Efficient utilization of EBUS-TBNA samples for both diagnosis and molecular analyses.
The assessment of an increasing number of molecular markers is becoming a standard requirement from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) specimens. However, it is unclear how many needle passes should be performed and the amount of lung cancer cells that should be sent for molecular analyses. The objective of this study was to determine if it is feasible to divide the material obtained by EBUS-TBNA to allow for molecular analysis without compromising the accuracy of mediastinal staging. We aimed to determine if dividing EBUS-TBNA specimens has a negative impact on either histopathological diagnosis or molecular analysis. EBUS-TBNA was performed in 249 enlarged lymph nodes. Negative or ambiguous histopathological results were confirmed by surgical means and clinical follow-up over 6 months. The tissue obtained by EBUS-TBNA was placed onto a glass slide and divided for histopathological workup and molecular analysis. The number of passes was recorded. Both the accuracy of the mediastinal lymph node staging and the applicability of the sample division for molecular analysis were assessed. Each lymph node was punctured an average of 3.18 times and division of the obtained material for diagnosis and molecular analysis was feasible in all cases. The sensitivity and accuracy of the mediastinal lymph node staging were 96.6% and 97.6%, respectively. A cytokeratin (CK)-19-mRNA concentration-based molecular test was feasible in 74.1% of cases. Dividing EBUS-TBNA samples for both histopathological diagnosis and molecular testing is feasible and does not compromise the accuracy of mediastinal staging. This method may be an alternative to taking additional needle passes for molecular analyses.


Elevated serum levels of macrophage migration inhibitory factor are associated with progressive chronic cardiomyopathy in patients with Chagas disease.
Clinical symptoms of chronic Chagas disease occur in around 30% of the individuals infected with Trypanosoma cruzi and are characterized by heart inflammation and dysfunction. The pathogenesis of chronic chagasic cardiomyopathy (CCC) is not completely understood yet, partially because disease evolution depends on complex host-parasite interactions. Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine that promotes numerous pathophysiological processes. In the current study, we investigated the link between MIF and CCC progression.Immunohistochemical analysis demonstrated MIF overexpression in the hearts from chronically T. cruzi-infected mice, particularly those showing intense inflammatory infiltration. We also found that MIF exogenously added to parasite-infected murine macrophage cultures is capable of enhancing the production of TNF-α and reactive oxygen species, both with pathogenic roles in CCC. Thus, the integrated action of MIF and other cytokines and chemokines may account for leukocyte influx to the infected myocardium, accompanied by enhanced local production of multiple inflammatory mediators. We further examined by ELISA the level of MIF in the sera from chronic indeterminate and cardiomyopathic chagasic patients, and healthy subjects. CCC patients displayed significantly higher MIF concentrations than those recorded in asymptomatic T. cruzi-infected and uninfected individuals. Interestingly, increased MIF levels were associated with severe progressive Chagas heart disease, in correlation with elevated serum concentration of high sensitivity C-reactive protein and also with several echocardiographic indicators of left ventricular dysfunction, one of the hallmarks of CCC. Our present findings represent the first evidence that enhanced MIF production is associated with progressive cardiac impairment in chronic human infection with T. cruzi, strengthening the relationship between inflammatory response and parasite-driven pathology. These observations contribute to unravel the elements involved in the pathogenesis of CCC and may also be helpful for the design of novel therapies aimed to control long-term morbidity in chagasic patients.


Willingness to Pay for Select Tick-Borne Disease Prevention Measures in Endemic Areas.
Tick-borne diseases (TBDs) are increasing despite prevention recommendations. We explored whether cost is a barrier to prevention use in Connecticut and Maryland, using a cross-sectional survey. Respondents were queried regarding their willingness to pay for chemical, natural, and rodent-targeted yard pesticide treatments and permethrin-treated clothing. We evaluated associations between demographics, TBD knowledge and attitudes, and willingness to pay for prevention methods. Most respondents would pay for yard treatments (85%); 95% preferring natural pesticide, and 82% would pay for permethrin-treated clothing. Most did not want to pay more than $99 for any of the yard treatments. Having a household income of $100 000 was associated with willingness to pay $100 or more for chemical, natural, or rodent-targeted treatments and $25 or more for permethrin self-treated and pretreated clothing. Yard treatments, especially natural pesticides, were acceptable for TBD prevention; however, current pricing may be cost-prohibitive. Permethrin-treated clothing may be an affordable and acceptable prevention method.


Overexpression of aldo-keto reductase 1C2 as a high-risk factor in bladder cancer.
Intravesical adjuvant chemotherapy and neoadjuvant chemotherapy has been respectively administered for superficial transitional cell carcinoma (TCC) of urinary bladder and advanced TCC for years. However, the therapeutic efficacy is limited. Recently, overexpression of aldo-keto reductase (AKR) in lung, esophageal, uterine cervical and ovarian cancers was shown to be closely associated with disease progression and drug resistance. In this study, we used immunohistochemistry to determine AKR expression in pathological specimens of 347 patients with urinary bladder cancer (UBC). Some of these patients were from areas with a high risk of black foot disease (BFD), a disease that is closely associated with arsenic contamination of drinking water. The presence of AKR was confirmed by immunoblotting, matrix-assisted laser desorption/ ionization time of flight mass spectrometry (MALDI-TOF) and reverse transcription-polymerase chain reaction (RT-PCR). AKR isotype was determined by cDNA sequencing. Our results showed overexpression of AKR1C2 in 226 (65.1%) patients. BFD areas had a higher frequency of patients expressing AKR1C2 in UBC. Among AKR1C2-positive UBC, 148 (65.5%) were invasive, 70 (31.0%) were non-invasive and 8 (3.5%) were carcinoma in situ (CIS). These data indicated that AKR1C2 expression could be significantly associated with cancer invasiveness (p<0.001) and disease progression. Because BFD has been closely related to arsenic ingestion, our results suggested that continual intake of arsenic in drinking water might provoke AKR1C2 expression that could in turn induce drug resistance in UBC, and AKR1C2 could be a tumor marker for UBC.


Students with mental illnesses in a university setting: faculty and student altitudes, beliefs, knowledge, and experiences.
Over the last decade, the topic of post-secondary supported education for people with severe and persistent mental illnesses has gained increasing attention and sparked interest in what colleges and universities can do to assist individuals with mental illnesses to achieve their educational goals. The purpose of this article is to discuss the issue and describe one university's strategy for improving the educational environment of students with psychiatric disabilities. We present findings from a survey designed to assess faculty and student attitudes, beliefs, knowledge, and experiences with students identified as having a mental illness.


PRDM8 internal promoter hyperhydroxymethylation correlates with increased expression of the corresponding transcript in Down syndrome.
Down syndrome (DS) is the most common form of intellectual disability associated with central nervous system abnormalities and results from an extra complete or partial copy of human chromosome 21. However, whether DNA hydroxymethylation is perturbed in a specific gene associated with DS phenotypes, or the alteration of DNA hydroxymethy-lation results in changes of gene expression in DS remains unidentified. The current study mapped 5‑methylcytosine and 5‑hydroxymethylcytosine at CpG islands of the PR domain containing 8 (PRDM8) in the peripheral blood of 16 DS and 19 normal samples by oxidative bisulfite-pyrosequencing. Furthermore, the association of the expression levels of the two transcripts and epigenetic modification in different genomic contexts of PRDM8 was analyzed. The results demonstrated hypermethylation and hyperhydroxymethylation at the internal promoter of PRDM8 in DS, and significantly increased the expression of PRDM8 transcript variant 2 in the DS patients (median 3.9 vs. 2.04; P=0.016), accompanied by a positive correlation between the expression of two PRDM8 transcripts and hydroxymethylation at the corresponding external and internal promoters in patients, although not in the controls. A similar association was observed between the expression of transcript variant 1 and intragenic methylation of PRDM8. Taken together, the results of the present study suggest a critical role for DNA hydroxymethylation and methylation in regulating abnormal PRDM8 overexpression in DS.


Local excision for rectal carcinoma.
Local excision is an alternative approach to radical proctectomy for rectal cancer, but from an oncologic standpoint, it is a compromise, and its role remains controversial. Careful patient selection is essential because local excision is generally considered only for early rectal cancer with no evidence of nodal metastasis, parameters that can be predicted by clinical examination, and various radiologic modalities with variable accuracy. In this review, we present the literature evaluating the oncologic adequacy of local excision, including transanal endoscopic microsurgery and the results of salvage surgery after local excision. An overview of local excision in the context of perioperative adjuvant therapies is included. Finally, we suggest a treatment algorithm for local excision in rectal cancer.


Reactivation of herpes simplex viral keratitis following the botulinum toxin injection.
We describe a case of 55-year-old male farmer presented with recurrent corneal abrasions with a spastic entropion in the left eye. Superior cornea showed typical nummular opacities suggestive resolved herpetic eye diseases. On further enquiry, he had similar episodes in the past. Contralateral eye was essentially normal. Following the botulinum toxin injection for the management of spastic entropion, subject developed reactivation of herpetic necrotizing stromal keratitis. Diagnostic corneal scrapings were negative for herpes simplex virus-1 antigen by immunofluorescence assay and for DNA by molecular techniques. The case was successfully managed with topical steroids and antiviral medications.


Functional amyloids in bacteria.
The term amyloidosis is used to refer to a family of pathologies altering the homeostasis of human organs. Despite having a name that alludes to starch content, the amyloid accumulations are made up of proteins that polymerize as long and rigid fibers. Amyloid proteins vary widely with respect to their amino acid sequences but they share similarities in their quaternary structure; the amyloid fibers are enriched in β-sheets arranged perpendicular to the axis of the fiber. This structural feature provides great robustness, remarkable stability, and insolubility. In addition, amyloid proteins specifically stain with certain dyes such as Congo red and thioflavin-T. The aggregation into amyloid fibers, however, it is not restricted to pathogenic processes, rather it seems to be widely distributed among proteins and polypeptides. Amyloid fibers are present in insects, fungi and bacteria, and they are important in maintaining the homeostasis of the organism. Such findings have motivated the use of the term "functional amyloid" to differentiate these amyloid proteins from their toxic siblings. This review focuses on systems that have evolved in bacteria that control the expression and assembly of amyloid proteins on cell surfaces, such that the robustness of amyloid proteins are used towards a beneficial end.


Osteoporosis guideline awareness among Iranian family physicians: results of a knowledge, attitudes, and practices survey.
AimThis study investigates the knowledge, attitudes, and practices (KAP) of family physicians in Iran, regarding osteoporosis and their experience with national osteoporosis guideline. Osteoporosis is a relatively preventable, chronic and progressive disease. Family physicians play a crucial role in relieving the burden of care. This cross-sectional study was addressed at all qualified family physicians who registered at urban family physicians and referral system program. Data collection included demographics, professional experience, and knowledge of guidelines based on a standardized KAP questionnaire. Student's t-test was used to measure the associations between KAP scores and demographic, professional experience variables.FindingsThe response rate was 72% (540/750). Based on Bloom's cut off scale, family physicians knowledge and practice scores were in moderate level, and only 14 and 38.5% of them had good knowledge and practice, respectively. Attitude score was in good level, and 64.1% of participants had positive attitude. Mean score of knowledge and practice were higher significantly among family physicians that practice in public settings. Family physicians, who completed osteoporosis training courses, had higher attitude score (P=0.03). Only 23.5% of family physicians were aware of the existence of national osteoporosis guideline. Although most family physicians believed in the importance of preventive measures, however, limited number of them had good knowledge and practice regarding osteoporosis and less than a quarter were aware of national guideline. This is a clear need to disseminate the guideline more effectively, make greater use of efficient training methods.


Biobeds for environmental protection from pesticide use--a review.
Biobeds originated in Sweden in response to the need for simple and effective methods to minimize environmental contamination from pesticide use, especially when filling spraying equipment, a typical point source of contamination. The biobed system has attracted attention in several countries, where work is being conducted to adapt it to local conditions and applications. As a consequence, the biobed system has been more or less modified and sometimes renamed, for example, as biomassbed in Italy, biofilter in Belgium, and Phytobac and biobac in France. The effectiveness and simplicity of the biobed also make it suitable for use in developing countries, and different adaptations of the biobed concept now exist in, for instance, Peru, Guatemala, and Ecuador. When the modification of the biobed includes an intention to use it for retention and degradation of pesticides in sprayer washings, the construction has to be adapted to, for example, lined biobeds to ensure that no pesticide leaching will occur. Replacement of some of the original materials in the Swedish biomixture (straw, peat, and soil) can also change the performance of the system, for instance, the amount, activity, and composition of the microbial community that develops. This review presents the state of the art of biobeds and similar systems in Sweden and worldwide and identifies future research needs. Factors affecting the efficiency of biobeds in terms of degradation and retention of pesticides are discussed, with particular emphasis on the microbial processes involved.


Peri-operative transfusion risk in classic bladder exstrophy closure: Results from a national database review.
Classic bladder exstrophy (CBE) is one of the most complex pediatric urologic conditions, with patients often requiring multiple procedures throughout their lives. Patients undergoing these complex surgeries may require blood transfusion, exposing them to the risks of transfusion including antibody reactions, transmission of infectious diseases, and transfusion-related immunomodulation. We sought to determine the prevalence of and risk factors for peri-operative transfusion in patients undergoing closure for CBE. Because of the complexity of CBE management, we hypothesized that a significant number of patients undergoing closure of CBE would require peri-operative transfusion. Patients undergoing CBE closure between 2012 and 2014 were retrospectively identified by Current Procedure Terminology codes from The National Surgical Quality Improvement Program Pediatric database, which includes data from 64 participating hospitals. Patient demographics, pre-operative characteristics including comorbidities, intra-operative characteristics, and post-operative outcomes were analyzed for associations with transfusion requirement intra-operatively or in the first 72 h post-operatively. Seventy-eight patients met our criteria, of whom 45 (57.7%) underwent transfusion. Patient characteristics and outcomes are noted in the Table. There was no difference between the groups in terms of age or gender. Patients who underwent transfusion were more likely to be over 3 days of age than those who did not (93.3% versus 75.8%; p = 0.046). Transfused patients were also more likely to have undergone osteotomy (82.2% versus 48.5%; p = 0.002), had an external fixation (46.7% versus 6.1%; p < 0.001), had longer median operative times (447 versus 295 min; p < 0.001), and had longer median post-operative lengths of stay (LOS) (35 versus 17 days; p = 0.003). There was no difference between the groups in terms of pre-operative risk factors or post-operative complications. A significant number of patients undergoing CBE closure required transfusion in the peri-operative period (57.7%). Patient characteristics found to have a higher rate of transfusion included osteotomy, external fixation, increased operative times, and longer post-operative LOS. In children undergoing closure for CBE, a large number require transfusion. The rate of transfusion is greater in older children and children undergoing osteotomy. Although osteotomy has a potentially important clinical role, especially in older patients, this study emphasizes the need for proper family counseling to include the increased likelihood of a blood transfusion and the risks associated with blood transfusion if osteotomies are performed.


[Injectable hydrogel functionalised with thrombocyte-rich solution and microparticles for accelerated cartilage regeneration].
Articular cartilage defects arise due to injury or osteochondral disease such as osteonecrosis or osteochondritis dissecans. In adult patients cartilage has minimal ability to repair itself and the lesions develop into degenerative arthritis. Overcoming the low regenerative capacity of the cartilage cells and the Hayflick limit poses a challenge for the therapy of osteochondral defects. Composite scaffolds with appropriate biomechanical properties combined with a suitable blend of proliferation and differentiation factors could be a solution. The aim of this in vitro study was to develop a novel functionalised hydrogel with an integrated drug delivery system stimulating articular cartilage regeneration. Injectable collagen/ hyaluronic acid/fibrin composite hydrogel was mixed with nanofibre-based microparticles. These were loaded with ascorbic acid and dexamethasone. In addition, the effect of thrombocyte-rich solution (TRS) was studied. The gels seeded with mesenchymal stem cells (MSCs) were cultivated for 14 days. The viability, proliferation and morphology of the cells were evaluated using molecular and microscopic methods. Scaffold degradation was also assessed. The cultivation study showed that MSCs remained viable in all experimental groups, which indicated good biocompatibility of the gel. However, the number of cells in the groups enriched with microparticles was lower than in the other groups. On the other hand, confocal microscopy showed higher cell viability and rounded morphology of the cells, which can be associated with chodrogenic differentiation. The scaffolds containing microparticles showed significantly higher stability during the 14-day experiment. Our results suggest that the addition of microparticles to the scaffold improved cell differentiation into the chondrogenic lineage, resulting in a lower proliferation rate. Cell viability was better in the groups enriched with microparticles that served as an efficient drug delivery system. In addition, the presence of microparticles slowed down gel degradation which can help achieve sufficient stability of the system for the time frame required for cartilage regeneration. The novel approach described here produced an efficient system where microparticles served as a drug delivery system and stabilised the gel for prolonged periods of time. These characteristics play an important role in the development of scaffolds for cartilage regeneration. In the future the results of these in vitro experiments will be verified in an in vivo study.


Thiopurine methyltransferase activity in a French population: h.p.l.c. assay conditions and effects of drugs and inhibitors.
1. Thiopurine methyltransferase (TPMT) is a cytosolic enzyme involved in the catabolism of thiopurine drugs, which are used to treat cancer patients and organ transplant recipients. Because TPMT activity is polymorphic and under genetic control, large interindividual variations in the immunosuppressive activity and toxicity of these drugs may, at least in part, be inherited. 2. We have developed a specific h.p.l.c. method for measuring 6-methyl mercaptopurine formed from 6-mercaptopurine (6-MP) in red blood cell lysates during the TPMT assay procedure. In blinded assays of 55 samples from adult blood donors, the results of the h.p.l.c. method correlated with those of the radiochemical reference method (r = 0.83, P < 0.001). 3. Using this h.p.l.c. assay, we tested the effect of known inhibitors of TPMT activity (syringic acid, p-anisic acid and tropolone) in vitro and showed that they were highly inhibitory. We also found that drugs often administered concomitantly with 6-MP (prednisone, prednisolone, 6-methylprednisolone, cyclophosphamide, methotrexate, and trimethoprim-sulphamethoxazole) had little or no effect on TPMT activity in vitro. 4. In a group of 300 French individuals, TMPT activity was highly variable, ranging from 4.7 to 35.3 nmol h-1 ml-1 of packed red blood cells (nmol h-1 ml-1 PRBC) with a mean value of 19.3 +/- 4.9. TMPT activity was not influenced by sex. 5. This sensitive and reproducible h.p.l.c. assay for TPMT activity in red blood cells may prove useful for prospective clinical studies designed to optimise dosage regimens of thiopurine drugs (detection limit for 6-methyl mercaptopurine is 5 ng ml-1, intra- and inter-assay variations are 6.8 and 8.2%, respectively).


Toothache: an unlikely presentation of secondary breast malignancy.
An 81-year-old female presented to the maxillo-facial department with a 6-month history of left-sided toothache and upper lip and cheek numbness. She had previously undergone a right mastectomy for breast adenocarcinoma, followed 6 years later by left mastectomy with pneumonectomy for contralateral breast and lung metastases. Following buccal biopsies and MRI of the head and neck, the patient was referred to our head and neck team. The MRI showed a large left maxillary sinus mass and transnasal endoscopic biopsies under general anaesthesia of this confirmed distant breast carcinoma metastasis. The patient was discussed at the Head and Neck Multidisciplinary Team meeting. Further surgical resection was not thought appropriate and the patient has subsequently undergone curative dose radiotherapy to the face. She remains alive with symptom control 8 months following this presentation.


[Mortality and risk factors for non-communicable diseases in Russia: Specific features, trends, and prognosis].
In the Russian Federation, the increase in all-cause and cardiovascular disease mortality began in the 1960s and lasted almost continuously until 2003. In our country, the characteristics of mortality are its substantially higher rates among men and a large regional variability, which is associated with economic, climatic, and geographic factors. Urbanization coupled with dietary changes and the higher prevalence of hypertension is the most likely initial impetus to the rise in mortality rates. The subsequent increase in mortality can be explained by the higher prevalence of behavioral and biological risk factors, alcoholism, and, since the 1990s, by heavy and protracted socioeconomic upheavals and lifestyle changes. The mortality decline since 2006 has been linked to the strengthening of the health system and to the reduction in the prevalence of smoking among men and hypertension in women. The slowing down of the pace of mortality decline may be due to the increase in the prevalence of hypertension and obesity among men. The modelling data show that by 2025, reductions in smoking prevalence rates by 23% among men and by 12% among women and increases in the efficiency of hypertension treatment by 17.2% in men and by 11.2% in women will reduce cardiovascular mortality rates by 15%.


Phase diagrams for three-strategy evolutionary prisoner's dilemma games on regular graphs.
Evolutionary prisoner's dilemma games are studied with players located on square lattice and random regular graph defining four neighbors for each one. The players follow one of the three strategies: tit-for-tat, unconditional cooperation, and defection. The simplified payoff matrix is characterized by two parameters: the temptation b to choose defection and the cost c of inspection reducing the income of tit-for-tat. The strategy imitation from one of the neighbors is controlled by pairwise comparison at a fixed level of noise. Using Monte Carlo simulations and the extended versions of pair approximation we have evaluated the b-c phase diagrams indicating a rich plethora of phase transitions between stationary coexistence, absorbing, and oscillatory states, including continuous and discontinuous phase transitions. By reasonable costs the tit-for-tat strategy prevents extinction of cooperators across the whole span of b determining the prisoner's dilemma game, irrespective of the connectivity structure. We also demonstrate that the system can exhibit a repetitive succession of oscillatory and stationary states upon changing a single payoff value, which highlights the remarkable sensitivity of cyclical interactions on the parameters that define the strength of dominance.


MRI and in vivo proton spectroscopy of the lesions of the globe.
MRI proved very valuable in the diagnosis of intraocular lesions. In this report, uveal melanomas, the most common intraocular tumors in adults, were seen as hyperintense lesions on T1W and PW images and as hypointense lesions on T2W images. MRI is not accurate for diagnosis when the melanoma is smaller than 3 mm. Associated retinal detachment as well as necrotic or hemorrhagic changes within the uveal melanoma can be identified by MRI. Choroidal metastasis may be difficult to differentiate from uveal melanoma. Choroidal hemangioma and hematoma often can be differentiated from uveal melanoma. Early experience with in vivo proton MR spectroscopy has the potential for obtaining biochemical information, thus enhancing the diagnostic sensitivity of MR studies. Future work on combined MRI with MR in vivo spectroscopy is needed to characterize abnormal conditions according to their patterns and for identification of tumor markers. A differential diagnosis list for ocular (globe) lesions can be found in the introduction to this issue. A discussion of the majority of the ocular lesions listed can be found in either this article or the article on congenital/pediatric lesions (Hopper et al) of the orbit, also in this issue.


Substitution of the Walker A lysine by arginine in the nucleotide-binding domains of sulphonylurea receptor SUR2B: effects on ligand binding and channel activity.
Sulphonylurea receptors (SURs) serve as regulatory subunits of ATP-sensitive K(+) channels. SURs are members of the ATP-binding cassette (ABC) protein superfamily and contain two conserved nucleotide-binding domains (NBDs) which bind and hydrolyse MgATP; in addition, they carry the binding sites for the sulphonylureas like glibenclamide (GBC) which close the channel and for the K(ATP) channel openers such as P1075. Here we have exchanged the conserved Lys in the Walker A motif by Arg in both NBDs of SUR2B, the regulatory subunit of the vascular K(ATP) channel. Then the effect of the mutation on the ATPase-dependent binding of GBC and P1075 to SUR2B and on the activity of the recombinant vascular (Kir6.1/SUR2B) channel was assessed. Surprisingly, in the absence of MgATP, the mutation weakened binding of P1075 and the extent of allosteric inhibition of GBC binding by P1075. The mutation abolished most, but not all, of the MgATP effects on the binding of GBC and P1075 and prevented nucleotide-induced activation of the channel which relies on SUR reaching the posthydrolytic (MgADP-bound) state; the mutant channel was, however, opened by P1075 at higher concentrations. The data provide evidence that mutant SUR2B binds MgATP but that the posthydrolytic state is insufficiently populated. This suggests that the mutation locks SUR2B in an MgATP-binding prehydrolytic-like state; binding of P1075 may induce a posthydrolytic-like conformation to open the channel.


Cerebral childhood and adolescent X-linked adrenoleukodystrophy. Clinical presentation, neurophysiological, neuroimaging and biochemical investigations.
Clinical, neurophysiological, neuroimaging and biochemical studies were performed in five boys with childhood and adolescent form of cerebral X-ALD, which is a very rare disease in developmental age. In all patients, rapidly progressive spasticity, ataxia and mental deterioration were found. Seizures occurred in four of them. Additionally, visual and hearing impairment were observed in four and three patients respectively. Adrenal insufficiency was also diagnosed in four cases. MR revealed extensive demyelination located mainly symmetrically in the parieto-occipital areas, in one patient in whom asymmetrical lesions in that region were found. All patients had abnormal visual, brainstem and somatosensory evoked potentials recording, reflecting the central demyelination occurring in X-ALD. The clinical diagnosis in every case was confirmed by the significantly elevated concentration of very long chain fatty acids (VLCFA) measured in plasma in comparison to normal values.


Juvenile myoclonic epilepsy--a generalized epilepsy syndrome?
Juvenile myoclonic epilepsy (JME) has been classified as a syndrome of idiopathic generalized epilepsy and is characterized by specific types of seizures, showing a lack of pathology using magnetic resonance imaging (MRI) and computed tomography scanning. However, JME is associated with a particular personality profile, and behavioral and neuropsychologic studies have suggested the possible involvement of frontal lobe dysfunction. The development of highly sensitive neuroimaging techniques has provided a means of elucidating the underlying mechanisms of JME. For example, positron emission tomography has demonstrated neurotransmitter changes in the cerebral cortex, quantitative MRI has revealed significant abnormalities of cortical gray matter in medial frontal areas, and 1H-magnetic resonance spectroscopy has shown evidence of thalamic dysfunction, which appears to be progressive. Such techniques provide evidence of multi-focal disease mechanisms, suggesting that JME is a frontal lobe variant of a multi-regional, thalamocortical 'network' epilepsy, rather than a generalized epilepsy syndrome.


Comparison of Diagnostic Efficacy among Transvaginal Sonography, Transabdominal Sonography, and 3.0 T Magnetic Resonance Imaging in Early Cesarean Scar Pregnancy.
To compare the diagnostic efficacy among transvaginal sonography (TVS), transabdominal sonography (TAS), and 3.0 T magnetic resonance imaging (MRI) in early cesarean scar pregnancy (CSP). The clinical data of 65 patients initially diagnosed with CSP in our hospital from November 2019 to November 2020 were selected for the retrospective analysis, and all patients received TVS, TAS, and 3.0 T MRI. Taking the pathological findings as the "gold standard", the diagnostic efficacy of different diagnostic modalities in early CSP was compared. In terms of the AUC value, the result was 3.0 T MRI > TVS > TAS, and among the three diagnosis methods, 3.0 T MRI had the highest diagnostic specificity, and TVS and 3.0 T MRI had the highest sensitivity; other than intragestational hemorrhage, the detection rates of other signs of disease by TVS and TAS were significantly higher than 3.0 T MRI (P < 0.05). 3.0 T MRI has better diagnostic efficacy in early CSP than TVS and TAS, while TVS and TAS work better in diagnosing uterine bleeding, plumule, yolk sac, and fetal heartbeat than 3.0 T MRI. The results are more beneficial to the guidance on selecting treatment modalities.


Factor IXa as a target for pharmacologic inhibition in acute coronary syndrome.
Anticoagulant therapy, combined with platelet-directed inhibitors, represents a standard-of-care in the management of patients with acute coronary syndrome, particularly those who require percutaneous coronary interventions. While a vast clinical experience, coupled with large clinical trials have collectively provided guidance, an optimal anticoagulant drug and applied strategy, defined as one that reduces thrombotic and hemorrhagic events consistently, with minimal off-target effects and active control of systemic anticoagulation according to patient and clinical-setting specific need, remains at large. An advancing knowledge of coagulation, hemostasis, and thrombosis suggests that factor IXa, a protease that governs thrombin generation in common thrombotic disorders may represent a prime target for pharmacologic inhibition.


Positive peer pressure: the effects of peer monitoring on children's disruptive behavior.
Classroom peers can serve as powerful sources of reinforcement in increasing or maintaining both the positive and negative behaviors of their classmates. In two experiments, we examined the effectiveness of a peer-monitored token system on reducing disruption and nonparticipation during a transition period of a kindergarten class for behaviorally impaired children. Additionally, the effect of providing and subsequently withholding corrective feedback to peer mediators on the accuracy of their point awards was evaluated. Results in Experiment 1 suggest that both teacher- and peer-monitored interventions were successful in decreasing disruption and increasing participation of monitored peers. Experiment 2 further demonstrated that peer monitors could successfully initiate the token system without prior adult implementation. Analysis of the point awards in both experiments indicates that peer monitors consistently awarded points that were earned. However, when corrective feedback was withdrawn the peer monitors frequently awarded points that were not earned, i.e., they rarely withheld points for undesirable behavior. Even so, the monitored peers' disruptive behavior was maintained at low rates.


Star-pseudopolyrotaxane organized in nanoplatelets for poly(ε-caprolactone)-based nanofibrous scaffolds with enhanced surface reactivity.
Herein, it is demonstrated that star pseudopolyrotaxanes (star-pPRs) obtained from the inclusion complexation of α-cyclodextrin (CD) and four-branched star poly(ε-caprolactone) (star-PCL) organize into nanoplatelets in dimethyl sulfoxide at 35 °C. This peculiar property, not observed for linear pseudopolyrotaxanes, allows the processing of star-pPRs while preserving their supramolecular assembly. Thus, original PCL:star-pPR core:shell nanofibers are elaborated by coaxial electrospinning. The star-pPR shell ensures the presence of available CD hydroxyl functions on the fiber surface allowing its postfunctionalization. As proof of concept, fluorescein isothiocyanate is grafted. Moreover, the morphology of the fibers is maintained due to the star-pPR shell that acts as a shield, preventing the fiber dissolution during chemical modification. The proposed strategy is simple and avoids the synthesis of polyrotaxanes, i.e., pPR end-capping to prevent the CD dethreading. As PCL is widely used for biomedical applications, this strategy paves the way for simple functionalization with any bioactive molecules.


Prevalence of accessory septations of sphenoid sinus in pediatric population: Applications to endoscopic sinus surgery.
Sphenoid sinus accessory septations and their possible insertion on internal carotid artery (ICA) may represent a risk for endoscopic sinus surgical procedures. However, scarce data on this variant for children are available so far. This retrospective study included 220 maxillofacial CT-scans equally divided among males (13.4 ± 2.1 years) and females (13.9 ± 2.2 years). On each CT-scan, prevalence of accessory septations, number of septations in sphenoid sinuses, and their possible insertion onto ICA bone walls were recorded. Significant differences in protrusion and insertion of septations onto the ICA bone walls according to sex were assessed through Chi-square test (p < .05). Possible correlations between the prevalence of accessory septations, ICA insertion, and number of accessory septations and age were assessed by means of Pearson's regression (p < .05). On average, 66% of males and 71% of females had at least one accessory septation, without significant differences according to sex or age (p > .05): septal insertion on ICA was found in 13% of subjects, without any significant difference for sex or age (p > .05). The number of septations was significantly increased with age (p < .05). The present study showed that the prevalence of accessory septations and insertion onto the ICA are independent of age and these results are similar to those reported in adults. Results will be useful for the management of endoscopic sinus surgery.


De-noising with a SOCK can improve the performance of event-related ICA.
Event-related ICA (eICA) is a partially data-driven analysis method for event-related fMRI that is particularly suited to analysis of simultaneous EEG-fMRI of patients with epilepsy. EEG-fMRI studies in epileptic patients are typically analyzed using the general linear model (GLM), often with assumption that the onset and offset of neuronal activity match EEG event onset and offset, the neuronal activation is sustained at a constant level throughout the epileptiform event and that associated fMRI signal changes follow the canonical HRF. The eICA method allows for less constrained analyses capable of detecting early, non-canonical responses. A key step of eICA is the initial deconvolution which can be confounded by various sources of structured noise present in the fMRI signal. To help overcome this, we have extend the eICA procedure by utilizing a fully standalone and automated fMRI de-noising procedure to process the fMRI data from an EEG-fMRI acquisition prior to running eICA. Specifically we first apply ICA to the entire fMRI time-series and use a classifier to remove noise-related components. The automated objective de-noiser, "Spatially Organized Component Klassificator" (SOCK) is used; it has previously been shown to distinguish a substantial fraction of noise from true activation, without rejecting the latter, in resting-state fMRI. A second ICA is then performed, this time on the event-related response estimates derived from the denoised data (according to the usual eICA procedure). We hypothesize that SOCK + eICA has the potential to be more sensitive than eICA alone. We test the effectiveness of SOCK by comparing activation obtained in an eICA analysis of EEG-fMRI data with and without the use of SOCK for 14 patients with rolandic epilepsy who exhibited stereotypical IEDs arising from a focus in the rolandic fissure.


Nanomaterial applications for neurological diseases and central nervous system injury.
The effectiveness of noninvasive treatment for neurological disease is generally limited by the poor entry of therapeutic agents into the central nervous system (CNS). Most CNS drugs cannot permeate into the brain parenchyma because of the blood-brain barrier thus, overcoming this problem has become one of the most significant challenges in the development of neurological therapeutics. Nanotechnology has emerged as an innovative alternative for treating neurological diseases. In fact, rapid advances in nanotechnology have provided promising solutions to this challenge. This review highlights the applications of nanomaterials in the developing neurological field and discusses the evidence for their efficacies.


In vitro cyclic tensile testing of combined peripheral and core flexor tenorrhaphy suture techniques.
Early tenorrhaphy mobilization increases repair site strength and decreases adhesions. Preliminary unpublished data suggest that early active mobilization improves clinical outcome compared with traditional passive motion protocols. We loaded cadaver flexor profundus tendon repairs to 8.0 kg (78.4 N) for up to 5,000 cycles to simulate the loads and cycle number of our active flexor tendon rehabilitation protocol. 3-0 Ethibond (Ethicon, Somerville, NJ) and 6-0 Prolene (Surgi-pro; US Surgical, Norwalk, CT) were used for core and peripheral sutures, respectively. Four different groups were tested: 2-strand Tajima core suture with either a running interlocking (2R) or a Silfverskiöld cross-stitch (2S) peripheral suture and 4-strand Tajima plus horizontal mattress core suture with either a running interlocking (4R) or a Silfverskiöld peripheral suture (4S). Repairs failed in the suture midsubstance or at the knot. There was considerable variability within groups and no significant difference in the number of cycles to failure between the 2R, 4R, and 2S repairs, which failed after 2 +/- 2, 304 +/- 249, and 560 +/- 987 cycles, respectively. All 4S repairs were intact after 5,000 cycles. Our data suggest that flexor tenorrhaphy with the 4S repair can withstand the cyclic loads we estimate would be present during an active rehabilitation protocol.


Environmental impact assessment of a package type IFAS reactor during construction and operational phases: a life cycle approach.
In the present study, a life cycle assessment (LCA) approach was used to analyse the environmental impacts associated with the construction and operational phases of an integrated fixed-film activated sludge (IFAS) reactor treating municipal wastewater. This study was conducted within the boundaries of a research project that aimed to investigate the implementation related challenges of a package type IFAS reactor from an environmental perspective. Along with the LCA results of the construction phase, a comparison of the LCA results of seven operational phases is also presented in this study. The results showed that among all the inputs, the use of stainless steel in the construction phase caused the highest impact on environment, followed by electricity consumption in raw materials production. The impact of the construction phase on toxicity impact indicators was found to be significant compared to all operational phases. Among the seven operational phases of this study, the dissolved oxygen phase III, having a concentration of ∼4.5 mg/L, showed the highest impact on abiotic depletion, acidification, global warming, ozone layer depletion, human toxicity, fresh water eco-toxicity, marine aquatic eco-toxicity, terrestrial eco-toxicity, and photochemical oxidation. However, better effluent quality in this phase reduced the eutrophication load on environment.


Prediction of Arctic plant phenological sensitivity to climate change from historical records.
The pace of climate change in the Arctic is dramatic, with temperatures rising at a rate double the global average. The timing of flowering and fruiting (phenology) is often temperature dependent and tends to advance as the climate warms. Herbarium specimens, photographs, and field observations can provide historical phenology records and have been used, on a localised scale, to predict species' phenological sensitivity to climate change. Conducting similar localised studies in the Canadian Arctic, however, poses a challenge where the collection of herbarium specimens, photographs, and field observations have been temporally and spatially sporadic. We used flowering and seed dispersal times of 23 Arctic species from herbarium specimens, photographs, and field observations collected from across the 2.1 million km2 area of Nunavut, Canada, to determine (1) which monthly temperatures influence flowering and seed dispersal times; (2) species' phenological sensitivity to temperature; and (3) whether flowering or seed dispersal times have advanced over the past 120 years. We tested this at different spatial scales and compared the sensitivity in different regions of Nunavut. Broadly speaking, this research serves as a proof of concept to assess whether phenology-climate change studies using historic data can be conducted at large spatial scales. Flowering times and seed dispersal time were most strongly correlated with June and July temperatures, respectively. Seed dispersal times have advanced at double the rate of flowering times over the past 120 years, reflecting greater late-summer temperature rises in Nunavut. There is great diversity in the flowering time sensitivity to temperature of Arctic plant species, suggesting climate change implications for Arctic ecological communities, including altered community composition, competition, and pollinator interactions. Intraspecific temperature sensitivity and warming trends varied markedly across Nunavut and could result in greater changes in some parts of Nunavut than in others.


[Risk management of hospital infections as a supporting tool for the improvement of hospital quality - some European examples].
Prevention and control of nosocomial infections is one of the main pillars of security in each medical facility. This affects the quality of services and helps to minimize the economic losses incurred as a result of such infections. (Prolonged hospitalization, expensive antibiotic therapies, court costs of damages). Nosocomial infections occur in every medical facility in the hospitals in terms of risk of infection compared to other medicinal entities are at greater risk of environmental (number of hospitalizations for one bed, the amount of disinfectants, etc.). The number and diverse category of employment of medical and auxiliary, which should meet certain standards for the prevention of hospital infections, has an impact on the incidence of infection. It is impossible to eliminate hospital-acquired infections, but can be limited by appropriate measures, ranging from monitoring through the use of risk management methods, which are one of the elements supporting the improvement of the quality of medical entities. Hospital infection is a threat not only for patients but also for workers exposed to the risk of so-called occupational exposure. A comprehensive approach including elements of active surveillance and effective monitoring can help to minimize the risk of nosocomial infections.


The interaction between SPARC and GRP78 interferes with ER stress signaling and potentiates apoptosis via PERK/eIF2α and IRE1α/XBP-1 in colorectal cancer.
Therapy-refractory disease is one of the main contributors of treatment failure in cancer. In colorectal cancer (CRC), SPARC can function as a sensitizer to conventional chemotherapy by enhancing apoptosis by interfering with the activity of Bcl-2. Here, we examine a novel mechanism by which SPARC further potentiates apoptosis via its modulation of the unfolded protein response (UPR). Using mass spectrometry to identify SPARC-associated proteins, GRP78 was identified as a protein partner for SPARC in CRC. In vitro studies conducted to assess the signaling events resulting from this interaction, included induction of ER stress with tunicamycin, 5-fluorouracil (5-FU), and irinotecan (CPT-11). We found that the interaction between GRP78 and SPARC increased during exposure to 5-FU, CPT-11, and tunicamycin, resulting in an attenuation of GRP78's inhibition of apoptosis. In addition, we also show that SPARC can sensitize CRC cells to PERK/eIF2α and IRE1α/XBP-1 UPR signaling by interfering with ER stress following binding to GRP78, which leads to ER stress-associated cell death in CRC cells. In line with these findings, a lower expression of GRP78 relative to SPARC in CRC is associated with a lower IC50 for 5-FU in either sensitive or therapy-refractory CRC cells. Interestingly, this observation correlates with tissue microarray analysis of 143 human CRC, where low GRP78 to SPARC expression level was prognostic of higher survival rate (P = 0.01) in individuals with CRC. This study demonstrates that modulation of UPR signaling by SPARC promotes ER stress-associated death and potentiates apoptosis. This may be an effective strategy that can be combined with current treatment options to improve therapeutic efficacy in CRC.


Effects of an inhaled bronchodilator on gas distribution and over-all ventilatory efficiency in patients with chronic obstructive pulmonary disease.
The effects of an inhaled bronchodilator on the distribution of inspired gas and over-all efficiency of ventilation were studied by the nitrogen washout technic in 16 patients with chronic obstructive pulmonary disease; three normal subjects and two patients with asymptomatic asthma (and normal spirometric values) were also studied. In normal and asthmatic subjects and in patients with chronic obstructive pulmonary disease and mild to moderate functional impairment, the nitrogen clearance did not vary significantly or showed changes suggesting less uniform gas distribution and reduced ventilatory efficiency. In most patients with advanced chronic obstructive pulmonary disease, the bronchodilator caused changes suggesting more uniform distribution of inspired gas and increased efficiency of ventilation. Multiple regression analysis showed that the behavior of the nitrogen clearance after treatment was also related to the response of the anatomic dead space. The effects of the bronchodilator varied with time. The results are consistent with the assumption that the changes in nitrogen clearance after bronchodilator therapy reflect the concourse of multiple factors, which may be expected to have favorable or unfavorable effects on the distribution of inspired gas and the efficiency of ventilation.


Positive cyclin T expression as a favorable prognostic factor in treating gastric gastrointestinal stromal tumors.
Positive transcriptional elongation factor b (P-TEFb) contains the catalytic subunit cyclin-dependent kinase 9 (Cdk9) and the regulatory subunit cyclin T. Cyclin T1 and Cdk9 are the key factors of the PTEFb pathways and are overexpressed in the human head and neck carcinoma cell line. However, there have been limited studies regarding the role of cyclin T1 and Cdk9 in gastric gastrointestinal stromal tumors (GISTs). The aim of the present study was to assess the association between cyclin T1 and Cdk9 and their clinical significance in gastric GISTs. A total of 30 gastric GIST patients who underwent either laparoscopic or laparotomic partial gastrectomy were enrolled in the study. The surgical tissue slides were stained with Cdk9 and cyclin T1 antibodies, and the immunohistochemistry scores and disease-free survival (DFS) were analyzed. Ten patients were cyclin T1-positive, and 20 were negative. All 11 patients with recurrent tumors or distant metastases were cyclin T1-negative patients. Old age, large tumor size, a high Ki67 IHC staining score, high mitotic count and negative cyclin T1 staining revealed a worse clinical outcome in univariate analysis. By contrast, the Cdk9 score was not associated with clinical parameters. The Kaplan-Meier survival curve illustrated that the DFS rate of the patients with negative cyclin T1 staining was significantly lower than that of the patients with positive cyclin T1 staining. Positive expression of cyclin T1 was a good prognostic factor in patients with gastric GISTs.


Paleobiological inferences from paleopathological occurrences in the Arctic ceratopsian Pachyrhinosaurus perotorum.
As a key tool for understanding how animals lived in the past, paleopathology informs us about the lives and deaths of fossil animals. We identify paleopathologies within an assemblage of bones of the pachyrostran centrosaurine Pachyrhinosaurus perotorum, an Arctic ceratopsian. More than 1,000 bones of this dinosaur were collected from the Prince Creek Formation of North Slope, Alaska from fossil sites along the Colville River. Our survey shows the occurrence of paleopathology to be very low and comparable to other populations of horned dinosaurs from the lower latitudes, suggesting that the ancient Arctic environment did not impose intense hardships on these dinosaurs greater than in other environments, as expressed by paleopathological modification of the skeleton. This result may be due to the more equable mean annual temperatures in the Arctic region during the Cretaceous. Also of interest, the frequency of occurrence of paleopathology in the Arctic Pachyrhinosaurus population is very low compared to populations of fossil and historic quadrupedal artiodactyls that are recognized as long distance wanderers.


[Production and molecular characterization of Plasmodium falciparum recombinant circumsporozoite protein with 37 NANP and 4 NVDP epitopes].
Malaria is caused by the protozoan parasite Plasmodium, the leading cause of death amongst the parasitic diseases. The disease is transmitted to human by the bites of female Anopheles mosquitoes. According to the World Health Organization (WHO) data, there were an estimated 214 million malaria cases and estimated 438.000 deaths occurred worldwide, in 2015. It is observed that 90% of all the deaths due to malaria occur in Africa. 78% of these cases were children who are under five years old. Intensive malaria interventions helped to reduce malaria incidence by 37% between 2000 and 2015. Malaria is a curable disease if diagnosed and treated promptly and correctly. Drug resistance has developed against almost all anti-malarial drugs and an effective vaccine against malaria has not been developed yet. Vaccine studies initiated 40 years ago by sterile immunity against falciparum malaria through immunization by exposure to 1000 irradiated mosquitoes. Complex structures, complicated life cycles and various antigenic structures of Plasmodium species make vaccination studies difficult. Circumsporozoite protein (CSP), the most extensively studied protein is also present in the content of the vaccine candidate RTS,S which is currently closest to get license. CSP was the first described Plasmodium antigen because of its important role during initiation of the parasitic infection. CSP is the major surface coat protein of Plasmodium parasite. CSP is a soluble protein and recombinant form of the CSP can be produced in Escherichia coli. NANP repeat region is a target site for host antibodies. Recently many DNA, RNA and protein vaccine candidates are being developed against malaria. According to WHO, in the next 20 years period, malaria vaccine can be developed. In this study we aimed to produce recombinant CSP (rCSP). Initially, P.falciparum CSP gene was amplified by PCR. CSP gene was cloned in to the pJET cloning vector. The gene subcloned to the pET100 protein expression vector. E.coli cells were used for protein expression. After this process, purification and endotoxin removal protocols were performed. As a result, 1182 bp CSP gene was obtained from P.falciparum genomic DNA. Accuracy of cloning and DNA sequence of the CSP gene was determined with DNA sequence analysis. The gene sequence was recorded to the GenBank with a registration no KT315396. rCSP was expressed in E.coli cells. The existence of rCSP was verifiedwith Western Blot method and was purified and removed from endotoxins. rCSP aminoacid sequence and 3D shape was obtained.We believe that the production of recombinant CSP will enable us to contribute to the further malaria vaccine studies in our laboratory and country.


Measuring picogram per liter concentrations of freely dissolved parent and alkyl PAHs (PAH-34), using passive sampling with polyoxymethylene.
Passive sampling with nondepletive sorbents is receiving increasing interest because of its potential to measure freely dissolved concentrations of hydrophobic organic compounds (HOCs) at very low concentrations, as well as its potential for both laboratory use and field deployment. However, consistent approaches have yet to be developed for the majority of HOCs of environmental and regulatory interest. In the present study, a passive sampling method was developed which allows the freely dissolved concentrations of 18 parent and 16 groups of alkyl polycyclic aromatic hydrocarbons (PAHs) on the U.S. Environmental Protection Agency (USEPA)'s "PAH-34" target compound list to be measured. Commercially available 76-μm-thick polyoxymethylene (POM) was placed in sediment/water slurries and exposed for up to 126 days, with 28 days found to be sufficient to obtain equilibrium among the sediment, water, and POM phases for the target 2- to 6-ring PAHs. The POM/water partition coefficients (K(POM)) necessary to calculate freely dissolved concentrations for parent PAHs were determined in two separate laboratories (one using pure standards, and the other using coal tar/petroleum-contaminated sediments) and agreed very well. Since the so-called "16" alkyl PAHs on the PAH-34 list actually include several hundreds of isomers for which no standards exist, sediments impacted by coal tar, or spiked with a coal tar/petroleum nonaqueous phase liquid (NAPL) were also used to measure K(POM) values for each alkyl PAH cluster. The log K(POM) values ranged from ca. 3.0 to 6.2 for 2- to 6-ring parent PAHs, and correlated well with SPARC octanol/water coefficients (K(OW)) (correlation coefficient of r(2) = 0.986). However, log K(POM) values for alkyl PAHs deviated increasingly from SPARC log K(OW) values with increasing degree of alkylation. A simple empirical model that incorporates the number of carbon atoms in a PAH gave a better fit to the experimental log K(POM) values, and was used to estimate log K(POM) for alkyl PAHs that could not be directly measured. Detection limits (as freely dissolved concentrations) ranged from ca. 1 part per trillion (ng/L) for the 2-ring PAH naphthalene, down to <1 pg/L (part per quadrillion) for the 5- and 6-ring PAHs. Sorption isotherms were linear (r(2) > 0.99) over at least 4 orders of magnitude.


Genetic basis and fitness correlates of dynamic carotenoid-based ornamental coloration in male and female common kestrels Falco tinnunculus.
Knowledge of the genetic basis of sexual ornaments is essential to understand their evolution through sexual selection. Although carotenoid-based ornaments have been instrumental in the study of sexual selection, given the inability of animals to synthesize carotenoids de novo, they are generally assumed to be influenced solely by environmental variation. However, very few studies have directly estimated the role of genes and the environment in shaping variation in carotenoid-based traits. Using long-term individual-based data, we here explore the evolutionary potential of a dynamic, carotenoid-based ornament (namely skin coloration), in male and female common kestrels. We first estimate the amount of genetic variation underlying variation in hue, chroma and brightness. After correcting for sex differences, the chroma of the orange-yellow eye ring coloration was significantly heritable (h2±SE=0.40±0.17), whereas neither hue (h2=0) nor brightness (h2=0.02) was heritable. Second, we estimate the strength and shape of selection acting upon chromatic (hue and chroma) and achromatic (brightness) variation and show positive and negative directional selection on female but not male chroma and hue, respectively, whereas brightness was unrelated to fitness in both sexes. This suggests that different components of carotenoid-based signals traits may show different evolutionary dynamics. Overall, we show that carotenoid-based coloration is a complex and multifaceted trait. If we are to gain a better understanding of the processes responsible for the generation and maintenance of variation in carotenoid-based coloration, these complexities need to be taken into account.


Aqueous flare in eyes with age-related macular degeneration.
It is unknown whether aqueous flare is increased in eyes with prominent fundus lesions other than choroidal malignant melanoma. Therefore, we studied the aqueous flare in eyes with age-related macular degeneration (ARMD) using the laser flare-cell meter. Forty-three eyes of 27 patients with ARMD (age 67.0 +/- 14.0 years, range 43-81 years), and 41 healthy eyes of 41 randomly selected age- and gender-matched control patients (age 68.9 +/- 9.8 years, range 43-89 years) were examined. The macular degeneration was diagnosed and classified using fluorescein angiograms. Flare values in eyes with ARMD were 0.28 +/- 0.18 mg/ml, being significant in comparison with the control (0.12 +/- 0.05 mg/ml). The differences among the subgroups of ARMD were not statistically significant (P > 0.5): macular drusenosis (0.21 +/- 0.05 mg/ml, n = 6), subretinal neovascularization without marked subretinal hemorrhage (0.27 +/- 0.15 mg/ml, n = 19), subretinal neovascularization with marked subretinal hemorrhage (0.29 +/- 0.24 mg/ml, n = 7), and disciform scar (0.31 +/- 0.24 mg/ml, n = 9).


The safety of women health workers at the frontlines.
This article, based on the report of the fact-finding team on the gang rape and death of an accredited social health activist (ASHA) in Muzaffarnagar in January 2016, attempts to analyse the issues of the safety and mobility of front-line women health workers. It argues that although the National Health Mission is often alluded to as a flagship programme of the government, it has failed in its basic responsibility as an ethical employer, since there is no support and back-up system that can be easily accessed by ASHAs in terms of dealing with the fallout of their social role as "change agents" in rural areas, and community reactions to their mobility and public exposure. The report stresses the need to consider the deeply patriarchal system within which ASHAs function in states such as Uttar Pradesh. It also discusses the fact that the workforce is increasingly shifting from the formal to the informal sector, which has given rise to an assumption that the employer is no longer accountable for women workers' safety at the workplace.


Alternative parameterizations of the multiple-trait random regression model for milk yield and somatic cell score via recursive links between phenotypes.
Multiple-trait random regression models with recursive phenotypic link from somatic cell score (SCS) to milk yield on the same test day and with different restrictions on co-variances between these traits were fitted to the first-lactation Canadian Holstein data. Bayesian methods with Gibbs sampling were used to derive inferences about parameters for all models. Bayes factor indicated that the recursive model with uncorrelated environmental effects between traits was the most plausible specification in describing the data. Goodness of fit in terms of a within-trait weighted mean square error and correlation between observed and predicted data was the same for all parameterizations. All recursive models estimated similar negative causal effects from SCS to milk yield (up to -0.4 in 46-115 days in milk in lactation). Estimates of heritabilities, genetic and environmental correlations for the first two regression coefficients (overall level of a trait and lactation persistency) within both traits were similar among models. Genetic correlations between milk and SCS were dependent on the restrictions on genetic co-variances for these traits. Recursive model with uncorrelated system genetic effects between milk and SCS gave estimates of genetic correlations of the opposite sign compared with a regular multiple-trait model. Phenotypic recursion between milk and SCS seemed, however, to be the only source of environmental correlations between these two traits. Rankings of sires for total milk yield in lactation, average daily SCS and persistency for both traits were similar among models. Multiple-trait model with recursive links between milk and SCS and uncorrelated random environmental effects could be an attractive alternative for a regular multiple-trait model in terms of model parsimony and accuracy.


Assessing and meeting the health needs of Roman Catholic priests in the archdiocese of Chicago.
In 1985, the Bishops' Committee on Priestly Life and Ministry recommended bishops form holistic health boards for their priests based on the results of a 1982 U.S. survey of Catholic priests. In 1995, a holistic health committee was formed under the office of the vicar for priests for the archdiocese of Chicago. One of the committee's first actions was to survey the priests of the archdiocese of Chicago to identify baseline health behaviors and needs. Survey results (n = 524; 52% response rate) revealed the need for the committee to promote health education, preventive care, and annual physicals. The committee conducted a series of health fairs, improved the insurance benefit for an annual physical, and conducted a series of health-related talks targeted to priests. A follow-up survey in 2006 (n = 389; 46% response rate) indicated improvements in health behaviors of the priests. Comparisons to statewide and national data indicate that overall, engagement in healthy behaviors is higher for priests than for men who are not priests.


Editorial: COVID-19: lessons learned for suicide prevention.
This editorial discusses lessons learned from the COVID-19 public health emergency as they relate to the prevention of suicide, the second leading cause of death in adolescents and young adults globally. Recognizing that COVID-19 impact and response varied across nations, we offer a US perspective, addressing two questions: (a) what have we learned from this pandemic and mitigation strategies used to reduce cases of COVID-19 illness and deaths; and (b) how can our research advance knowledge and be advanced by work aimed at understanding the impact of this 'unusual' period? Provisional data indicate that during the pandemic and lockdown period, there were some declines in suicide rates for the total US population and no change in youth. However, data also indicate increases in reported suicidal ideation and behavior, mental health-related ED visits, and ED visits for suicidal ideation and behavior in youth. Heterogeneity of pandemic effects is noteworthy, with ethnic and racial minority populations suffering the most from COVID-19, COVID-19-related risk factors, and possibly suicide deaths. As vaccinations can prevent severe COVID-19 cases and deaths, we also have demonstrations of effective 'psychological inoculations' such as community-based interventions for reducing suicide attempts and deaths. During COVID-19, we mobilized to provide clinical care through telehealth and digital interventions. The challenge now is to continue to put our science to work to mitigate the adverse impacts of the pandemic on suicide and suicide risk factors, our children's mental health, and enhance mental health and well-being in our communities.


Concentrations of particulate matter in schools in southwest Germany.
During the winter season 2005/2006, measurements of small particulate matter were taken in 22 schools in southwest Germany. PM2.5 was measured gravimetrically. Laser particle counter (LPC) and condensation particle counter (CPC) were used to determine different particle fractions. The investigation included measurements inside (in classrooms) and outside of school buildings. During the whole investigation period continuous reference measurements were taken near the State Health Office in the city of Stuttgart. Information on building-specific data and traffic near the schools was collected via questionnaire. Although distances between the different schools and the location of the State Health Office building in Stuttgart in some cases exceeded 100 km, the concentration levels of particles > 0.3 microm measured by LPC near the different schools were similar to those measured in Stuttgart. The differences between the measurements in Stuttgart and at the other locations were smaller than the variation in time. In the winter season, the impaction of particulate matter was strongly influenced by specific weather conditions. Time resolution of measurements in classrooms showed variation in particle concentration depending on the type of building and indoor activities like cleaning or moving during breaks. Concentrations of very small particles in buildings and in ambient air measured by CPC were influenced by traffic emissions. The observed data give reason to assume that the influence of high traffic emissions to indoor particle concentration may have been overestimated. Furthermore, there is an urgent need for standardization of measurement protocols, sampling, and determination of indoor particulate matter. The classical gravimetric methods are less appropriate since they do not allow for a time resolution of measurements.


[Study on the correlation between Chinese medicine syndrome types in influenza A (H1N1) virus and potential biomarkers].
To investigate the contents changes of potential biomarkers of patients infected with influenza A (H1N1) virus of different Chinese medicine (CM) syndrome types. Eighty-two patients with influenza A (H1N1) virus were differentiated as three syndrome types, i. e., wind-heat invading weifen syndrome (51 cases), heat-toxicity attacking Fei syndrome (22 cases), and superficies tightened by wind cold syndrome (9 cases) according to Chinese medicine syndrome typing. According to patients' willingness and clinical conditions, they were treated by three therapeutic schedules, i. e., herbal therapy, symptomatic treatment, and antiviral therapy. The changes of potential biomarkers contents were detected in the serum of patients of various syndrome types before and after treatment. Results There was no statistical difference in the potential biomarkers contents correlated to symptoms of fever, inflammation and cough, such as PGG2, 20-COOH-LTB4, homocystein, and so on in the serum of patients of various syndrome types before treatment (P > 0.05). There was statistical difference in the potential biomarkers such as 20-OH-LTE4, LTA4, and linolenic acid, etc. between superficies tightened by wind cold syndrome and wind-heat invading weifen syndrome (P < 0.05, P < 0.01). There was statistical difference in the potential biomarkers such as PGF1alpha, prostanoic acid, and etc. between superficies tightened by wind cold syndrome and heat-toxicity attacking Fei syndrome (P < 0.05, P < 0.01). Statistical difference existed in other indices other than dUTP; 5,10-methylene-THF and PGF1alpha in wind-heat invading weifen syndrome and superficies tightened by wind cold syndrome; prostanoic acid, homocysteine, and glucose in superficies tightened by wind cold syndrome when compared with before treatment in the same group (P < 0.05, P < 0.01). The changing tendency of potential biomarkers among different syndrome types was identical. Of them, the change of 6-keto-PGF1alpha content was the most obviously of all indices. There was difference in the contents of potential biomarkers of patients infected with influenza A (H1N1) virus of different syndrome types, and our study provided experimental data support for the objectiveness of CM syndrome differentiation from the perspective of metabolic substances.


Direct measurement of local chromatin fluidity using optical trap modulation force spectroscopy.
Chromatin assembly is condensed by histone tail-tail interactions and other nuclear proteins into a highly compact structure. Using an optical trap modulation force spectroscopy, we probe the effect of tail interactions on local chromatin fluidity. Chromatin fibers, purified from mammalian cells, are tethered between a microscope coverslip and a glass micropipette. Mechanical unzipping of tail interactions, using the micropipette, lead to the enhancement of local fluidity. This is measured using an intensity-modulated optically trapped bead positioned as a force sensor on the chromatin fiber. Enzymatic digestion of the histone tail interactions of tethered chromatin fiber also leads to a similar increase in fluidity. Our experiments show that an initial increase in the local fluidity precedes chromatin decompaction, suggesting possible mechanisms by which chromatin-remodeling machines access regulatory sites.


Real-time attack of LL-37 on single Bacillus subtilis cells.
Time-lapse fluorescence microscopy of single, growing Bacillus subtilis cells with 2-12s time resolution reveals the mechanisms of antimicrobial peptide (AMP) action on a Gram-positive species with unprecedented detail. For the human cathelicidin LL-37 attacking B. subtilis, the symptoms of antimicrobial stress differ dramatically depending on the bulk AMP concentration. At 2μM LL-37, the mean single-cell growth rate decreases, but membrane permeabilization does not occur. At 4μM LL-37, cells abruptly shrink in size at the same time that Sytox Green enters the cytoplasm and stains the nucleoids. We interpret the shrinkage event as loss of turgor pressure (and presumably the membrane potential) due to permeabilization of the membrane. Movies of Sytox Green staining at 0.5frame/s show that nucleoid staining is initially local, more consistent with pore formation than with global permeabilization models. In a novel "growth recovery" assay, cells are incubated with LL-37 for a variable period and then rinsed with fresh growth medium lacking LL-37. The growth rate attenuation observed at 2μM LL-37 is a recoverable symptom, while the abrupt cell shrinkage observed at 4μM LL-37 is not.


Exploring neuropsychological and socio-emotional task performance in anorexia nervosa: A cluster analytic approach.
The aim of this study was to characterise heterogeneity in neuropsychological and socio-emotional task performance in young women with anorexia nervosa (AN) using hierarchical cluster analysis. Further, we aimed to test whether cognitive profiles were associated with differences in clinical variables (body mass index, illness duration and age at diagnosis), psychopathology (eating disorder, autistic symptoms, anxiety and depression) and functional impairment. Set-shifting, central coherence and theory of mind abilities were measured in 118 women with acute or remitted AN. A hierarchical cluster analysis using Ward's method with a Euclidean distance measure was performed with the neuropsychological and socio-emotional variables. Differences between clusters were assessed using ANOVAs. Four clusters emerged, with significant differences in neuropsychological and socio-emotional task performance. There were no significant differences between clusters in clinical variables, psychopathology or functional impairment, however, these analyses lacked power due to small cluster sizes. Our results demonstrate significant heterogeneity in cognitive profiles in AN, supporting a more personalised approach to treatment. Studies in larger samples are required to establish whether these variables map onto clinically significant differences in aetiology, clinical presentation, comorbidity patterns and/or treatment responses.


The informal use of antiretroviral medications for HIV prevention by men who have sex with men in South Florida: initiation, use practices, medications and motivations.
Limited data suggest that some gay and other men who have sex with men are using antiretroviral medications informally, without a prescription, for HIV prevention. This qualitative study examined this phenomenon among gay and other men who have sex with men in South Florida. Participants initiated informal antiretroviral medication use as a means of protecting each other and because of the confidence in knowledge of antiretroviral medications shared by their friends and sex partners. The most commonly used medications included Truvada and Stribild. Motivations for use included condom avoidance, risk reduction, and fear of recent HIV exposure. Participants described positive and negative sentiments related to informal use, including concerns about informal antiretroviral medications offering sufficient protection against HIV, and limited knowledge about pre-exposure prophylaxis (PrEP). Because the antiretroviral medications used for PrEP have the potential to prevent HIV infection, future research must consider the informal antiretroviral medication use and related concerns, including adherence, diversion and viral resistance.


Predicting stature from knee height in Chinese elderly subjects.
The main aim of this study was to validate the use of the Caucasian-based knee height equations for predicting stature of Chinese elderly subjects and to compare the predicted height to those estimated by equations derived from elderly subjects of Chinese origin. The study was performed by a survey by measurement of convenience samples. Twenty-one women and 26 men were recruited to validate the use of the Caucasian-based equations. The Chinese-based predictive equations were derived from 164 women and 89 men. The sample included ambulatory elderly subjects of Chinese origin, 60 years of age or older. These subjects were without spinal curvature and able to stand erect. Measurements were taken for height by a standard hospital scale. Calipers was used to measure knee height while the subject was in the sitting position. The measured stature and that predicted by the Caucasian-based equations were significantly different in Chinese elderly women but not in men. New regression models are being developed for the elderly Chinese population in Hong Kong. The relationship between stature, knee height and age appears to be ethnicity- and gender-dependent. While stature of elderly Chinese men can be estimated by either the Caucasian-based or Chinese-based equation, the regression model developed in the present study will better estimate the stature in elderly Chinese women.


An Increase of Seawater Temperature Upregulates the Expression of Vibrio parahaemolyticus Virulence Factors Implicated in Adhesion and Biofilm Formation.
Climate change driven seawater temperature (SWT) increases results in greater abundance and geographical expansion of marine pathogens, among which Vibrio parahaemolyticus (Vp) causes serious economic and health issues. In addition, plastic pollution in the ocean constitutes a vector for harmful pathogens dissemination. We investigate the effect of elevated SWT on the expression of genes implicated in adhesion and biofilm formation on abiotic surfaces in the clinical Vp strain RIMD2210633, which expresses hemolysins. Among the genes studied, the multivalent adhesion molecule-7 and the GlcNAc-binding protein A were involved in the adhesion of Vp to abiotic and biotic surfaces, whereas the type IV pili, the mannose-sensitive hemagglutinin, and the chitin-regulated pilins facilitate attachment and biofilm formation. Data presented here show that at 21°C, Vp is still viable but does not either proliferate or express the virulence factors studied. Interestingly, at 27°C and as early as 1 h of incubation, all factors are transiently expressed in free-living bacteria only and even more upregulated at 31°C. These results clearly show that increased SWT has an important impact on the adhesion properties of free-living Vp to plastic support and thus emphasize the role of climate change in the spread of this pathogenic bacteria.


CD4% is the best predictor of development of AIDS in a cohort of HIV-infected homosexual men.
To determine the relationships between individuals' baseline T-cell subsets, their rates of change with time, and AIDS-free survival time, data were collected at 6-monthly intervals from 379 HIV-seropositive homosexual Sydney men, of whom 31 developed AIDS during the 3-year observation period. Both CD4% and rate of change of CD4% in an individual had significant prognostic value in determining AIDS-free survival time. Compared with subjects whose CD4% remained stable, subjects whose CD4% dropped by 7% or more in a year had a relative hazard of 35.1 (95% confidence interval = 11.7-105.6, P less than 0.001) of developing AIDS. Increasing CD4% had a significant protective effect, reducing the risk of developing AIDS. CD4%, CD4 cell count and CD4: CD8 ratios showed steeper declines in subjects who were later diagnosed with AIDS than in those who remained AIDS-free. The rates of immunological change in AIDS-free seroconverters and seropositives were similar, despite indeterminate differences in durations of infections. In the multivariate Cox regression analysis, baseline CD4%, the rate of change of CD4%, and baseline lymphocyte count were associated with AIDS-free survival time. Baseline CD4% had greater prognostic value than baseline CD4 cell count. Baseline CD8%, baseline CD8 count, their rates of change and their mean square errors were not independently significant in this analysis. These findings are important for clinicians monitoring HIV infection in an individual and for entry criteria and monitoring procedures in clinical trials. They also have implications for resource-poor settings; prognosis based on CD4% can be made with a flow cytometer without a full blood count.(ABSTRACT TRUNCATED AT 250 WORDS)


Biokinetics of radiotellurium in rats.
Radiotellurium is present in the environment primarily due to its release during nuclear reactor accidents. Little is known of tellurium metabolism in juveniles, although the element is relatively abundant and has a number of industrial uses. A biokinetic study of radiotellurium in rats was performed using gamma-ray counting. Wistar strain rats were used to determine the uptake of H2(123m)TeO3 by the whole-body retention of juvenile rats and the conceptus in relation to its gestational stages, by measurements in the placenta, fetal membranes, fetal fluid and fetus. The whole-body retention of 123mTe in juvenile rats was higher than that of adult rats. The relative concentration in the placenta and fetal membranes was higher than in the fetus. No activity was observed in the fetal fluid. These results indicate that the placenta and fetal membranes play significant roles as barriers to the transfer of 123mTe into the fetus. The ratio, relative concentration in fetus/relative concentration in mother (C(F)/C(M)), was calculated. The C(F)/C(M) ratio was dependent on the stage of gestation and ranged from 0.2 to 0.5. A little 123mTe was transferred to the suckling rats through the mother's milk when the isotope was administered intravenously to the mother.


Unravelling the biology of SCLC: implications for therapy.
Small-cell lung cancer (SCLC) is an aggressive malignancy associated with a poor prognosis. First-line treatment has remained unchanged for decades, and a paucity of effective treatment options exists for recurrent disease. Nonetheless, advances in our understanding of SCLC biology have led to the development of novel experimental therapies. Poly [ADP-ribose] polymerase (PARP) inhibitors have shown promise in preclinical models, and are under clinical investigation in combination with cytotoxic therapies and inhibitors of cell-cycle checkpoints.Preclinical data indicate that targeting of histone-lysine N-methyltransferase EZH2, a regulator of chromatin remodelling implicated in acquired therapeutic resistance, might augment and prolong chemotherapy responses. High expression of the inhibitory Notch ligand Delta-like protein 3 (DLL3) in most SCLCs has been linked to expression of Achaete-scute homologue 1 (ASCL1; also known as ASH-1), a key transcription factor driving SCLC oncogenesis; encouraging preclinical and clinical activity has been demonstrated for an anti-DLL3-antibody-drug conjugate. The immune microenvironment of SCLC seems to be distinct from that of other solid tumours, with few tumour-infiltrating lymphocytes and low levels of the immune-checkpoint protein programmed cell death 1 ligand 1 (PD-L1). Nonetheless, immunotherapy with immune-checkpoint inhibitors holds promise for patients with this disease, independent of PD-L1 status. Herein, we review the progress made in uncovering aspects of the biology of SCLC and its microenvironment that are defining new therapeutic strategies and offering renewed hope for patients.


TEPIC 2-an extended framework for transcription factor binding prediction and integrative epigenomic analysis.
Prediction of transcription factor (TF) binding from epigenetics data and integrative analysis thereof are challenging. Here, we present TEPIC 2 a framework allowing for fast, accurate and versatile prediction, and analysis of TF binding from epigenetics data: it supports 30 species with binding motifs, computes TF gene and scores up to two orders of magnitude faster than before due to improved implementation, and offers easy-to-use machine learning pipelines for integrated analysis of TF binding predictions with gene expression data allowing the identification of important TFs. TEPIC is implemented in C++, R, and Python. It is freely available at https://github.com/SchulzLab/TEPIC and can be used on Linux based systems. Supplementary data are available at Bioinformatics online.


Psb28 protein is involved in the biogenesis of the photosystem II inner antenna CP47 (PsbB) in the cyanobacterium Synechocystis sp. PCC 6803.
The role of the Psb28 protein in the structure and function of the photosystem II (PSII) complex has been studied in the cyanobacterium Synechocystis sp. PCC 6803. The protein was localized in the membrane fraction and, whereas most of the protein was detected as an unassembled protein, a small portion was found in the PSII core complex lacking the CP43 antenna (RC47). The association of Psb28 with RC47 was further confirmed by preferential isolation of RC47 from the strain containing a histidine-tagged derivative of Psb28 using nickel-affinity chromatography. However, the affinity-purified fraction also contained a small amount of the unassembled PSII inner antenna CP47 bound to Psb28-histidine, indicating a structural relationship between Psb28 and CP47. A psb28 deletion mutant exhibited slower autotrophic growth than wild type, although the absence of Psb28 did not affect the functional properties of PSII. The mutant showed accelerated turnover of the D1 protein, faster PSII repair, and a decrease in the cellular content of PSI. Radioactive labeling revealed a limitation in the synthesis of both CP47 and the PSI subunits PsaA/PsaB in the absence of Psb28. The mutant cells contained a high level of magnesium protoporphyrin IX methylester, a decreased level of protochlorophyllide, and released large quantities of protoporphyrin IX into the medium, indicating inhibition of chlorophyll (Chl) biosynthesis at the cyclization step yielding the isocyclic ring E. Overall, our results show the importance of Psb28 for synthesis of Chls and/or apoproteins of Chl-binding proteins CP47 and PsaA/PsaB.


Optical sensor network interrogation system based on nonuniform microwave photonic filters.
Based on the nonuniformly spaced microwave photonic delay-line filter technology, a new design of a generic optical fiber sensor network interrogation platform is proposed and demonstrated. Sensing information from different types of optical sensors embedded in filter taps is converted into the variations of delay time and amplitude of each filter tap individually. Information to be measured can be decoded from the complex temporal impulse response of the microwave photonic filter. As proof-of-concept, our proposed approach is verified by simulations and experimental demonstrations successfully. Four optical sensors of different types are simultaneously interrogated via inverse Fourier transform of the filter frequency response. The experiment results show good linearity between the variation of temporal impulse response and the variations of the twist, the lateral pressure, the transversal loading and the temperature. The sensitivity of the sensors in the proposed platform is -2.130×10-5 a.u/degree, 6.1039 ps/kPa, -1.9146×10-5 a.u/gram, and 5.1497 ps/°C, respectively. Compared to the conventional optical sensors interrogation system, the presented approach provides a centralized solution that works for different types of optical sensors and can be easily expanded to cover larger optical sensor networks.


Equilibrium of phosphointermediates of sodium and potassium ion transport adenosine triphosphatase: action of sodium ion and Hofmeister effect.
Sodium and potassium ion transport adenosine triphosphatase accepts and donates a phosphate group in the course of its reaction sequence. The phosphorylated enzyme has two principal reactive states, E1P and E2P. E1P is formed reversibly from ATP in the presence of Na+ and is precursor to E2P, which equilibrates with P(i) in the presence of K+. We studied equilibrium between these states at 4 degrees C and the effect of Na+ on it. To optimize the reaction system we used a Hofmeister effect, replacing the usual anion, chloride, with a chaotropic anion, usually nitrate. We phosphorylated enzyme from canine kidney with [32P]ATP. We estimated interconversion rate constants for the reaction E1P <--> E2P and their ratio. To estimate rate constants we terminated phosphorylation and observed decay kinetics. We observed E1P or E2P selectively by adding K+ or ADP respectively. K+ dephosphorylates E2P leaving E1P as observable species; ADP dephosphorylates E1P leaving E2P as observable species. We fitted a 2-pool model comprising two reactive species or a twin 2-pool model, comprising a pair of independent 2-pool models, to the data and obtained interconversion and hydrolysis rate constants for each state. Replacing Na+ with Tris+ or lysine+ did not change the ratio of interconversion rate constants between E1P and E2P. Thus Na+ binds about equally strongly to E1P and E2P. This conclusion is consistent with a model of Pedemonte (1988. J. Theor. Biol. 134:165-182.). We found that Na+ affected another equilibrium, that of transphosphorylation between ATP x dephosphoenzyme and ADP x E1P. We used the reactions and model of Pickart and Jencks (1982. J. Biol. Chem. 257:5319-5322.) to generate and fit data. Decreasing the concentration of Na+ 10-fold shifted the equilibrium constant 10-fold favoring ADP x E1P over ATP x dephosphoenzyme. Thus Na+ can dissociate from E1P x Na3. Furthermore, we found two characteristics of Hofmeister effects on this enzyme.


TP53 alterations in primary and secondary Sézary syndrome: A diagnostic tool for the assessment of malignancy in patients with erythroderma.
Recent massive parallel sequencing data have evidenced the genetic diversity and complexity of Sézary syndrome mutational landscape with TP53 alterations being the most prevalent genetic abnormality. We analyzed a cohort of 35 patients with SS and a control group of 8 patients with chronic inflammatory dermatoses. TP53 status was analyzed at different clinical stages especially in 9 patients with a past-history of mycosis fungoides (MF), coined secondary SS. TP53 mutations were only detected in 10 patients with either primary or secondary SS (29%) corresponding to point mutations, small insertions and deletions which were unique in each case. Interestingly, TP53 mutations were both detected in sequential unselected blood mononuclear cells and in skin specimens. Cytogenetic analysis of blood specimens of 32 patients with SS showed a TP53 deletion in 27 cases (84%). Altogether 29 out of 35 cases exhibited TP53 mutation and/or deletion (83%). No difference in prognosis was observed according to TP53 status while patients with secondary SS had a worse prognosis than patients with primary SS. Interestingly, patients with TP53 alterations displayed a younger age and the presence of TP53 alteration at initial diagnosis stage supports a pivotal oncogenic role for TP53 mutation in SS as well as in erythrodermic MF making TP53 assessment an ancillary method for the diagnosis of patients with erythroderma as patients with inflammatory dermatoses did not display TP53 alteration.


Outcomes of Tracheostomy on Burn Inhalation Injury.
Tracheostomy has been proposed for patients with expected prolonged intubation. This study aims to determine the outcomes of tracheostomy on patients with burn inhalation injuries requiring mechanical ventilation. This study is a retrospective review from 2011 to 2019. Inclusion criteria were recording of inhalation injury, ventilator support (at least 24 hours), and total body surface area of <15%. The patients were stratified into 2 groups: tracheostomy (group 1) versus no tracheostomy (group 2). The outcome measures were in-hospital mortality rate, hospital length of stay, intensive care unit length of stay, ventilator days, and ventilator- associated pneumonia (VAP). A total of 33 burn patients met our inclusion criteria. Group 1 consisted of 10 patients and group 2 of 23 patients. There was no statistically significant difference in terms of percent total body surface area. There was a higher intensive care unit length of stay at 23.8 days in group 1 compared with 3.16 days in group 2, a higher hospital length of stay at 28.4 days in group 1 compared with 5.26 days in group 2, and higher ventilator days in group 1 with 20.8 days compared with 2.5 days in group 2. There was no statistically significant difference between the 2 groups in terms of mortality. The incidence of VAP was also significantly higher in group 1 than in group 2. The ideal timing and implementation of tracheostomy with inhalation injury has yet to be determined. In this study, tracheostomy was associated with much longer lengths of stay and pneumonia. The impact of the underlying lung injury versus the tracheostomy itself on these observations is unclear. The challenge of characterizing the severity of an inhalation injury based on early visual inspection remains.


Transcription Factor JunB Suppresses Hepatitis C Virus Replication.
We previously reported that hepatitis C virus (HCV) infection activates the reactive oxygen species (ROS)/c-Jun N-terminal kinase (JNK) signaling pathway. Activation of JNK contributes to the development of liver diseases, including metabolic disorders, steatosis, liver cirrhosis and hepatocellular carcinoma. JNK is known to have numerous target genes, including JunB, a member of activator protein-1 transcription factor family. However, the roles of JunB in the HCV life cycle and HCV-associated pathogenesis remain unclear. To clarify a physiological role of JunB in HCV infection, we investigated the phosphorylation of JunB in HCV J6/JFH1-infected Huh-7.5 cells. Immunoblot analysis revealed that HCV-induced ROS/JNK activation promoted phosphorylation of JunB. The small interfering RNA (siRNA) knockdown of JunB significantly increased the amount of intracellular HCV RNA as well as the intracellular and extracellular HCV infectivity titers. Conversely, overexpression of JunB significantly reduced the amount of intracellular HCV RNA and the intracellular and extracellular HCV infectivity titers. These results suggest that JunB plays a role in inhibiting HCV propagation. Additionally, HCV-mediated JunB activation promoted hepcidin promoter activity and hepcidin mRNA levels, a key factor in modulating iron homeostasis, suggesting that JunB is involved in HCV-induced transcriptional upregulation of hepcidin. Taken together, we propose that the HCV-induced ROS/JNK/JunB signaling pathway plays roles in inhibiting HCV replication and contributing to HCV-mediated iron metabolism disorder.


Potential triggering factors of intracerebral hemorrhage.
The distributions of intracerebral hemorrhage (ICH) according to place of onset, degree of physical activity at onset and potential triggering factors were analyzed in 848 patients with ICH. Patients were grouped according to the presumed cause of ICH: hypertensive ICH, secondary ICH and ICH of undetermined origin. The influence of demographic and temporal factors on the relative frequency of events was also assessed. In 30% of the cases, ICH occurred during inactivity or sedentary activity, in 50% during light exertion and in 20% during moderate/vigorous exertion. During inactivity or sedentary activity, hypertensive ICH was significantly less frequent than secondary ICH (OR 0.32; 95% CI 0.21-0.47) and undetermined ICH (OR 0.36; 95% CI 0.23-0.55), whereas during moderate or vigorous exertion hypertensive ICH was more frequent than secondary (OR 1.88; 95% CI 1.16-3.05) and undetermined ICH (OR 2.29; 95% CI 1.31-4.00) Potential triggering factors were observed in 27% of patients and were significantly more frequent in patients with hypertensive ICH than in patients with secondary ICH (OR 2.90; 95% CI 1.85-4.54) or undetermined ICH (OR 2.44; 95% CI 1.54-3.87). Our findings suggest that many potential external triggers that act mainly by raising blood pressure may interact, and their concurrence may favor cerebral hemorrhage, particularly in hypertensive patients. In many cases, these circumstances of increased risk may be mitigated by preventive measures.