Efficient manufacturing of tissue engineered cartilage in vitro by a multiplexed 3D cultured method.
Cell culture has become an indispensable tool to uncover fundamental biophysical and biomolecular mechanisms of cells assembling into tissues. An important advancement in cell culture techniques was the introduction of three-dimensional (3D) culture systems. In this study, the mutual fusion of chondrocyte pellets was promoted in order to produce large-sized tissue-engineered cartilage by a multiplexed 3D hanging drop culture and agarose mold method to optimize the means of cultivation. Cell proliferation, aggregation, cell morphology maintenance as well as cartilage related gene expression and matrix secretion in vitro and subcutaneous implantation models were evaluated. These results indicated that the multiplexed 3D hanging drop culture involving the fusion of small pellets into a large structure enabled the efficient production of 3D tissue engineered cartilage that was closer to physiological cartilage tissue in comparison to that of the agarose mold method.


Ph2 encodes the mismatch repair protein MSH7-3D that inhibits wheat homoeologous recombination.
Meiotic recombination is a critical process for plant breeding, as it creates novel allele combinations that can be exploited for crop improvement. In wheat, a complex allohexaploid that has a diploid-like behaviour, meiotic recombination between homoeologous or alien chromosomes is suppressed through the action of several loci. Here, we report positional cloning of Pairing homoeologous 2 (Ph2) and functional validation of the wheat DNA mismatch repair protein MSH7-3D as a key inhibitor of homoeologous recombination, thus solving a half-century-old question. Similar to ph2 mutant phenotype, we show that mutating MSH7-3D induces a substantial increase in homoeologous recombination (up to 5.5 fold) in wheat-wild relative hybrids, which is also associated with a reduction in homologous recombination. These data reveal a role for MSH7-3D in meiotic stabilisation of allopolyploidy and provides an opportunity to improve wheat's genetic diversity through alien gene introgression, a major bottleneck facing crop improvement.


Use of statistical process control in the production of blood components.
Introduction of statistical process control in the setting of a small blood centre was tested, both on the regular red blood cell production and specifically to test if a difference was seen in the quality of the platelets produced, when a change was made from a relatively large inexperienced occasional component manufacturing staff to an experienced regular manufacturing staff. Production of blood products is a semi-automated process in which the manual steps may be difficult to control. This study was performed in an ongoing effort to improve the control and optimize the quality of the blood components produced and gives an example of how to meet EU legislative requirements in a small-scale production centre. Data included quality control measurements in 363 units of red blood cells, 79 units of platelets produced by an occasional staff with 11 technologists and 79 units of platelets produced by an experienced staff with four technologists. We applied statistical process control to examine if time series of quality control values were in statistical control. Leucocyte count in red blood cells was out of statistical control. Platelet concentration and volume of the platelets produced by the occasional staff were out of control, which was not the case with the experienced staff. Introduction of control charts to a small blood centre has elucidated the difficulties in controlling the blood production and shown the advantage of using experienced regular component manufacturing staff.


[Variants of meningeal tuberculosis in adults].
The article describes the versions of meningeal tuberculosis in 300 patients observed by the author from 1975 to 1990. In the majority of the patients, the onset of the disease was gradual and its course, typical. For an acute onset of the disease, certain types of serous meningitis (6.7%), influenza (2.3%), acute psychosis (3%), purulent meningitis (1.3%), craniocerebral injury (1%), seriously disturbed cerebral circulation (4%) and lethargic encephalitis (0.66%) were identified. Chronic forms were mainly characterized by fibroplastic processes, local focal neurologic symptoms and congestive changes in the eye ground. The full-scale picture of the disease was sometimes observed at the terminal stage only. In 5% of the patients, such neurologic symptoms, as aphasias and paralyses, were prevalent in the clinical picture. The final diagnosis of a follow-up and repeated examination of the cerebrospinal fluid.


[Computer monitoring of the effectiveness of the operator's adaptation to shift work].
Shift work necessitates operators' reliable and effective activities equally in various parts of the shift despite of diurnal changes of functional activities, occurrence of fatigue and other unfavorable conditions. Computer monitoring of adaptation efficacy in operators could be based on evaluation of changes in test results during various parts of the shift. Analysis of the data in group revealed unfavorable factors of work management. Analysis of the individual data helps to diagnose those who need prophylactic or rehabilitation measures. Thus, computer monitoring is an effective diagnostic tool in work management and aimed to higher reliability of operators.


Scapular dyskinesis in trapezius myalgia and intraexaminer reproducibility of clinical tests.
The aims were to test the intraexaminer reproducibility and report the presence of specific clinical variables of scapular dyskinesis in cases with trapezius myalgia and healthy controls, along with general health and work ability. A total of 38 cases and 23 controls were tested for scapular dyskinesis, general health, and work ability, and 19 cases and 14 controls participated in the reproducibility study. Intraexaminer reproducibility was good to excellent for 6 of 10 clinical variables (Intraclass Correlation Coefficient [ICC] 0.76-0.91; kappa 0.84-1.00), and fair to good for four variables (ICC 0.42-0.74), test for muscular weakness having the lowest ICC (0.42). Cases showed significantly larger medial border misalignment, larger lower horizontal distance of the inferior scapular angle and larger passive shoulder internal rotation, by 110% (1.02 cm), 15% (1.38 cm), and 8% (5.5°), respectively. Cases with the highest degree of scapular dyskinesis showed reduced work ability and general health. The present specific clinical variables on scapular dyskinesis showed satisfactory intraexaminer reproducibility. An increased standardization must be implemented to increase reproducibility of tests for muscular weakness, and the interexaminer reproducibility must be tested for all variables. Finally, scapular dyskinesis in cases with trapezius myalgia must be followed longitudinally for clinical importance.


Rapid-quench and isotope-trapping studies on fructose-1,6-bisphosphatase.
Rapid-quench kinetic measurements yielded presteady-state rate data for rabbit liver fructose-1,6-bisphosphatase (FBPase) (a tetramer of four identical subunits) that are triphasic: the rapid release of Pi (complete within 5 ms), followed by a second reaction phase liberating additional Pi that completes the initial turnover of two or four subunits of the enzyme (requiring 100-150 ms), and a steady-state rate whose magnitude depends on the [alpha-Fru-1,6-P2]/[FBPase] ratio. With Mg2+ in the presence of excess alpha-fructose 1,6-bisphosphate (alpha-Fru-1,6-P2) all four subunits turn over in the pre steady state; with Mn2+ only two of the four are active. Thus the expression of half-site reactivity is a consequence of the nature of the metal ion and not a subunit asymmetry. In the presence of limiting alpha-anomer concentrations only two of the four subunits now remain active with Mg2+ as well as with Mn2+ in the pre steady state. However, so that the amount of Pi released can be accounted for, a beta leads to alpha anomerization or direct beta utilization is required at the active site of one subunit. Such behavior is consistent with the two-state conformational hysteresis displayed by the enzyme and altered affinities manifested within these states for alpha and beta substrate analogues. Under these limiting conditions the subsequent steady-state rate is limited by the beta leads to alpha solution anomerization. These data in combination with pulse--chase experiments permit evaluation of the internal equilibrium, which in the case of Mg2+ is unequivocally higher in favor of product complexes and represents a departure from balanced internal substrate-product complexes.


Mothers' sleep deficits and cognitive performance: Moderation by stress and age.
There are well-known associations between stress, poor sleep, and cognitive deficits, but little is known about their interactive effects, which the present study explored in a sample of mothers of toddlers. Since certain types of cognitive decline start during the 20s and continue into later ages, we also explored whether mothers' age interacted with stress and sleep in the prediction of cognitive functioning. We hypothesized that poorer sleep [measured using one week of 24-hour wrist actigraphy data] and having more chronic stressors [e.g., life events, household chaos, work/family role conflict] would be linked with poorer cognitive performance [both executive function and standardized cognitive ability tasks], and that the interactive combination of poorer sleep and more stressors would account for the effect. We also explored whether this process operated differently for younger versus older women. In a socioeconomically and geographically diverse community sample of 227 women with toddler-age children [age, M = 32.73 yrs, SD = 5.15 yrs], poorer cognitive performance was predicted by greater activity during the sleep period, shorter sleep duration, and lower night-to-night consistency in sleep; it was not associated with higher levels of stress. The interactive effects hypothesis was supported for sleep activity [fragmented sleep] and sleep timing [when mothers went to bed]. The combination of more exposure to stressors and frequent night waking was particularly deleterious for older women's performance. For younger women, going to bed late was associated with poorer performance if they were experiencing high levels of stress; for those experiencing low levels of stress, going to bed late was associated with better performance.


Is Fetal Endoscopic Tracheal Occlusion (FETO) a Predisposing Factor for Acid Gastro-Esophageal Reflux in Infants With Congenital Diaphragmatic Hernia?
Introduction: Various anatomical defects predispose patients with congenital diaphragmatic hernia (CDH) to develop gastroesophageal reflux disease (GERD). The fetal endoscopic tracheal occlusion (FETO) has increased the survival of patients with severe CDHs. The aim of this study was to study GERD in patients who underwent FETO. Materials and Methods: We included patients with CDH treated with or without FETO ("FETO" and "no-FETO" group, respectively) from 2013 to 2016. Data on gestational age (GA), birth weight (BW), initial observed/expected lung to head ratio (O/E LHR), final O/E LHR, duration of ventilation and hospitalization, maximal tracheal diameter, and pulmonary volume were collected. All patients underwent pH-metry after 1 year of life, and the results were compared between groups and correlated to risk factors. Results: Thirty-two patients were included in the study: 10 FETO and 22 no-FETO. No significant differences were observed in the pH-metric results of the two groups. No correlation was found between GA, BW, initial O/E LHR, maximal tracheal diameter, pulmonary volume, and pH-metric results. pH-metric results were correlated with the total duration of ventilation (R = 0.5, p = 0.003) and of hospitalization (R = 0.54, p = 0.001). Gastric herniation is associated with the worse pH-metric result. Conclusions: The FETO procedure does not seem to represent an independent risk factor for GERD. However, patients with the most severe CDH have the worst GERD.


Cell cycle regulation of histone H1 kinase activity associated with the adenoviral protein E1A.
Several cellular proteins form stable complexes with the proteins encoded by the adenovirus early region 1A (E1A) gene in extracts derived from adenovirus infected or transformed cells. Two of the cellular proteins that bind to E1A have been identified; one, a 105-kilodalton protein (pRb), is the product of the retinoblastoma gene, and the other, a 60-kilodalton protein, is a human cyclin A. Two other proteins that bind E1A have now been shown to be related to p34cdc2. This E1A complex displayed histone H1-specific kinase activity; the kinase activity was modulated during the cell division cycle, and association of pRb with E1A apparently was not required for this activity.


To stay or not to stay: The stability of choice perseveration in value-based decision making.
In real life, decisions are often naturally embedded in decision sequences. In contrast, in the laboratory, decisions are oftentimes analysed in isolation. Here, we investigated the influence of decision sequences in value-based decision making and whether the stability of such effects can be modulated. In our decision task, participants needed to collect rewards in a virtual two-dimensional world. We presented a series of two reward options that were either quick to collect but were smaller in value or took longer to collect but were larger in value. The subjective value of each option was driven by the options' value and how quickly they could be reached. We manipulated the subjective values of the options so that one option became gradually less valuable over the course of a sequence, which allowed us to measure choice perseveration (i.e., how long participants stick to this option). In two experiments, we further manipulated the time interval between two trials (inter-trial interval), and the time delay between the onsets of both reward options (stimulus onset asynchrony). We predicted how these manipulations would affect choice perseveration using a computational attractor model. Our results indicate that both the inter-trial interval and the stimulus onset asynchrony modulate choice perseveration as predicted by the model. We discuss how our findings extend to research on cognitive stability and flexibility.


RIFM fragrance ingredient safety assessment, methyl 2-octynoate, CAS Registry Number 111-12-6.
Methyl 2-octynoate was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that methyl 2-octynoate is not genotoxic. Data provided methyl 2-octynoate a NESIL of 110 μg/cm2 for the skin sensitization endpoint. The repeated dose, developmental and reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class II material, and the exposure to methyl 2-octynoate is below the TTC (0.009 mg/kg/day, 0.009 mg/kg/day, and 0.47 mg/day, respectively). The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; methyl 2-octynoate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; methyl 2-octynoate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.


Collagen membrane barrier therapy to guide regeneration in Class II furcations in humans.
This study was undertaken to evaluate the effectiveness of resorbable collagen membranes in guided tissue regeneration. The study participants were 38 adults with moderate to advanced periodontitis. Each patient had at least one Class II furcation defect which could serve as either a test or control tooth. The cases were randomized prior to selection, so that investigators did not known whether the patient would be a test case or a control case until the time of surgery. Sites were surgically exposed and measurements were recorded from the cemento-enamel junction (CEJ) directly coronal to the furcation area to the alveolar crest, and to the base of the defect. Horizontal furcation measurements were also made, using a color coded furcation probe. The test patients had a trimmed and shaped collagen membrane barrier placed over the prepared furcation area. The control patients received the identical surgical management, except that no collagen membrane barrier was placed. All patients received normal post-surgical care, and at 12 weeks post-surgery, were scheduled for re-entry surgery. The re-entry mucoperiosteal flaps were designed to expose the furcation area for measurements, as described above. There was clinical improvement in all measurements made in both the test and control patients over the 3-month period. The horizontal furcation measurement and the CEJ to base of alveolar defect measurements did yield a statistically significant improvement when comparing the test patients to the controls.


Evaluation of Developmental Toxicity, Developmental Neurotoxicity, and Tissue Dose in Zebrafish Exposed to GenX and Other PFAS.
Per- and polyfluoroalkyl substances (PFAS) are a diverse class of industrial chemicals with widespread environmental occurrence. Exposure to long-chain PFAS is associated with developmental toxicity, prompting their replacement with short-chain and fluoroether compounds. There is growing public concern over the safety of replacement PFAS. We aimed to group PFAS based on shared toxicity phenotypes. Zebrafish were developmentally exposed to 4,8-dioxa-3H-perfluorononanoate (ADONA), perfluoro-2-propoxypropanoic acid (GenX Free Acid), perfluoro-3,6-dioxa-4-methyl-7-octene-1-sulfonic acid (PFESA1), perfluorohexanesulfonic acid (PFHxS), perfluorohexanoic acid (PFHxA), perfluoro-n-octanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), or 0.4% dimethyl sulfoxide (DMSO) daily from 0-5 d post fertilization (dpf). At 6 dpf, developmental toxicity and developmental neurotoxicity assays were performed, and targeted analytical chemistry was used to measure media and tissue doses. To test whether aliphatic sulfonic acid PFAS cause the same toxicity phenotypes, perfluorobutanesulfonic acid (PFBS; 4-carbon), perfluoropentanesulfonic acid (PFPeS; 5-carbon), PFHxS (6-carbon), perfluoroheptanesulfonic acid (PFHpS; 7-carbon), and PFOS (8-carbon) were evaluated. PFHxS or PFOS exposure caused failed swim bladder inflation, abnormal ventroflexion of the tail, and hyperactivity at nonteratogenic concentrations. Exposure to PFHxA resulted in a unique hyperactivity signature. ADONA, PFESA1, or PFOA exposure resulted in detectable levels of parent compound in larval tissue but yielded negative toxicity results. GenX was unstable in DMSO, but stable and negative for toxicity when diluted in deionized water. Exposure to PFPeS, PFHxS, PFHpS, or PFOS resulted in a shared toxicity phenotype characterized by body axis and swim bladder defects and hyperactivity. All emerging fluoroether PFAS tested were negative for evaluated outcomes. Two unique toxicity signatures were identified arising from structurally dissimilar PFAS. Among sulfonic acid aliphatic PFAS, chemical potencies were correlated with increasing carbon chain length for developmental neurotoxicity, but not developmental toxicity. This study identified relationships between chemical structures and in vivo phenotypes that may arise from shared mechanisms of PFAS toxicity. These data suggest that developmental neurotoxicity is an important end point to consider for this class of widely occurring environmental chemicals. https://doi.org/10.1289/EHP5843.


Use of secondary prevention pharmacotherapy after first myocardial infarction in patients with diabetes mellitus.
Despite recommended pharmacotherapies the use of secondary prevention therapy after myocardial infarction (MI) remains suboptimal. Patients with diabetes mellitus (DM) have worse prognosis after MI compared to patients without DM and aggressive secondary prevention pharmacotherapy in this population is therefore warranted. We examined the changes in use of evidence-based secondary prevention pharmacotherapy in patients with and without DM discharged after first MI. All patients aged 30 years or older admitted with first MI in Denmark during 1997-2006 were identified by individual-level linkage of nationwide registries of hospitalizations. Univariate and multivariate logistic regression models were used to identify patient characteristics associated with initiation of acetylsalicylic acid, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers, and clopidogrel within 90 days, and statins within 180 days of discharge, respectively. A total of 78,230 patients were included, the mean age was 68.3 years (SD 13.0), 63.5% were men and 9,797 (12.5%) had diabetes. Comparison of claimed prescriptions in the period 1997-2002 and 2003-2006 showed significant (p < 0.001) increases in claims for acetylsalicylic acid (38.9% vs. 69.7%), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (38.7% vs. 50.4%), β-blockers (69.2% vs. 77.9%), clopidogrel (16.7% vs. 66.3%), and statins (41.3% vs. 77.3%). During 2003-2006, patients with DM claimed significantly less acetylsalicylic acid (odds ratio [OR] 0.81 [95% confidence interval [CI] 0.74-0.88) and clopidogrel (OR 0.91 [95% CI 0.83-1.00]) than patients without DM. Despite sizeable increase in use of evidence-based secondary prevention pharmacotherapy after MI from 1997 to 2006, these drugs are not used in a substantial proportion of subjects and patients with DM received significantly less antiplatelet therapy than patients without DM. Increased focus on initiation of secondary prevention pharmacotherapy after MI is warranted, especially in patients with DM.


Structural abnormalities and deficient maintenance of peripheral nerve myelin in mice lacking the gap junction protein connexin 32.
Mutations affecting the connexin 32 (Cx32) gene are associated with the X-linked form of the hereditary peripheral neuropathy Charcot-Marie-Tooth disease (CMTX). We show that Cx32-deficient mice develop a late-onset progressive peripheral neuropathy with abnormalities comparable to those associated with CMTX, thus providing proof of the critical role of Cx32 in the maintenance of peripheral nerve myelin and an animal model for CMTX. Frequently observed features include abnormally thin myelin sheaths, cellular onion bulb formation reflecting myelin degeneration-induced Schwann cell proliferation, and enlarged periaxonal collars while nerve conductance properties are altered only slightly. These observations are consistent with earlier hypotheses suggesting a function of Cx32 as a channel-forming protein that facilitates the communication between the abaxonal and adaxonal aspects of Schwann cell cytoplasm.


Characterization of multiple platelet activation pathways in patients with bleeding as a high-throughput screening option: use of 96-well Optimul assay.
Up to 1% of the population have mild bleeding disorders, but these remain poorly characterized, particularly with regard to the roles of platelets. We have compared the usefulness of Optimul, a 96-well plate-based assay of 7 distinct pathways of platelet activation to characterize inherited platelet defects in comparison with light transmission aggregometry (LTA). Using Optimul and LTA, concentration-response curves were generated for arachidonic acid, ADP, collagen, epinephrine, Thrombin receptor activating-peptide, U46619, and ristocetin in samples from (1) healthy volunteers (n = 50), (2) healthy volunteers treated with antiplatelet agents in vitro (n = 10), and (3) patients with bleeding of unknown origin (n = 65). The assays gave concordant results in 82% of cases (κ = 0.62, P < .0001). Normal platelet function results were particularly predictive (sensitivity, 94%; negative predictive value, 91%), whereas a positive result was not always substantiated by LTA (specificity, 67%; positive predictive value, 77%). The Optimul assay was significantly more sensitive at characterizing defects in the thromboxane pathway, which presented with normal responses with LTA. The Optimul assay is sensitive to mild platelet defects, could be used as a rapid screening assay in patients presenting with bleeding symptoms, and detects changes in platelet function more readily than LTA. This trial was registered at www.isrctn.org as #ISRCTN 77951167.


[Fluorine-containing analog of diazoxide prevented apoptosis in neonatal cardiomyocytes during anoxia-reoxygenation].
In experiments on the primary culture of isolated neonatal rat cardiomyocytes it was established that anoxia-reoxygenation activated the process of programmed cell death, apoptosis. The amount of apoptotic cells (defined by fragmentation of a nucleus with Hoechst 33342 staining) during anoxia-reoxygenation was increased in 2.1 fold (P < 0.05). The amount of living and necrotic cells was not changed significantly. Apoptosis of neonatal cardiomyocytes during anoxia-reoxygenation was prevented by activation of ATP-dependent potassium (K(ATP)) channels with diazoxide. Synthesized by us the fluorine-containing analogue of diazoxide had the similar effect: the amount of apoptotic cells was decreased to 3.7% that was similar to control meaning. Application of glybenclamide, which completely abrogated the action of diazoxide and its fluorine-containing analogue, allows us to assert that antiapoptotic effect of the substances mentioned above depends on K(ATP) channels opening.


Relationship between cycloplegic and wavefront-derived refraction.
To compare cycloplegic refractions to preoperative wavefront-derived refractions from three Hartmann-Shack-based wavefront devices. Ninety-nine eyes of 55 subjects were evaluated preoperatively using the LADARWave, WaveScan, and Zywave aberrometers. With cycloplegic refraction as the standard, the spherical equivalent refraction, sphere, and cylinder were compared to the wavefront-derived refractions using the three wavefront devices. The LADARWave unit showed the highest correlation between wavefront-derived sphere and mean spherical equivalent refraction values relative to cycloplegic refraction, followed by Zywave and WaveScan. The WaveScan unit exhibited higher variability than the LADARWave or Zywave. Although Alcon Laboratories (LADARWave) and Bausch & Lomb Surgical (Zywave) recommend dilation, VISX specifically recommends against dilation in their WaveScan unit. All devices showed high cylinder error vectors when the cycloplegic cylinder was greater than 1.00 D. Although wavefront-derived refractions appeared to correlate well to cycloplegic refractions, further research is required to reduce variability and improve the calculation of cylinder terms.


High-risk infrastructure projects pose imminent threats to forests in Indonesian Borneo.
Indonesian Borneo (Kalimantan) sustains ~37 million hectares of native tropical forest. Numerous large-scale infrastructure projects aimed at promoting land-development activities are planned or ongoing in the region. However, little is known of the potential impacts of this new infrastructure on Bornean forests or biodiversity. We found that planned and ongoing road and rail-line developments will have many detrimental ecological impacts, including fragmenting large expanses of intact forest. Assuming conservatively that new road and rail projects will influence only a 1 km buffer on either side, landscape connectivity across the region will decline sharply (from 89% to 55%) if all imminently planned projects proceed. This will have particularly large impacts on wide-ranging, rare species such as rhinoceros, orangutans, and elephants. Planned developments will impact 42 protected areas, undermining Indonesian efforts to achieve key targets under the Convention on Biological Diversity. New infrastructure will accelerate expansion in intact or frontier regions of legal and illegal logging and land colonization as well as illicit mining and wildlife poaching. The net environmental, social, financial, and economic risks of several imminent projects-such as parallel border roads in West, East, and North Kalimantan, new Trans-Kalimantan road developments in Central Kalimantan and North Kalimantan, and freeways and rail lines in East Kalimantan-could markedly outstrip their overall benefits. Such projects should be reconsidered in light of rigorous cost-benefit frameworks.


Examining the Interaction Between Medical Information Seeking Online and Understanding: Exploratory Study.
Online information seeking on medical topics by patients can have beneficial effects by helping them decide on treatment options and fostering better relationships with doctors. The quality of websites and processes of seeking information online have mostly been studied, with a focus on the accuracy and reliability of websites; however, few studies have examined the relationship between other aspects of quality and the processes of seeking medical information online. This exploratory study aimed to shed light on the quality of websites used for information seeking from the perspective of understanding medical information in combination with seeking it online. The study participants were 15 Japanese university students with no problem using the internet. A questionnaire survey about health literacy (47 items on a 4-point Likert scale) and information navigation skills on the internet (8 items on a 5-point Likert scale) was conducted before participants engaged in online information seeking and qualitative interviews. The students searched for information on a disease and its treatment. The websites viewed were gathered from search behavior recorded by software and browser logs. Follow-up interviews were conducted to elicit explanations from the participants about the assignments and their views of online information seeking. The explanations were evaluated by 55 health care professionals on a 3-point Likert scale and then assessed based on their comments and the participant interviews. The mean age of the participants was 20.6 years (median 21; SD 1.06). All participants were able to access reliable websites with information relevant to the assignments. The mean ratings of the students' explanations were 108.6 (median 109; range=83-134) for the disease and 105.6 (median 104; range=87-117) for its treatment. The inter-rater reliability were 0.84 (95% CI 0.77-0.90) and 0.95 (95% CI 0.93-0.97), indicating good and excellent, respectively. The mean of the sum of the health literacy skills was 115.1 (median 115; range=80-166) and the mean for information navigation skills was 25.9 (median 26; range=17-36), respectively. Health literacy and information navigation skills were moderately correlated (r=0.54; 95% CI 0.033-0.822; P=.04). Among the four stages of health literacy, understanding and appraising (r=0.53; 95% CI 0.025-0.820; P=.04) were moderately correlated with information navigation skills (r=0.52; 95% CI 0.013-0.816; P=.046). The participants had no difficulties operating and browsing the internet and considered medical and public institution websites to be reliable; however, due to unfamiliarity with medical terms, they had difficulties choosing a site from the results obtained and comparing and synthesizing information provided by different sites. They also looked for sites providing orderly information in plain language but provided explanations from sites that gave inadequate interpretations of information. This study revealed interactions between searching the internet for, and understanding, medical information by analyzing the processes of information seeking online, physicians' evaluations and comments about the participants' explanations, and the participants' perceptions.


Defective processing and expression of thiazide-sensitive Na-Cl cotransporter as a cause of Gitelman's syndrome.
Gitelman's syndrome is an autosomal recessive disorder of salt wasting and hypokalemia caused by mutations in the thiazide-sensitive Na-Cl cotransporter. To investigate the pathogenesis of Gitelman's syndrome, eight disease mutations were introduced into the mouse thiazide-sensitive Na-Cl cotransporter and studied by functional expression in Xenopus oocytes. Sodium uptake into oocytes that expressed the wild-type clone was more than sevenfold greater than uptake into control oocytes. Uptake into oocytes that expressed the mutated transporters was not different from control. Hydrochlorothiazide reduced Na uptake by oocytes expressing the wild-type gene to control values but had no effect on oocytes expressing the mutant clones. Western blots of oocytes injected with the wild-type clone showed bands representing glycosylated (125 kDa) and unglycosylated (110 kDa) forms of the transport protein. Immunoblot of oocytes expressing the mutated clones showed only the unglycosylated protein, indicating that protein processing was disrupted. Immunocytochemistry with an antibody against the transport protein showed intense membrane staining of oocytes expressing the wild-type protein. Membrane staining was completely absent from oocytes expressing mNCC(R948X); instead, diffuse cytoplasmic staining was evident. In summary, the results show that several mutations that cause Gitelman's syndrome are nonfunctional because the mutant thiazide-sensitive Na-Cl cotransporter is not processed normally, probably activating the "quality control" mechanism of the endoplasmic reticulum.


Os Acromiale in Reverse Total Shoulder Arthroplasty: A Cohort Study.
Increased passive deltoid tension after reverse total shoulder arthroplasty (RTSA) potentially leads to displacement or tilting of a preexisting os acromiale. To analyze patients with an os acromiale who underwent RTSA and compare their outcomes and complications with a matched control group without an os acromiale. Cohort study; Level of evidence, 3. In this study, 45 shoulders in 42 patients with an os acromiale (cases) were matched to 133 patients without os acromiale (controls) who underwent RTSA between 2005 and 2016. The mean follow-up was 52 ± 32 months. Matching criteria included sex, type of surgery, duration of follow-up, and age. The Constant score (CS), Subjective Shoulder Value (SSV), and radiological outcomes were assessed postoperatively at 1-year, 2-year, and final follow-up visits. The mean CS, SSV, and range of motion improved from preoperative levels to the final follow-up in both groups (P < .01). Patients with an os acromiale had a relative CS of 70 ± 23 versus 76 ± 21 points (P = .15) and an SSV of 70 ± 30 versus 73 ± 24 (P = .52) compared with controls at the final follow-up visit. Patients with an os acromiale had significantly decreased active flexion of 104° ± 33° versus 114° ± 33° (P = .03) at 1 year and active abduction of 103° ± 37° versus 121° ± 38° at 2 years postoperatively (P = .02). A postoperatively painful os acromiale was found in 12 cases (27%) and spontaneously resolved in 8 cases after a mean of 33 months (range, 12-47 months; P = .04). RTSA reliably restores patient satisfaction despite the presence of an os acromiale, with a slightly impaired range of motion. Postoperative local tenderness at the os acromiale can be expected in 1 out of 4 patients, but this resolves spontaneously over time in the majority of patients.


Experimental argon laser photocoagulation. I. Effects on retinal nerve fiber layer.
Eight rhesus monkeys were photocoagulated with varying intensities of argon laser energy to determine the effects on the retinal nerve fiber layer. Photocoagulation of arterioles and venules always resulted in largely irreversible and permanent perivascular axonal destruction. Photocoagulation of areas free of major vessels showed variable responses to identical dosages, ranging from minimal destruction of the outer part of the retina to full-thickness destruction involving the nerve fiber layer. Variations in retinal thickness, vascularity, pigment epithelial pigmentation, and focus of the laser beam are responsible for differences in severity of each burn. Even when major vessels are avoided, it is impossible to predict accurately the degree of damage. However, our studies suggest that much of the initial damage is extracellular, sparing nerve fiber layer axons. Therefore, some acute damage might be reversible following resorption of the edema.


Unscheduled bleeding with continuous oral contraceptive pills: a comparison of progestin dose.
Although the use of continuous oral contraceptive pills (OCPs) eliminates scheduled uterine bleeding, unscheduled bleeding is common. The objective of this study was to determine whether progestin dose influences bleeding with use of continuous OCPs. This was a secondary data analysis of two other studies of continuous OCPs. Women were eligible if they were switching from a cyclic hormonal contraceptive to a continuous OCP. Women took a 20-mcg ethinyl estradiol (EE)/100-mcg levonorgestrel (LNG) pill or a 20-mcg EE/90-mcg LNG pill for 112 days. The number of bleeding/spotting days was compared between groups using a t test. Sample size was adequate to detect a difference of 8 days of bleeding/spotting over the 112 day study period (β=0.80, α=0.05). Sixty-six subjects were enrolled, 33 in each group. There were no differences in baseline characteristic, missed OCPs or side effects. There were no differences in the mean number of bleeding/spotting days in the first 84 days of the study (90 mcg LNG mean 20.8 (SE 3.6) days versus 100 mcg LNG 17.8 (SE 2.3) days, p=.48), nor was there a difference in the time to amenorrhea (p=.35). Our results do not support the use of one LNG dose over another to decrease the amount of unscheduled bleeding women experience when initiating a continuous OCP.


Gender differences in multiple sclerosis: induction of estrogen signaling in male and progesterone signaling in female lesions.
The basis of gender differences in the prevalence and clinical progression of multiple sclerosis (MS) is not understood. Here, we identify gender-specific responses in steroid synthesis and signaling in the brains of MS patients as possible contributors to these differences. We investigated gene expression changes in these pathways and of inflammatory cytokines in MS lesions and normal-appearing white matter (NAWM) of male and female patients (n=21) and control NAWM (n=14) using quantitative polymerase chain reaction (25 MS lesions, 21 MS NAWM, and 14 control NAWM) and immunohistochemistry (3-4 sections per group). In MS lesions in males, there was local upregulation of aromatase (an enzyme involved in estrogen biosynthesis), estrogen receptor-β (ERβ), and tumor necrosis factor (TNF) mRNA; whereas in females, there was local upregulation of 3β-hydroxysteroid-dehydrogenase, a progesterone synthetic enzyme, and of progesterone receptor. Astrocytes in the rim and center of MS lesions were found to be the primary source of steroidogenic enzyme and receptor expression. Aromatase and ERα mRNA levels were positively correlated with that of TNF in primary cultures of human microglia and astrocytes; TNF caused increased ERα, suggesting that inflammatory signals stimulate estrogen signaling in this cell type. Together, these findings suggest that there are gender differences in the CNS of MS patients that may affect lesion pathogenesis, that is, in males, estrogen synthesis and signaling are induced; whereas in females, progestogen synthesis and signaling are induced. These differences may represent contributing factors to gender differences in the prevalence and course of MS.


Role of the anterior visceral endoderm in restricting posterior signals in the mouse embryo.
Recent genetic and embryological experiments have demonstrated that head formation in the mouse embryo is dependent on signals provided by two organising centers during gastrulation, the anterior visceral endoderm (AVE) and the anterior primitive streak (also called the Early Gastrula Organiser, EGO). However the molecular nature of the signals triggering anterior neural formation from the epiblast is not clearly understood. The analysis of mouse mutants has allowed the identification of some of the molecular players involved in the process of head formation. In this review, we describe different mutant embryos in which impairment of visceral endoderm function leads to similar defects in antero-posterior axis specification. These phenotypes are consistent with a role of the AVE in protecting anterior embryonic regions from signals that promote posterior development. We propose that a genetic cascade in the AVE, involving HNF3beta, Lim1, Otx2, Smad2 and ActRIB, leads to the production of secreted TGFbeta antagonists that protect the anterior epiblast region from Nodal signalling.


Assessment of the cost-effectiveness of Australia's risk-sharing agreement for direct-acting antiviral treatments for hepatitis C: a modelling study.
Hepatitis C elimination may be possible with broad uptake of direct-acting antiviral treatments (DAAs). In 2016 the Australian government committed A$1.2 billion for five years of unlimited DAAs (March 2016 to February 2021) in a risk-sharing agreement with pharmaceutical companies. We assess the impact, cost-effectiveness and net economic benefits likely to be realised from this investment. Mathematical modelling to project outcomes for 2016-2030 included: (S1) a counter-factual scenario (testing/treatment maintained at pre-2016 levels); (S2) the current status-quo (testing/treatment as actually occurred 2016-2019, with trends maintained to 2030); and (S3) elimination scenario (S2 plus testing/treatment rates increased between 2021-2030 to achieve the WHO elimination targets). S1 resulted in 68,800 new hepatitis C infections and 18,540 hepatitis C-related deaths over 2016-2030. The total health system cost (HCV testing, treatment, disease management) was A$3.01 billion and the cost of lost productivity due to absenteeism, presenteeism and premature deaths was A$26.14 billion. S2 averted 15,700 (23%) new infections and 8,500 (46%) deaths by 2030, with a total health system cost of A$3.48 billion, A$472 million more than S1 (A$1.65 billion more in testing/treatment but A$1.20 billion less in disease costs; A$5,752 per QALY gained from a health systems perspective). Productivity loss over 2016-2030 was A$19.96 billion, A$6.17 less than S1, making S2 cost-saving from a societal perspective by 2022 with a net economic benefit of A$5.70 billion by 2030. S3 averted an additional 10,000 infections and 930 deaths compared with S2 and increased the longer-term economic benefit. Five years of unrestricted access to DAAs in Australia has led to significant health benefits and is likely to become cost-saving from a societal perspective by 2022. Burnet Institute.


Carbon Monoxide Activates PERK-Regulated Autophagy to Induce Immunometabolic Reprogramming and Boost Antitumor T-cell Function.
Mitochondria and endoplasmic reticulum (ER) share structural and functional networks and activate well-orchestrated signaling processes to shape cells' fate and function. While persistent ER stress (ERS) response leads to mitochondrial collapse, moderate ERS promotes mitochondrial function. Strategies to boost antitumor T-cell function by targeting ER-mitochondria cross-talk have not yet been exploited. Here, we used carbon monoxide (CO), a short-lived gaseous molecule, to test whether engaging moderate ERS conditions can improve mitochondrial and antitumor functions in T cells. In melanoma antigen-specific T cells, CO-induced transient activation of ERS sensor protein kinase R-like endoplasmic reticulum kinase (PERK) significantly increased antitumor T-cell function. Furthermore, CO-induced PERK activation temporarily halted protein translation and induced protective autophagy, including mitophagy. The use of LC3-GFP enabled differentiation between the cells that prepare themselves to undergo active autophagy (LC3-GFPpos) and those that fail to enter the process (LC3-GFPneg). LC3-GFPpos T cells showed strong antitumor potential, whereas LC3-GFPneg cells exhibited a T regulatory-like phenotype, harbored dysfunctional mitochondria, and accumulated abnormal metabolite content. These anomalous ratios of metabolites rendered the cells with a hypermethylated state and distinct epigenetic profile, limiting their antitumor activity. Overall, this study shows that ERS-activated autophagy pathways modify the mitochondrial function and epigenetically reprogram T cells toward a superior antitumor phenotype to achieve robust tumor control. Transient activation of ER stress with carbon monoxide drives mitochondrial biogenesis and protective autophagy that elicits superior antitumor T-cell function, revealing an approach to improving adoptive cell efficacy therapy.


Evaluation of the GlideScope Direct: A New Video Laryngoscope for Teaching Direct Laryngoscopy.
Background. Teaching direct laryngoscopy is limited by the inability of the instructor to simultaneously view the airway with the laryngoscopist. Our primary aim is to report our initial use of the GlideScope Direct, a video-enabled, Macintosh laryngoscope intended primarily as a training tool in direct laryngoscopy. Methods. The GlideScope Direct was made available to anyone who planned on performing direct laryngoscopy as the primary technique for intubation. Novices were those who had performed <30 intubations. Results. The GlideScope Direct was used 123 times as primarily a direct laryngoscope while the instructor viewed the intubation on the monitor. It was highly successful as a direct laryngoscope (93% success). Salvage by indirect laryngoscopy occurred in 7/9 remaining patients without changing equipment. Novices performed 28 intubations (overall success rate of 79%). In 6 patients, the instructor took over and successfully intubated the patient. Instructors used the video images to guide the operator in 16 (57%) of those patients. Seven different instructors supervised the 28 novices, all of who subjectively felt advantaged by having the laryngoscopic view available. Conclusions. The GlideScope Direct functions similarly to a Macintosh laryngoscope and provides the instructor subjective reassurance, while providing the ability to guide the trainee laryngoscopist.


Disease Resistance and Molecular Variations in Irradiation Induced Mutants of Two Pea Cultivars.
Induced mutation is useful for improving the disease resistance of various crops. Fusarium wilt and powdery mildew are two important diseases which severely influence pea production worldwide. In this study, we first evaluated Fusarium wilt and powdery mildew resistance of mutants derived from two elite vegetable pea cultivars, Shijiadacaiwan 1 (SJ1) and Chengwan 8 (CW8), respectively. Nine SJ1 and five CW8 M3 mutants showed resistant variations in Fusarium wilt, and the same five CW8 mutants in powdery mildew. These resistant variations were confirmed in M4 and M5 mutants as well. Then, we investigated the genetic variations and relationships of mutant lines using simple sequence repeat (SSR) markers. Among the nine effective SSR markers, the genetic diversity index and polymorphism information content (PIC) values were averaged at 0.55 and 0.46, which revealed considerable genetic variations in the mutants. The phylogenetic tree and population structure analyses divided the M3 mutants into two major groups at 0.62 genetic similarity (K = 2), which clearly separated the mutants of the two cultivars and indicated that a great genetic difference existed between the two mutant populations. Further, the two genetic groups were divided into five subgroups at 0.86 genetic similarity (K = 5) and each subgroup associated with resistant phenotypes of the mutants. Finally, the homologous PsMLO1 cDNA of five CW8 mutants that gained resistance to powdery mildew was amplified and cloned. A 129 bp fragment deletion was found in the PsMLO1 gene, which was in accord with er1-2. The findings provide important information on disease resistant and molecular variations of pea mutants, which is useful for pea production, new cultivar breeding, and the identification of resistance genes.


Internet-based cognitive behavior therapy vs. cognitive behavioral group therapy for social anxiety disorder: a randomized controlled non-inferiority trial.
Cognitive behavioral group therapy (CBGT) is an effective, well-established, but not widely available treatment for social anxiety disorder (SAD). Internet-based cognitive behavior therapy (ICBT) has the potential to increase availability and facilitate dissemination of therapeutic services for SAD. However, ICBT for SAD has not been directly compared with in-person treatments such as CBGT and few studies investigating ICBT have been conducted in clinical settings. Our aim was to investigate if ICBT is at least as effective as CBGT for SAD when treatments are delivered in a psychiatric setting. We conducted a randomized controlled non-inferiority trial with allocation to ICBT (n=64) or CBGT (n=62) with blinded assessment immediately following treatment and six months post-treatment. Participants were 126 individuals with SAD who received CBGT or ICBT for a duration of 15 weeks. The Liebowitz Social Anxiety Scale (LSAS) was the main outcome measure. The following non-inferiority margin was set: following treatment, the lower bound of the 95 % confidence interval (CI) of the mean difference between groups should be less than 10 LSAS-points. Both groups made large improvements. At follow-up, 41 (64%) participants in the ICBT group were classified as responders (95% CI, 52%-76%). In the CBGT group, 28 participants (45%) responded to the treatment (95% CI, 33%-58%). At post-treatment and follow-up respectively, the 95 % CI of the LSAS mean difference was 0.68-17.66 (Cohen's d between group=0.41) and -2.51-15.69 (Cohen's d between group=0.36) favoring ICBT, which was well within the non-inferiority margin. Mixed effects models analyses showed no significant interaction effect for LSAS, indicating similar improvement across treatments (F=1.58; df=2, 219; p=.21). ICBT delivered in a psychiatric setting can be as effective as CBGT in the treatment of SAD and could be used to increase availability to CBT. ClinicalTrials.gov NCT00564967.


Hominid mandibular remains from Sangiran: 1952-1986 collection.
Eight hominid mandibular and associated dental remains discovered between 1952-1986 from the Early Pleistocene deposits of Sangiran, Central Java, are described. Although the specimens are surface finds, their original stratigraphic positions can be reasonably inferred on the basis of coincidental sources of information. These specimens significantly increase the dento-gnathic sample available for intensive morphological investigation of the earliest Javanese hominids [Kaifu et al., 2005].


An approach to using recombinant erythropoietin for neuroprotection in very preterm infants.
Erythropoietin has been shown to be protective against hypoxic-ischemic and inflammatory injuries in cell culture, animal models of brain injury, and clinical trials of adult humans. The rationale for our study was that early administration of high-dose recombinant human erythropoietin may reduce perinatal brain injury (intraventricular hemorrhage and periventricular leukomalacia) in very preterm infants and improve neurodevelopmental outcome. We investigated whether administration of high-dose recombinant human erythropoietin to very preterm infants shortly after birth and subsequently during the first 2 days is safe in terms of short-term outcome. This was a randomized, double-masked, single-center trial with a 2:1 allocation in favor of recombinant human erythropoietin. Preterm infants (gestational age: 24 to 31 weeks) were given recombinant human erythropoietin or NaCl 0.9% intravenously 3, 12 to 18, and 36 to 42 hours after birth. The percentage of infants who survived without brain injury or retinopathy was 53% in the recombinant human erythropoietin group and 60% in the placebo group. There were no relevant differences regarding short-term outcomes such as intraventricular hemorrhage, retinopathy, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. For 5 infants who were in the recombinant human erythropoietin group and had a gestational age of <26 weeks, withdrawal of intensive care was decided (3 of 5 with severe bilateral intraventricular hemorrhage, 2 of 5 with pulmonary insufficiency); no infant of the control group died. Recombinant human erythropoietin treatment did not result in significant differences in blood pressure, cerebral oxygenation, hemoglobin, leukocyte, and platelet count. No significant adverse effects of early high-dose recombinant human erythropoietin treatment in very preterm infants were identified. These results enable us to embark on a large multicenter trial with the aim of determining whether early high-dose administration of recombinant human erythropoietin to very preterm infants improves neurodevelopmental outcome at 24 months' and 5 years' corrected age.


High viral load in the cerebrospinal fluid and brain correlates with severity of simian immunodeficiency virus encephalitis.
AIDS dementia and encephalitis are complications of AIDS occurring most frequently in patients who are immunosuppressed. The simian immunodeficiency virus (SIV) model used in this study was designed to reproducibly induce AIDS in macaques in order to examine the effects of a neurovirulent virus in this context. Pigtailed macaques (Macaca nemestrina) were coinoculated with an immunosuppressive virus (SIV/DeltaB670) and a neurovirulent molecularly cloned virus (SIV/17E-Fr), and more than 90% of the animals developed moderate to severe encephalitis within 6 months of inoculation. Viral load in plasma and cerebrospinal fluid (CSF) was examined longitudinally to onset of AIDS, and viral load was measured in brain tissue at necropsy to examine the relationship of systemic and central nervous system (CNS) viral replication to the development of encephalitis. In all animals, plasma viral load peaked at 10 to 14 days postinfection and remained high throughout infection with no correlation found between plasma viremia and SIV encephalitis. In contrast, persistent high levels of CSF viral RNA after the acute phase of infection correlated with the development of encephalitis. Although high levels of viral RNA were found in the CSF of all macaques (six of six) during the acute phase, this high level was maintained only in macaques developing SIV encephalitis (five of six). Furthermore, the level of both viral RNA and antigen in the brain correlated with the severity of the CNS lesions. The single animal in this group that did not have CNS lesions had no detectable viral RNA in any of the regions of the brain. The results substantiate the use of CSF viral load measurements in the postacute phase of SIV infection as a marker for encephalitis and CNS viral replication.


Translating the transcriptome into tools for the early detection and prevention of lung cancer.
Despite advances in the management of lung cancer, this disease remains a significant global health burden with survival rates that have not significantly improved in decades. The mortality reduction achieved by low-dose helical CT (LDCT) screening of select high-risk patients is challenged by the high false positive rate of this screening modality and the potential for morbidity associated with follow-up diagnostic evaluation in patients with high risk for iatrogenic complications. The diagnostic dilemma of the indeterminate nodule incidentally identified on diagnostic or screening CT has created a need for reliable biomarkers capable of distinguishing benign from malignant disease. Furthermore, there is an urgent need to develop molecular biomarkers to supplement clinical risk models in order to identify patients at highest risk for having an early stage lung cancer that may derive the greatest benefit from LDCT screening, as well as identifying patients at high-risk for developing lung cancer that may be candidates for emerging chemopreventive strategies. Evolving bioinformatic techniques and the application of these algorithms to analyse the transcriptomic changes associated with lung cancer promise translational discoveries that can bridge these large clinical gaps. The identification of lung cancer associated transcriptomic alterations in readily accessible tissue sampling sites offers the potential to develop early diagnostic and risk stratification strategies applicable to large populations. This review summarises the challenges associated with the early detection, screening and chemoprevention of lung cancer with an emphasis on how genomic information encapsulated by the transcriptome can facilitate future innovations in these clinical settings.


Administration of erythropoietin prevents bone loss in osteonecrosis of the femoral head in mice.
Long‑term administration of glucocorticoid hormones is considered one of predominant pathological factors inducing osteonecrosis of the femoral head (ONFH) development and progression, in which reduction of blood supply leads to a progressive bone loss and impairment of bone structure in the majority of cases. In a non‑hematopoietic system, erythropoietin (EPO) can stimulate angiogenesis and bone regeneration. However, the specific mechanism underlying the role of EPO in ONFH remains to be elucidated. Therefore, the purpose of this study was to determine the effect of EPO on the prevention of bone loss in ONFH. Male C57BL/6J mice 3 months old were divided into two groups: EPO group and control groups. ONFH was established by the administration prednisolone (PDS, 100 mg/kg) with co‑treatment of lipopolysaccharide (LPS, 1 mg/kg). ONFH mice received recombinant mouse EPO (500 U/kg/day) or saline intramuscularly. The mice were sacrificed at 2, 4, 6 and 8 weeks following the initiation of treatment. Alterations in the general architecture and histomorphology of the right femoral head were determined by hematoxylin and eosin staining and micro computed tomography (micro‑CT). The expression of runt‑related transcription factor 2 (Runx2), osteocalcin, vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule (CD31) in the femoral head was tested by immunohistochemistry. Terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling (TUNEL) assay was performed to detect apoptosis in femoral heads. Micro‑CT data revealed that EPO significantly improved bone volume/total volume and bone mineral density following 6 and 8 weeks of treatment. Histological analysis further demonstrated that EPO treatment improved the arrangement of trabeculae, thinning of trabeculae and other fractures in femoral heads, especially following 6 and 8 weeks of treatment. Immunohistochemical analysis suggested that EPO treatment up‑regulated the expressions of Runx2, osteocalcin, VEGF and CD31 at 4 and 8 weeks. The TUNEL apoptosis assay suggested that EPO intervention reduced apoptosis in avascular ONFH. Therefore, EPO prevents bone loss in ONFH in mice through enhancing Runx2‑mediated osteogenesis, VEGF‑mediated angiogenesis and inhibition of cell apoptosis.


New high-resolution computed tomography data of the Taung partial cranium and endocast and their bearing on metopism and hominin brain evolution.
Falk and colleagues [Falk D, Zollikofer CP, Morimoto N, Ponce de León MS (2012) Proc Natl Acad Sci U S A 109(22):8467-8470] hypothesized that selective pressures favored late persistence of a metopic suture and open anterior fontanelle early in hominin evolution, and they put an emphasis on the Taung Child (Australopithecus africanus) as evidence for the antiquity of these adaptive features. They suggested three mutually nonexclusive pressures: an "obstetric dilemma," high early postnatal brain growth rates, and neural reorganization in the frontal cortex. To test this hypothesis, we obtained the first high-resolution computed tomography (CT) data from the Taung hominin. These high-resolution image data and an examination of the hominin fossil record do not support the metopic and fontanelle features proposed by Falk and colleagues. Although a possible remnant of the metopic suture is observed in the nasion-glabella region of the Taung partial cranium (but not along the frontal crest), this character state is incongruent with the zipper model of metopic closure described by Falk and colleagues. Nor do chimpanzee and bonobo endocast data support the assertion that delayed metopic closure in Taung is necessary because of widening (reorganization) of the prefrontal or frontal cortex. These results call into question the adaptive value of delaying metopic closure, and particularly its antiquity in hominin evolution. Further data from hominoids and hominins are required to support the proposed adaptive arguments, particularly an obstetric dilemma placing constraints on neural and cranial development in Australopithecus.


Hepatic plasma flow during sodium nitroprusside-induced hypotension in humans.
Changes in hepatic plasma flow (HPF) during sodium nitroprusside (SNP) induced hypotension were studied in 14 patients undergoing intracranial aneurysm surgery under neurolept anesthesia. Patients were monitored with the use of a radial artery catheter and a thermistor-tipped Swan-Ganz catheter. Hypotension was induced with incremental increases in the rate of SNP infusion until a stable mean arterial pressure (MAP) 35-55 mmHg had been achieved. In one group (Group A) of 10 patients, indocyanine green (ICG) clearance was determined simultaneously with hemodynamic variables, before and during SNP hypotension. In a second group (Group B) of four patients, a catheter was inserted into a hepatic vein to determine the ICG hepatic extraction (HE) coefficient. In Group A, MAP decreased from 73 +/- 10 (SD) to 41 +/- 9 mmHg, while cardiac index (CI) decreased in six patients and increased in four patients. However, the mean value of CI did not change significantly. The mean value of ICG clearance was not significantly affected by SNP hypotension. Nevertheless, a positive linear correlation existed between individual variation in CI and ICG clearance (r = 0.96). On the other hand, no correlation was noted between the change in MAP and ICG clearance. In Group B patients, the ICG HE coefficient remained unchanged during SNP hypotension, suggesting that ICG clearance varies only according to the variation in HPF. In conclusion, this study demonstrated that HPF did not decrease, despite a range of 20-60% decrease in blood pressure when CI is maintained during SNP hypotension.


Bacteria recovered from dental pulp induce apoptosis of lymph node cells.
Apoptosis is critical in the pathogenesis of several infectious diseases. The induction of apoptosis was assessed in mouse lymph node cells by four bacteria recovered from infected human dental pulp: Gemella morbillorum, Clostridium butyricum, Fusobacterium nucleatum and Bifidobacterium adolescentis. Smaller lymph nodes and smaller numbers of cells were observed after experimental dental pulp infection with C. butyricum, suggesting that this bacterium induces cell death. Apoptosis was evaluated by determination of cell ploidy and detection of DNA degradation in cells cultured with killed bacteria. Paraformaldehyde-killed C. butyricum and heat-killed G. morbillorum induced substantial cell death, while F. nucleatum and B. adolescentis induced cell death at lower levels. No bacterial preparations induced apoptosis in cells from mice genetically deficient for tumour necrosis factor receptor p55 (TNFRp55), implicating this receptor directly or indirectly as a mediator in the process. It was concluded that apoptosis may be induced during periapical lesions of pulpal origin.


Mass transport limitations reduce the effective stereospecificity in enzyme-catalyzed kinetic resolution.
[reaction-see text] The kinetic resolution of seudenol catalyzed by Candida antarctica lipase B in hexane was investigated. Large differences in reaction rate and stereospecificity were observed when different enzyme preparations were used. These differences were ascribed to mass transport limitations which reduced both reaction rate and stereospecificity. Lyophilized enzyme preparations were more apt to give this problem than immobilized preparations. Further, low substrate concentrations enhanced the effect. Thus, high alcohol concentrations and enzyme immobilization can be recommended.


The Potential Role of Cardiokines in Heart and Kidney Diseases.
As the engine that maintains blood circulation, the heart is also an endocrine organ that regulates the function of distant target organs by secreting a series of cardiokines. As endocrine factors, cardiokines play an indispensable role in maintaining the homeostasis of the heart and other organs. Here, we summarize some of the cardiokines that have been defined thus far and explore their roles in heart and kidney diseases. Finally, we propose that cardiokines may be a potential therapeutic target for kidney diseases.


Flow-through electrode system (FES): An effective approach for biofouling control of reverse osmosis membranes for municipal wastewater reclamation.
Emerging electrochemical disinfection techniques provide a promising pathway to the biofouling control of reverse osmosis (RO) process. However, the comparative effectiveness and mechanism of it under flow-through conditions with low voltage remains unclear. This study investigated the effect of a flow-through electrode system (FES) with both direct current (DC) and alternating pulse current (AC) on RO biofouling control compared with chlorine disinfection. At the initial stage of biofouling development, the normalized flux of AC-FES (67% on Day 5) was saliently higher than the control group (56% on Day 5). Subsequently, the normalized fluxes of each group tended similarity in their differences until the 20th day. After mild chemical cleaning, the RO membrane in the AC-FES group reached the highest chemical cleaning efficiency of 58%, implying its foulant was more readily removable and the biofouling was more reversible. The biofouling layer in the DC-FES group was also found to be easily cleanable. Morphological analysis suggested that the thickness and compactness of the fouling layers were the major reasons for the fouling behavior difference. The abundance of 4 fouling-related abundant genera (>1%), which were Pseudomonas, Thiobacillus, Sphingopyxis, and Mycobacterium exhibited a salient correlation with the biofouling degree. The operating cost of FES was also lower than that of chlorine disinfection. In summary, AC-FES is a promising alternative to chlorine disinfection in RO biofouling control, as it caused less and easy-cleaning biofouling layer mainly due to two advantages: a) reducing the regrowth potential after disinfection of the bacteria, leading to alleviated initial fouling, (b) reshaping the microbial community to those with weaker biofilm formation capacity.


Acute-on-chronic liver failure: to admit to intensive care or not?
Acute-on-chronic liver failure is used to describe an acute decline in liver function in a patient with existing liver disease combined with other organ failure. Acute-on-chronic liver failure is associated with high short-term mortality, and the greater the number and severity of organ failures, the higher the mortality. The most commonly identified precipitants of acute-on-chronic liver failure include bacterial infection, gastrointestinal haemorrhage, viral hepatitis and recent excessive alcohol intake. Since some of these aetiologies are treatable, organ failure may return to pre-decompensation levels in up to 55% of patients. As a result, a trial of critical care treatment may be appropriate for many of these patients. Clinical scoring tools may help clinicians recognise futility, allowing timely withdrawal of organ support and shifting the focus of care toward palliation.


miR-375 inhibits cell growth and correlates with clinical outcomes in tongue squamous cell carcinoma.
miR-375 has been implicated in various types of cancers. However, its role in tongue squamous cell carcinoma (TSCC) remains unclear. This study aimed to investigate the effects of miR-375 on cell growth and the prognosis of TSCC patients. Using quantitative reverse transcription-polymerase chain reaction, we evaluated miR-375 expression in TSCC samples and TSCC cell lines. The results showed that miR-375 expression was significantly reduced in the TSCC tissues and cell lines. A low level expression of miR-375 in TSCC patients was related to poor of prognosis. Moreover, the effects of miR-375 overexpression on cell proliferation, the cell cycle and the expression of Sp1 and cyclin D1 were examined in TSCC cells. We demonstrated that overexpression of miR-375 significantly inhibited the cell proliferation and cell cycle progression in TSCC cell lines. Overexpression of miR-375 inhibited Sp1 expression by targeting the 3' untranslated region of the Sp1 transcript. The knockdown of Sp1 expression resulted in the subsequent downregulation of cyclin D1. Taken together, our study suggests that miR-375 inhibits the cell growth, and its expression is correlated with clinical outcomes in TSCC.


Real-World Observational Study on the Characteristics and Treatment Patterns of Allergic Asthma Patients Receiving Omalizumab in Canada.
Omalizumab is a treatment option for pediatric and adult patients with moderate to severe allergic asthma poorly controlled with standard inhaled therapies. Clinical trials and observational studies have demonstrated the efficacy of omalizumab. There is limited real-world evidence on the characteristics and treatment patterns of Canadian asthma patients receiving omalizumab. We profiled Canadian omalizumab users to estimate time to omalizumab discontinuation and to assess changes in concurrent medication usage before, during, and after therapy. This was a retrospective, observational, cohort study that analyzed data from Canadian prescription claims databases. An algorithm was used to select naïve users of omalizumab with an inferred diagnosis of GINA 5-asthma who made a claim for omalizumab from February 1, 2007, to June 2, 2015. Demographic and baseline characteristics were assessed at index. Outcomes examined over the analysis period included (i) daily omalizumab dose per patient and per claim; (ii) omalizumab discontinuation (defined as ≥100-day gap in making omalizumab claims) and its potential predictors (ie, age, sex, province of residence, drug insurer; assessed by Cox Proportional Hazards Model); and (iii) for patients who discontinued omalizumab, changes in concurrent medication usage before, during, and 6 months after omalizumab usage. The final study cohort consisted of 1160 patients (mean age: 45.8 ± 15.2 years; 64.7% female). During the first year of omalizumab therapy, 29.5% of patients discontinued treatment. The singular characteristic that predicted omalizumab discontinuation with statistical significance was age group (20‒34 years vs 12‒19 years; hazard ratio 1.75, 95% confidence interval 1.11-2.76; P<0.05). There were significant reductions in the use of some concurrent inhaled and oral asthma medications during and/or after omalizumab use (P<0.05). Nearly one-third of patients who initiated omalizumab in Canada for refractory, moderate to severe allergic asthma discontinued treatment during the first year.


Less is More: A Novel Feature Extraction Method for Heart Sound Classification via Fractal Transformation.
Cardiovascular diseases (CVDs) are the leading cause of death globally. Heart sound signal analysis plays an important role in clinical detection and physical examination of CVDs. In recent years, auxiliary diagnosis technology of CVDs based on the detection of heart sound signals has become a research hotspot. The detection of abnormal heart sounds can provide important clinical information to help doctors diagnose and treat heart disease. We propose a new set of fractal features - fractal dimension (FD) - as the representation for classification and a Support Vector Machine (SVM) as the classification model. The whole process of the method includes cutting heart sounds, feature extraction, and classification of abnormal heart sounds. We compare the classification results of the heart sound waveform (time domain) and the spectrum (frequency domain) based on fractal features. Finally, according to the better classification results, we choose the fractal features that are most conducive for classification to obtain better classification performance. The features we propose outperform the widely used features significantly (p < .05 by one-tailed z-test) with a much lower dimension.Clinical relevance-The heart sound classification model based on fractal provides a new time-frequency analysis method for heart sound signals. A new effective mechanism is proposed to explore the relationship between the heart sound acoustic properties and the pathology of CVDs. As a non-invasive diagnostic method, this work could supply an idea for the preliminary screening of cardiac abnormalities through heart sounds.


Integrative approaches for predicting protein function and prioritizing genes for complex phenotypes using protein interaction networks.
With the rapid development of biotechnologies, many types of biological data including molecular networks are now available. However, to obtain a more complete understanding of a biological system, the integration of molecular networks with other data, such as molecular sequences, protein domains and gene expression profiles, is needed. A key to the use of networks in biological studies is the definition of similarity among proteins over the networks. Here, we review applications of similarity measures over networks with a special focus on the following four problems: (i) predicting protein functions, (ii) prioritizing genes related to a phenotype given a set of seed genes that have been shown to be related to the phenotype, (iii) prioritizing genes related to a phenotype by integrating gene expression profiles and networks and (iv) identification of false positives and false negatives from RNAi experiments. Diffusion kernels are demonstrated to give superior performance in all these tasks, leading to the suggestion that diffusion kernels should be the primary choice for a network similarity metric over other similarity measures such as direct neighbors and shortest path distance.


Isolation and identification of 25-hydroxydihydrotachysterol2 1 alpha,25-dihydroxydihydrotachysterol2 and 1 beta,25-dihydroxydihydrotachysterol2.
Three metabolites of orally administered dihydrotachysterol2 have been isolated in impure form from serum of rats. These metabolites have been identified as 25-hydroxydihydrotachysterol2 and two epimers of formula 1-ambo,25-dihydroxydihydrotachysterol2 by means of gas chromatography-mass spectrometry and ultraviolet absorption spectrometry. For the first time this provides evidence for 9,10-seco steroid hydroxylation at pseudo C3. The stereochemistry of the 1-hydroxyl group of the two epimers could be established tentatively by quantitative comparison of the mass spectra of their respective trimethylsilyl derivatives. Since purity requirements were not achieved, biological activities could not be determined.


Accounting for rate-dependent category boundary shifts in speech perception.
The perception of temporal contrasts in speech is known to be influenced by the speech rate in the surrounding context. This rate-dependent perception is suggested to involve general auditory processes because it is also elicited by nonspeech contexts, such as pure tone sequences. Two general auditory mechanisms have been proposed to underlie rate-dependent perception: durational contrast and neural entrainment. This study compares the predictions of these two accounts of rate-dependent speech perception by means of four experiments, in which participants heard tone sequences followed by Dutch target words ambiguous between /ɑs/ "ash" and /a:s/ "bait". Tone sequences varied in the duration of tones (short vs. long) and in the presentation rate of the tones (fast vs. slow). Results show that the duration of preceding tones did not influence target perception in any of the experiments, thus challenging durational contrast as explanatory mechanism behind rate-dependent perception. Instead, the presentation rate consistently elicited a category boundary shift, with faster presentation rates inducing more /a:s/ responses, but only if the tone sequence was isochronous. Therefore, this study proposes an alternative, neurobiologically plausible account of rate-dependent perception involving neural entrainment of endogenous oscillations to the rate of a rhythmic stimulus.


Strategies for expanding colorectal cancer screening at community health centers.
Community health centers are uniquely positioned to address disparities in colorectal cancer (CRC) screening as they have addressed other disparities. In 2012, the federal Health Resources and Services Administration, which is the funding agency for the health center program, added a requirement that health centers report CRC screening rates as a standard performance measure. These annually reported, publically available data are a major strategic opportunity to improve screening rates for CRC. The Patient Protection and Affordable Care Act enacted provisions to expand the capacity of the federal health center program. The recent report of the Institute of Medicine on integrating public health and primary care included an entire section devoted to CRC screening as a target for joint work. These developments make this the ideal time to integrate lifesaving CRC screening into the preventive care already offered by health centers. This article offers 5 strategies that address the challenges health centers face in increasing CRC screening rates. The first 2 strategies focus on improving the processes of primary care. The third emphasizes working productively with other medical providers and institutions. The fourth strategy is about aligning leadership. The final strategy is focused on using tools that have been derived from models that work.


[Computed tomographic correlates of the cognitive disorders in Parkinson disease].
There were observed of 88 patients with Parkinson's disease. According to data of computer tomography 3 groups of patients were determined: with external type of cerebral atrophy (CA) mainly, with internal type of CA mainly and combined type too. Neuropsychologic study revealed differences among CA types both in degree of manifestation and in character of alteration of high mental functions. Together with neuropsychologic symptoms of the damages of mediobasal structures which were quite characteristic for this disease, there were also revealed the damages of convex cortical areas of frontal, parietal and temporal lobes. Pathologic inertia, inactivity of remembering and impairment of the processes of generalization were found more frequently at internal type of CA. Meanwhile at external CA type both difficulties of learning and disorders of motor programs' control were observed. The obvious correlations were also established between the degree of cognitive alterations and a presence of CA. Moreover, CA type had certain influence mainly on the structure but not on the manifestation of the cognitive disorders.


Tc-99m-Human Serum Albumin Transit Time as a Measure of Arm Breast Cancer-Related Lymphedema.
Lymphoscintigraphy has often been used for evaluating arm lymphatic dysfunction, but no optimal approach for quantification has so far emerged. We propose a quantifiable measure of lymphatic function that we applied in patients treated for breast cancer. Eleven patients, aged 34-68 years, with unilateral arm lymphedema following breast cancer treatment underwent bilateral lymphoscintigraphy using intradermal injection in both hands of technetium-99m-labeled human serum albumin and sequential 5 min imaging for 5 hours. The mean transit time (MTT) in the arms was calculated based on time activity curves generated from injection site and arm regions. Visual lymphedema scoring was performed based on dermal backflow and lymph node presence. Excess arm volume was calculated from circumference measurements. The MTT (mean ± SD) was significantly longer in the lymphedema arm than in the normal arm: 60.1 ± 27.7 versus 5.4 ± 2.5 minutes (mean difference, 54.7 minutes; 95% confidence interval, 36.5-72.9 minutes; P < 0.0001). Patients with previous erysipelas infection had significantly longer MTT than other patients (mean difference, 43.7 minutes; 95% confidence interval, 18.6-68.7 minutes; P < 0.001). There was a positive correlation between MTT and excess arm volume (r = 0.64; P = 0.04) and number of lymph nodes removed (r = 0.65; P = 0.03) but no correlation between visual score and MTT. Measurements of MTT were able to discriminate lymphedema from healthy arm and MTT correlated with relevant markers for lymphedema severity. We encourage further research using the MTT approach for monitoring lymphedema and evaluation of treatment response.


Planes of phenomenological experience: The psychology of deafness as an early example of American Gestalt psychology, 1928-1940.
When, in 1928, the Clarke School for the Deaf in Northampton, Massachusetts, opened a psychological research division, it was nothing unusual in a time fascinated with the sciences of education. Yet with its longstanding ties to Northampton's Smith College, the school was able to secure the collaboration of eminent Gestalt psychologist Kurt Koffka, who, in turn, engaged 2 more German-speaking emigrants, Margarete Eberhardt and social psychologist Fritz Heider, and Heider's American wife Grace Moore Heider. This collaboration has seen little attention from historians, who have treated Koffka's and Heider's time in Northampton as a transitory phase. I argue, however, that their research on deafness adds to the history of emigration and knowledge transfer between European and American Schools of psychology, and to historical understanding of the interrelation of Gestalt, child, and social psychology. Professionals in child studies and developmental psychology were keenly interested in the holistic and introspective approach Gestalt psychology offered. Deaf children were considered a particularly fascinating research population for exploring the relationship between thought and language, perception and development, Gestalt, and reality. At the Clarke School, Grace Moore Heider was among the first Americans to apply Gestalt principles to child psychology. In a time in which pejorative eugenic beliefs dominated professional perceptions of disability, the Heiders' groundbreaking work defined the deaf as a social and phenomenological minority. This was in opposition to dominant beliefs in deaf education, yet it points to early roots of a social model of deafness and disability, which historians usually locate in 1960s and '70s activism. (PsycINFO Database Record


Association between dietary fiber intake and physical performance in older adults: a nationwide study in Taiwan.
Physical performance is a major determinant of health in older adults, and is related to lifestyle factors. Dietary fiber has multiple health benefits. It remains unclear whether fiber intake is independently linked to superior physical performance. We aimed to assess the association between dietary fiber and physical performance in older adults. This was a cross-sectional study conducted with community-dwelling adults aged 55 years and older (n=2680) from the ongoing Healthy Aging Longitudinal Study (HALST) in Taiwan 2008-2010. Daily dietary fiber intake was assessed using a validated food frequency questionnaire. Physical performance was determined objectively by measuring gait speed, 6-minute walk distance, timed "up and go" (TUG), summary performance score, hand grip strength. Adjusting for all potential confounders, participants with higher fiber intake had significantly faster gait speed, longer 6-minute walk distance, faster TUG, higher summary performance score, and higher hand grip strength (all P <.05). Comparing with the highest quartile of fiber intake, the lowest quartile of fiber intake was significantly associated with the lowest sex-specific quartile of gait speed (adjusted OR, 2.18 in men [95% CI, 1.33-3.55] and 3.65 in women [95% CI, 2.20-6.05]), 6-minute walk distance (OR, 2.40 in men [95% CI, 1.38-4.17] and 4.32 in women [95% CI, 2.37-7.89]), TUG (OR, 2.42 in men [95% CI, 1.43-4.12] and 3.27 in women [95% CI, 1.94-5.52]), summary performance score (OR, 2.12 in men [95% CI, 1.19-3.78] and 5.47 in women [95% CI, 3.20-9.35]), and hand grip strength (OR, 2.64 in men [95% CI, 1.61-4.32] and 4.43 in women [95% CI, 2.62-7.50]). Dietary fiber intake was independently associated with better physical performance.


The histone acetyltransferase KAT6A is recruited to unmethylated CpG islands via a DNA binding winged helix domain.
The lysine acetyltransferase KAT6A (MOZ, MYST3) belongs to the MYST family of chromatin regulators, facilitating histone acetylation. Dysregulation of KAT6A has been implicated in developmental syndromes and the onset of acute myeloid leukemia (AML). Previous work suggests that KAT6A is recruited to its genomic targets by a combinatorial function of histone binding PHD fingers, transcription factors and chromatin binding interaction partners. Here, we demonstrate that a winged helix (WH) domain at the very N-terminus of KAT6A specifically interacts with unmethylated CpG motifs. This DNA binding function leads to the association of KAT6A with unmethylated CpG islands (CGIs) genome-wide. Mutation of the essential amino acids for DNA binding completely abrogates the enrichment of KAT6A at CGIs. In contrast, deletion of a second WH domain or the histone tail binding PHD fingers only subtly influences the binding of KAT6A to CGIs. Overexpression of a KAT6A WH1 mutant has a dominant negative effect on H3K9 histone acetylation, which is comparable to the effects upon overexpression of a KAT6A HAT domain mutant. Taken together, our work revealed a previously unrecognized chromatin recruitment mechanism of KAT6A, offering a new perspective on the role of KAT6A in gene regulation and human diseases.


Co-production for the integration of migrant human capital into the decent work.
During the last few years, the mass exodus of Venezuelan citizens to other countries has turned Venezuela into an emigration country, with Peru receiving the second-highest number of migrants. This article explains the co-production process of integrating Venezuelan migrants and refugees into the host society under decent work conditions. This is a qualitative, cross-sectional explanatory case study covering the second half of 2022. It shows that within the co-production effort, civil society organisations entail a role in creating collective mechanisms and spaces to enable communication and information, helping to identify existing problems and vulnerabilities, and finding alternatives to mitigate them. Additionally, in the process of integrating migrants' human capital under the decent work condition there is the relevance of migrant-based civil society organisations, due to the fact that they can enhance trust and the quality of the interaction and dialogue with the beneficiary public, identify their specific needs and potential solutions and, therefore, increase the quality and efficiency of the services provided.


Preventing misdiagnosis in amniotic band sequence: a case report.
Amniotic band sequence (ABS) is an uncommon and heterogeneous congenital disorder caused by entrapment of fetal parts by fibrous amniotic bands, causing distinctive structural abnormalities involving limbs, trunk, and craniofacial regions. The incidence ranges between 1/1200 and 1/15,000 live births, but is higher in stillbirths and previable fetuses. The intrinsic theory attributes the constriction band syndrome as an inherent development defect of embryogenesis while the extrinsic theory proposes that an early amnion rupture is responsible for the adherent bands. It is also suggested that amputations and constriction rings might be due to vascular disturbances. Anomalies resulting from amniotic bands are quite variable and sometimes may simulate chromosomal abnormalities. The authors report a case of a 36-week-gestation male neonate who lived for 29 hours after a vaginal delivery with an Apgar score of 8/9/9. The mother was primipara, and the prenatal was uneventful except for two episodes of urinary tract infections. The newborn examination depicted multiple anomalies characterized by exencephaly, bilateral labial cleft with distorted nostrils and palate cleft. There was also facial skin tag band, exophthalmos with hypoplasia of the eyelids. The limbs showed distal amputation of the fingers in both hands and feet, oligodactyly associated with syndactyly in the left foot, ring constriction in the right leg, the presence of right hyperextension, and clubfoot. The upper limbs showed length discrepancies. Karyotype analysis was normal at 46 XY. The authors conclude that the recognition of the malformations secondary to ABS is important in genetic counseling to prevent misdiagnosis between chromosomal and secondary disruption disorders.


Servo-control for maintaining abdominal skin temperature at 36C in low birth weight infants.
Randomized trials have shown that the neonatal mortality rate of low birth-weight babies can be reduced by keeping them warm. For low birth-weight babies nursed in incubators, warm conditions may be achieved either by heating the air to a desired temperature, or by servo-controlling the baby's body temperature at a desired set-point. In low birth weight infants, to determine the effect on death and other important clinical outcomes of targeting body temperature rather than air temperature as the end-point of control of incubator heating. Standard search strategy of the Cochrane Neonatal Collaborative Review Group. Randomized or quasi-randomized trials which test the effects of having the heat output of the incubator servo-controlled from body temperature compared with setting a constant incubator air temperature. Trial methodologic quality was systematically assessed. Outcome measures included death, timing of death, cause of death, and other clinical outcomes. Categorical outcomes were analyzed using relative risk and risk difference. Meta-analysis assumed a fixed effect model. Compared to setting a constant incubator air temperature of 31.8C, servo-control of abdominal skin temperature at 36C reduces the neonatal death rate among low birth weight infants: relative risk 0.72 (95% CI 0.54, 0.97); risk difference -12.7% (95% CI -1.6, -23.9). This effect is even greater among VLBW infants. During at least the first week after birth, low birth weight babies should be provided with a carefully regulated thermal environment that is near the thermoneutral point. For LBW babies in incubators, this can be achieved by adjusting incubator temperature to maintain an anterior abdominal skin temperature of at least 36C, using either servo-control or frequent manual adjustment of incubator air temperature.


Determinants of Alcohol, Khat, and Bhang Use in Rural Kenya.
The study investigated local determinants of substance use in rural Kenya. Over the years, there has been a growing concern over increased use of substances across ages, gender, religious persuasions, and social class in Kenya. It is still unclear what psychosocial individual and/or community factors might be that offer some explanation for the high levels of alcohol and drug use. The study investigated community members' social status in areas of gender, education, employment, self-esteem, and availability of substances. The sample was comprised of Kenyan rural participants, and included 153 men and 64 women with a mean age of 34.2 years. The participants completed a survey measuring possible psychosocial determinants of alcohol, khat and bhang (i.e., marijuana) use patterns. The sample evidenced high levels of substance use particularly involving the locally available substances (i.e., bottled beer, local brews, chewing khat, smoking bhang). Males in comparison to females were more likely to drink alcohol, chew khat, and smoke bhang. Women compared to men reported higher education and employment status, which were associated with less substance use. Females had higher self-esteem when they did not use bottled beer whereas males had higher self-esteem when they use bottled beer. The implications of these findings are discussed.


Nonlinear approaches for the single-distance phase retrieval problem involving regularizations with sparsity constraints.
The phase retrieval process is a nonlinear ill-posed problem. The Fresnel diffraction patterns obtained with hard x-ray synchrotron beam can be used to retrieve the phase contrast. In this work, we present a convergence comparison of several nonlinear approaches for the phase retrieval problem involving regularizations with sparsity constraints. The phase solution is assumed to have a sparse representation with respect to an orthonormal wavelets basis. One approach uses alternatively a solution of the nonlinear problem based on the Fréchet derivative and a solution of the linear problem in wavelet coordinates with an iterative thresholding. A second method is the one proposed by Ramlau and Teschke which generalizes to a nonlinear problem the classical thresholding algorithm. The algorithms were tested on a 3D Shepp-Logan phantom corrupted by white Gaussian noise. The best simulation results are obtained by the first method for the various noise levels and initializations investigated. The reconstruction errors are significantly decreased with respect to the ones given by the classical linear phase retrieval approaches.


Binding of transition metal ions to albumin: sites, affinities and rates.
Serum albumin is the most abundant protein in the blood and cerebrospinal fluid and plays a fundamental role in the distribution of essential transition metal ions in the human body. Human serum albumin (HSA) is an important physiological transporter of the essential metal ions Cu(2+), and Zn(2+) in the bloodstream. Its binding of metals like Ni(2+), Co(2+), or Cd(2+) can occur in vivo, but is only of toxicological relevance. Moreover, HSA is one of the main targets and hence most studied binding protein for metallodrugs based on complexes with Au, Pt and V. We discuss i) the four metal-binding sites so far described on HSA, their localization and metal preference, ii) the binding of the metal ions mentioned above, i.e. their stability constants and association/dissociation rates, their coordination chemistry and their selectivity versus the four binding sites iii) the methodology applied to study issues of items i and ii and iv) oligopeptide models of the N-terminal binding site. Albumin has four partially selective metal binding sites with well-defined metal preferences. It is an important regulator of the blood transport of physiological Cu(II) and Zn(II) and toxic Ni(II) and Cd(II). It is also an important target for metal-based drugs containing Pt(II), V(IV)O, and Au(I). The thorough understanding of metal binding properties of serum albumin, including the competition of various metal ions for specific binding sites is important for biomedical issues, such as new disease markers and design of metal-based drugs. This article is part of a Special Issue entitled Serum Albumin.


Exotic venomous snakebites in Switzerland reported to the National Poisons Information Centre over 22 years.
The private keeping of exotic venomous snakes is legally permitted in Switzerland. The aim of the present study was to characterise the epidemiological and clinical features of bites by exotic venomous snakes over a period of 22 years in Switzerland. We included all calls related to exotic snakebites recorded at the Swiss National Poisons Information Centre (Tox Info Suisse) from 1997 to 2018. Exclusion criteria comprised indigenous snakes, non-venomous exotic snakes such boas or pythons, clinical courses incompatible with a snakebite or calls from abroad. Follow-up information was graded according to the Poisoning Severity Score. Within the study period, 1,364 calls related to snakebites were recorded at Tox Info Suisse; 148 (11%) cases were attributed to exotic venomous snakes and fulfilled the study criteria. A total of 112 (98%) of 114 patients with medical follow-up information exhibited sufficient causality between exposure and clinical effects. Only adult patients were affected. The median age was 40 years (range 16-71) and the male gender was predominant (n = 136, 92%). Viperidae were involved in 87 (78%) and Elapidae in 25 (22%) patients. Overall, the main affected body part was the hand (89 patients, 79%). In the majority of the patients the clinical course was mild (46, 41%) or moderate (40, 36%), in a lower proportion asymptomatic (6, 5%) or with severe symptoms (20, 18%). No fatalities were reported in the study period. Severe symptoms were observed after elapid bites in six patients (24%) and after viper bites in 14 patients (16%). Besides local effects, neurological disorders after elapid bites and haematological disorders after viper bites were most frequently reported. Antivenom was administered in 24% (27 patients: 18 Viperidae, 21% and 9 Elapidae, 36%; 5 patients (4%) required multiple doses), overall, with good resolution of symptoms. Exotic snakebite is a rare occurrence in Switzerland but has led to medically relevant morbidity, sometimes requiring antivenom treatment. Over half of the envenomed patients required symptomatic or specific treatment. No fatalities or bites in children were reported.