Structural diversity of class 1 integrons and their associated gene cassettes in Klebsiella pneumoniae isolates from a hospital in China.
Klebsiella pneumoniae strains carrying class 1 integrons are becoming more common worldwide, and their role in the dissemination of drug resistance is significant. The aim of this study was to characterize the structural diversity of class 1 integrons and their associated gene cassettes in K. pneumoniae isolates from hospital settings. We analyzed a total of 176 K. pneumoniae isolates in a tertiary-care hospital in Beijing, China for the period of November 1, 2010-October 31, 2011. The presence of class 1 integrons and gene cassettes was analyzed by PCR and sequencing. The prevalence of class 1 integrons was 51.1% (90/176). Fourteen different gene cassettes and 10 different gene cassette arrays were detected. dfrA and aadA cassettes were predominant and cassette combination dfrA1-orfC was most frequently found (13.6%, 24/176). Strong association between resistance to a variety of drugs (both phenotypes and the associated genes) and the presence of class 1 integrons was observed. In addition, we also identified an association between some previously identified prevalent sequence types (such as ST11, ST15, ST147, ST562, and ST716) and the presence of class 1 integrons. Data from this study demonstrated that class 1 integrons are highly diverse and are associated with a variety of drug resistance phenotypes, drug resistance genes, as well as genotypes among K. pneumoniae isolates. Continuous monitoring of gene cassettes in class 1 integrons is warranted to improve the understanding and control of drug resistance among hospital settings.


Circulating anti-p53 antibodies in lung cancer and relationship to histology and smoking.
Anti-p53 antibodies were examined in the plasma of 112 lung cancer patients by ELISA in order to study the distributions in lung cancer patients and the determinants of these antibodies in relation to lung cancer. Twenty (17.9 %) lung cancer patients were found to have anti-p53 antibodies. The distribution of the antibodies by histological type was 7/48 (14.6 %) adenocarcinoma, 8/32 (25.0 %) squamous cell carcinoma, 3/7 (42.9 %) small cell lung cancer, 0/4 large cell carcinoma, 0/8 adenosquamous cell carcinoma and 2/13 (15.4 %) other types. By ethnicity, 8/44 (18.2 %) Caucasians, 4/20 (20.0 %) Hispanics and 8/48 (16.7 %) African-Americans were positive for anti-p53 antibodies, with no significant differences among the groups (p=0.5137). The antibody positivity rates were higher in lung cancer patients 55 years or older (21.2 %) than in the patients under 55 years (7.4 %). The positive rates of the antibodies were 14.3 % in non-smokers, 16.7 % in ex-smokers and 19.1 % in current smokers, with heavy smokers (41 pack-years) having the highest positive rate (28.6 %), but none of these differences were statistically significant (p > 0.05). Seven controls who had anti-p53 antibodies were all ex-smokers or current smokers and some had occupational exposures. No anti-p53 antibodies were found in 41 non-smoking controls. These results suggest that the development of anti-p53 antibodies in pulmonary carcinogenesis and its association with smoking and other carcinogenic exposures deserve further study.


Median Nerve Compression in the Forearm: A Clinical Diagnosis.
Background: Median nerve entrapment in the forearm (MNEF) without motor paralysis is a challenging diagnosis. This retrospective study evaluated the clinical presentation, diagnostic studies, and outcomes following surgical decompression of MNEF. Methods: The study reviewed 147 patient medical charts following MNEF surgical decompression. With exclusion of patients with combined nerve entrapments (radial and ulnar), polyneuropathy, neurotmetic nerve injury, or median nerve motor palsy, the study sample included 27 patients. Data collected include: clinical presentation and pain, strength, provocative testing, functional outcomes, and Disabilities of the Arm, Shoulder and Hand (DASH) scores. Results: The study included 27 patients (mean follow-up = 7 months), and 13 patients had previous carpal tunnel release (CTR). Clinical presentation included pain (n = 27) (forearm, n = 22; median nerve innervated digits, n = 21; and palm, n = 21) and positive clinical tests (forearm scratch collapse test, n = 27; pain with compression over the flexor digitorum superficialis arch/pronator, n = 24; Tinel sign, n = 11). Positive electrodiagnostic studies were found for MNEF (n = 2) and carpal tunnel syndrome (n = 11). Primary CTR was performed in 10 patients and revision CTR in 7 patients. Postoperatively, there were significant (P < .05) improvements in strength, pain, quality of life, and DASH scores. Conclusions: The MNEF without motor paralysis is a clinical diagnosis supported by pain drawings, pain quality, and provocative tests. Patients with persistent forearm pain and median nerve symptoms (especially after CTR) should be evaluated for MNEF. Surgical decompression provides satisfactory outcomes.


CYP1A1 polymorphisms and lung cancer risk: a meta-analysis.
To examine the risk of lung cancer associated with the MspI-restriction fragment length polymorphism and Exon7-Val polymorphisms of CYP1A1, a meta-analysis of published case-control studies was undertaken using a random effects model. The principal outcome measure was the odds ratio for the risk of lung cancer, using homozygosity of the 'wild-type allele' as the reference group. Fifteen reports detailing the relationship between the lung cancer and the MspI and Ile-Val polymorphisms of CYP1A1 were identified. The odds ratio of lung cancer associated with the MspI combined variant and homozygous genotypes were 1.09 (0.94-1.25) and 1.27 (0.91-1.77), respectively. The odds ratio of lung cancer associated with the Ile-Val combined variant and homozygous genotypes were 1.16 (0.92-1.48) and 1.62 (0.93-2.82), respectively. The hypothesis that the modulation of carcinogen metabolism is under genetic control is a plausible and attractive mechanism for explaining inter-individual susceptibility of lung cancer. However, the results from this analysis provide little support for the role of variation in the CYP1A1 gene defined by either polymorphisms represents as lung cancer risk factor. Additional well-designed studies based on sample sizes commensurate with the detection of small genotypic risks may allow a more definitive conclusion.


Metapopulation structure of Vibrionaceae among coastal marine invertebrates.
Although animal-associated microbial communities (microbiomes) are increasingly recognized to influence health, the extent to which animals represent highly selective habitats for microbes leading to predominance of high host specificity remains poorly understood. Here, we show that vibrios, which are well-known commensals and opportunistic pathogens of marine animals, overall display little host preference, likely because of efficient dispersal-colonization dynamics mediated by food items. We isolated 1753 strains from water and animal samples, which are linked in a food chain and display different degrees of similarity (respiratory and digestive tract of mussels and crabs, live and dead zooplankton, and whole water samples). Multilocus sequence data served as input for modelling and statistical analysis of spatiotemporal population structure. These data showed that the majority of populations occurred broadly within and among hosts, with the dominant population being a near perfect generalist with regard to seasons, host taxa and body regions. Zooplankton harboured the fewest and most specific populations, while crabs and mussels contained the highest diversity with little evidence for host preferences. Most mussel- and crab-associated populations were detected in water samples at similar frequencies, particularly in filter-feeding mussels where populations were also evenly distributed across host individuals. The higher variation among individuals observed in crabs and zooplankton is consistent with stochastic clonal expansions. These patterns suggest that evolution of a high degree of host specificity is surprisingly rare even though these animals represent long-lived habitats, and vibrios are consistent members of their microbiome. Instead, many of the populations show stronger association with planktonic (micro)habitats while the microbiome may be a fairly open system for vibrios in which high rates of immigration can outpace selection for specialization.


SUMOylation of synapsin Ia maintains synaptic vesicle availability and is reduced in an autism mutation.
Synapsins are key components of the presynaptic neurotransmitter release machinery. Their main role is to cluster synaptic vesicles (SVs) to each other and anchor them to the actin cytoskeleton to establish the reserve vesicle pool, and then release them in response to appropriate membrane depolarization. Here we demonstrate that SUMOylation of synapsin Ia (SynIa) at K687 is necessary for SynIa function. Replacement of endogenous SynIa with a non-SUMOylatable mutant decreases the size of the releasable vesicle pool and impairs stimulated SV exocytosis. SUMOylation enhances SynIa association with SVs to promote the efficient reclustering of SynIa following neuronal stimulation and maintain its presynaptic localization. The A548T mutation in SynIa is strongly associated with autism and epilepsy and we show that it leads to defective SynIa SUMOylation. These results identify SUMOylation as a fundamental regulator of SynIa function and reveal a novel link between reduced SUMOylation of SynIa and neurological disorders.


Association of the Ghrelin receptor gene region with left ventricular hypertrophy in the general population: results of the MONICA/KORA Augsburg Echocardiographic Substudy.
Growth hormone (GH) can influence left ventricular myocardial growth, structure, and function. The GH secretagogue receptor (GHSR, ghrelin receptor) is known to be involved in GH release and is expressed in the myocardium. We hypothesized that genetic variants within the GHSR are associated with parameters of left ventricular mass (LVM) and geometry. Ten single-nucleotide polymorphisms (SNPs) covering the gene region were genotyped in 1230 members of the general population (Monitoring Trends and Determinants on Cardiovascular Diseases Augsburg Echocardiographic Substudy). Linkage disequilibrium analysis revealed a linkage disequilibrium block consisting of 5 SNPs forming 2 common haplotypes. One haplotype was found significantly more often in subjects without left ventricular hypertrophy ([LVH] 69% versus 59%; permutated P=0.0015), whereas the second haplotype was significantly more frequent in individuals with LVH (32% versus 26%; P=0.019). Homozygous subjects presented with an increase of risk with respect to all heart size parameters. A significantly increasing frequency of the risk haplotype could be observed from the lowest (20.9%) to the highest quintile (31.0%) of gender-specific LVM distributions (P=0.0096). We found association of the minor alleles of individual single nucleotide polymorphisms contributing to the haplotypes with higher LVM indices, septal wall thickness, and different LVH criteria consistent in men and women in matched cases and controls (LVM, women: 144.8+/-30.9 [noncarrier] versus 171.3+/-36.0 [homozygous], P=0.001; men: 186.7+/-42.4 versus 236.3+/-64.5, P=0.002). These data suggest that common variants in the GHSR region are associated with parameters of LVM and geometry independent of blood pressure and body mass in the general population and, thus, may be involved in the pathogenesis of LVH.


[Treatment of type c fractures of the distal radius with volar locking compression plate and radial styloid process plate].
To analyze the effectiveness ofvolar locking compression plate (LCP) and radial styloid process plate for the treatment of type C fractures of the distal radius. Between May 2010 and May 2011, 24 cases of type C fractures of the distal radius were treated, including 8 males and 16 females with an average age of 52 years (range, 23-73 years). Injury was caused by falling in 20 cases and by traffic accident in 4 cases. All were fresh closed fractures. The locations were the left side in 15 cases and the right side in 9 cases. According to AO typing, there were 16 cases of type C2 and 8 cases of type C3. The preoperative palmar tilt angle ranged from 60 to 25 degrees (mean, -45.3 degrees); the preoperative ulnar inclination angle ranged from 16 to 13 degrees (mean, 8.2 degrees); and the preoperative radial length shortening was 8-18 mm (mean, 12 mm). The time from injury to operation was 3-10 days (mean, 5.2 days). All operation incisions healed primarily. All patients were followed up 9-16 months (mean, 13.5 months). The healing time of fracture was 8-12 weeks (mean, 10.2 weeks). The articular surface was smooth and the radial length was recovered. The postoperative palmar tilt angle ranged from 8 to 15 degrees (mean, 12.3 degrees); the postoperative ulnar inclination angle ranged from 18 to 26 degrees (mean, 22.3 degrees). No loss of reduction, refracture, or carpal tunnel syndrome occurred during follow-up. The average range of motion of the wrist was 45.3 degrees (range, 30-70 degrees) in dorsal extension, was 50.2 degrees (range, 26-78 degrees) in palmar flexion, was 13.5 degrees (range, 8-25 degrees) in radial inclination, was 23.6 degrees (range, 15-32 degrees) in ulnar inclination, was 65.7 degrees (range, 35-90 degrees) in pronation, and was 72.5 degrees (range, 20-90 degrees) in supination at last follow-up. According to the wrist function by Gartland-Werley scoring, the results were excellent in 12 cases, good in 8 cases, and fair in 4 cases; and the excellent and good rate was 83.3%. Treatment of type C fractures of the distal radius with volar LCP and radial styloid process plate can reconstruct normal anatomic structures and get good functional recovery.


Aortic arch rupture in a child following minor blunt trauma.
We report the case of a seven-year-old boy who sustained near-total transection of the aortic arch following apparently minor blunt injury. The radiological and operative findings and the successful outcome of urgent surgical repair support an aggressive approach to the diagnosis and management of suspected aortic injuries in children.


Cutaneous lymphoproliferative disorders in organ transplant recipients: update 2014.
Post-transplant lymphoproliferative disorders (PTLD) are lymphoid or plasmacytic proliferations that develop after solid organ, bone marrow or stem cell transplantation. PTLD are the leading cause of cancer-related mortality and graft loss in both pediatric and adult solid organ transplant recipients (ORT). These disorders comprise a spectrum ranging from usually EBV-driven, mostly B-cell polyclonal proliferations to B- and T-cell lymphomas indistinguishable from their counterparts occurring in immunocompetent individuals. PTLD usually present in extranodal sites; isolated skin involvement of PTLD is rare. A recent multicenter European case series showed that primary cutaneous T-cell PTLD are more common than primary cutaneous B-cell PTLD, and along with its folliculotropic variant, mycosis fungoides (MF) is the most frequent form of posttransplant primary cutaneous T-cell lymphoma (CTCL). This case series also disclosed that primary cutaneous CD30+ lymphoproliferative disorders is the second most common posttransplant CTCL subtype, indicating that the spectrum of primary CTCL in OTR is similar to that in the general population. However, in contrast with the immunocompetent individuals, the prognosis of primary cutaneous CD30+ anaplastic large T-cell lymphoma is worse than posttransplant MF and than its counterpart in the general population which has an excellent prognosis. The recent case series indicated that the spectrum of primary cutaneous B-cell PTLD differs significantly from cutaneous B-cell lymphoma in the general population, with a predominance of EBV-associated forms. Currently, the best therapeutic intervention(s) for primary cutaneous PTLD remains unknown.


A comparison of drug use and dependence between blunt smokers and other cannabis users.
Ethnographic studies have suggested that blunt smokers represent a subculture of cannabis users whose drug use is moderated by social norms. The objective of this study was to compare rates of cannabis dependence/abuse and nicotine dependence between blunt and other cannabis smokers. The sample included adolescents and young adults (n = 4348) who reported some form of past-month cannabis use in the 2004 National Survey on Drug Use and Health. Compared to smokers who never used blunts, blunt smokers had significantly greater odds of being dependent on cannabis and tobacco. Associations with cannabis dependence/abuse remained statistically significant with adjustment for smoking frequency and demographic characteristics. These findings highlight the need for differentiating types of cannabis users in epidemiologic studies. The study's limitations are noted.


Computational prediction of virus-human protein-protein interactions using embedding kernelized heterogeneous data.
Pathogenic microorganisms exploit host cellular mechanisms and evade host defense mechanisms through molecular pathogen-host interactions (PHIs). Therefore, comprehensive analysis of these PHI networks should be an initial step for developing effective therapeutics against infectious diseases. Computational prediction of PHI data is gaining increasing demand because of scarcity of experimental data. Prediction of protein-protein interactions (PPIs) within PHI systems can be formulated as a classification problem, which requires the knowledge of non-interacting protein pairs. This is a restricting requirement since we lack datasets that report non-interacting protein pairs. In this study, we formulated the "computational prediction of PHI data" problem using kernel embedding of heterogeneous data. This eliminates the abovementioned requirement and enables us to predict new interactions without randomly labeling protein pairs as non-interacting. Domain-domain associations are used to filter the predicted results leading to 175 novel PHIs between 170 human proteins and 105 viral proteins. To compare our results with the state-of-the-art studies that use a binary classification formulation, we modified our settings to consider the same formulation. Detailed evaluations are conducted and our results provide more than 10 percent improvements for accuracy and AUC (area under the receiving operating curve) results in comparison with state-of-the-art methods.


The HIV-1(Lai) RNA dimerization. Thermodynamic parameters associated with the transition from the kissing complex to the extended dimer.
Retroviruses contain dimeric RNA consisting of two identical copies of the genomic RNA. The interaction between these two RNA molecules occurs near their 5' ends. A region upstream from the splice donor comprising an auto-complementary sequence has been identified as being responsible for the initiation of the formation of dimeric HIV-1(Lai) RNA. This region (SL1), part of the PSI encapsidation domain, can adopt a stem-loop structure. It has already been shown that this stem-loop structure can initiate the formation of two distinct dimers differing in their thermostability: a loop-loop dimer or 'kissing complex' and an extended dimer. We report here a study using UV and 1D NMR spectroscopy of the dimerization of a short oligoribonucleotide (23 nucleotides) spanning nucleotides 248-270 of the HIV-1(Lai) SL1 sequence, in order to derive the thermodynamic parameters associated with the transition from the loop-loop complex to the extended dimer. The temperature dependence of the UV absorbency shows an hypochromicity for this transition with a small enthalpy change equal to - 29.4 +/- 5 kcal x mol-1, together with a concentration independent transition which implies a monomolecular reaction. On the other hand, our NMR results don't indicate a dissociation of the GCGCGC sequence engaged in the loop-loop interaction during the rearrangement of the loop-loop complex into the extended dimer. Our data suggest that the loop-loop interaction is maintained during the temperature dependent conformational change while the intramolecular base-pairing of the stems is disrupted and then reconstituted to form an intermolecular base-pairing leading to an extended dimer.


Prostaglandins contribute to activation of baroreceptors in rabbits. Possible paracrine influence of endothelium.
The purpose of this study was to test the hypothesis that prostaglandins released from vascular endothelial cells contribute to activation of baroreceptors during increases in arterial pressure. Baroreceptor activity was recorded from the vascularly isolated carotid sinus in rabbits anesthetized with chloralose. Baroreceptor activity was measured during ramp or step increases in nonpulsatile carotid sinus pressure over a range of 0-175 mm Hg. Exposure of the isolated carotid sinus to inhibitors of prostaglandin formation (indomethacin [n = 10] or aspirin [n = 6]) decreased baroreceptor activity significantly (p less than 0.05). The slope of the pressure-activity relation averaged 0.80 +/- 0.07 %/mm Hg (mean +/- SEM) during control measurements and 0.72 +/- 0.06 and 0.63 +/- 0.05 %/mm Hg during exposure to 10 and 20 microM indomethacin, respectively. Exposure of the carotid sinus to exogenous prostacyclin (PGI2 [n = 11]) increased baroreceptor activity significantly. The slope of the pressure-activity relation averaged 0.89 +/- 0.10, 1.09 +/- 0.09, and 1.26 +/- 0.16 %/mm Hg during control and during exposure to 10 and 20 microM PGI2, respectively. Activity returned to control after removal of PGI2 (0.89 +/- 0.12 %/mm Hg). Removal of endothelium with either a balloon catheter (n = 4) or a jet of a 95% O2-5% CO2 gas mixture (n = 6) decreased the slope of the pressure-activity relation from 0.92 +/- 0.09 to 0.56 +/- 0.08 %/mm Hg (p less than 0.05). Exposure of the denuded sinus to exogenous PGI2 (20 microM [n = 4]) restored activity (slope = 1.09 +/- 0.24 %/mm Hg). Neither indomethacin (n = 5) nor PGI2 (n = 5) nor denudation (n = 5) significantly altered the pressure-diameter relation of the carotid sinus (sonomicrometers), suggesting that the effects on baroreceptor discharge are not caused by altered stretch of the carotid sinus at a given pressure. The results suggest that prostaglandins (e.g., PGI2) released from endothelium contribute in a paracrine manner to activation of baroreceptors during increases in arterial pressure.


The Parkland Protocol's modified Berne-Norwood criteria predict two tiers of risk for traumatic brain injury progression.
As a basis for venous thromboembolism (VTE) prophylaxis after traumatic brain injury (TBI), we have previously published an algorithm known as the Parkland Protocol. Patients are classified by risk for spontaneous progression of hemorrhage with chemoprophylaxis regimens tailored to each tier. We sought to validate this schema. In our algorithm, patients with any of the following are classified "low risk" for spontaneous progression: subdural hemorrhage ≤8 mm thick; epidural hemorrhage ≤8 mm thick; contusions ≤20 mm in diameter; a single contusion per lobe; any amount of subarachnoid hemorrhage; or any amount of intraventricular hemorrhage. Patients with any injury exceeding these are "moderate risk" for progression, and any patient receiving a monitor or craniotomy is "high risk." From February 2010 to November 2012, TBI patients were entered into a dedicated database tracking injury types and sizes, risk category at presentation, and progression on subsequent computed tomgraphies (CTs). The cohort (n=414) was classified as low risk (n=200), moderate risk (n=75), or high risk (n=139) after first CT. After repeat CT scan, radiographic progression was noted in 27% of low-risk, 53% of moderate-risk, and 58% of high-risk subjects. Omnibus analysis of variance test for differences in progression rates was highly significant (p<0.0001). Tukey's post-hoc test showed the low-risk progression rate to be significantly different than both the moderate- and high-risk arms; no difference was noted between the moderate- and high-risk arms themselves. These criteria are a valid tool for classifying TBI patients into two categories of risk for spontaneous progression. This supports tailored chemoprophylaxis regimens for each arm.


Stem-like and highly invasive prostate cancer cells expressing CD44v8-10 marker originate from CD44-negative cells.
In human prostate cancer (PCa), the neuroendocrine cells, expressing the prostate cancer stem cell (CSC) marker CD44, may be resistant to androgen ablation and promote tumor recurrence. During the study of heterogeneity of the highly aggressive neuroendocrine PCa cell lines PC3 and DU-145, we isolated and expanded in vitro a minor subpopulation of very small cells lacking CD44 (CD44neg). Unexpectedly, these sorted CD44neg cells rapidly and spontaneously converted to a stable CD44high phenotype specifically expressing the CD44v8-10 isoform which the sorted CD44high subpopulation failed to express. Surprisingly and potentially interesting, in these cells expression of CD44v8-10 was found to be induced in stem cell medium. CD44 variant isoforms are known to be more expressed in CSC and metastatic cells than CD44 standard isoform. In agreement, functional analysis of the two sorted and cultured subpopulations has shown that the CD44v8-10pos PC3 cells, resulting from the conversion of the CD44neg subpopulation, were more invasive in vitro and had a higher clonogenic potential than the sorted CD44high cells, in that they produced mainly holoclones, known to be enriched in stem-like cells. Of interest, the CD44v8-10 is more expressed in human PCa biopsies than in normal gland. The discovery of CD44v8-10pos cells with stem-like and invasive features, derived from a minoritarian CD44neg cell population in PCa, alerts on the high plasticity of stem-like markers and urges for prudency on the approaches to targeting the putative CSC.


Clinical management of rheumatologic conditions co-occurring with inflammatory bowel diseases.
Spondyloarthritis (SpA) is the most common extra-intestinal manifestation in patients with inflammatory bowel diseases (IBD). Articular disorders may also appear as 'paradoxical' effects during biologic therapy with anti-tumor necrosis factor (TNF). Areas covered: In this narrative review, we report the current knowledge about the pathogenesis, the diagnosis and the therapeutic management of articular diseases occurring in patients with IBD. Expert commentary: Evidence-based recommendations for the management of IBD-associated SpA and paradoxical arthritis are lacking. Then, collaboration between gastroenterologists and rheumatologists is mandatory to guarantee the best outcomes for these patients, from a prompt diagnosis to an appropriate therapeutic strategy. Among therapies currently available, steroids, sulfasalazine, methotrexate and anti-TNFs are recommended for both gastrointestinal and articular diseases, whereas non-steroidal anti-inflammatory drugs (NSAIDs) and etanercept are contraindicated in IBD. Thiopurines are not effective for the treatment of articular symptoms. Several agents have been recently introduced for the treatment of IBD, such as vedolizumab, a gut-selective anti-α4β7integrin, and ustekinumab, an anti-interleukin 12/23. Their effects on SpA still need to be clarified; however, the possible contemporary administration of biologics with different molecular targets is becoming an intriguing option to cover multiple inflammatory manifestations in the same patient and is worthy of further investigation.


[Efficacy of a chair with magnets in the prevention of musculo-skeletal disorders caused by prolonged sitting].
The aim of the present paper was to evaluate the effectiveness of a sitting system based on the application of magnetic fields in the prevention of posture-related musculoskeletal disorders. We studied 5 healthy male volunteers during laboratory simulation tests including 60-minute sessions of "driving" and computer-work. Two subjects performed a 60-minute driving test on an isotonic dynamometer with a steering wheel, in which they had to steer for 2 min and drive normally for 3 min, alternatively. They repeated the test with and without the magnet-based sitting system. Three subjects performed a 60-minute computer-work test in a seated position with and without the magnet-based sitting system. EMG activity was registered in the trapezius muscles and at L1 and L5 lumbar level bilaterally with surface electrodes. The EMG trapezius activity continuously recorded was analysed with the APDF method, as proposed by Jonsson. Before and after the tests, the subjects performed a 60-sec isometric back extension at 60% MVC with a specific back dynamometer, while paraspinal EMG was recorded. The slope of decay of the median frequency of the EMG power spectrum was then calculated as an index of localised muscle fatigue. The results showed a decreased myoelectric activity both at shoulder and lumbar level by using the magnet-based sitting system for prolonged seated work tasks. Thus, the system appears to be an effective tool in preventing muscle contractures secondary to prolonged, constrained positions.


Seafood graded oral food challenge outcomes in a pediatric tertiary care center.
There are sparse data regarding the predictors of positive oral food challenges and reaction severity for seafood in children. Identify clinical characteristics in children with seafood allergy who were most likely to experience a negative oral food challenge (OFC). A retrospective chart review was performed for children who had a graded OFC to seafood at a pediatric tertiary care center from 2008 through 2019. Sixty-three (60% male; average age 8 years; range 1-21 years) OFCs were performed, of which 21 were fish and 42 were shellfish. There were 10 (16%) positive OFCs and positive OFC rate was similar between fish (19%) and shellfish (14%). Forty-three children who underwent OFC had a reported history of IgE-mediated symptoms. Five of six children who had a history of anaphylaxis had a negative OFC. There was no difference in positive OFCs due to age, history of atopy, or initial allergic reaction history. The clinical characteristics of the positive OFCs were similar between fish and shellfish. A positive skin prick test to fish or shellfish did not increase the risk of a positive OFC. While the positive OFC rate did not differ for the shellfish food-specific IgE (FSIgE) level, there was a significant difference for fish (median <0.34 kUA/L vs. 1.63 kUA/L for pass and fail, respectively; P = 0.023). A retrospective study of OFCs to seafood showed that the rate of a positive OFC was low. While seafood allergy is thought to be rarely outgrown, children who have a low FsIgE and/or skin testing can successfully tolerate seafood.


[Mannheim concept of preoperative autologous blood donation and perioperative autologous blood transfusion in hip endoprosthesis surgery].
To investigate the efficiency of preoperative autologous deposit and intra- and postoperative cell salvage (CS) to reduce homologous transfusion in hip arthroplasty and revision hip arthroplasty. In a retrospective study, the data of 1402 patients scheduled for hip arthroplasty and for revision hip arthroplasty were analysed. 767 women and 635 men, age 62.9 +/- 9.8 years (x +/- s) were included in the study. 1270 were scheduled for hip arthroplasty, 132 for revision hip arthroplasty. Of the autologous donors, 51 patients predeposited four units, 1020 patients three, 204 patients two, 39 patients one unit. 88 patients who had not enrolled in the autologous donation program but received CS served as a control group. Blood loss in autologous donors amounted to 1620 (220-5620) ml in hip arthroplasty and 2830 (950-7910) ml in revision arthroplasty. CS was employed in part of the cases in arthroplasty and in all revision operations. 470 (0-2200) ml and 705 (0-2200) were retransfused. In hip arthroplasty 227 of 1182 patients (19.2%) received homologous blood. Homologous transfusion in patients with coxarthrosis due to acetabular protrusio, avascular necrosis of the femoral head and hip dysplasia showed a trend to higher values. Patients who had donated 3 units and received CS required homologous transfusion in 12.4% of the cases. CS reduced the homolgous transfusion rate significantly if the preoperative hemoglobin concentration was < or = 12 g/dl. A group of autologous donors receiving CS was matched with patients receiving CS only. 12 of 76 (15.8%) vs. 45 of 76 (59.2%) required homologous transfusion. In revision hip arthroplasty 58 of 132 patients (43.9%) required homologous blood. Preoperative deposit reduces homologous transfusion requirements considerably in hip surgery. Under the conditions studied CS should be employed in hip arthroplasty in addition to preoperative deposit if the preoperative hemoglobin concentration falls below 12 g/dl. In revision arthroplasty, 4 or more autologous units should be predeposited and CS should be used regularly.


Factors related to work ability and well-being among women on sick leave due to long-term pain in the neck/shoulders and/or back: a cross-sectional study.
Musculoskeletal pain is one of the leading causes of sick leave, especially among women, in Western countries. The aim of the present study was to identify factors associated with work ability and well-being, respectively, among women on sick leave due to long-term pain in the neck/shoulders and/or back. A cross-sectional study with a correlational design was conducted on women who were sick-listed due to long-term pain in the neck/shoulders and/or back. A total of 208 participants responded to a survey comprising eight instruments: Multidimensional Pain Inventory scale, General Self-Efficacy scale, Sense of Coherence scale, Coping Strategies Questionnaire, Demand-Control-Support Questionnaire, Hospital Anxiety and Depression Scale, Work Ability Index and Life Satisfaction questionnaire. Multiple linear regression analyses were performed to identify factors associated with work ability and well-being, respectively. Women who more strongly believed they would return to the same work had greater work ability (β = 0.39, p < 0.001), whereas women with higher pain intensity (β = - 0.30, p < 0.001) and higher job strain (β = - 0.12, p < 0.05) had lower work ability. Women with higher self-efficacy rated greater well-being (β = 0.14, p < 0.05). As the women's scores for depression increased, their well-being decreased by 48%, which was statistically significant (p < 0.001). The regression models for work ability and well-being were significant (p < 0.001), and their adjusted R- square values were 48% and 59%, respectively. The study suggests that the factors beliefs to be back at the same work, pain intensity and job strain are predictive of work ability. Moreover, the factors self-efficacy and depression seem to be predictive of well-being. The findings highlight factors that should be considered by health care professionals and policy-makers to guide attempts to reduce sick leave.


Cerebral arterial blood flow and aneurysm surgery. Part 1: local arterial flow dynamics.
Cerebral arterial blood flow was monitored in 22 patients undergoing surgery for intracranial saccular aneurysms. An electromagnetic flow probe was used to record the internal carotid artery (ICA) flow in the neck or intracranially in seven patients. The ICA flow ranged between 100 and 175 ml/min (average 144 ml/min). Intracranial flow measurements with specially designed probes were made in 17 patients. The middle cerebral artery (MCA) showed flow values between 75 and 120 ml/min (average 97 ml/min). Flow figures recorded from the proximal anterior cerebral artery (ACA) were lower (average 65 ml/min), and had a wider range from 30 to 110 ml/min. Test occlusion of the terminal ICA showed a retrograde flow in the proximal ACA to the MCA ranging from 15 to 125 ml/min (average 78 ml/min). This test was used to investigate the collateral potential of the anterior portion of the circle of Willis, which is essential to the decision of whether to undertake trap ligation procedures in this location. Flow monitoring in the parent vessel was also of use in some patients to assess flow conditions after the clipping of the aneurysm neck.


PKCbetaII augments NF-kappaB-dependent transcription at the CCL11 promoter via p300/CBP-associated factor recruitment and histone H4 acetylation.
The transcription factor NF-kappaB plays a pivotal role in regulating inflammatory gene expression. Its effects are optimized by various coactivators, including histone acetyltransferases (HATs) such as CREB-binding protein/p300 and p300/CBP-associated factor (p/CAF). The molecular mechanisms regulating cofactor recruitment are poorly understood. In this study, we describe a novel role for protein kinase C (PKC) betaIotaIota in augmenting NF-kappaB-mediated TNF-alpha-induced transcription of the target gene CCL11 in human airway smooth muscle cells by phosphorylating the HAT p/CAF. Studies using reporters, overexpression strategies, kinase-dead and HAT-defective mutants, and chromatin immunoprecipitation showed that PKCbetaII activation was not involved in NF-kappaB translocation, but facilitated NF-kappaB-mediated CCL11 transcription by colocalizing with and phosphorylating p/CAF, and thereby acetylating histone H4 and promoting p65 association with the CCL11 promoter. The effect was dependent on p/CAF's HAT activity. Furthermore, mouse embryonic fibroblasts from PKCbeta knockout mice showed markedly reduced TNF-alpha-induced CCL11 expression and NF-kappaB reporter activity that was restored on PKCbetaII overexpression, suggesting a critical role for this pathway. These data suggest a novel important biological role for PKCbetaIotaIota in NF-kappaB-mediated CCL11 transcription by p/CAF activation and histone H4 acetylation.


Design, Synthesis, Biological Activity, and Structural Analysis of Novel Des-C-Ring and Aromatic-D-Ring Analogues of 1α,25-Dihydroxyvitamin D3.
The toxic calcemic effects of the natural hormone 1α,25-dihydroxyvitamin D3 (1,25D3, 1,25-dihydroxycholecalciferol) in the treatment of hyperproliferative diseases demand the development of highly active and noncalcemic vitamin D analogues. We report the development of two highly active and noncalcemic analogues of 1,25D3 that lack the C-ring and possess an m-phenylene ring that replaces the natural D-ring. The new analogues (3a, 3b) are characterized by an additional six-carbon hydroxylated side chain attached either to the aromatic nucleus or to the triene system. Both compounds were synthesized by the Pd-catalyzed tandem cyclization/cross coupling approach starting from alkyne 6 and diphenol 8. Key steps include a stereoselective Cu-assisted addition of a Grignard reagent to an aromatic alkyne and a Takai olefination of an aromatic aldehyde. The new compounds are noncalcemic and show transcriptional and antiproliferative activities similar to 1,25D3. Structural analysis revealed that they induce a large conformational rearrangement of the vitamin D receptor around helix 6.


Staging classification of omicron variant SARS-CoV-2 infection based on dual-spectrometer LIBS (DS-LIBS) combined with machine learning.
Effective differentiation of the infection stages of omicron can provide significant assistance in transmission control and treatment strategies. The combination of LIBS serum detection and machine learning methods, as a novel disease auxiliary diagnostic approach, has a high potential for rapid and accurate staging classification of Omicron infection. However, conventional single-spectrometer LIBS serum detection methods focus on detecting the spectra of major elements, while trace elements are more closely related to the progression of COVID-19. Here, we proposed a rapid analytical method with dual-spectrometer LIBS (DS-LIBS) assisted with machine learning to classify different infection stages of omicron. The DS-LIBS, including a broadband spectrometer and a narrowband spectrometer, enables synchronous collection of major and trace elemental spectra in serum, respectively. By employing the RF machine learning models, the classification accuracy using the spectra data collected from DS-LIBS can reach 0.92, compared to 0.84 and 0.73 when using spectra data collected from single-spectrometer LIBS. This significant improvement in classification accuracy highlights the efficacy of the DS-LIBS approach. Then, the performance of four different models, SVM, RF, IGBT, and ETree, is compared. ETree demonstrates the best, with cross-validation and test set accuracies of 0.94 and 0.93, respectively. Additionally, it achieves classification accuracies of 1.00, 0.92, 0.92, and 0.89 for the four stages B1-acute, B1-post, B2, and B3. Overall, the results demonstrate that DS-LIBS combined with the ETree machine learning model enables effective staging classification of omicron infection.


Neuroplasticity of auditory cortex after stape surgery for otosclerosis: a magnetoencephalographic study.
Aim of the present study was to investigate the tonotopic reorganization of the primary auditory cortex in otosclerotic patients following functional stapedioplasty. Characteristics of auditory cortex activation have been evaluated in a series of 10 otosclerotic patients before and after surgery. In these patients, a magnetoencephalographic recording of evoked magnetic fields has been performed by means of tone-burst monoaural stimulation with frequency octaves between 250 and 2000 Hz. Brain topography of cortex response generators (wave N100m) in patients with otosclerosis has been compared with that observed in a control group of 10 healthy subjects: changes before and after surgery have also been correlated with the functional result as far as concerns improvement in hearing. A significant reduction has been observed in the cortical tonotopic extension in response to the acoustic stimulus in patients "pre-surgery" in comparison with controls: after surgery, tonotopic mapping showed an increase, dimensions becoming comparable to those in control subjects. This increase in size was found to be significantly correlated with duration of the post-operative period. Data emerging from the present study suggest that the cortical auditory areas in man are involved in a "plastic" functional reorganization following changes in the receptor or peripheral deprivation. Reduction in the cortical tonotopic mapping resulting from prolonged lowering of auditory "input" is modified by reorganization of the cortex after the recovery of auditory function: this process occurs over a period of a few weeks.


Thermal tolerance and survival responses to scenarios of experimental climatic change: changing thermal variability reduces the heat and cold tolerance in a fly.
Climate change poses one of the greatest threats to biodiversity. Most analyses of the impacts have focused on changes in mean temperature, but increasing variance will also impact organisms and populations. We assessed the combined effects of the mean and the variance of temperature on thermal tolerances-i.e., critical thermal maxima, critical thermal minima, scope of thermal tolerance, and survival in Drosophila melanogaster. Our six experimental climatic scenarios were: constant mean with zero variance or constant variance or increasing variance; changing mean with zero variance or constant variance or increasing variance. Our key result was that environments with changing thermal variance reduce the scope of thermal tolerance and survival. Heat tolerance seems to be conserved, but cold tolerance decreases significantly with mean low as well as changing environmental temperatures. Flies acclimated to scenarios of changing variance-with either constant or changing mean temperatures-exhibited significantly lower survival rate. Our results imply that changing and constant variances would be just as important in future scenarios of climate change under greenhouse warming as increases in mean annual temperature. To develop more realistic predictions about the biological impacts of climate change, such interactions between the mean and variance of environmental temperature should be considered.


Polymorphisms of the D2 dopamine receptor gene and alcoholism and other substance use disorders.
The A1 (minor) allele of the D2 dopamine receptor (DRD2) gene has been shown to be associated with alcoholism, particularly the severe form of this disorder. This allele has also been found to be involved in a variety of other substance use disorders including, cocaine and nicotine dependence, polysubstance abuse and obesity. Moreover, reduced dopaminergic function has been found in subjects carrying the DRD2 A1 allele, suggesting that the DRD2 may be a reinforcement or reward gene. Analysis of the available data suggests that the DRD2 variants represent one of the most prominent single-gene determinants of susceptibility to severe alcoholism and other substance use disorders. However, environmental factors and other genes must, in combination, play the larger role.


Startle eyeblink modulation: detecting changes in directed attentional allocation during early preattentive processing.
Startle eyeblink modification was examined as a measure of allocation of attentional resources during active attention tasks in the early stage of information processing. Fifty-five participants were presented with a series of 250- and 40-ms tones of either high or low pitch which were followed by startle-eliciting stimuli at a lead interval of 120 ms. Attentional allocation was manipulated by instructing one group (Passive) to simply listen to the tones; the second group (Active 1) to count the number of low tones and the third group (Active 2) to count the long high-pitched tones and the short low-pitched tones. Startle eyeblink was significantly more inhibited for the Active 1 group than the Passive group (control) with no significant difference between the two directed attentional conditions (Active 1 and Active 2 groups). However, across the three attentional groups, the degree of startle eyeblink modulation appeared to reflect the degree of attention allocated to the task. The results support the utility of the startle probe in evaluating controlled attentional allocation during the early stages of information processing.


Reporting dental trauma and its inclusion in an injury surveillance system in Victoria, Australia.
This study investigated the frequency, patterns and causes of dental trauma in patients seeking emergency treatment at a dental hospital, and evaluated the impact of an electronic structured injury history form to collect key information. A retrospective audit was undertaken of all emergency presentations at the Royal Dental Hospital of Melbourne from 2009 to 2012. Dental trauma and injury surveillance data were collected and evaluated with reference to the criteria of the Victorian Emergency Minimum Dataset. Statistical analysis included chi-squared and Fisher's exact tests. A total of 88,610 new emergency courses of care were created, with 3642 (4.1%) identified as new dental trauma cases in 3574 patients. A total of 6001 teeth were injured with a mean of 1.7 teeth per patient (range: 1-8 teeth). The improvement of injury surveillance information collected using the electronic form compared with the paper form was statistically significant (p<0.001). The dental trauma findings of this study are consistent with other studies regarding age, gender, location, cause and injury type. This study also confirmed the benefits of electronic collection of dental injury surveillance data that can assist policy planners and health service providers in designing and delivering effective dental injury prevention and management services.


Differential expression of protease activity in serum samples of prostate carcinoma patients with metastases.
We present here the results from MS peptide profiling experiments of prostate carcinoma patients and controls with a specific focus on protease activity-related protein fragments. After purification with surface-active magnetic beads, MALDI-TOF profiling experiments were performed on tryptic digests of serum samples of prostate cancer patients with metastases (n=27) and controls (n=30). This resulted in the reproducible detection of eight differentially expressed peptides, which were then identified by nanoLC-MALDI-TOF/TOF and confirmed by MALDI-FTMS exact mass measurements. All differentially expressed peptides are derived from two homologous parts of human serum albumin; two of the eight peptides were tryptic and six were nontryptic. The presence of the nontryptic fragments indicates that a proteolysis process occurs which is not mediated by trypsin. Since the nontryptic fragments were found at significantly higher levels in control samples compared with metastases samples, it is proposed that a specific proteolytic inhibition process is in effect in the serum of prostate cancer patients. Experiments using synthetic peptides showed that this proteolytic activity occurs ex vivo and is sequence specific. Importantly, the observed prostate carcinoma-related inhibition of the proteolysis was reproduced ex vivo using synthetic peptides.


Trait conscientiousness and the personality meta-trait stability are associated with regional white matter microstructure.
Establishing the neural bases of individual differences in personality has been an enduring topic of interest. However, while a growing literature has sought to characterize grey matter correlates of personality traits, little attention to date has been focused on regional white matter correlates of personality, especially for the personality traits agreeableness, conscientiousness and openness. To rectify this gap in knowledge we used a large sample (n > 550) of older adults who provided data on both personality (International Personality Item Pool) and white matter tract-specific fractional anisotropy (FA) from diffusion tensor MRI. Results indicated that conscientiousness was associated with greater FA in the left uncinate fasciculus (β = 0.17, P < 0.001). We also examined links between FA and the personality meta-trait 'stability', which is defined as the common variance underlying agreeableness, conscientiousness, and neuroticism/emotional stability. We observed an association between left uncinate fasciculus FA and stability (β = 0.27, P < 0.001), which fully accounted for the link between left uncinate fasciculus FA and conscientiousness. In sum, these results provide novel evidence for links between regional white matter microstructure and key traits of human personality, specifically conscientiousness and the meta-trait, stability. Future research is recommended to replicate and address the causal directions of these associations.


Sugar-Responsive Layer-by-Layer Film Composed of Phenylboronic Acid-Appended Insulin and Poly(vinyl alcohol).
Previous studies have shown that reversible chemical bond formation between phenylboronic acid (PBA) and 1,3-diol can be utilized as the driving force for the preparation of layer-by-layer (LbL) films. The LbL films composed of a PBA-appended polymer and poly(vinyl alcohol) (PVA) disintegrated in the presence of sugar. This type of LbL films has been recognized as a promising approach for sugar-responsive drug release systems, but an issue preventing the practical application of LbL films is combining them with insulin. In this report, we have proposed a solution for this issue by using PBA-appended insulin as a component of the LbL film. We prepared two kinds of PBA-appended insulin derivatives and confirmed that they retained their hypoglycemic activity. The LbL films composed of PBA-appended insulin and PVA were successfully prepared through reversible chemical bond formation between the boronic acid moiety and the 1,3-diol of PVA. The LbL film disintegrated upon treatment with sugars. Based on the results presented herein, we discuss the suitability of the PBA moiety with respect to hypoglycemic activity, binding ability, and selectivity for D-glucose.


Cigarette smoke induced autophagy-impairment regulates AMD pathogenesis mechanisms in ARPE-19 cells.
Age related macular degeneration (AMD) is one of the leading causes of blindness. Genetics, environmental insult, and age-related factors all play a key role in altering proteostasis, the homeostatic process regulating protein synthesis, degradation and processing. These factors also play a role in the pathogenesis of AMD and it has been well established that cigarette smoking (CS) initiates AMD pathogenic mechanisms. The primary goal of this study is to elucidate whether CS can induce proteostasis/autophagy-impairment in retinal pigment epithelial (RPE) cells. In our preliminary analysis, it was found that cigarette smoke extract (CSE) induces accumulation of ubiquitinated proteins in the insoluble protein fraction (p < 0.01), which was subsequently mitigated through cysteamine (p < 0.01) or fisetin (p < 0.05) treatment. Further, it was verified that these CSE induced ubiquitinated proteins accumulated in the peri-nuclear spaces (p<0.05) that were cleared- off with cysteamine (p < 0.05) or fisetin (p < 0.05). Moreover, CSE-induced aggresome-formation (LC3B-GFP and Ub-RFP co-localization) and autophagy-flux impairment was significantly (p<0.01) mitigated by cysteamine (p<0.05) or fisetin (p<0.05) treatment, indicating the restoration of CSE-mediated autophagy-impairment. CSE treatment was also found to induce intracellular reactive oxygen species (ROS, p < 0.001) while impacting cell viability (p < 0.001), which was quantified using CMH2DCFDA-dye (ROS) and MTS (proliferation) or propodium iodide staining (cell viability) assays, respectively. Moreover, cysteamine and fisetin treatment ameliorated CS-mediated ROS production (p < 0.05) and diminished cell viability (p < 0.05). Lastly, CSE was found to induce cellular senescence (p < 0.001), which was significantly ameliorated by cysteamine (p < 0.001) or fisetin (p < 0.001). In conclusion, our study indicates that CS induced proteostasis/autophagy-impairment regulates mechanisms associated with AMD pathogenesis. Moreover, autophagy-inducing drugs such as cysteamine or fisetin can ameliorate AMD pathogenesis mechanisms that warrant further investigation in pre-clinical murine models.


Acquisition of aryl hydrocarbon hydroxylase inducibility by aromatic hydrocarbons in monolayer-cultured hepatocytes from nonresponsive mouse strains.
The expression of P1450 and P3450 genes isolated from C57BL26 mouse liver in mouse hepatocytes from responsive (BALB/c, C3H/He, C57BL/6, and CBA) and nonresponsive (AKR, DBA/2, NZB, and NZW) strains in primary culture after exposure to aromatic hydrocarbons was investigated with respect to aryl hydrocarbon hydroxylase (AHH) activity and corresponding P450 transcript levels. Constitutive AHH activity in all strains decreased with an increasing culture period. The AHH activity of cells treated with either benz(a)anthracene, benzo(a)pyrene, 3-methylcholanthrene, or TCDD continuously or 24 h before harvesting was measured during observation periods for up to 5 days. Slight induction of AHH activity by benz(a)anthracene, benzo(a)pyrene, and 3-methylcholanthrene was observed in hepatocytes from the CBA and C3H/He strains during the first half of the observation period, followed by a steep increase thereafter. Enzyme activities in hepatocytes from BALB/c mice were the same as or lower than the control values during the first half of the observation period, and in the C57BL/6 mouse high levels of AHH activities were observed even during this period. AHH activities in hepatocytes from the AKR, DBA/2, NZB, and NZW mice after treatment with aromatic hydrocarbons were lower than control levels during the first half of the observation period; however, significant induction was observed thereafter. P450 transcripts including both P1450 and P3450 RNA species were detected when the treatment was started during the early incubation period, whereas only P1450 RNA was found at the later periods. The amounts of P1450 transcript also correlated well with AHH activity, higher levels being found after starting treatment with benz(a)anthracene at day 3 or 4 than at day 1. Our observations indicate that, although AHH induction was genetically determined in each strain, activity can be induced in hepatocytes of so-called nonresponsive as well as responsive mouse strains by treatment with aromatic hydrocarbons after transfer of the cells to primary culture.


Stable storage of helium in nanoscale platelets at semicoherent interfaces.
He implanted into metals precipitates into nanoscale bubbles that may later grow into voids, degrading the properties of engineering alloys. Using multiscale modeling, we show that a different class of He precipitates may form at semicoherent interfaces: nanoscale platelets. These platelets grow by wetting high-energy interface regions, remain stable under irradiation, and reduce He-induced swelling. Stable storage of He at interfaces may impart unprecedented He resistance to future structural materials.


Ego development and self-image complexity in early adolescence. Longitudinal studies of psychiatric and diabetic patients.
Ego development and multiple self-images were studied in nonpsychotic psychiatric patients, diabetic patients, and healthy high school students. The results reported are drawn from the first year of a four-year longitudinal project investigating the psychosocial development and family interactions of impaired and at-risk adolescents. Both groups of patients, especially the psychiatric group, were significantly lower in their ego development and showed less self-image complexity than the high school students. These findings are discussed both in terms of understanding developmental deviation in these two chronically ill groups, and as a strategy for investigating formulations being proposed in the new self-psychology framework.


Comparison of the effects of five dietary fibers on mucosal transcriptional profiles, and luminal microbiota composition and SCFA concentrations in murine colon.
The aim of our study was to investigate and compare the effects of five fibers on the mucosal transcriptome, together with alterations in the luminal microbiota composition and SCFA concentrations in the colon. Mice were fed fibers that differed in carbohydrate composition or a control diet for 10 days. Colonic gene expression profiles and luminal microbiota composition were determined by microarray techniques, and integrated using multivariate statistics. Our data showed a distinct reaction of the host and microbiota to resistant starch, a fiber that was not completely fermented in the colon, whereas the other fibers induced similar responses on gene expression and microbiota. Consistent associations were revealed between fiber-induced enrichment of Clostridium cluster IV and XIVa representatives, and changes in mucosal expression of genes related to energy metabolism. The nuclear receptor PPAR-γ was predicted to be an important regulator of the mucosal responses. Results of this exploratory study suggest that despite different sources and composition, fermentable fibers induce a highly similar mucosal response that may at least be partially governed by PPAR-γ.


Effect of halothane on the pulmonary vascular response to hypoxia in dogs.
The pulmonary vascular response to alveolar hypoxia with and without halothane exposure was measured in dogs. Hypoxia increased pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR) so that in each case inverse linear relationships were found with arterial oxygen saturation. These responses were highly significant and reproduceable but varied greatly between individuals. Halothane administration resulted in an increased slope of PVR against oxygen saturation due to the fact that reduction in cardiac output exceeded the reduction in Ppa. An analysis of variance showed that it was possible to predict accurately the hypoxic PVR and Ppa responses under halothane anaesthesia from the control hypoxic responses. Animals with low PVR responses showed the greatest arterial oxygen desaturation with hypoxia, whereas high responders showed least oxygen desaturation. Thus it was possible to predict those individuals at risk from severe arterial oxygen desaturation under halothane anaesthesia.


Characterization of an anaerobic population digesting a model substrate for maize in the presence of trace metals.
The influence of a defined trace metal solution and additionally Ni(2+) on anaerobic digestion of biomass was investigated. A novel synthetic model substrate was designed consisting of cellulose, starch and urea as carbon and nitrogen source in a ratio mimicking the basic composition of maize silage. Two independent batch fermentations were carried out over 21 d with the synthetic model substrate in the presence of the trace metal solution. Particularly an increase in nickel concentrations (17 and 34 microM) enhanced methane formation by up to 20%. This increased activity was also corroborated by fluorescence microscopy measurements based on cofactor F(420). The eubacterial and methanogenic population was characterized with the single strand conformational polymorphism analysis and the amplified 16S rDNA restriction analysis of 16S rRNA genes amplified by different primer systems. Nearly the half of the analyzed bacteria were identified as Firmicutes while 70% in this phylum belonged to the class of Clostridiales and 30% to the class of Bacilli. Bacteroides and uncultured bacteria represented each a quarter of the analyzed community. Methanogenic archaea were investigated with ARDRA, too. The hydrogenotrophic Methanoculleus sp. was the dominant genus which is commonly described for maize digestion thus confirming the value of the model substrate.


Ctdp1 deficiency leads to early embryonic lethality in mice and defects in cell cycle progression in MEFs.
RNA polymerase II subunit A Carboxy-Terminal Domain Phosphatase 1 (CTDP1), a member of the haloacid dehalogenase superfamily phosphatases, has a defined role in transcriptional regulation, but emerging evidence suggests an expanded functional repertoire in the cell cycle and DNA damage response. In humans, a splice site mutation in CTDP1 gives rise to the rare Congenital Cataracts Facial Dysmorphism and Neuropathy syndrome, and recent evidence from our lab indicates CTDP1 is required for breast cancer growth and proliferation. To explore the physiological function of CTDP1 in a mammalian system, we generated a conditional Ctdp1 knockout mouse model by insertion of loxP sites upstream of exon 3 and downstream of exon 4. Biallelic deletion of Ctdp1 results in lethality before embryonic day 7.5, with morphological features indicating embryo cell death and resorption. However, Ctdp1+/- mice are haplosufficient for phenotypic traits including body weight, hematological parameters, exploratory and locomotive functions. To investigate the potential mechanisms of the embryonic death caused by biallelic Ctdp1 knockout, mouse embryonic fibroblasts (MEFs) were established from Ctdp1+/+ and Ctdp1flox/flox mice. Lentivirus delivered Cre-mediated biallelic deletion of Ctdp1 in MEFs results in cell death preceded by impaired proliferation characterized by an increase in G1- and G2-phase populations and a reduction in the S-phase population. These cell cycle alterations caused by deletion of Ctdp1 are associated with an increase in p27 protein expression and a decrease in phosphorylated RB, phosphorylated Histone H3, and Cyclin B expression. Together, these results reveal that Ctdp1 plays an essential role in early mouse embryo development and cell growth and survival in part by regulating the cell cycle.


Conference Report 33rd European Congress on Clinical Microbiology and Infectious Diseases (ECCMID): New developments in pediatric oncology infectious disease supportive care.
Infections continue to be major causes of morbidity and mortality in immunocompromised children and adolescents with cancer or undergoing allogeneic hematopoietic cell transplantation. This report summarizes new clinical research data presented at the 33rd European Congress on Clinical Microbiology and Infectious Diseases on infections in this vulnerable population, with a focus on the epidemiology, diagnosis, and prevention of invasive fungal diseases and de-escalation strategies in neutropenic patients with fever of unknown origin.


Research with cognitively impaired subjects. Unfinished business in the regulation of human research.
In 1978, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research issued an important report that addressed the difficult ethical issues arising in research involving subjects with mental disabilities. However, because of irreconcilable conflicts between the scientific community and rights-oriented advocacy groups, the federal government never issued the special regulations pertaining to these issues that had been envisioned by the National Commission. Because these important ethical issues have not yet been adequately addressed by policy-making bodies, protection of cognitively impaired subjects depends too heavily on the diverse ethical sensitivities of individual investigators and on ad hoc responses of particular institutional review boards. Researchers should support a credible and authoritative process for reexamining and resolving ethical issues relating to research with cognitively impaired subjects. This can be accomplished without leading to the stalemate that doomed the National Commission's proposals. The challenge is to forge a consensus on ethical guidelines and safeguards that will most reasonably accommodate the goals of protecting the dignity and well-being of research subjects while avoiding undue impediments to valuable scientific inquiry.


Developmental changes of beta-adrenergic receptor-linked adenylate cyclase of rat liver.
beta-Adrenergic agonist-sensitive adenylate cyclase activity and binding of the beta-adrenergic antagonist(-)-[125I]iodopindolol were studied in rat liver during development of male Fischer 344 rats ages 6-60 days. In liver homogenates maximum adenylate cyclase response to beta-adrenergic agonist (10(-5) M isoproterenol or epinephrine) decreased by 73% (P less than 0.01) between 6 and 60 days, with most of the decrease (56%; P less than 0.01) occurring by 20 days. beta-adrenergic receptor density (Bmax) showed a corresponding decrease of 66% (P less than 0.01) by 20 days without subsequent change. Binding characteristics of stereospecificity, pharmacological specificity, saturability with time, and reversibility were unchanged with age. GTP-, fluoride-, forskolin-, and Mn2+-stimulated adenylate cyclase activities also decreased during development, suggesting a decrease of activity of the catalytic component and/or guanine nucleotide regulatory component of adenylate cyclase. These results indicate that the developmental decrease of beta-adrenergic agonist-sensitive adenylate cyclase activity may result from decreased numbers of beta-adrenergic receptors. Developmental alterations of nonreceptor components of the enzyme may also contribute to changes of catecholamine-sensitive adenylate cyclase.


The association between body mass index and brain morphology in children: a population-based study.
Brain morphology is altered in both anorexia nervosa and obesity. However, it is yet unclear if the relationship between Body Mass Index-Standard Deviation Score (BMI-SDS) and brain morphology exists across the BMI-SDS spectrum, or is present only in the extremes. The study involved 3160 9-to-11 year-old children (50.3% female) who participate in Generation R, a population-based study. Structural MRI scans were obtained from all children and FreeSurfer was used to quantify both global and surface-based measures of gyrification and cortical thickness. Body length and weight were measured to calculate BMI. Dutch growth curves were used to calculate BMI-SDS. BMI-SDS was analyzed continuously and in two categories (median split). The relationship between BMI-SDS (range - 3.82 to 3.31) and gyrification showed an inverted-U shape curve in children with both lower and higher BMI-SDS values having lower gyrification in widespread areas of the brain. BMI-SDS had a positive linear association with cortical thickness in multiple brain regions. This study provides evidence for an association between BMI-SDS and brain morphology in a large sample of children from the general population and suggests that a normal BMI during childhood is important for brain development. Future studies could determine whether lifestyle modifications optimize BMI-SDS result in return to more typical patterns of brain morphology.


Multiple desmoid tumors in a patient with familial adenomatous polyposis caused by the novel W421X mutation.
Familial adenomatous polyposis (FAP) is a rare syndrome characterized by the presence of hundreds to thousands of colorectal adenomas and is responsible for less than 1% of all colorectal cancers. The syndrome is also characterized by extra-colorectal features including amongst others upper gastrointestinal tract polyps and desmoid tumors. The syndrome is inherited by an autosomal dominant gene, the adenomatous polyposis coli (APC) gene. We present the physical history, clinical presentation, diagnosis and treatment of a patient with a novel germline APC mutation, the W421X mutation, which resulted in FAP presenting with about a hundred colorectal polyps, gastric hyperplastic polyps and multiple aggressive intra-abdominal and extra-abdominal desmoid tumors.


Inhibition of thromboxane A2 production does not improve post-ischemic brain hypoperfusion in the dog.
In a canine model of global brain ischemia, six dogs received a selective thromboxane A2 synthetase inhibitor, UK 38,485 (dazmagrel) before the ischemic event; six received a saline placebo. Cerebral blood flow (CBF), systolic and diastolic arterial pressure, cardiac output, pH, PaCO2, PaO2, and arterial and jugular-vein thromboxane B2 (a stable metabolite of thromboxane A2) and 6-keto PGF1 alpha (a stable metabolite of prostacyclin) were measured at baseline, after release of aortic and venae caval occlusion and at intervals up to 120 min thereafter. Treated animals showed nearly complete post-ischemic inhibition of thromboxane B2 production; control animals showed increases in jugular venous thromboxane B2. Arterial and jugular venous levels of 6-keto PGF1 alpha were significantly higher in treated animals at most post-ischemic intervals. CBF in both groups was similar to baseline values at time 0, then declined similarly in both groups by 30 min to approximately equal to 35% of baseline values where it remained thereafter. There were no significant differences in other variables at any interval. We conclude that inhibition of thromboxane A2 production does not alter post-ischemic brain hypoperfusion.


Differential Treatment and Outcomes for Patients With Heart Attacks in Advantaged and Disadvantaged Communities.
Background Racially and ethnically minoritized groups, people with lower income, and rural communities have worse access to percutaneous coronary intervention (PCI) than their counterparts, but PCI hospitals have preferentially opened in wealthier areas. Our study analyzed disparities in PCI access, treatment, and outcomes for patients with acute myocardial infarction based on the census-derived Area Deprivation Index. Methods and Results We obtained patient-level data on 629 419 patients with acute myocardial infarction in California between January 1, 2006 and December 31, 2020. We linked patient data with population characteristics and geographic coordinates, and categorized communities into 5 groups based on the share of the population in low or high Area Deprivation Index neighborhoods to identify differences in PCI access, treatment, and outcomes based on community status. Risk-adjusted models showed that patients in the most advantaged communities had 20% and 15% greater likelihoods of receiving same-day PCI and PCI during the hospitalization, respectively, compared with patients in the most disadvantaged communities. Patients in the most advantaged communities also had 19% and 16% lower 30-day and 1-year mortality rates, respectively, compared with the most disadvantaged, and a 15% lower 30-day readmission rate. No statistically significant differences in admission to a PCI hospital were observed between communities. Conclusions Patients in disadvantaged communities had lower chances of receiving timely PCI and a greater risk of mortality and readmission compared with those in more advantaged communities. These findings suggest a need for targeted interventions to influence where cardiac services exist and who has access to them.


Expression of KAI1/CD82 in human colorectal tumor.
To study the expression of KAI1/CD82 in human colorectal tumor and its significance. Immunohistochemistry was used to detect the expression of CD82 in 40 colorectal carcinoma, 20 lymphatic metastasis, 18 adenoma and 20 normal colorectal epithelium specimens, respectively. The expression of CD82 was rather low in adenoma and normal colorectal epithelium, with the positivity rates of 25% and 10% respectively; 28 of the 40 colorectal carcinoma specimens were positive for CD82, resulting in a positivity rate of 70%. The rate for lymphatic metastasis was only 5%. The differences between the 4 groups were significant (P <0.05), and the expression of CD82 in the carcinoma was not related to the histological grades (P >0.05), but was associated with the presence of metastasis (P <0.05). CD82 is related to the progression of colorectal carcinoma.


Automated tracing of the adventitial contour of aortoiliac and peripheral arterial walls in CT angiography (CTA) to allow calculation of non-calcified plaque burden.
Aortoiliac and lower extremity arterial atherosclerotic plaque burden is a risk factor for the development of visceral and peripheral ischemic and aneurismal vascular disease. While prior research allows automated quantification of calcified plaque in these body regions using CT angiograms, no automated method exists to quantify soft plaque. We developed an automatic algorithm that defines the outer wall contour and wall thickness of vessels to quantify non-calcified plaque in CT angiograms of the chest, abdomen, pelvis, and lower extremities. The algorithm encodes the search space as a constrained graph and calculates the outer wall contour by deriving a minimum cost path through the graph, following the visible outer wall contour while minimizing path tortuosity. Our algorithm was statistically equivalent to a reference standard made by two reviewers. Absolute error was 1.9 ± 2.3% compared to the inter-observer variability of 3.9 ± 3.6%. Wall thickness in vessels with atherosclerosis was 3.4 ± 1.6 mm compared to 1.2 ± 0.4 mm in normal vessels. The algorithm shows promise as a tool for quantification of non-calcified plaque in CT angiography. When combined with previous research, our method has the potential to quantify both non-calcified and calcified plaque in all clinically significant systemic arteries, from the thoracic aorta to the arteries of the calf, over a wide range of diameters. This algorithm has the potential to enable risk stratification of patients and facilitate investigations into the relationships between asymptomatic atherosclerosis and a variety of behavioral, physiologic, pathologic, and genotypic conditions.


Effects of ethylene glycol ethers on the reproduction of Ceriodaphnia dubia.
Seven-day static renewal tests with Ceriodaphnia dubia were used to document the chronic toxicity of ethylene glycol ethers and acetates to this invertebrate. The 7-d EC10 (effective concentrations inducing an inhibition of 10% of the reproduction of the tested organisms) values ranged from 0.06 to 1025 mg/l. While a survey of the literature showed that the acute toxicity of these chemicals appeared negligible, our results clearly revealed the potential chronic effects of some of them to this organism occupying an important trophic level in the aquatic ecosystems. The usefulness of this kind of test to better estimate the adverse effects of glycol ethers was stressed.


Human Fibrinogen Concentrate and Fresh Frozen Plasma in the Management of Severe Acquired Hypofibrinogenemia in Children With Acute Lymphoblastic Leukemia: Results of a Retrospective Survey.
In this study we aimed to retrospectively evaluate how centers, belonging to the Associazione Italiana Ematologia e Oncologia Pediatrica (AIEOP), manage severe acquired hypofibrinogenemia in children with acute lymphoblastic leukemia, particularly evaluating the therapeutic role of human fibrinogen concentrate (HFC) and fresh frozen plasma (FFP). We conducted a survey among AIEOP centers; thereafter, we collected and analyzed data with regard to the treatment of episodes of severe acquired hypofibrinogenemia occurring during the induction and reinduction phases of the AIEOP-BFM ALL 2009 protocol. In total, 15 of the 37 AIEOP centers invited to join the survey agreed to collect the data, with 10 and 5 centers declaring to react to severe acquired hypofibrinogenemia (<70 mg/dL) by administering HFC or FFP, respectively. Of the 150 episodes of severe hypofibrinogenemia occurring in 101 patients, 47.3% were treated with HFC and 52.7% with FFP, with a normalization of fibrinogen levels achieved in greater proportion and in a shorter amount of time in the HFC group as compared with the FFP group. None of the patients presented with bleeding or thrombosis during the observation period. Even with the limitations of the retrospective nature of this study, HFC seems to be a safe and effective alternative to FFP for replacement therapy in case of severe hypofibrinogenemia in children with acute lymphoblastic leukemia.


The 2019 PGDIS position statement on transfer of mosaic embryos within a context of new information on PGT-A.
A recently published Position Statement (PS) by the Preimplantation Genetics Diagnosis International Society (PGDIS) regarding utilization of preimplantation genetic testing for aneuploidy (PGT-A) in association with in vitro fertilization (IVF) contained inaccuracies and misrepresentations. Because opinions issued by the PGDIS have since 2016 determined worldwide IVF practice, corrections appear of importance. The International Do No Harm Group in IVF (IDNHG-IVF) is a spontaneously coalesced body of international investigators, concerned with increasing utilization of add-ons to IVF. It is responsible for the presented consensus statement, which as a final document was reached after review of the pertinent literature and again revised after the recent publication of the STAR trial and related commentaries. In contrast to the PGDIA-PS, we recommend restrictions to the increasing, and by IVF centers now often even mandated, utilization of PGT-A in IVF cycles. While PGT-A has been proposed as a tool for achieving enhanced singleton livebirth outcomes through embryo selection, continued false-positive rates and increasing evidence for embryonic self-correction downstream from the testing stage, has led IDNHG-IVF to conclude that currently available data are insufficient to impose overreaching recommendations for PGT-A utilization. Here presented consensus offers an alternative to the 2019 PGDIS position statement regarding utilization of preimplantation genetic testing for aneuploidy (PGT-A) in association with in vitro fertilization (IVF). Mindful of what appears to offer best outcomes for patients, and in full consideration of patient autonomy, here presented opinion is based on best available evidence, with the goal of improving safety and efficacy of IVF and minimizing wastage of embryos with potential for healthy births. As the PGDIS never suggested restrictions on clinical utilization of PGT-A in IVF, here presented rebuttal represents an act of self-regulation by parts of the IVF community in attempts to control increasing utilization of different unproven recent add-ons to IVF.


Neoplastic alterations induced in mammalian skin following mancozeb exposure using in vivo and in vitro models.
Mancozeb, ethylene(bis)dithiocarbamate fungicides, has been well documented in the literature as a multipotent carcinogen, but the underlying mechanism remains unrevealed. Thus, mancozeb has been selected in this study with the objective to decipher the molecular mechanism that culminates in carcinogenesis. We employed two-dimensional gel electrophoresis and mass spectrometry to generate a comparative proteome profile of control and mancozeb (200 mg/kg body weight) exposed mouse skin. Although many differentially expressed proteins were found, among them, two significantly upregulated proteins, namely, S100A6 (Calcyclin) and S100A9 (Calgranulin-B), are known markers of keratinocyte differentiation and proliferation, which suggested their role in mancozeb-induced neoplastic alterations. Therefore, we verified these alterations in the human system by using HaCaT cells as an in vitro model for human skin keratinocyte carcinogenesis. Upregulation of these two proteins upon mancozeb (0.5 μg/mL) exposure in HaCaT cells indicated its neoplastic potential in human skin also. This potential was confirmed by increase in number of colonies in colony formation and anchorage-independent growth assays. Modulation of S100A6/S100A9 targets, elevated phosphorylation of extracellular signal regulated kinase (ERK1/2), Elk1, nuclear factor- kappa B and cell division cycle 25 C phosphatase, and cyclin D1 and cyclooxygenase-2 upregulation was seen. In addition, PD98059 (ERK1/2 inhibitor) reduced cell proliferation induced by mancozeb, confirming the involvement of ERK1/2 signaling. Conclusively, we herein present the first report asserting that the mechanism involving S100A6 and S100A9 regulated ERK1/2 signaling underlies the mancozeb-induced neoplastic potential in human skin.


[Sympathetic ophthalmia 21 years after penetrating eye injury].
Sympathetic ophthalmia developed 21 years after penetrating wound during a relapse of posttraumatic uveitis 10 days after enucleation of the injured eye and discontinuation of dexamethasone. The diagnosis was confirmed histologically. The authors believe that enucleation and discontinuation of steroids provoked the development of inflammation in the paired eye.


Enlarging the scenario of site directed 19F labeling for NMR spectroscopy of biomolecules.
The possibility of using selectively incorporated 19F nuclei for NMR spectroscopic studies has retrieved increasing interest in recent years. The high gyromagnetic ratio of 19F and its absence in native biomolecular systems make this nucleus an interesting alternative to standard 1H NMR spectroscopy. Here we show how we can attach a label, carrying a 19F atom, to protein tyrosines, through the use of a specific three component Mannich-type reaction. To validate the efficacy and the specificity of the approach, we tested it on two selected systems with the aid of ESI MS measurements.


Inhibition of capacitative Ca2+ entry into cells by farnesylcysteine analogs.
Capacitative Ca2+ influx, which occurs in response to mobilization of intracellular Ca2+ stores, is a general feature of many cell types. Although the mechanism of capacitative Ca2+ entry is not known, evidence suggests the involvement of small G proteins that are prenylated on a cysteine residue near their carboxyl termini. We have investigated the actions of farnesyl-cysteine analogs on capacitative Ca2+ influx. Using human embryonic kidney 293 cells, we found that S-farnesylthioacetic acid, N-acetyl-S-farnesyl-L-cysteine, N-pivaloyl-S-farnesyl-L-cysteine, and N-acetyl-S-gernylgernyl-L-cysteine blocked the activation of capacitative Ca2+ influx, whereas N-benzoyl-S-farnesyl-S-cysteine had no effect on capacitative Ca2+ entry. Inhibition by S-farnesylthioacetic acid was concentration dependent (5-20 microM) and specific for Ca2+ influx through non-voltage-gated Ca2+ channels. A single protein band of 26-28 kDa was labeled specifically with a photoaffinity analog of farnesylcysteine. GTP binding to the photoaffinity-labeled band was demonstrated. These findings suggest, but do not prove, that a prenylated substrate, possibly a small G protein, is linked functionally to capacitative Ca2+ entry in human embryonic kidney 293 cells.


Subnational variation for care at birth in Tanzania: is this explained by place, people, money or drugs?
Tanzania achieved the Millennium Development Goal for child survival, yet made insufficient progress for maternal and neonatal survival and stillbirths, due to low coverage and quality of services for care at birth, with rural women left behind. Our study aimed to evaluate Tanzania's subnational (regional-level) variations for rural care at birth outcomes, i.e., rural women giving birth in a facility and by Caesarean section (C-section), and associations with health systems inputs (financing, health workforce, facilities, and commodities), outputs (readiness and quality of care) and context (education and GDP). We undertook correlation analyses of subnational-level associations between health system inputs, outputs, context, and rural care at birth outcomes; and constructed implementation readiness barometers using benchmarks for each health system input indicator. We used geographical information system (GIS) mapping to visualise subnational variations in care at birth for rural women, with a focus on service availability and readiness, and collected qualitative data to investigate financial flows from national to council level to understand variation in financing inputs. We found wide subnational variation for rural care at birth outcomes, health systems inputs, and contextual indicators. There was a positive association between rural women giving birth in a facility and by C-section; maternal education; workforce and facility density; and quality of care. There was a negative association between these outcomes and proportion of all births to rural women, total fertility rate, and availability of essential commodities at facilities. Per capita recurrent expenditure was positively associated with facility births (correlation coefficient = 0.43; p = 0.05) but not with C-section. Qualitative results showed that the health financing system is complex and insufficient for providing care at birth services. Bottlenecks for care at birth included low density of health workers, poor availability of essential commodities, and low health financing in Lake and Western Zones. No region meets the benchmarks for the four health systems building blocks including health finance, health workforce, health facilities, and commodities. Strategies for addressing health system inequities, including overall increases in health expenditure, are needed in rural populations and areas of highest unmet need for family planning to improve coverage of care at birth for rural women in Tanzania.


UKPDS 60: risk of stroke in type 2 diabetes estimated by the UK Prospective Diabetes Study risk engine.
People with type 2 diabetes are at elevated risk of stroke compared with those without diabetes. Relative risks have been examined in earlier work, but there is no readily available method for predicting the absolute risk of stroke in a diabetic individual. We developed mathematical models to estimate the risk of a first stroke using data from 4549 newly diagnosed type 2 diabetic patients enrolled in the UK Prospective Diabetes Study. During 30 700 person-years of follow-up, 188 first strokes (52 fatal) occurred. Model fitting was carried out by maximum likelihood estimation using the Newton-Raphson method. Diagnostic plots were used to compare survival probabilities calculated by the model with those calculated using nonparametric methods. Variables included in the final model were duration of diabetes, age, sex, smoking, systolic blood pressure, total cholesterol to high-density lipoprotein cholesterol ratio and presence of atrial fibrillation. Not included in the model were body mass index, hemoglobin A1c, ethnicity, and ex-smoking status. The use of the model is illustrated with a hypothetical study power calculation. This model forecasts the absolute risk of a first stroke in people with type 2 diabetes using variables readily available in routine clinical practice.


Genetic relatedness of indigenous ethnic groups in northern Borneo to neighboring populations from Southeast Asia, as inferred from genome-wide SNP data.
The region of northern Borneo is home to the current state of Sabah, Malaysia. It is located closest to the southern Philippine islands and may have served as a viaduct for ancient human migration onto or off of Borneo Island. In this study, five indigenous ethnic groups from Sabah were subjected to genome-wide SNP genotyping. These individuals represent the "North Borneo"-speaking group of the great Austronesian family. They have traditionally resided in the inland region of Sabah. The dataset was merged with public datasets, and the genetic relatedness of these groups to neighboring populations from the islands of Southeast Asia, mainland Southeast Asia and southern China was inferred. Genetic structure analysis revealed that these groups formed a genetic cluster that was independent of the clusters of neighboring populations. Additionally, these groups exhibited near-absolute proportions of a genetic component that is also common among Austronesians from Taiwan and the Philippines. They showed no genetic admixture with Austro-Melanesian populations. Furthermore, phylogenetic analysis showed that they are closely related to non-Austro-Melansian Filipinos as well as to Taiwan natives but are distantly related to populations from mainland Southeast Asia. Relatively lower heterozygosity and higher pairwise genetic differentiation index (FST ) values than those of nearby populations indicate that these groups might have experienced genetic drift in the past, resulting in their differentiation from other Austronesians. Subsequent formal testing suggested that these populations have received no gene flow from neighboring populations. Taken together, these results imply that the indigenous ethnic groups of northern Borneo shared a common ancestor with Taiwan natives and non-Austro-Melanesian Filipinos and then isolated themselves on the inland of Sabah. This isolation presumably led to no admixture with other populations, and these individuals therefore underwent strong genetic differentiation. This report contributes to addressing the paucity of genetic data on representatives from this strategic region of ancient human migration event(s).


Significance of Scapholunate Gap Width as Measured by Probe from Midcarpal.
Background Geissler's classification is widely accepted in arthroscopic diagnostics of scapholunate (SL) ligament injury. Thereby, probe insertion into the SL gap from the midcarpal would indicate treatment necessity in patients with SL tear as seen from radiocarpal view. Purpose In this review, the SL gap width, examined by the probe from midcarpal, was arthroscopically assessed in patients with intact SL ligaments, who were treated for ulnar impaction syndrome. The review examined how often lax SL joints can be found in patients with no complaints with respect to the SL ligaments and in which the SL ligaments were proven to be intact from radiocarpal view. We suspected that probe insertion, as an indicator for a lax joint, does not affect the outcome in ulnar impaction treatment. Patients and Methods A total of 32 patients with clinically diagnosed ulnar impaction syndrome were arthroscopically treated by central resection and debridement of the triangular fibrocartilage; 8 patients underwent concurrent ulnar shortening, and 4 of them finally hardware removal. All patients were examined preoperatively as well as after 3, 6, and 12 months following arthroscopy, respectively, after ulnar shortening or hardware removal. Results In 14 patients, the probe could not, in 18 patients, the probe could be inserted into the SL gap. There was neither any significant difference in the improvement of pain, grip strength, Krimmer, or DASH score, nor for any of the radiographic angles between the two groups. Conclusion Laxity of the SL ligament allows the probe to be inserted into the SL gap from midcarpal in some patients. This finding, therefore, does not necessarily imply the necessity of treatment when there is partial rupture seen from radiocarpal view. Level of Evidence Level III, case-control study.


HIV treatment as prevention: modelling the cost of antiretroviral treatment--state of the art and future directions.
Policy discussions about the feasibility of massively scaling up antiretroviral therapy (ART) to reduce HIV transmission and incidence hinge on accurately projecting the cost of such scale-up in comparison to the benefits from reduced HIV incidence and mortality. We review the available literature on modelled estimates of the cost of providing ART to different populations around the world, and suggest alternative methods of characterising cost when modelling several decades into the future. In past economic analyses of ART provision, costs were often assumed to vary by disease stage and treatment regimen, but for treatment as prevention, in particular, most analyses assume a uniform cost per patient. This approach disregards variables that can affect unit cost, such as differences in factor prices (i.e., the prices of supplies and services) and the scale and scope of operations (i.e., the sizes and types of facilities providing ART). We discuss several of these variables, and then present a worked example of a flexible cost function used to determine the effect of scale on the cost of a proposed scale-up of treatment as prevention in South Africa. Adjusting previously estimated costs of universal testing and treatment in South Africa for diseconomies of small scale, i.e., more patients being treated in smaller facilities, adds 42% to the expected future cost of the intervention.


Avicularin Alleviates Osteoporosis in Ovariectomized Mice by Inhibiting Osteoclastogenesis through NF-κB Pathway Inhibition.
Osteoporosis (OP) is mainly manifested by bone loss and bone degeneration. OP is considered a risk factor for pathological fractures, as well as impacts the health of middle-aged and elderly individuals. Drug therapy remains the main treatment scheme for OP; however, its efficacy is limited and has been associated with serious side effects. Therefore, it is important to develop new, effective, and safe treatment methods for OP. Avicularin (AL) is a flavonoid and quercetin derivative from various plants. Our study showed that AL disrupts osteoclast activation and resorptive function via inhibition of the RANKL-induced osteoclast differentiation together with the resorption capacity of bone marrow-derived macrophages (BMMs). Hence, AL prevents the activation and resorptive activity of osteoclasts. The results of qPCR showed that genes related to osteoclasts exhibited downregulated expression after AL treatment. Furthermore, AL inhibited RANKL-induced phosphorylation as well as degradation of the inhibitor IκBα of the NF-κB pathway, together with P65 phosphorylation in BMMs. We used an OP mouse model that was established by ovariectomy (OVX). Relative to untreated OP mice, mice that received AL treatment showed a significant increase in bone mineral density; however, the expression of TRAP, NFATC1, mmp9, and CTX-1 was significantly reduced. These results indicate that AL disrupts osteoclastogenesis via inhibition of the NF-κB pathway, which in turn improves OVX-induced OP.


Assessing Drug Efficacy in a Miniaturized Pancreatic Cancer In Vitro 3D Cell Culture Model.
Pancreatic cancer continues to have one of the poorest prognoses among all cancers. The drug discovery efforts for this disease have largely failed, with no significant improvement in survival outcomes for advanced pancreatic cancer patients over the past 20 years. Traditional in vitro cell culture techniques have been used extensively in both basic and early drug discovery; however, these systems offer poor models to assess emerging therapeutics. More predictive cell-based models, which better capture the cellular heterogeneity and complexities of solid pancreatic tumors, are urgently needed not only to improve drug discovery success but also to provide insight into the tumor biology. Pancreatic tumors are characterized by a unique micro-environment that is surrounded by a dense stroma. A complex network of interactions between extracellular matrix (ECM) components and the effects of cell-to-cell contacts may enhance survival pathways within in vivo tumors. This biological and physical complexity is lost in traditional cell monolayer models. To explore the predictive potential of a more complex cellular system, a three-dimensional (3D) micro-tumor assay was evaluated. Efficacy of six current chemotherapeutics was determined against a panel of primary and metastatic pancreatic tumor cell lines in a miniaturized ECM-based 3D cell culture system. Suitability for potential use in high-throughput screening applications was assessed, including ascertaining the effects that miniaturization and automation had on assay robustness. Cellular health was determined by utilizing an indirect population-based metabolic activity assay and a direct imaging-based cell viability assay.


Reversibility of Ia EPSP investigated with intracellularly iontophoresed QX-222.
1. Cat lumbosacral motoneurons were impaled by two individually advanced microelectrodes: one to record membrane potential (EM), the second to pass depolarizing currents. 2. During the passage of depolarizing current ramps the repetitive action-potential firing and the later high conductance (GM) state obscured and distorted Ia excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation of hindlimb muscle afferents. 3. Intracellular iontophoresis of QX-222 (a trimethyl analogue of lignocaine) or methylxylocholine, prevented action-potential generation and reduced the GM increase during current depolarization so that positive levels of EM could be reached. 4. Following QX-222 treatment it was possible to demonstrate a reversal of the Ia EPSP including its first part, at EM values between -13 and +32 mV. Reversal was seen in 13 of the 22 motoneurons tested. 5. Reversal was easiest to obtain in motoneurons of the deep peroneal group. More positive levels of EM were needed to show a reversal in neurons of the gastrocnemius-so-leus group. (The 10-90% rise times of the EPSPs were rather similar for both groups.) 6. In a few motoneurons the initial part of the Ia EPSP reversed at a more negative EM than a later part. This was best seen after subtraction of the extracellular field potentials from the records.