. Here, we report on a derivative of Cyanine 5 (sCy5a) that passes through the α-hemolysin (αHL) nanopore silently. Simultaneously acquired single-molecule fluorescence and single-channel electrical recordings from bilayers formed over a closed microcavity demonstrate that translocation does indeed take place, albeit infrequently. We report observations of silent translocation as a function of time, dye concentration, and nanopore population in the bilayer. Lastly, measurement of the translocation rate as a function of applied potential permits estimation of an effective energy barrier for transport through the pore as well as the effective charge on the dye, all in the absence of an information-containing electrical signature.


Gender and racial differences in smoking of long/ultra-long and king size cigarettes among U.S. adult smokers, NHANES 1999-2012.
Cigarette rod length as a design feature may play a specific role in harm perception and tobacco use. Internal tobacco industry documents have shown targeting of females with long/ultra-long cigarettes. This study assessed trends and differences in smoking of long/ultra-long cigarettes among U.S. smokers aged ≥20 years during 1999 through 2012. Data were obtained from the 1999/2000 through 2011/2012 National Health and Nutrition Examination Survey. The proportion of current smokers who reported using long/ultra-long cigarettes during each survey year was calculated and compared using χ(2) statistics. Linear and quadratic trends during 1999 through 2012 were assessed using binary logistic regression (p<0.05). Multi-variable analyses were performed to assess current disparities in smoking of long/ultra-long cigarettes. Despite overall declines in current smoking of long/ultra-long cigarettes during the 1999 through 2012 period (p<0.001 for both linear and quadratic trends), the proportion of smokers of long/ultra-long brands increased in recent years, with over a third (38.7%) of current smokers reporting smoking of long/ultra-long cigarettes during 2011/2012. Current smokers of long/ultra-long cigarettes were more likely to be female compared to males (aOR=3.09; 95%CI: 2.09-4.58), of black race compared to whites (aOR=2.07; 95%CI: 1.30-3.28), or aged 45-64, or ≥65 years (aOR=2.39 and 5.27, respectively), compared to 18-24 year olds. Specific gender, age and race/ethnic characteristics of smokers of long/ultra-long cigarettes were noted, hence potentially contributing to the widening of health disparities. Cigarette rod length should be considered an important aspect of cigarette engineering/design in regulatory efforts to reduce the burden of tobacco-related disease.


Registration of magnetic resonance and computed tomography images in patients with oral squamous cell carcinoma for three-dimensional virtual planning of mandibular resection and reconstruction.
The aim of this study was to evaluate and present an automated method for registration of magnetic resonance imaging (MRI) and computed tomography (CT) or cone beam CT (CBCT) images of the mandibular region for patients with oral squamous cell carcinoma (OSCC). Registered MRI and (CB)CT could facilitate the three-dimensional virtual planning of surgical guides employed for resection and reconstruction in patients with OSCC with mandibular invasion. MRI and (CB)CT images were collected retrospectively from 19 patients. MRI images were aligned with (CB)CT images employing a rigid registration approach (stage 1), a rigid registration approach using a mandibular mask (stage 2), and two non-rigid registration approaches (stage 3). Registration accuracy was quantified by the mean target registration error (mTRE), calculated over a set of landmarks annotated by two observers. Stage 2 achieved the best registration result, with an mTRE of 2.5±0.7mm, which was comparable to the inter- and intra-observer variabilities of landmark placement in MRI. Stage 2 was significantly better aligned compared to all approaches in stage 3. In conclusion, this study demonstrated that rigid registration with the use of a mask is an appropriate image registration method for aligning MRI and (CB)CT images of the mandibular region in patients with OSCC.


Anabolic Hormones Deficiencies in Heart Failure With Preserved Ejection Fraction: Prevalence and Impact on Antioxidants Levels and Myocardial Dysfunction.
Purpose: In heart failure with reduced ejection fraction, catabolic mechanisms have a strong negative impact on mortality and morbidity. The relationship between anabolic hormonal deficiency and heart failure with preserved ejection fraction (HFpEF) has still been poorly investigated. On the other hand, oxidative stress is recognized as a player in the pathogenesis of HFpEF. Therefore, we performed a cohort study in HFpEF aimed to (1) define the multi-hormonal deficiency prevalence in HFpEF patients; (2) investigate the relationships between hormonal deficiencies and echocardiographic indexes; (3) explore the modulatory activity of anabolic hormones on antioxidant systems. Methods: 84 patients with diagnosis of HFpEF were enrolled in the study. Plasma levels of N-terminal pro-brain natriuretic peptide, fasting glucose, insulin, lipid pattern, insulin-like growth factor-1, dehydroepiandrosterone-sulfate (DHEA-S), total testosterone (T, only in male subjects) were evaluated. Hormonal deficiencies were defined according to T.O.S.C.A. multi-centric study, as previously published. An echocardiographic evaluation was performed. Plasma total antioxidant capacity (TAC) was measured using the system metmyoglobin -H2O2 and the chromogen ABTS, whose radical form is spectroscopically revealed; latency time (LAG) in the appearance of ABTS• is proportional to antioxidants in sample. Results: Multiple deficiencies were discovered. DHEA-S deficiency in 87% of patients, IGF-1 in 67% of patients, T in 42%. Patients with DHEA-S deficiency showed lower levels of TAC expressed by LAG (mean ± SEM 91.25 ± 9.34 vs. 75.22 ± 4.38 s; p < 0.05). No differences between TAC in patients with or without IGF-1 deficiency were found. A trend toward high level of TAC in patients without hormonal deficiencies compared with patients with one or multiple deficiencies was found. Regarding echocardiographic parameters, Left Atrial and Left Atrial Volume Index were significantly higher in patients with low IGF-1 values (mean ± SD 90.84 ± 3.86 vs. 72.83 ± 3.78 mL; 51.03 ± 2.33 vs. 40.56 ± 2.46 mL/m2, respectively; p < 0.05). Conclusions: Our study showed high prevalence of anabolic deficiencies in HFpEF. DHEA-S seems to influence antioxidant levels; IGF-1 deficiency was associated with alteration in parameters of myocardial structure and dysfunction. These data suggest a role of anabolic hormones in the complex pathophysiological mechanisms of HFpEF and could represent the basis for longitudinal studies and investigations on possible benefits of replacement therapy.


Prevalence of Physical Activity, Screen Time, and Sleep, and Associations with Adiposity and Motor Development among Preschool-Age Children in Vietnam: The SUNRISE Vietnam Pilot Study.
Global childhood obesity is of great concern. In 2019, the World Health Organization released global guidelines on movement behaviors for the children under 5 y of age to combat this epidemic. This study aimed to estimate the prevalence of Vietnamese preschoolers meeting the guidelines, and examined whether guideline compliance is associated with adiposity and motor development. A cross-sectional study was conducted on 103 healthy preschoolers who were conveniently sampled from preschools in urban and rural areas around Ho Chi Minh city. Time spent in different intensities of physical activity and sedentary behavior was measured using Actigraph GT3X + accelerometers over three consecutive days. Sleep and screen time were obtained via parent questionnaires. Children were classified as meeting or not meeting the global guidelines. Height, weight, and motor skills were measured by the research staff. Regression models were applied to quantify the association between guideline compliance and adiposity and motor development, adjusting for age and sex. While 17.5% of children met all three guidelines, 5.8% met no guidelines. The prevalences of children who met guidelines for physical activity time, sleep duration, and screen time were 50.4%, 81.4%, and 44.7%, respectively. There was no association between guideline compliance and adiposity and motor development. This study found a low proportion of children who met the global guidelines, whereas a high proportion of those with overweight and obesity was reported. Health programs should promote more physical activities of various intensities in young children.


Objects that induce face pareidolia are prioritized by the visual system.
The human visual system has evolved specialized neural mechanisms to rapidly detect faces. Its broad tuning for facial features is thought to underlie the illusory perception of faces in inanimate objects, a phenomenon called face pareidolia. Recent studies on face pareidolia suggest that the mechanisms underlying face processing, at least at the early stages of visual encoding, may treat objects that resemble faces as real faces; prioritizing their detection. In our study, we used breaking continuous flash suppression (b-CFS) to examine whether the human visual system prioritizes the detection of objects that induce face pareidolia over stimuli matched for object content. Similar to previous b-CFS results using real face stimuli, we found that participants detected the objects with pareidolia faces faster than object-matched control stimuli. Given that face pareidolia has been more frequently reported amongst individuals prone to hallucinations, we also explored whether this rapid prioritization is intact in individuals with schizophrenia, and found evidence suggesting that it was. Our findings suggest that face pareidolia engages a broadly tuned mechanism that facilitates rapid face detection. This may involve the proposed fast subcortical pathway that operates outside of visual awareness.


Water depth effects on impact loading, kinematic and physiological variables during water treadmill running.
The purpose of this study was to compare impact loading, kinematic and physiological responses to three different immersion depths (mid-shin, mid-thigh, and xiphoid process) while running at the same speed on a water based treadmill. Participants (N=8) ran on a water treadmill at three depths for 3min. Tri-axial accelerometers were used to identify running dynamics plus measures associated with impact loading rates, while heart rate data were logged to indicate physiological demand. Participants had greater peak impact accelerations (p<0.01), greater impact loading rates (p<0.0001), greater stride frequency (p<0.05), shorter stride length (p<0.01), and greater rate of acceleration development at toe-off (p<0.0001) for the mid-shin and mid-thigh compared to running immersed to the xiphoid process. Physiological effort determined by heart rate was also significantly less (p<0.0001) when running immersed to the xiphoid process. Water immersed treadmill running above the waistline alters kinematics of gait, reduces variables associated with impact, while decreasing physiological demand compared to depths below the waistline.


The pathophysiology of idiopathic mitral valve prolapse.
Left ventricular structure, function, and the coronary circulation were studied in a subset of patients with mitral valve leaflet prolapse. This group of 26 patients (21 females, five males, with mean age of 46 years), had the syndrome identified as idiopathic mitral valve prolapse (IMVP), which was characterized by a systolic click-murmur, clinical symptoms that were highly variable in duration and intensity, angiographically-documented mitral prolapse, and no obvious associated systemic or cardiovascular disease. Mitral regurgitation was of moderate degree in four, mild in 14, and absent in eight. The left ventricular (LV) end-diastolic volume index was elevated in ten of 25 (40%), the LV mass index was elevated in six of 17 (35%), but the LV anterior wall thickness was increase in only one of 17. Three major patterns of ventricular contraction were identified: 1) normal in seven; 2) abnormal, usually an inferior deformity and/or anterior asynergy, in eight; and 3) hyperkinetic in 11. Normal resting left ventricular function, assessed as an ejection fraction greater than 55%, was present in 17 of 25 (68%). Selective coronary arteriography was essentially normal in all 25 patients studied. An ischemic ECG response was detected during only one of 12 maximal treadmill exercise tests and in none of ten atrial pacing stress tests (AP). Myocardial lactate extraction did not change significantly during AP in six patients. We conclude that cardiomyopathy does not appear to be a primary cause or an important associated component of the IMVP syndrome. Abnormalities of the coronary circulation or of myocardial metabolism were not demonstrated by available methods. A proposed pathophysiological mechanism to explain the clinical and angiographic findings in IMVP is discussed.


Glutamine supplementation and immune function during heavy load training.
Athletes with heavy training loads are prone to infectious illnesses, suggesting that their training may suppress immune function. This study sought to determine whether supplementation with the amino acid glutamine, which supports immune health, alters immune function in athletes during heavy load training. 24 athletes were randomly assigned to either an experimental group (n = 12) or a control group (n = 12). Athletes exercised using heavy training loads for 6 weeks. Athletes in the experimental group took 10 g glutamine orally once a day beginning 3 weeks after initial testing, while athletes in the control group were given a placebo. Immune function was assessed by measuring the following immunity markers: CD4⁺ and CD8⁺ T cell counts, serum IgA, IgG, and IgM levels, and natural killer (NK) cell activity both before and after the completion of training. The percentages of circulating CD8⁺ T cells were significantly different before (39.13 ± 5.87%) and after (26.63 ± 3.95%) training in the experimental group (p < 0.05). Although CD8⁺ T cell percentages in the control group were similar before (38.57 ± 5.79%) and after (37.21 ± 5.58%) training, the post-training CD8⁺ T cell percentages were significantly different between the two groups (p < 0.05). The ratios of CD4⁺/CD8⁺ cells in the experimental group were significantly different before (0.91 ± 0.14) and after (1.39 ± 0.19) training (p < 0.05). The CD4⁺/CD8⁺ ratios in the control group were similar before (0.93 Â ± 0.15) and after (0.83 ± 0.11) training, but the post-training CD4⁺T/CD8⁺ T cell ratio was higher in the experimental group than in the control group (p < 0.05). NK cell activity was also significantly different between the two groups after training (experimental, 25.21 ± 3.12 vs. control, 20.21 ± 2.59; p < 0.05). However, no differences were observed in serum IgA, IgG, or IgM levels. Thus, glutamine supplementation may be able to restore immune function and reduce the immunosuppressive effects of heavy-load training.


[Structural stability of DNA of the transposon derivatives of pCA25 plasmid].
Mutants of Erwinia carotovora subsp. carotovra 48A carrying plasmid pCA25 and its transposon variant and resistant to mitomycin C, nalidixic acid and streptomycin were used in the research. It has been shown that the presence of transposon in plasmid pCA25 (strain 48A-7/4b[pCA25::Tn9]) does not practically affect the frequency of appearance of the stable bacterial mutants under the effect of all three antibiotics. Several variants, the plasmid profile of which differs from the initial one were found only in the case of this strain clones resistant to mitomycin C. Electrophoretic mobility of the plasmid DNA of the mutant clones 31 and 32 decreased and approached mobility of the initial plasmid pCA25, the mutant plasmid 13 had high electrophoretic mobility compared to pCA25::Tn9. Some plasmids are the deletion variants of pCA25::Tn9, one of two IS1-elements of the transposon Tn9 being absent in them. The obtained results indicate that the studied plasmid pCA25 is stable, is not eliminated from the cells under different treatments and confirm once more the hypothesis of the prophage origin of the plasmid. The paper is presented in Russian.


Prototype Foamy Virus Integrase Displays Unique Biochemical Activities among Retroviral Integrases.
Integrases of different retroviruses assemble as functional complexes with varying multimers of the protein. Retroviral integrases require a divalent metal cation to perform one-step transesterification catalysis. Tetrameric prototype foamy virus (PFV) intasomes assembled from purified integrase and viral DNA oligonucleotides were characterized for their activity in the presence of different cations. While most retroviral integrases are inactive in calcium, PFV intasomes appear to be uniquely capable of catalysis in calcium. The PFV intasomes also contrast with other retroviral integrases by displaying an inverse correlation of activity with increasing manganese beginning at relatively low concentrations. The intasomes were found to be significantly more active in the presence of chloride co-ions compared to acetate. While HIV-1 integrase appears to commit to a target DNA within 20 s, PFV intasomes do not commit to target DNA during their reaction lifetime. Together, these data highlight the unique biochemical activities of PFV integrase compared to other retroviral integrases.


The place of radiation therapy in the treatment of squamous cell carcinoma of the nasal vestibule. A review.
Radiation therapy and limited resection give equally good results in early squamous cell carcinomas of the nasal vestibule, each producing local control rates of 90% or more. For more extensive disease, primary radiation therapy with surgery reserved for residual or recurrent carcinoma is recommended in view of the significant cosmetic defects which generally follow major resection. Small and superficial lesions can be treated by external beam therapy or interstitial implants. Large or infiltrative lesions are best managed by external beam therapy. Serious late morbidity following irradiation is uncommon and has been reported in fewer than 5% of patients. Regional nodal metastases are diagnosed at the time of first presentation in about 5% of patients and signal a very poor prognosis. However, the data available do not support elective treatment of clinically uninvolved regional nodes. Fewer than 5% of patients manifest late nodal metastases when the primary tumor area remains free of recurrence, and most of these metastases can be controlled by neck dissection and/or irradiation.


Quantitative volatile metabolite profiling of common indoor fungi: relevancy for indoor air analysis.
Microorganisms such as bacteria and molds produce an enormous variety of volatile metabolites. To determine whether typical microbial volatile metabolites can be used as indicator compounds for the detection of hidden mold in indoor environments, we examined 14 typical indoor fungal strains for their growth rates and their capability to produce volatile organic compounds (VOC) on standard clinical media and on agar medium made from building materials. Air samples from Headspace Chambers (HSC) were adsorbed daily on Tenax TA tubes and analyzed by thermal desorption gas chromatography and mass spectrometry. In parallel, metabolic activity was measured by determining oxygen demand, the microbial biomass was assessed by dry weighing. Profiling of the volatile metabolites showed that VOC production depended greatly on fungal strain, culture medium, biological activity, and time. The laboratory-derived maximum emission rates were extrapolated to approximate indoor air concentrations in a hypothetical mold-infested room. The extrapolated indoor air data suggest that most of the microbial-produced VOC concentrations were below the analytical detection limit for conventional indoor air analysis. Additionally, conducted indoor air analysis in mold homes confirmed these findings for the most part. The present findings raise doubts about the utility of indicator VOC for the detection of hidden mold growth in indoor environments.


Accuracy of acetabular component position in hip arthroplasty.
Acetabular component malposition is linked to higher bearing surface wear and component instability. Outcomes following total hip arthroplasty and surface replacement arthroplasty depend on multiple surgeon and patient-dependent factors. The purpose of this study was to examine the frequency in which acetabular components are placed within a predetermined target range. We evaluated postoperative anteroposterior pelvic radiographs for every consecutive primary total hip arthroplasty and surface replacement arthroplasty completed from 2004 to 2009 at a single institution. Acetabular component abduction and anteversion angles were determined using Martell Hip Analysis Suite software. We defined target ranges for abduction and anteversion for both total hip arthroplasty (30° to 55° and 5° to 35°, respectively) and surface replacement arthroplasty (30° to 50° and 5° to 25°, respectively). Surgeon and patient-related factors were analyzed for risk associated with placing the acetabular component outside the target range. Of the 1549 total hip arthroplasties, 1435 components (93%) met our abduction target, 1472 (95%) met our anteversion target, and 1363 (88%) simultaneously met both targets. Of the 263 surface replacement arthroplasties, 233 components (89%) met our abduction target, 247 (94%) met our anteversion target, and 220 (84%) simultaneously met both targets. When previously published target ranges of abduction (30° to 45°) and anteversion (5° to 25°) angles were used, only 665 total hip replacements (43%) met the abduction target, 1325 (86%) met the anteversion target, and 584 (38%) simultaneously met both targets. Of the surface replacement arthroplasties, 181 (69%) met the abduction target, 247 (94%) met the anteversion target, and 172 (65%) simultaneously met both targets. Low-volume surgeons were 2.16 times more likely to miss target component position compared with high-volume surgeons (p = 0.002). The odds of missing the target increased by ≥ 0.2 for every 5 kg/m2 increase in body mass index. Minimally invasive approaches, diagnosis, years of surgical experience, femoral head size, and age of the patient did not affect component position. Increased odds of component malposition were found with lower-volume surgeons and higher body mass index. No other variables had a significant effect on component placement. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Microbiological profile and antibiotic susceptibility pattern of Gram-positive isolates at a tertiary care hospital.
Gram-positive infections such as those by Staphylococcus aureus have contributed to the disease burden by increasing the morbidity and mortality rates in India. This study aims to determine the prevalence and the antibiotic susceptibility pattern of Gram-positive pathogens at a tertiary care hospital, Mumbai, Maharashtra, India. This retrospective cross-sectional study was carried out from January, 2015 to December, 2017, at a tertiary care hospital in Mumbai, India. The clinical isolates were cultured, and identification was done using Vitek 2 culture system. The antibiotic susceptibility testing was done as per the Clinical Laboratory Standard Institute guidelines. Out of 2132 (29%) Gram-positive isolates, S. aureus (49%) was the most common encountered pathogen, followed by Enterococcus spp. (24.5%) and coagulase-negative Staphylococcus (16%). Majority of the S. aureus were observed in patients with skin and soft-tissue infections (61.2%) followed by those suffering from respiratory (41%) and bloodstream infections (35%). Among the infections caused by S. aureus, the prevalence of methicillin resistance was 30%. While the MRSA isolates showed lower sensitivity toward co-trimoxazole (39%), clindamycin (30%), erythromycin (23%), and ciprofloxacin (10%), they showed higher susceptibility to linezolid (98%), vancomycin (98%), and teicoplanin (98%). All the isolates were found to be sensitive to daptomycin and tigecycline. While vancomycin-resistant enterococci (VRE) formed 7.5%, the linezolid-resistant enterococcus species was as high as 4.1%. The study showed a high prevalence of MRSA and VRE, thereby emphasizing the increasing antimicrobial resistance pattern of the Gram-positive pathogens. Therefore, there is an urgent need for novel antimicrobial stewardship to restrict the ongoing resistance rate among the isolates.


Etomidate infusion for resection of phaeochromocytoma. A report of 2 cases.
Anaesthesia in patients undergoing resection of phaeochromocytomas is associated with fluctuations in blood pressure and cardiac dysrhythmias. Two patients in whom an etomidate (Hypnomidate; Janssen Pharmaceutica) infusion was used as a supplement to droperidol, fentanyl, pancuronium, air and oxygen anaesthesia are described. Cardiovascular stability was well maintained; the advantages of this technique are discussed.


Near-Infrared-Triggered Dynamic Surface Topography for Sequential Modulation of Macrophage Phenotypes.
Immune response is critical to tissue repair. Designing biomaterials with immunomodulatory functions has become a promising strategy to facilitate tissue repair. Considering the key roles of macrophages in tissue repair and the significance of the balance of M1 and M2, smart biomaterials, which can harness macrophage phenotypes dynamically to match the tissue healing process on demand, have attracted a lot of attention to be set apart from the traditional anti-inflammatory biomaterials. Here, we prepare a gold nanorod-contained shape memory polycaprolactone film with dynamic surface topography, which has the ability to be transformed from flat to microgrooved under near-infrared (NIR) irradiation. Based on the close relationships between the morphologies and the phenotypes of macrophages, the NIR-triggered surface transformation induces the elongation of macrophages, and consequently the upregulated expressions of arginase-1 and IL-10 in vitro, indicating the change of macrophage phenotypes. The sequential modulation of macrophage phenotypes by dynamic surface topography is further confirmed in an in vivo implantation test. The healing-matched modulation of macrophage phenotypes by dynamic surface topography without the stimuli of cytokines offers an effective and noninvasive strategy to manipulate tissue regenerative immune reactions to achieve optimized healing outcomes.