Estimating the wave 1 and wave 2 infection fatality rates from SARS-CoV-2 in India.
There has been much discussion and debate around the underreporting of COVID-19 infections and deaths in India. In this short report we first estimate the underreporting factor for infections from publicly available data released by the Indian Council of Medical Research on reported number of cases and national seroprevalence surveys. We then use a compartmental epidemiologic model to estimate the undetected number of infections and deaths, yielding estimates of the corresponding underreporting factors. We compare the serosurvey based ad hoc estimate of the infection fatality rate (IFR) with the model-based estimate. Since the first and second waves in India are intrinsically different in nature, we carry out this exercise in two periods: the first wave (April 1, 2020-January 31, 2021) and part of the second wave (February 1, 2021-May 15, 2021). The latest national seroprevalence estimate is from January 2021, and thus only relevant to our wave 1 calculations. Both wave 1 and wave 2 estimates qualitatively show that there is a large degree of "covert infections" in India, with model-based estimated underreporting factor for infections as 11.11 (95% credible interval (CrI) 10.71-11.47) and for deaths as 3.56 (95% CrI 3.48-3.64) for wave 1. For wave 2, underreporting factor for infections escalate to 26.77 (95% CrI 24.26-28.81) and to 5.77 (95% CrI 5.34-6.15) for deaths. If we rely on only reported deaths, the IFR estimate is 0.13% for wave 1 and 0.03% for part of wave 2. Taking underreporting of deaths into account, the IFR estimate is 0.46% for wave 1 and 0.18% for wave 2 (till May 15). Combining waves 1 and 2, as of May 15, while India reported a total of nearly 25 million cases and 270 thousand deaths, the estimated number of infections and deaths stand at 491 million (36% of the population) and 1.21 million respectively, yielding an estimated (combined) infection fatality rate of 0.25%. There is considerable variation in these estimates across Indian states. Up to date seroprevalence studies and mortality data are needed to validate these model-based estimates.


Practical recommendations for hypomethylating agent therapy of patients with myelodysplastic syndromes.
Clinicians commonly administer one or the other of the two hypomethylating agents currently approved in the United States--azacitidine or decitabine--to patients with aggressive forms of myelodysplastic syndromes (MDS). However, there continues to be uncertainty about the optimal choice of agent, the best initial dose and treatment schedule, the role of hypomethylating agents in patients with more indolent disease, the most appropriate management of treatment-associated adverse events, and the most desirable approach to maintain responses. The evidence base supporting clinical decisions around these questions varies widely in depth and quality. This article discusses practical considerations for clinicians who use hypomethylating agents to treat patients with MDS.


Microbacterium sediminicola sp. nov. and Microbacterium marinilacus sp. nov., isolated from marine environments.
Two novel Microbacterium species are described on the basis of phenotypic, chemotaxonomic and genotypic studies. The two strains, designated YM10-847(T) and YM11-607(T), were isolated from river sediment and unidentified hydroid, respectively, of a marine lake. The strains were Gram-positive, catalase-positive bacteria with l-ornithine as the diagnostic diamino acid of the peptidoglycan. The acyl type of the peptidoglycan was N-glycolyl. The major menaquinones were MK-10 and MK-11 for YM10-847(T), and MK-11 and MK-12 for YM11-607(T). Mycolic acids were not detected. The DNA G+C content of strains YM10-847(T) and YM11-607(T) was 67.8 and 71.6 mol%, respectively. Comparative 16S rRNA gene sequence analysis revealed that the two strains belong to the genus Microbacterium. DNA-DNA relatedness data showed that YM10-847(T) and YM11-607(T) are two novel species of this genus. On the basis of these results, strains YM10-847(T) and YM11-607(T) represent two novel species of the genus Microbacterium, for which the names Microbacterium sediminicola sp. nov. and Microbacterium marinilacus sp. nov. are proposed. The type strains are YM10-847(T) (=MBIC08264(T)=DSM 18905(T)) and YM11-607(T) (=MBIC07778(T)=DSM 18904(T)), respectively.


Periarticular malacoplakia.
Malacoplakia is a granulomatous process that occasionally affects the musculoskeletal system. It is thought to be caused by a dysfunction in mononuclear cells and their inability to lyse bacteria effectively. A strong correlation between this entity and immunosuppression has been noted. When a granulomatous mass is present in an immunosuppressed patient, the diagnosis of malacoplakia should be considered.


Genetic heterogeneity of group b streptococci isolated from Romanian pregnant women.
Although testing for group B streptococcus (GBS) carriage is mandatory during pregnancy, the laboratory data regarding the characteristics of GBS circulating strains among Romanian female population are scarce. This study aimed to evaluate the genetic diversity of 39 GBS isolates originating from the vaginal microbiota of pregnant women. All the isolates were susceptible to penicillin, ampicillin, cefotaxime, and vancomycin, whereas 18% of them were resistant to either erythromycin or erythromycin and clindamycin. Serotyping based on capsular polysaccharide antigens revealed eleven isolates of type III (28%), seven of type II (18%), six of type la (15%), six of type Ib (15%), six of type IV (15%), and three of type V (8%), respectively. Pulsed-field gel electrophoresis (PFGE) of the Smal macrorestriction DNA fragments yielded 39 PFGE distinct profiles for the studied isolates. Computer-assisted cluster analysis of the band profiles, using unweighted-pair group method and Dice similarity coefficient, showed that at a minimum of 80% similarity, the GBS isolates gathered into 25 pulsotypes, irrespective of their serotype. Our results provided information about the genomic heterogeneity of GBS isolates circulating in our area, supporting the benefit of using PFGE as an adjunct to conventional typing methods for future epidemiological studies.


Trefoil factor 1 stimulates both pancreatic cancer and stellate cells and increases metastasis.
Trefoil factor 1 (TFF1) is a stable secretory protein expressed widely in the gastrointestinal mucosa that is also expressed in pancreatic ductal adenocarcinoma (PDAC). In the current study, we documented the extent and timing of TFF1 expression and investigated the effects of TFF1 on PDAC cells and stellate cells, the primary cells of the PDAC stroma. Trefoil factor 1 expression in pancreatic cancer tissues and cell lines was analyzed using microarray, quantitative reverse transcriptase-polymerase chain reaction, and immunohistochemistry. The effects of recombinant TFF1 on cell growth, migration, and invasion of pancreatic cancer cell lines and immortalized human pancreatic stellate cells (HPSCs) were analyzed using MTS and Matrigel-coated invasion chambers. In vivo studies were also conducted in which Mpanc-96 cells stably expressing TFF1 were implanted orthotopically into nude mice. Trefoil factor 1 was highly increased in preneoplastic lesions. Recombinant TFF1 stimulated motility of both cancer and HPSCs. In contrast, only HPSC cell growth was increased by TFF1. In vivo studies showed that overexpression of TFF1 in PDAC cells did not affect primary tumor growth but greatly increased metastasis. The present data demonstrate that TFF1 influences both PDAC cells and stellate cells and stimulates metastasis.


Copper-Catalyzed Enantioselective Difluoromethylation-Alkynylation of Olefins by Solving the Dilemma between Acidities and Reduction Potentials of Difluoromethylating Agents.
Molecules containing a difluoromethyl group or a propargylic stereocenter are widely used in pharmaceuticals and agrochemicals, and 1,2-functionalization of olefins is an important method for introducing the two groups into molecules simultaneously. The construction of the propargylic stereocenter with terminal alkynes usually requires bases. However, difluoromethylating agents with high reduction potentials often decompose in the presence of bases because of their acidities, and those with low reduction potentials are stable but difficult to undergo the desired single electron transfer (SET) reduction. Using the linear relationship between reduction potential differences (ΔE) and Hammett substituent constants (σ) of difluoromethyl aryl sulfones, we solved the dilemma between acidities and reduction potentials of difluoromethylating agents. Herein, we report the first enantioselective difluoromethylation-alkynylation of olefins with difluoromethyl 4-chlorophenyl sulfone with high enantioselectivity (>90 % ee). We also extended this asymmetric fluoroalkylation-alkynylation reaction with other fluoroalkyl sulfones, which enabled efficient installation of trifluoromethyl, difluoroalkyl, difluorobenzyl, (benzenesulfonyl)-difluoromethyl and monofluoromethyl groups into products.


Inhibitory effects of dietary soy isoflavone and gut microbiota on contact hypersensitivity in mice.
Soy isoflavones (SIs) are abundant in soybeans and have inhibitory effects on contact hypersensitivity (CHS), which is often used as a mouse model for allergic contact dermatitis (ACD); however, their therapeutic mechanisms remain unknown. We studied the suppressive activity of dietary SI and gut microbiota on dinitrofluorobenzene (DNFB)-induced CHS. Low-dose SI diets alleviated DNFB-induced ear swelling and oedema and decreased infiltration of Gr-1-positive cells into ear tissue. In addition, dietary SIs also decreased interleukin-1β and chemokine (C-X-C motif) ligand 1 production in ear tissue compared to controls. Furthermore, ciprofloxacin and metronidazole treatments blocked the suppressive activity of dietary SIs on CHS, whereas vancomycin treatment had a marginal effect. These antibiotic treatments differed in their effects on the gut microbiota composition. These results demonstrated that consumption of physiologically relevant doses of SIs reduced CHS symptoms, and suggested that the gut microbiota influenced their suppressive activities on CHS.


Primary veloplasty: long-term results without maxillary deformity. a twenty-five year report.
Primary veloplasty during the first year of life enables normal growth of the upper jaw and of the facial skeleton in patients with clefts. In spite of the remaining cleft in the hard palate, intelligible speech can be learned. The closure of the residual cleft of the hard palate is generally postponed until the age of 12 to 14 years, when the normal growth of the jaw is virtually completed. This method has been used in the clinic by the author and his father for thirty years. The results after primary veloplasty for some hundred adult patients show normal maxillary and cranial growth both clinically and radiologically. Primary veloplasty operations constitute acceptable restorative surgical treatment of the maxilla. Various problems of timing and methods of cleft palate treatment are discussed. The author's cases are summarized.


Anisotropic polyethersulfone foam for bicycle helmet liners to reduce rotational acceleration during oblique impact.
Although current standard bicycle helmets protect cyclists against linear acceleration, they still lack sufficient protection against rotational acceleration during oblique impact events. Rotational acceleration is correlated with serious traumatic brain injuries such as acute subdural haematoma and thus should be minimized. This study proposes using highly anisotropic polyethersulfone foam for bicycle helmet liners in order to limit the rotational acceleration. Helmet prototypes, made of polyethersulfone foam with cell anisotropy direction perpendicular to the head, have been produced and compared to a standard commercial helmet. Standard helmets consist of expanded polystyrene foam. Oblique impact tests were performed to measure both linear and rotational accelerations and impact pulse duration. Results demonstrate that the peak rotational acceleration of the polyethersulfone prototype helmet showed a decrease of around 40% compared to the reference expanded polystyrene helmet. Moreover, the peak linear acceleration showed an average decrease of about 37%. Upon impact, the polyethersulfone helmet showed improved head injury protection when analysed based on global biomechanical head injury criteria such as HIC15 and HICrot as well as generalized acceleration model for brain injury threshold, brain injury criterion and head impact power, with a predicted sixfold decrease in likelihood of concussion.


Absorbable sandwich-like membrane for retinal-sheet transplantation.
Neural retinal transplantation has great potential for the alleviation of different degenerative and hereditary retinal disorders. However, because of the fragile and soft nature of retina, retinal-sheet transplantation is relatively difficult to achieve. To overcome this difficulty, we developed a technique for lamellar tissue transplantation. Biodegradable gelatin membranes were fabricated into a sandwich and encapsulated retinal grafts for transplantation. Before transplantation, we characterized the in vivo and in vitro properties of such membranes to determine the optimal sterilization procedure, that is, a sterile membrane with suitable degradability and good mechanical properties and without cytotoxicity. Three sterilization methods were conducted, with hydrogen peroxide gas plasma (HPGP), ethylene oxide (EO), and gamma-ray irradiation (gamma). The results were compared with those of a control (no disinfection). Initial studies revealed that the gelatin membranes sterilized with HPGP or EO exhibited retinal pigment epithelium (RPE) cytotoxicity, whereas the membrane sterilized by 16.6-kGy gamma ray irradiation had no RPE cytotoxicity and had enhanced mechanical properties. In the in vivo rabbit study, implanted gelatin membranes demonstrated satisfactory biocompatibility without any inflammation. Transplanted retinal sheets survived well and developed laminar structures. Such a method using gelatin membranes for tissue transportation has great potential for future routine retinal-sheet transplantation.


Identification of FLOT2 as a novel target for microRNA-34a in melanoma.
To confirm whether flotillin 2 (FLOT2) is a direct target of miR-34a and miR-34a/FLOT2 pathway plays a key role in melanoma proliferation and metastasis. First, miR-34a and FLOT2 expressions were both detected in human tissues and cell lines by qRT-PCR. Then, after transfection of mimics/inhibitor of miR-34a into melanoma cell lines, MTT, colony formation, scratch migration assays and transwell invasion assays were performed to evaluate the impact of miR-34a on cell proliferation and metastasis. Western blot, qRT-RCR and dual luciferase reporter gene assays were carried out to confirm whether FLOT2 is a direct target gene of miR-34a. In functional recovery experiments, proliferation and metastasis ability of WM35 and WM451 was tested after being co-transfected with miR-34a inhibitor/si-FLOT2 or miR-34a mimics/FLOT2 cDNA to confirm that FLOT2 is downregulated by miR-34a. The miR-34a significantly lower-expressed in metastasis melanoma tissues compared to in situ melanoma, nevi and normal skin whereas FLOT2 has an opposite trend. The level of miR-34a and FLOT2 in different melanoma cell lines was also tested and found that metastatic melanoma cell lines has lower miR-34a expression and higher FLOT2 expression compare to in situ melanoma cell line. MiR-34a overexpression profoundly inhibits WM451 cell proliferation and metastasis, whereas miR-34a reduction had a promoting effect to proliferation and metastasis of WM35. Results of Western blot, qRT-RCR and dual luciferase reporter gene assays revealed that FLOT2 is a direct target gene of miR-34a. Furthermore, overexpression/blockage of FLOT2 could attenuate effect of miR-34a overexpression/inhibition which indicated miR-34a suppresses melanoma biological behavior partially through FLOT2 inhibition. Our study confirmed that miR-34a is involved in the tumor inhibition of melanoma by directly targeting FLOT2 gene. This finding provides potential novel strategies for therapeutic interventions of melanoma.


[Central hemodynamic changes in children with locomotor system diseases during surgery and anesthesia].
Various neurovegetative reactions and disorders of circulation are observed in children with consequences of infantile cerebral paralysis (ICP). The manifestation of these reactions depends on the severity of motor disorders and the local painful syndrome. This study was aimed at detecting the changes in the central hemodynamics and development of measures preventing these changes during narcosis in patients with orthopedic consequences of ICP subjected to surgical treatment in an outpatient setting. In addition, we studied the possibility of wide use of calypsol in this category of patients in a one-day hospital. Autonomic reactivity was studied by cardiointervalography after Baevskiĭ. The stroke and minute volume were assessed by tetrapolar thoracic rheography after Kubecik. A total of 120 patients aged 7-14 years with ICP consequences were divided into 3 groups with motor disorders of different severity. Examinations during preparation to narcosis and narcosis revealed a relationship between autonomic and hemodynamic disorders and the severity of motor disorders. An optimal method for preventing hemodynamic changes associated with narcosis in an outpatient setting is proposed.


Erythema ab igne: new technology rebounding upon its users?
Erythema ab igne (EAI) is a persistent, chronic skin condition resulting from prolonged exposure to infrared radiation, experienced as heat. Once associated with traditional warming sources like wood burning stoves or open fires, modern, infrared exposure originates also from newer sources like laptops and heating pads and may be creating a rebound of EAI. The epidemiology may be different too, with younger patients than previously seen. Localized EAI over an area of pain in the abdomen or lower back can be a sign of an underlying disorder, including cancer. Prognosis of EAI is good, with removal of the heat source resulting in complete remission. In chronic cases in which premalignant cutaneous dysplasia has resulted, additional treatments may be necessary including topical retinoids, 5-fluorouracil cream, and laser treatments. Rarely, cancers such as squamous cell carcinoma, Merkel cell carcinoma, and cutaneous marginal zone B cell lymphoma have been associated with longstanding EAI.


[The Risk Factors of Cancer Chemotherapy in Elderly Patients].
The aging rate in Japan is the highest in the world, and it is entering a very aging society that has never happened before. The first cause of death is a malignant neoplasm, and opportunities of the treatment for elderly cancer patients are rapidly increasing. The elderly have increased chronic diseases and complications with aging, and the adverse event in medication therapy also increases. Also, the form of medical provision is diversified, home medical care and nursing care are recommended. Therefore, it is important to appreciate the various aspects including psychophysiological, living, social aspects in addition to changes in physical function caused by aging and appropriately evaluate them, for selecting treatment methods in elderly cancer patients. Geriatric assessment(GA)is recommended for this evaluation, and it is expected to contribute to improvement of treatment outcome and quality of life(QOL). In this article, we will outline the role of aged general comprehensive functional evaluation in elderly cancer treatment and the problems of chemotherapy in the elderly.


[Specific chemical modification of ribosomes in the vicinity of their mRNA-binding center].
4-N-2-chloroethyl-N-methylamino-benzaldehyde acetal derivatives (RCL-derivatives) of octauridylic and nanauridylic acids were used to localize the structures organizing mRNA-binding site of ribosomes. These derivatives, like free oligonucleotides, stimulate binding of 14C-phenylalanyl-tRNA to ribosomes. They effectively alkylate ribosomes within the specific complex. The extent of 30S subunit alkylations is much greater than that of 50S subunit, alkylation being completely inhibited by preincubation with polyridylic acid, suggesting that the chemical alteration occurs near mRNA-binding site. Both rRNA and proteins undergo modification in 30S subunit (75% and 25% of the total 30S subunit modification, respectively).


Two new triterpenes from Euphorbia alatavica.
A phytochemical investigation on Euphorbia alatavica Boiss resulted in the isolation of nine compounds, including two new ones, alatavolide and alatavoic acid (1-2). Chemical structures of these compounds were established on the basis of 1D, 2D NMR, and HR-MS techniques, and by comparison with data reported in the literature. Compounds 1, 2, 4, 6, 8, and 9 were screened for cytotoxicity using the MTT assay. Among these compounds, the new compound 2 showed moderate cytotoxicity against Hela, MCF-7 and A549 cell lines (IC50 values of 16.4 ± 3.2, 14.5 ± 2.8, 22.3 ± 3.1 μM, respectively), while the known compound 8 exhibited the most potent cytotoxicity with the IC50 values of 6.5 ± 3.1, 1.9 ± 0.9, 8.6 ± 3.5 μM, respectively.


A case of Mycobacterium fortuitum prosthetic joint infection successfully treated medically without prosthesis explantation or joint debridement.
A 58-year-old man with a history of end-stage degenerative joint disease developed a postsurgical infection at the right hip 4 weeks after hip replacement surgery. He underwent surgical washout of the right hip without opening the joint capsule. Arthrocentesis returned positive for Mycobacterium fortuitum He was started on antibiotics with the recommendation to remove the prosthesis. The prosthesis was retained. Based on antimicrobial susceptibilities, he was treated with 4 weeks of intravenous therapy using cefoxitin and amikacin and later switched to oral ciprofloxacin and doxycycline for 5 additional months. Eighteen months from his initial hip replacement surgery, he continues to do well. Joint aspiration culture is important to make a diagnosis of prosthetic joint infection (PJI) when periprosthetic culture is not available. In the absence of serious systemic or comorbid joint conditions, PJI due to M. fortuitum can be managed medically without having to remove the prosthesis or debride the joint.


Detecting breast cancer in a general practice - Like finding needles in a haystack?
Breast cancer contributes the largest burden of cancer related disease in Australian women. Early detection is an important part of the general practitioner's work, with clinical audit recommended to help improve the quality of such work. A clinical database was analysed for newly diagnosed breast cancer patients of one GP for the years 1986-2006. Thirty new cases of breast cancer were diagnosed, with 87% in the 'early' stages. Fifty-seven percent were outside the target age of 50-69 years used by BreastScreen to recruit women for screening. Apparent false-negative investigations occurred in 33% of cases. The mean time interval between women noting symptoms and consulting the GP was 84 days and the mean time interval from first presentation to final diagnosis was 54 days. The diagnosis of breast cancer in this series was relatively infrequent, and prior apparent false-negative investigations were not uncommon. As many women diagnosed were outside the usual mammography screening age range of 50-69 years, there is a need for constant awareness of the possibility of breast cancer in all female patients. Encouraging women to present early with breast symptoms and adherence to the 'triple test' recommendation of clinical breast examination, imaging and biopsy for women with breast symptoms is important to minimise the risk of diagnostic delay.


Helicobacter pylori virulence genes and host genetic polymorphisms as risk factors for peptic ulcer disease.
Helicobacter pylori infection plays an important role in the pathogenesis of peptic ulcer disease (PUD). Several factors have been proposed as possible H. pylori virulence determinants; for example, bacterial adhesins and gastric inflammation factors are associated with an increased risk of PUD. However, differences in bacterial virulence factors alone cannot explain the opposite ends of the PUD disease spectrum, that is duodenal and gastric ulcers; presumably, both bacterial and host factors contribute to the differential response. Carriers of the high-producer alleles of the pro-inflammatory cytokines IL-1B, IL-6, IL-8, IL-10, and TNF-α who also carry low-producer allele of anti-inflammatory cytokines have severe gastric mucosal inflammation, whereas carriers of the alternative alleles have mild inflammation. Recent reports have suggested that the PSCA and CYP2C19 ultra-rapid metabolizer genotypes are also associated with PUD.


[Etiology and clinical manifestations of hepatic space-occupying lesions].
Hepatic space-occupying lesions refer to the lesions which are located in the abnormal echo area or density area of the liver parenchyma, have the appearance of nodule or mass, occupy a certain space, and may cause pressure, displacement, or invasion of adjacent liver tissue and vessels, as determined by imaging examination. Hepatic space-occupying lesions have various causes, as well as similarities and differences in clinical manifestations. An understanding of the etiology and clinical manifestations of hepatic space-occupying lesions helps with their diagnosis and differential diagnosis and the development of targeted therapeutic regimens to improve prognosis. This article introduces related issues, in order to help clinical physicians to expand their thoughts in diagnosis and treatment.


Natural antioxidants and hypertension: promise and challenges.
Hypertension reigns as a leading cause of cardiovascular morbidity and mortality worldwide. Excessive reactive oxygen species (ROS) have emerged as a central common pathway by which disparate influences may induce and exacerbate hypertension. Potential sources of excessive ROS in hypertension include nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, mitochondria, xanthine oxidase, endothelium-derived NO synthase, cyclooxygenase 1 and 2, cytochrome P450 epoxygenase, and transition metals. While a significant body of epidemiological and clinical data suggests that antioxidant-rich diets reduce blood pressure and cardiovascular risk, randomized trials and population studies using natural antioxidants have yielded disappointing results. The reasons behind this lack of efficacy are not completely clear, but likely include a combination of (1) ineffective dosing regimens, (2) the potential pro-oxidant capacity of some of these agents, (3) selection of subjects less likely to benefit from antioxidant therapy (too healthy or too sick), and (4) inefficiency of nonspecific quenching of prevalent ROS versus prevention of excessive ROS production. Commonly used antioxidants include Vitamins A, C and E, L-arginine, flavanoids, and mitochondria-targeted agents (Coenzyme Q10, acetyl-L-carnitine, and alpha-lipoic acid). Various reasons, including incomplete knowledge of the mechanisms of action of these agents, lack of target specificity, and potential interindividual differences in therapeutic efficacy preclude us from recommending any specific natural antioxidant for antihypertensive therapy at this time. This review focuses on recent literature evaluating naturally occurring antioxidants with respect to their impact on hypertension.


Variation in the mortality rate of turkeys during transport to the slaughterhouse with travel distance and month.
Failure to comply with animal welfare requirements during the transport of turkeys to the slaughterhouse increases stress in animals, which is manifested by increased mortality rate during transport. The numbers of turkeys that died during transport or soon after arrival may serve as an important parameter to indicate the level of animal welfare during transport of turkeys. The number of turkeys that died during transport to slaughterhouses in the Czech Republic in the period from 1997 to 2004 was investigated. The mortality rate found was 0.28% +/- 0.06% but varied with travel distance. The lowest mortality rate was found in case of travel distance below 50 km (0.18% +/- 0.08%) while long travel distances resulted in considerable increase in the mortality rates of turkeys (between 0.28% +/- 0.07 and 0.37% +/- 0.10%). The mortality rate of transported turkeys was also affected by the particular month of the year. Thus, the highest overall mortality rate occurred at long travel distances during winter months, i.e. in December (0.34% +/- 0.18%), January (0.32% +/- 0.06%), and February (0.36% +/- 0.07%). The comparison of individual years has shown a long-term trend towards a decrease in turkeys' mortality during transportation to slaughterhouses from 0.32% in 1998 to 0.20% in 2004. The decrease was statistically significant (Spearman's rank correlation coefficient r = -0.86, p < 0.01). This trend can be evaluated as positive.


Tiresias and the breast: thinking of Lacan, interpretation, and caring.
Lacan's intellectual complexity and fascination with language are too often taken as an indication that in his conception of analysis there is no room for caring and love. In this paper we argue that this impression represents a misunderstanding of Lacan. We explore the role of the analyst according to Lacan, both as the 'subject of absolute knowledge', 'supporting the function Tiresias' and the 'man of care' with breasts. To Lacan, the process of analysis is an adventure into the realm of the exotic where there is a complexity of excitement and deep anxiety, an interplay of words and illusive exploding breasts, the birth and death of desire, and the confrontation with the illusion of 'self'. The analyst recognises the patience and courage necessary to face this and to understand that 'life is a foreign language; all men mispronounce it' (Morley, 1925, p. 188).


Different case definitions to describe the prevalence of occupational carpal tunnel syndrome in meat industry workers.
The aim of this study was to assess the prevalence of carpal tunnel syndrome (CTS) in a group of meat industry workers, using typical symptoms, median nerve conduction studies (NCSs) and their combinations. In the case definition including the NCSs, we tested the electrodiagnostic reference values derived from the general healthy population and from the asymptomatic study population. One-hundred fourteen workers were examined by clinical interviews and median NCSs. The prevalence of CTS varied from 11% to 53%, with a progressive reduction passing from symptoms to NCSs to the their combinations. The prevalence was identical and the highest at the same time (53%) considering the case definitions based only on the symptoms and only on the NCSs with Kimura's reference values. Using the asymptomatic workers' electrodiagnostic reference values, alone or in combination with symptoms, the prevalence of CTS was the lowest (respectively, 15% and 11%). In the epidemiological studies, median NCSs should be considered desirable, if not essential, for confirming a clinical diagnosis, most of all in the longitudinal studies. In the future of CTS diagnosis, attention should be paid to the electrodiagnostic reference values that are discriminating to confirm the presence or not of the disease.


Functioning of adults in alcohol use disorder treatment: Role of concerned others.
This study examined patients in treatment for alcohol use disorders ("Patients") and their "concerned others" (COs-family and friends): (1) Did Patients' functioning differ according to COs' study participation? Among Patients with participating COs, (2) did Patients and COs agree on Patients' functioning, and (3) was Patients' functioning associated with COs' functioning and quality of CO-Patient relationships? Four-hundred and two Patients (mean age = 44, majority white men) and 277 COs (mean age = 52, majority white women) completed validated assessments. (1) Unexpectedly, Patients who did not identify a CO for potential study participation had more protective factors against future substance use and more readiness to participate in Alcoholics Anonymous (AA) than patients who did identify a CO. (2) Patients had higher scores than COs did when rating the Patient's protective factors, viewed the Patient-CO relationship as having more resources and fewer stressors than COs did, and reported fewer incidents of violence toward the CO than the CO did. (3) Patients had higher risk factors scores when their COs binge drank, and the Patient-CO relationship had more stressors and violence. Patients had higher protective factors scores when COs had greater readiness for Al-Anon participation, and Patients had attended more AA meetings, reported more resources in their relationship with their CO, and used more negotiation tactics when in conflict with their CO. Findings suggest that interventions to improve Patients' functioning should be broadened beyond COs who are spouses or partners, decrease COs' binge drinking, facilitate 12-step participation, decrease relationship stressors and conflict, and increase relationship resources.


[Thinking about vertigo effectiveness evaluation methods in clinical research of Chinese medicine].
Vertigo is a kind of patients' subjective feelings. The severity of vertigo is closely related to many factors. But we are short of a well accepted quantitative evaluation method capable of accurately and comprehensively evaluating vertigo in clinics. Reducing the onset of vertigo, enhancing the re- covery of equilibrium function, and improving the quality of life of vertigo patients should be taken as the focus of evaluating therapeutic effects. As for establishing a Chinese medical effectiveness evaluation system for vertigo, we believe we should distinguish different "diseases". We could roughly identify it as systemic vertigo and non-systemic vertigo. For systemic vertigo, the efficacy of vertigo could be comprehensively evaluated by UCLA vertigo questionnaire or dizziness handicap inventory combined with equilibrium function testing indices. But for non-systemic vertigo, the efficacy of vertigo could be comprehensively evaluated by taking UCLA vertigo questionnaire or dizziness handicap inventory as main efficacy indices. Secondly, we should analyze different reasons for vertigo, choose symptoms and signs in line with vertigo features as well as with Chinese medical theories, and formulate corresponding syndrome effectiveness standards according to different diseases. We should not simply take syndrome diagnosis standards as efficacy evaluation standards.


Emerging Trends in Behavioral Genetic Studies of Child Temperament.
In this article, we describe three emerging trends in the application of behavioral genetic methods to the study of temperament. The trends-using multiple methods to assess temperament, considering contextual influences on temperament, and evaluating the structure of temperament-have been well studied in the phenotypic literature, but adding a behavioral genetic perspective can enrich our understanding of temperament. We review recent behavioral genetic research in each of these areas and discuss its implications.


Natural combinatorial biosynthesis involving two clusters for the synthesis of three pyrrolamides in Streptomyces netropsis.
The pyrrolamides constitute a small family of secondary metabolites that are known for their ability to bind noncovalently to the DNA minor groove with some sequence specificity. To date, only a single pyrrolamide biosynthetic gene cluster has been reported, directing the synthesis of congocidine (netropsin) in Streptomyces ambofaciens. In this study, we improve our understanding of pyrrolamide biosynthesis through the identification and characterization of the gene cluster responsible for the production of distamycin in Streptomyces netropsis DSM40846. We discover that the strain produces two other pyrrolamides, the well-characterized congocidine and a congocidine/distamycin hybrid that we named disgocidine. S. netropsis DSM40846 genome analysis led to the identification of two distinct pyrrolamide-like biosynthetic gene clusters. We show here that these two clusters are reciprocally dependent for the production of the three pyrrolamide molecules. Furthermore, based on detailed functional analysis of these clusters, we propose a biosynthetic route to congocidine and distamycin and an updated model for pyrrolamide assembly. The synthesis of disgocidine, the distamycin/congocidine hybrid, appears to constitute the first example of "natural combinatorial biosynthesis" between two related biosynthetic pathways. Finally, we analyze the genomic context of the two biosynthetic gene clusters and suggest that the presently interdependent clusters result from the coevolution of two ancestral independent pyrrolamide gene clusters.


Effectiveness of Various Endodontic Irrigants on the Micro-Hardness of the Root Canal Dentin: An in vitro Study.
Irrigating solutions used for the elimination of micro-organisms during root canal preparation may affect the chemical and the physical properties of dentin thereby rendering the tooth more susceptible to fracture. Therefore careful and judicious selection of irrigant is required which have maximum benefits with minimum undesirable properties. The aim of the present study was to evaluate the effect of various endodontic irrigants on the micro-hardness of the root canal dentin. This in vitro study was carried out on eighty freshly extracted mandibular premolars with single canals. They were decoronated at the cemento-enamel junction. Roots were sectioned longitudinally into two halves. They were then polished and placed in autopolymerised resin moulds with the polished surface facing outside. The samples were divided into four groups based on the irrigants in which they were immersed i.e., 3% Sodium Hypochlorite (3% NaOCl), 17% Ethylene Dioxide Tetra Acetic Acid (17% EDTA), 0.2% Chitosan and 6% Morindacitrifolia Juice (MCJ) for 15 minutes each. All the specimens were then subjected to micro-hardness testing using a Vickers micro-hardness tester. Statistical analysis was done using one way Analysis of Variance (ANOVA), Post-Hoc Tukey test and Paired t-test to compare the pre and post immersion micro-hardness values of the selected samples. The results of the present study indicated that 17% EDTA and 0.2% Chitosan, significantly decreased the micro-hardness of root dentin whereas 6% MCJ and 3% NaOCl had no significant effect on the microhardness before and after immersing in the irrigants. A 6% MCJ and 3% NaOCl which have significant antibacterial, antifungal, anti-inflammatory and smear layer removing properties showed negligible effect on the micro-hardness of root canal dentin making them suitable endodontic irrigating solution.


Absence of Fer protein-tyrosine kinase exacerbates leukocyte recruitment in response to endotoxin.
The group IV cytoplasmic protein-tyrosine kinase Fer has been linked to cellular signaling responses to many different stimuli, including growth factors and cytokines. However, the biological relevance of Fer activation in vivo has not been demonstrated to date. Recently, we generated a transgenic mouse line in which Fer protein is expressed but lacks catalytic activity. Homozygous mutant mice were viable and fertile, and showed no overt defects. In this study, we used intravital microscopy to examine the role of Fer kinase in leukocyte recruitment (rolling adhesion and emigration) in response to LPS challenge in skeletal muscle microcirculation. In addition, we measured vascular permeability changes (FITC-albumin leakage, venular-to-interstitial space) in response to Ag to examine general endothelial cell function. Local administration of LPS induced decreased leukocyte rolling velocity and increased leukocyte adhesion and emigration in wild-type mice. LPS-induced changes in leukocyte rolling velocity and rolling flux were not significantly different in Fer mutants. However, LPS-induced leukocyte adhesion (23 +/- 3 vs 11 +/- 3 cells/100 microm) and emigration (100 +/- 5 vs 28 +/- 7 cells/field) were significantly elevated in Fer-mutant mice relative to wild-type mice, respectively, suggesting an essential role for the Fer kinase in regulating inflammation-induced leukocyte emigration. Vascular permeability increases in response to Ag were similar between the two groups, indicating that the ability of endothelial cells to retract is intact in the absence of Fer kinase. These data provide the first evidence for a biological role for Fer in regulation of leukocyte recruitment during the innate immune response.


Small bowel metastasis from primary neuroendocrine small cell lung carcinoma.
Small bowel metastases from a primary lung carcinoma are rare. We report a case of a 76-year-old male with a primary neuroendocrine small cell carcinoma of the lung, treated by chemotherapy, who developed fever and bowel symptoms (subocclusion and pain). On CT examination, he was found to have a tumour in the small bowel. The patient then underwent abdominal surgery. At operation we found small bowel occlusion by neoplasia and we therefore resected 15 cm of ileum with a side-to-side anastomosis. Early recognition of this rare condition is important due to the fact that complicated intestinal metastases from lung carcinoma can lead to high mortality rates and poor short-term outcomes. With advances in chemotherapy and palliative care, patients with metastatic lung carcinoma can sometimes survive more than a year with a reasonable quality of life.


Identification of WDR12 as a novel oncogene involved in hepatocellular carcinoma propagation.
Hepatocellular carcinoma (HCC) is one of the most common malignant cancer worldwide. Importantly, the precise mechanisms causing HCC pathogenicity are still unknown. The identification of potential oncogenes plays significant roles in finding novel therapeutic targets for human HCC. WDR12 (WD repeat protein 12), a member of WD repeats family, plays crucial roles in the ribosome biogenesis pathway. However, Whether WDR12 contributes to HCC development remains unknown. The objective of this study was to elucidate the role of WDR12 in HCC development. The expression level of WDR12 in HCC tissues and adjacent non-tumor tissues were detected form Gene Expression Omnibus (GEO) database. The expression level of WDR12 in HCC cell lines were examined by RT-PCR and western blot. Kaplan-Meier analysis were used to analyze the effect of WDR12 level on overall and disease-free survival of HCC patients. To examine whether WDR12 supports development of HCC, we inhibited expression of WDR12 by using an shRNA-encoding lentivirus system. Effects of WDR12 knockdown were evaluated on cell-growth, cell-proliferation and cell-migration. The mechanisms involved in HCC cells growth, proliferation and migration were analyzed by western blot assay. In silico analysis of HCC data sets showed that elevated expression of WDR12 correlated with high serum AFP level, high vascular invasion, high histologic grade and high TNM stage in HCC patients. Furthermore, up-regulated expression of WDR12 significantly correlated with the short overall survival and recurrence time of HCC patients. The shRNA-mediated knockdown of WDR12 expression resulted in reduced proliferation and migration of HepG2 and Huh-7 cells. Notably, inhibition of WDR12 resulted in decreased phosphorylation of AKT, mTOR and S6K1. Our study indicates that WDR12 contributes to HCC propagation, and indicates that suppression of WDR12 may be a potential strategy for human HCC treatment.


Advances in emerging drugs for the treatment of neuroblastoma.
Neuroblastoma is the most common solid extracranial tumor of childhood. Outcome for children with high-risk neuroblastoma remains suboptimal. More than half of children diagnosed with high-risk neuroblastoma either do not respond to conventional therapies or relapse after treatment with dismal prognosis. Areas covered: This paper presents a short review of the state of the art in the current treatment of high-risk neuroblastoma. An updated review of new targeted therapies in this group of patients is also presented. Expert opinion: In order to improve prognosis for high-risk patients there is an urgent need to better understand spatial and temporal heterogeneity and obtain new predictive preclinical models in neuroblastoma. Combination strategies with conventional chemotherapy and/or other targeted therapies may overcome current ALK inhibitors resistance. Improvement of international and transatlantic cooperation to speed clinical trials accrual is needed.


Association of the neutrophil to lymphocyte ratio and white blood cell count with response to pharmacotherapy in unipolar psychotic depression: An exploratory analysis.
Low-grade inflammation occurs in a subgroup of patients with Major Depressive Disorder (MDD) and may be associated with response to antidepressant medications. The Neutrophil to Lymphocyte Ratio (NLR) and total White Blood cell Count (WBC) are markers of systemic inflammation which have not been investigated as predictors for outcome to pharmacotherapy in unipolar depression yet. Moreover, the association between inflammation and treatment response has not been studied in unipolar Psychotic Depression (PD). We conducted an exploratory analysis to examine the prognostic significance of NLR and WBC in pharmacotherapy of PD. Baseline NLR and WBC were examined in their association with response to seven weeks of treatment with antidepressants (venlafaxine or imipramine) and the combination of an antidepressant with an antipsychotic (venlafaxine plus quetiapine) in 87 patients with PD. Logistic regression models were adjusted for age, gender, Body Mass Index (BMI), depression severity, duration of the current episode and number of previous depressive episodes. Secondary outcomes were remission of depression and disappearance of psychotic symptoms. Higher NLR was associated with increased response to pharmacotherapy (Exp(B) 1.66, 95 % CI 1.03-2.66, p = 0.036), but not with remission of depression or disappearance of psychotic symptoms. WBC was not associated with any of the outcome measures. NLR may be a novel, inexpensive and widely available biomarker associated with response to pharmacotherapy in PD. The association between white blood cell measures and treatment outcome should be further investigated for different types of antidepressants in PD and in non-psychotic MDD.


Effect of tannic acid on the transcriptome of the soil bacterium Pseudomonas protegens Pf-5.
Tannins are a diverse group of plant-produced, polyphenolic compounds with metal-chelating and antimicrobial properties that are prevalent in many soils. Using transcriptomics, we determined that tannic acid, a form of hydrolysable tannin, broadly affects the expression of genes involved in iron and zinc homeostases, sulfur metabolism, biofilm formation, motility, and secondary metabolite biosynthesis in the soil- and rhizosphere-inhabiting bacterium Pseudomonas protegens Pf-5.


[Treatment for high-risk localized prostate cancer].
High-risk localized prostate cancer encompasses a significant heterogeneity and the treatment strategy for this group of prostate cancer patients remains controversial. The definition of high-risk localized prostate cancer is not consistent in that which clinicopathological parameters are included as risk factors. Therefore, we need to be careful in comparing the treatment outcome of each report. Recently, there have been significant improvements in the radiotherapeutic and surgical management. High radiation dose levels, long-term androgen deprivation therapy, and the combination of brachytherapy may contribute to the improvement of radiation-based treatment. Although some patients can be cured by standard surgical approach, extended lymph node dissection and multimodal treatment with radiation and chemohormonal therapy may improve surgical outcome. This review focuses on the recent treatment strategy for high-risk localized prostate cancer.


Advancing Target Identification of Nitrated Phospholipids in Biological Systems by HCD Specific Fragmentation Fingerprinting in Orbitrap Platforms.
Nitrated phospholipids have recently been detected in vitro and in vivo and associated with beneficial health effects. They were identified and quantified in biological samples by lipidomics methodologies using liquid chromatography-collision-induced dissociation (CID) tandem mass spectrometry (MS/MS) acquired with the linear ion trap mass spectrometer. Only a few studies have used higher-energy collision dissociation (HCD)-MS/MS in high-resolution Orbitraps to characterize nitrated phosphatidylserines and nitrated cardiolipins, highlighting the marked differences in the fragmentation patterns when using CID or HCD fragmentation methods. In this study, we aimed to evaluate the fragmentation of nitrated phosphatidylcholine and nitrated phosphatidylethanolamine species under HCD-MS/MS. We studied the effect of normalized collision energy (NCE) in the fragmentation pattern to identify the best acquisition conditions and reporter ions to detect nitrated phospholipids. The results showed that the intensity of the typical neutral loss of nitrous acid (HNO2) diminishes with increasing NCE, becoming non-detectable for a higher NCE. Thus, the loss of HNO2 could not be the most suitable ion/fragment for the characterization of nitrated phospholipids under HCD. In HCD-MS/MS new fragment ions were identified, corresponding to the nitrated fatty acyl chains, NO2-RCOO-, (NO2-RCOOH-H2O + H)+, and (NO2-RCOOH + H)+, suggested as potential reporter ions to detect nitrated phospholipids when using the HCD-MS/MS lipidomics analysis.


A randomized multicenter trial on a lung ultrasound-guided treatment strategy in patients on chronic hemodialysis with high cardiovascular risk.
Lung congestion is a risk factor for all-cause and cardiovascular mortality in patients on chronic hemodialysis, and its estimation by ultrasound may be useful to guide ultrafiltration and drug therapy in this population. In an international, multi-center randomized controlled trial (NCT02310061) we investigated whether a lung ultrasound-guided treatment strategy improved a composite end point (all-cause death, non-fatal myocardial infarction, decompensated heart failure) vs usual care in patients receiving chronic hemodialysis with high cardiovascular risk. Patient-Reported Outcomes (Depression and the Standard Form 36 Quality of Life Questionnaire, SF36) were assessed as secondary outcomes. A total of 367 patients were enrolled: 183 in the active arm and 180 in the control arm. In the active arm, the pre-dialysis lung scan was used to titrate ultrafiltration during dialysis and drug treatment. Three hundred and seven patients completed the study: 152 in the active arm and 155 in the control arm. During a mean follow-up of 1.49 years, lung congestion was significantly more frequently relieved in the active (78%) than in the control (56%) arm and the intervention was safe. The primary composite end point did not significantly differ between the two study arms (Hazard Ratio 0.88; 95% Confidence Interval: 0.63-1.24). The risk for all-cause and cardiovascular hospitalization and the changes of left ventricular mass and function did not differ among the two groups. A post hoc analysis for recurrent episodes of decompensated heart failure (0.37; 0.15-0.93) and cardiovascular events (0.63; 0.41-0.97) showed a risk reduction for these outcomes in the active arm. There were no differences in patient-reported outcomes between groups. Thus, in patients on chronic hemodialysis with high cardiovascular risk, a treatment strategy guided by lung ultrasound effectively relieved lung congestion but was not more effective than usual care in improving the primary or secondary end points of the trial.


Differential response of archaeal and bacterial communities to nitrogen inputs and pH changes in upland pasture rhizosphere soil.
Grassland management regimens influence the structure of archaeal communities in upland pasture soils, which appear to be dominated by as yet uncultivated non-thermophilic Crenarchaeota. In an attempt to determine which grassland management factors select for particular crenarchaeal community structures, soil microcosm experiments were performed examining the effect of increased pH, application of inorganic fertilizer (ammonium nitrate) and sheep urine deposition on both archaeal and bacterial communities in unmanaged grassland soil. As grassland management typically increases pH, a further experiment examined the effect of a reduction in pH, to that typical of unimproved grassland soils, on archaeal and bacterial communities. The RT-PCR amplification of 16S rRNA followed by denaturing gradient gel electrophoresis analysis demonstrated a distinct and reproducible effect on bacterial communities after incubation for 28 or 30 days. In contrast, none of the treatments had a significant effect on the structure of the crenarchaeal community, indicating that these factors are not major drivers of crenarchaeal community structures in grassland soils.


Illuminating the conceptual structure of the space of moral violations with searchlight representational similarity analysis.
Characterizing how representations of moral violations are organized, cognitively and neurally, is central to understanding how people conceive and judge them. Past work has identified brain regions that represent morally relevant features and distinguish moral domains, but has not yet advanced a broader account of where and on what basis neural representations of moral violations are organized. With searchlight representational similarity analysis, we investigate where category membership drives similarity in neural patterns during moral judgment of violations from two key moral domains: Harm and Purity. Representations converge across domains in a network of regions resembling the mentalizing network. However, Harm and Purity violation representations respectively converge in different regions: precuneus (PC) and left inferior frontal gyrus (LIFG). Examining substructure within moral domains, Harm violations converge in PC regardless of subdomain (physical harms, psychological harms), while Purity subdomains (pathogen-related violations, sex-related violations) converge in distinct sets of regions - mirroring a dissociation observed in principal-component analysis of behavioral data. Further, we find initial evidence for representation of morally relevant features within these two domain-encoding regions. The present analyses offer a case study for understanding how organization within the complex conceptual space of moral violations is reflected in the organization of neural patterns across the cortex.


[Thinking on teaching experiences of acupuncture manipulation and moxibustion method in western medicine college].
For the problems existed in the teaching of acupuncture manipulation and moxibustion method in western medicine college, for instance, the lack of credit hours and divorce from theory and practice, in addition to visualization teaching, this paper introduced case study and problem-centered teaching approaches. Besides clinical teaching, this paper emphasized anatomical knowledge which strengthen memory. In this way, the quality of teaching and teaching effects will be improved in the education of acupuncture manipulation and moxibustion method in western medicine college.


Quantification of Residual Germinal Center Activity and HIV-1 DNA and RNA Levels Using Fine Needle Biopsies of Lymph Nodes During Antiretroviral Therapy.
HIV-1 reservoirs are most often studied in peripheral blood (PB), but not all lymphocytes recirculate, particularly T follicular helper (Tfh) CD4+ T cells, as well as germinal center (GC) B cells, in lymph nodes (LNs). Ultrasound-guided fine needle biopsies (FNBs) from inguinal LNs and PB samples were obtained from 10 healthy controls (HCs) and 21 HIV-1-infected subjects [11 antiretroviral therapy (ART) naive and 10 on ART]. Tfh cells and GC B cells were enumerated by flow cytometry. HIV-1 DNA and cell-associated (CA) RNA levels in LNs and PB were quantified by real-time polymerase chain reaction. FNBs were obtained without adverse events. Tfh cells and GC B cells were highly elevated in ART-naive subjects, with a median GC B cell count >300-fold higher than HCs, but also remained higher in 4 out of the 10 subjects on ART. GC B cell counts and Tfh cell counts were highly correlated with each other, and also with activated T cells in LNs but not in blood. Levels of HIV-1 DNA and CA RNA viral burden in highly purified CD4+ T cells from FNBs were significantly elevated compared with those in CD4+ T cells from PB in the ART-naive group, but only trended toward an increase in the ART patients. FNBs enabled minimally invasive access to, and parallel measurement of residual activated T and B cells and viral burden within LNs in HIV-1-infected patients. These FNBs revealed significant GC activity that was not apparent from corresponding PB samples.


Effects of laterally wedged insoles on symptoms and disease progression in medial knee osteoarthritis: a protocol for a randomised, double-blind, placebo controlled trial.
Whilst laterally wedged insoles, worn inside the shoes, are advocated as a simple, inexpensive, non-toxic self-administered intervention for knee osteoarthritis (OA), there is currently limited evidence to support their use. The aim of this randomised, double-blind controlled trial is to determine whether laterally wedges insoles lead to greater improvements in knee pain, physical function and health-related quality of life, and slower structural disease progression as well as being more cost-effective, than control flat insoles in people with medial knee OA. Two hundred participants with painful radiographic medial knee OA and varus malalignment will be recruited from the community and randomly allocated to lateral wedge or control insole groups using concealed allocation. Participants will be blinded as to which insole is considered therapeutic. Blinded follow up assessment will be conducted at 12 months after randomisation. The outcome measures are valid and reliable measures recommended for OA clinical trials. Questionnaires will assess changes in pain, physical function and health-related quality-of-life. Magnetic resonance imaging will measure changes in tibial cartilage volume. To evaluate cost-effectiveness, participants will record the use of all health-related treatments in a log-book returned to the assessor on a monthly basis. To test the effect of the intervention using an intention-to-treat analysis, linear regression modelling will be applied adjusting for baseline outcome values and other demographic characteristics. Results from this trial will contribute to the evidence regarding the effectiveness of laterally wedged insoles for the management of medial knee OA. ACTR12605000503628; NCT00415259.


Continental-scale effects of nutrient pollution on stream ecosystem functioning.
Excessive nutrient loading is a major threat to aquatic ecosystems worldwide that leads to profound changes in aquatic biodiversity and biogeochemical processes. Systematic quantitative assessment of functional ecosystem measures for river networks is, however, lacking, especially at continental scales. Here, we narrow this gap by means of a pan-European field experiment on a fundamental ecosystem process--leaf-litter breakdown--in 100 streams across a greater than 1000-fold nutrient gradient. Dramatically slowed breakdown at both extremes of the gradient indicated strong nutrient limitation in unaffected systems, potential for strong stimulation in moderately altered systems, and inhibition in highly polluted streams. This large-scale response pattern emphasizes the need to complement established structural approaches (such as water chemistry, hydrogeomorphology, and biological diversity metrics) with functional measures (such as litter-breakdown rate, whole-system metabolism, and nutrient spiraling) for assessing ecosystem health.


Abnormal frontal activations related to decision-making in current and former amphetamine and opiate dependent individuals.
There is converging evidence for impairments in decision-making in chronic substance users. In the light of findings that substance abuse is associated with disruptions of the functioning of the striato-thalamo-orbitofrontal circuits, it has been suggested that decision-making impairments are linked to frontal lobe dysfunction. We sought to investigate this possibility using functional neuroimaging. Decision-making was investigated using the Cambridge Risk Task during H2(15)O PET scans. A specific feature of the Risk Task is the decisional conflict between an unlikely high reward option and a likely low reward option. Four groups, each consisting of 15 participants, were compared: chronic amphetamine users, chronic opiate users, ex-drug users who had been long-term amphetamine/opiate users but are abstinent from all drugs of abuse for at least 1 year and healthy matched controls without a drug-taking history. During decision-making, control participants showed relatively greater activation in the right dorsolateral prefrontal cortex, whereas participants engaged in current or previous drug use showed relatively greater activation in the left orbitofrontal cortex. Our results indicate a disturbance in the mediation by the prefrontal cortex of a risky decision-making task associated with amphetamine and opiate abuse. Moreover, this disturbance was observed in a group of former drug users who had been abstinent for at least 1 year.


Effects of basic medical insurance integration on subjective wellbeing of residents in China: empirical evidence from a quasi-experiment.
Enhancing the wellbeing of residents through universal health coverage (UHC) is a long-term policy goal for China. In 2016, China integrated the New Rural Cooperative Medical Scheme (NRCMS) and the Urban Resident Basic Medical Insurance (URBMI) into the Urban and Rural Resident Basic Medical Insurance (URRBMI) to address the problem of fragmentation. The objective of this study was to investigate whether the integration of basic medical insurance had an impact on the subjective wellbeing of Chinese residents. Using the China Household Finance Survey data of 2015 and 2019, we empirically estimated the influence of the integration of basic medical insurance on Chinese residents through the difference-in-difference method based on propensity score matching (PSM-DID). Our findings indicate that the integration of basic medical insurance improved the subjective wellbeing of the insured population. Additionally, through heterogeneity testing, we validated that the integration increased the subjective wellbeing of residents from less developed regions in West China and rural areas, as well as those with older adult dependents. However, the subjective wellbeing of low-income groups, who were expected to benefit more from the URRBMI, did not improve significantly, at least in the short term. According to our research, the integration of basic medical insurance in China supports the country's objective of achieving equality and providing universal benefits for its residents. The introduction of the URRBMI has had a positive impact on the subjective wellbeing of insured individuals. This is particularly beneficial for disadvantaged groups in less developed regions, as well as for residents with older adult dependents. However, the subjective wellbeing of the middle-income group has improved significantly, whereas that of the low-income group, despite being the intended beneficiaries of the integration, did not show significant improvement. From a funding perspective, we recommend establishing a dynamic adjustment funding system that links residents' medical insurance funding standards with their disposable income. Regarding the utilization of the URRBMI, the benefit packages should be expanded, particularly by covering more outpatient services through risk pooling. We call for further research with additional data and continued efforts on improving wellbeing of residents, particularly for disadvantaged populations.


Severe Hypernatremia Caused by Acute Exogenous Salt Intake Combined with Primary Hypothyroidism.
This report describes a case of severe hypernatremia with a serum sodium concentration of 188.1mmol/L caused by exogenous salt intake. A 26-year-old man diagnosed with Crohn's disease 5 years previously visited our clinic due to generalized edema and personality changes, with aggressive behavior. He had compulsively consumed salts, ingesting approximately 154 g of salt over the last 4 days. Despite careful fluid management that included not only hypotonic fluid therapy for 8 hours but also hypertonic saline administration, his serum sodium level decreased sharply at 40.6 mmol/L; however, it returned to normal within 72-hour of treatment without any neurological deficits. Primary hypothyroidism was also diagnosed. He was discharged after 9 days from admission, with a stable serum sodium level. We have described the possibility of successful treatment in a patient with hypernatremia caused by acute salt intoxication without sustained hypotonic fluid therapy.


The Distance between N and C Termini of Tau and of FTDP-17 Mutants Is Modulated by Microtubule Interactions in Living Cells.
The microtubule (MT)-associated protein Tau is a natively unfolded protein, involved in a number of neurodegenerative disorders, collectively called tauopathies, aggregating in neurofibrillary tangles (NFT). It is an open question how the conversion from a MT bound molecule to an aggregation-prone Tau species occurs and, also, if and how tauopathy-related mutations affect its behavior in the cell. To address these points, we exploited a genetically encoded FRET sensor based on the full length Tau protein, to monitor in real time Tau conformational changes in different conditions in live cells. By studying the FRET signal we found that soluble Tau molecules, detached from MTs, display an unfolded structure. On the contrary, we observed an increased FRET signal generated by Tau monomers bound to MT, indicating that the association with MTs induced a folding of Tau protein, decreasing the distance between its N and C termini. We exploited the FRET sensor to investigate the impact of FTDP-17 mutations and of phosphorylation-site mutations on Tau folding and mobility in live cells. We demonstrated that the FTDP-17 Tau mutations weaken the interaction of Tau with cellular MTs, shifting the equilibrium towards the soluble pool while, conversely, phosphorylation site mutations shift the equilibrium of Tau towards the MT-bound state and a more closed conformation.


Taxifolin Glycoside Blocks Human ether-a-go-go Related Gene K(+) Channels.
Taxifolin glycoside is a new drug candidate for the treatment of atopic dermatitis (AD). Many drugs cause side effects such as long QT syndrome by blocking the human ether-a-go-go related gene (hERG) K(+) channels. To determine whether taxifolin glycoside would block hERG K(+) channels, we recorded hERG K(+) currents using a whole-cell patch clamp technique. We found that taxifolin glycoside directly blocked hERG K(+) current in a concentration-dependent manner (EC(50)=9.6±0.7 µM). The activation curve of hERG K(+) channels was negatively shifted by taxifolin glycoside. In addition, taxifolin glycoside accelerated the activation time constant and reduced the onset of the inactivation time constant. These results suggest that taxifolin glycoside blocks hERG K(+) channels that function by facilitating activation and inactivation process.


Effect of the ratio of vessel-specific volume to fractional myocardial mass on fractional flow reserve.
This study aimed to examine whether the ratio of vessel-specific coronary arterial lumen volume to the fraction of myocardial mass (VR/MR) affects myocardial ischemia. We proposed a calculation method for VR/MR, and compared the ratio of total epicardial coronary arterial lumen volume to left ventricular myocardial mass (V/M) with VR/MR in predicting myocardial ischemia. VR/MR and V/M were computed using data from 205 patients with 241 stenosis vessel who underwent coronary computed tomography angiography (CTA), quantitative coronary angiography, and fractional flow reserve. The vessel-specific coronary arterial lumen volume (VR) was obtained from CTA by segmenting the coronary arterial lumen volume, while the vessel-specific fraction of myocardial mass (MR) was obtained by allometric scaling. The VR/MR was then calculated. The cut-off values of V/M (23.55 mm3/g) and VR/MR (12.98 mm3/g) were used to define equal groups of ischemic and non-ischemic patients, respectively. Using these cut-off values, the accuracy, specificity, sensitivity, positive predictive value, and negative predictive value of V/M were 60%, 76%, 45%, 57%, and 66%, and of VR/MR were 87%, 92%, 77%, 89%, and 83%, respectively. Patients have different VR/MR values in different stenotic coronary arteries. Clinically, VR/MR is a quantitative indicator of the risk of myocardial ischemia.


Critical Test of the Beneficial Consequences of Lifting the Ban on Direct-to-Consumer Advertising for Prescription Drugs in Italy: Experimental Exposure and Questionnaire Study.
There are only two countries in the world (the United States and New Zealand) that allow the pharmaceutical branch to advertise prescription medication directly to consumers. There is pressure on governments to allow direct-to-consumer advertising (DTCA) for prescription drugs elsewhere too. One argument the industry uses frequently is the claim that exposure to DCTA, through various methods and occasions, is supposed to improve customers' knowledge of a disease and treatment. This argument has been part of the health care community's wider discussion of whether DTCA of prescription drugs benefits the population's general interest or is only an attempt to increase the sales of the pharmaceutical branch. Belief in true learning by DTCA is rooted in concepts of empowered consumers and their autonomous and empowered decision-making. In this study, we tested the hypotheses that contact with DTCA increases recipients' literacy/knowledge, especially regarding the side effects of treatment (hypothesis 1), and empowerment (hypothesis 2). We further hypothesized that DTCA exposure would not increase depression knowledge (ie, about treatments, symptoms, and prevalence) (hypothesis 3). A snowball sample of 180 participants was randomly split into three experimental groups receiving (1) a traditional information sheet, (2) a DTCA video clip for an antidepressant prescription drug, or (3) both. The video was original material from the United States translated into Italian for the experiment. Dependent variables were measures of depression knowledge (regarding treatments, symptoms and prevalence, and antidepressant side effects), depression literacy, and empowerment. None of the experimental groups differed significantly from the others in the empowerment measure (hypothesis 2 not confirmed). Partial confirmation of hypothesis 1 was obtained. Lower values on the depression literacy scale were obtained when participants had been given the video compared to the sheet condition. However, the general depression knowledge and its subscale on side effects reached higher scores when participants were exposed to the DTCA, alone or in combination with the information sheet. Finally, participants showed lower scores on knowledge about treatment and symptoms or prevalence after watching the video compared to the sheet condition (hypothesis 3 confirmed). Symptoms and prevalence knowledge increased only when the video was presented in combination with the sheet. There is no evidence for an increase in empowerment following DTCA exposure. An increase in knowledge of the side effects of the medication was observed in the group exposed to the DTCA video. This was the only result that confirmed the hypothesis of the beneficial effect of DTCA videos on knowledge. Written information proved to be the most suitable way to convey knowledge on treatments and symptoms prevalence. Our findings support the necessity of studying health literacy and patient empowerment together and the consequences of such an increase in knowledge in terms of help-seeking behavior.


Arabidopsis AGO4 loses its Cajal body localization when heterologously expressed in Nicotiana benthamiana.
In plants, the RNA-directed DNA methylation (RdDM) pathway plays a major role in establishing DNA methylation. At least some components of the RdDM machinery, including the central component AGO4, are known to concentrate in a subnuclear compartment called the Cajal body in the model plant Arabidopsis thaliana. The molecular underpinnings of Cajal body localization, however, have remained elusive so far. Here, we found that Arabidopsis AGO4 (AtAGO4) fused to GFP does not present its typical Cajal body localization, when transiently expressed in Nicotiana benthamiana. Nevertheless, the endogenous AGO4 protein from N. benthamiana shows a clear accumulation in the Cajal body. Thus, our results suggest that the Cajal body localization of AtAGO4 requires specific molecular machinery that cannot be replaced by orthologues in N. benthamiana. This study presents an experimental system that could lead to mechanistic insights into the targeting of proteins to and localization in the Cajal body in plants.


The effect of YNK-01 (an oral prodrug of cytarabine) on hepatocellular carcinoma.
Thirty-two patients with hepatocellular carcinoma (HCC) were treated with YNK-01, a prodrug of cytarabine for oral administration. A dose of 200 mg/d of YNK-01 was administered to 17 cases and 300 mg/d to 15 cases. One course was 2 weeks in duration, and this was repeated every 4 weeks for as long as the patients were able to tolerate it. There were five partial responses (15%) and 13 patients with no change (41%). A higher partial response rate was observed in the 300 mg/d group (27%) compared with the 200 mg/d group (6%). The average durations of partial response and no change were approximately 4 and 3 months, respectively. The main side effects of YNK-01 were anemia, leukopenia, thrombocytopenia, and symptoms of the alimentary tract (nausea, anorexia, diarrhea, etc). These results suggest that YNK-01 is a potentially useful oral agent for chemotherapy of hepatocellular carcinoma.


Management of children with non-organic (hysterical) disorders of motor function.
Five children aged between 10 and 13 years are discribed whose disorders of motor function were found to have a non-organic (hysterical) cause. In most cases extensive investigations had been made to establish an organic cause before the hysterical basis was diagnosed. The three essentials of management of such cases are to limit further investigations to the essential minimum, to institute quickly a programme of graduated physical rehabilitation, and to establish and treat the underlying psychological problems.


Chemotherapy of disseminated seminoma.
Nineteen patients with disseminated seminoma were treated with platinum + vinblastine + bleomycin +/- Adriamycin. All patients have been followed for at least 1 year. Nine patients had elevated HCG and two also had elevated AFP. Twelve of 19 patients (63%) achieved a complete remission, with a median duration of 18 months, and none of these patients have relapsed. Four of these patients have been in a continuous complete remission for over 2 years. The results of chemotherapy in metastatic seminoma are comparable to those achieved in nonseminomatous germ-cell tumors, and similar treatment strategies should be employed.


LC-MS/MS assay for protein amino acids and metabolically related compounds for large-scale screening of metabolic phenotypes.
A modified LC-MS/MS method for large-scale screening of metabolic phenotypes was developed and validated. Twenty amino acids and 5 metabolically related compounds are measured within 4 min using multiple reaction monitoring (MRM) transitions selective for each compound. Separation with a short C18 column and rapid gradient using the ion-pairing reagent perfluoroheptanoic acid allows chromatographic resolution of the isomers Ile and Leu and improved chromatographic peak shapes for Lys, Arg, and His. MRM transitions were established with capability to distinguish isomers Leu from Ile and Thr from homoserine even when chromatographic resolution is incomplete. The reproducibility of the assay was tested by adding eight stable isotope-labeled amino acid standards (AA*) to extracts of Arabidopsis thaliana seeds. In intra- and interday assay comparisons, mean coefficients of variation of the peak area ratios of AA/AA* were less than 5% for all but Gly/Gly-D2-15N1. Recoveries of these eight amino acids ranged from 62 to 94% and suppression of signal by the matrix were 31-65%. Dilution of seed extracts reduced ion suppression for early-eluting amino acids but had minimal effects for those eluting later. The intra- and interday accuracies for these eight amino acids were 77-131 and 88-133% of nominal concentrations, respectively.


Pharmacoangiographic evaluation of the hemodynamic significance of coronary artery stenoses.
Acute stenoses of varying degree were produced in the circumflex arteries of 5 calves, and chronic stenoses which reduced blood flow by about 50% were effected in the left anterior descending coronary arteries of 14 dogs. Selective vasodilators or amyl nitrite increased blood flow more than 100% in nonstenotic arteries, but less in stenotic ones. Increased transstenotic blood flow was associated with an increased pressure gradient and increased frequency of collateral circulation. Collateral circulation was sometimes recognizable when the pre- and postvasodilatory angiograms were compared but not when the angiograms were examined individually. The altered flow patterns demonstrated by comparative studies may be a very sensitive index of collateral circulation.


Local administration of a synthetic cell-penetrating peptide antagonizing TrkA function suppresses inflammatory pain in rats.
Novel agents that inhibit nerve growth factor signaling are required for the treatment of inflammatory pain. The present study investigated the effect of local administration of inhibitory peptide of TrkA (IPTRK3), a synthetic cell-penetrating peptide that antagonizes TrkA function, in complete Freund's adjuvant (CFA)-induced hyperalgesia in rats. Three hours after subcutaneous injection of CFA into the plantar surface of the rat's left hind paw, 10 mM IPTRK3 was injected at the same site. Thermal and mechanical hyperalgesia were tested in the ipsilateral hind paw until 7 days after CFA injection. The ipsilateral dorsal root ganglion (DRG) was dissected out for immunohistochemical analysis of transient receptor potential vanilloid subfamily member 1 (TRPV1) channels and TrkA. Local injection of this peptide significantly suppressed both thermal and mechanical hyperalgesia produced by CFA and also significantly reduced TRPV1 expression at the DRG. These results suggest that local administration of IPTRK3 is likely effective in the treatment of inflammatory pain in rats.


New aspects of molecular imaging in prostate cancer.
Nowadays several new imaging modalities are available for investigating prostate cancer (PCa) such as magnet resonance imaging (MRI) in the form of whole body MRI and pelvic multiparametric MRI and positron emission tomography (PET) using choline as radiotracers. Nevertheless, these modalities proved sub-optimal accuracy for detecting PCa metastases, particularly in the recurrence setting. A new molecular probe targeting the prostate specific membrane antigen (PSMA) has been recently developed for PET imaging. PSMA, the glutamate carboxypeptidase II, is a membrane bound metallo-peptidase over-expressed in PCa cells. It has been shown that PSMA based imaging offers higher tumor detection rate compared to choline PET/CT and radiological conventional imaging, especially at very low PSA levels during biochemical recurrence. In addition PSMA, as theranostics agent, allows both radiolabeling with diagnostic (e.g. 68Ga, 18F) or therapeutic nuclides (e.g. 177Lu, 225Ac). Initial results show that PSMA-targeted radioligand therapy can potentially delay disease progression in metastatic castrate-resistant PCa. Despite still investigational, the bombesin-based radiotracers and antagonist of gastrin releasing-peptide receptor (GRP) (RM2) and anti1-amino-3-18Ffluorocyclobutane-1-carboxylic acid (18F-FACBC) are emerging as possible alternatives for investigating PCa. Considering the wide diffusion of PCa in the Europe and the United States, the presence of these new diagnostic techniques able to detect the disease with high sensitivity and specificity might have a clinical impact on the management of patients. PET/CT imaging with new radiopharmaceuticals can implement the patient management identifying lesion(s) not detectable with conventional imaging procedures. In this review article will be discussed the most promising new PET radiopharmaceuticals (68Ga-PSMA-11, 18F-FACBC, 68Ga-RM2) available at the moment, focusing the attention on their accuracy and their impact on treatment strategy.


Epidemiology and associated risk factors of hepatitis e virus infection in plateau state, Nigeria.
A cross-sectional study in Nigeria was undertaken to determine the epidemiology, seroprevalence, and associated risk factors, of hepatitis E virus (HEV). A total of 462 subjects were used for the study, categorized into four groups: apparently healthy persons, pregnant women, HIV positive subjects, and animal handlers. Information was obtained from subjects using interviewer-administered questionnaire. Blood samples were collected and analyzed for HEV antibodies (IgG and IgM) using enzyme-linked immunosorbent assay (ELISA) technique. Results obtained were analyzed using Statistical Package for Social Sciences (SPSS) version 17.0 statistical software. The overall seroprevalence of IgG and IgM was 42.7 and 0.9%, respectively. Animal handlers had the highest seroprevalence (66.7%). The associated risk factors for IgM seroprevalence were rural dwelling (P = 0.039, odds ratio (OR) 3.3, 95% confidence interval (CI) 0.7-15.4), blood transfusion (P < 0.001, OR 9.6, 95% CI 2.6-35.6), attending to animals (P = 0.032, OR 4.9, 95% CI 0.9-26.6), and waste disposal (P < 0.001). Factors associated with IgG were age (P = 0.044), location (P < 0.001), marital status (P < 0.001), formal education (P < 0.001), farming as occupation (P < 0.001), rural dwelling (P = 0.001), waste disposal (P < 0.001), alcohol consumption (P = 0.001, OR 2.4, 95% CI 1.4-4.0), open defecation (P < 0.001, OR 2.9, 95% CI 1.4-5.7), attending to animals (P < 0.001, OR 2.3, 95% CI 1.6-3.4), consuming unwashed fruits/vegetables (P < 0.001, OR 4.2, 95% CI 0.3-54.1), and stream/river as a source of drinking water (P < 0.001, OR 3.6, 95% CI 1.6-7.8). Preventive public health measures should be reinforced among all communities, particularly domestic animal handlers and pregnant women. Potable water should be provided for all communities. Data suggest that HEV remains an under-recognized and significant public health problem, warranting further attention and research.


Transfer effects of fall training on balance performance and spatiotemporal gait parameters in healthy community-dwelling older adults: a pilot study.
This study examined transfer effects of fall training on fear of falling (Falls Efficacy Scale-International [FES-I]), balance performance, and spatiotemporal gait characteristics in older adults. Eighteen community-dwelling older adults (ages 65-85) were randomly assigned to an intervention or control group. The intervention group completed 12 training sessions (60 min, 6 weeks). During pre- and posttesting, we measured FES-I, balance performance (double limb, closed eyes; single limb, open eyes; double limb, open eyes with motor-interfered task), and gait parameters (e.g., velocity; cadence; stride time, stride width, and stride length; variability of stride time and stride length) under single- and motor-interfered tasks. Dual tasks were applied to appraise improvements of cognitive processing during balance and gait. FES-I (p = .33) and postural sway did not significantly change (0.36 < p < .79). Trends toward significant interaction effects were found for step width during normal walking and stride length variability during the motor dual task (p = .05, ηp 2 = .22). Fall training did not sufficiently improve fear of falling, balance, or gait performance under single- or dual-task conditions in healthy older adults.


Methylene Blue Facilitates Memory Retention in Zebrafish in a Dose-Dependent Manner.
Methylene blue (MB) is an FDA-grandfathered drug with memory-enhancing effects at low doses, but opposite effects at high doses. We investigated the effects of four MB doses (0.1, 0.5, 5.0, or 10.0 μM) on zebrafish memory retention in the T-maze task. After training fish to swim into a certain arm of the T-maze, the fish were placed into a tank containing one of the four MB doses or a control tank containing blue food dye. Subsequently, fish were placed into the T-maze for memory retention testing. Results indicated that MB produced hormetic dose-response effects on memory. Fish that received the 0.5 μM dose performed significantly better at the T-maze than those that received higher doses. Fish who received 5.0 μM did not exhibit a significant difference in performance from control fish, and the fish that received the 10.0 μM dose performed significantly worse than lower doses. These findings support the utility of zebrafish in comparative research and their potential value for testing of MB and other neuropsychopharmacological treatments in animal models of memory disorders.


Auditory habituation to simple tones: reduced evidence for habituation in children compared to adults.
Habituation-the response decrement to repetitively presented stimulation-is a basic cognitive capability and suited to investigate development and integrity of the human brain. To evaluate the developmental process of auditory habituation, the current study used magnetoencephalography (MEG) to investigate auditory habituation, dishabituation and stimulus specificity in children and adults and compared the results between age groups. Twenty-nine children (M age = 9.69 years, SD ± 0.47) and 14 adults (M age = 29.29 years, SD ± 3.47) participated in the study and passively listened to a habituation paradigm consisting of 100 trains of tones which were composed of five 500 Hz tones, one 750 Hz tone (dishabituator) and another two 500 Hz tones, respectively while focusing their attention on a silent movie. Adults showed the expected habituation and stimulus specificity within-trains while no response decrement was found between trains. Sensory adaptation or fatigue as a source for response decrement in adults is unlikely due to the strong reaction to the dishabituator (stimulus specificity) and strong mismatch negativity (MMN) responses. However, in children neither habituation nor dishabituation or stimulus specificity could be found within-trains, response decrement was found across trains. It can be speculated that the differences between children and adults are linked to differences in stimulus processing due to attentional processes. This study shows developmental differences in task-related brain activation and discusses the possible influence of broader concepts such as attention, which should be taken into account when comparing performance in an identical task between age groups.


Regulation of sigma factor competition by the alarmone ppGpp.
Many regulons controlled by alternative sigma factors, including sigma(S) and sigma(32), are poorly induced in cells lacking the alarmone ppGpp. We show that ppGpp is not absolutely required for the activity of sigma(S)-dependent promoters because underproduction of sigma(70), specific mutations in rpoD (rpoD40 and rpoD35), or overproduction of Rsd (anti-sigma(70)) restored expression from sigma(S)-dependent promoters in vivo in the absence of ppGpp accumulation. An in vitro transcription/competition assay with reconstituted RNA polymerase showed that addition of ppGpp reduces the ability of wild-type sigma(70) to compete with sigma(32) for core binding and the mutant sigma(70) proteins, encoded by rpoD40 and rpoD35, compete less efficiently than wild-type sigma(70). Similarly, an in vivo competition assay showed that the ability of both sigma(32) and sigma(S) to compete with sigma(70) is diminished in cells lacking ppGpp. Consistently, the fraction of sigma(S) and sigma(32) bound to core was drastically reduced in ppGpp-deficient cells. Thus, the stringent response encompasses a mechanism that alters the relative competitiveness of sigma factors in accordance with cellular demands during physiological stress.


Presence of ventricular dyssynchrony and haemodynamic impact of right ventricular pacing in adults with repaired Tetralogy of Fallot and right bundle branch block.
Late after surgical repair, adults with Tetralogy of Fallot (TOF) commonly present with right ventricular (RV) dysfunction and right bundle branch block (RBBB). We aimed at (i) investigating whether this prolonged RV conduction induced detrimental electromechanical dyssynchrony in both RV and left ventricle (LV) and (ii) determining the acute haemodynamic effects of pacing at different RV sites. A total of 42 adults with surgically repaired TOF and RBBB were investigated by echocardiography. Intra-RV dyssynchrony (IRVD) and intra-left ventricular dyssynchrony (ILVD) were compared with measurements performed in 30 healthy matched control subjects. An acute haemodynamic study was subsequently performed in a subgroup of 10 patients with New York Heart Association functional class II or class III and echocardiographic signs of RV dysfunction. Cardiac index was measured by a thermodilution technique during spontaneous rhythm (SR) and during atrio-synchronized RV pacing at four different sites (infundibulum, apex, septal, and lateral walls). Fifty-five per cent of the patients with repaired TOF demonstrated abnormal RV and/or LV dyssynchrony. We observed an increased IRVD (37 +/- 12 vs. 18 +/- 8 ms; P= 0.02) and ILVD (34 +/- 12 vs. 20 +/- 10 ms; P= 0.04) in TOF patients when compared with control subjects. We did not observe any significant acute improvement in the cardiac output during atrio-synchronized ventricular pacing vs. SR. Similarly, RV pacing did not induce any significant reduction in the QRS duration. Some TOF adults with RBBB exhibit biventricular electromechanical dyssynchrony. However, in symptomatic patients with RV dysfunction, atrio-synchronized RV pacing does not induce significant acute haemodynamic improvement.


Harnessing chemical exchange: 19F magnetic resonance OFF/ON zinc sensing with a Tm(iii) complex.
A fluorinated, thulium(iii) complex (Tm-PFZ-1) serves as an off-on 19F magnetic resonance probe for Zn(ii). Rapid exchange among different conformations combined with paramagnetic relaxation and chemical shift effects of Tm(iii) effectively eliminate the 19F NMR/MRI signal in Tm-PFZ-1. Chelation of Zn(ii) induces increased structural rigidity and reduces exchange rate, affording a robust 19F NMR/MRI signal. Tm-PFZ-1 represents a first-in-class paramagnetic 19F MR agent that exploits a novel sensing mechanism for Zn(ii) and is the first 19F MR-based scaffold to provide an "off-on" response to Zn(ii) in aqueous solution.


Comparing youth with and without type 1 diabetes on perceived parenting and peer functioning: a propensity weighting approach.
The premise of this study was to gain more insight into whether type 1 diabetes (T1D) can impact how youth perceive parents and peers. To address limitations of previous observational studies comparing youth with T1D to control youth, propensity weighting was used to mimic a randomized controlled trial. A total of 558 youth with T1D and 426 control youth (14-26y) completed questionnaires on parental responsiveness, psychological control, overprotection, friend support, extreme peer orientation, and a host of background and psychological functioning variables. The groups were statistically weighted to become as comparable as possible except for disease status. The analysis plan and hypotheses were preregistered on the open science framework. Youth with T1D perceived their mothers to be more overprotective, perceived fewer friend support, and were less extremely oriented toward peers than control youth. There were no group differences for paternal overprotection and paternal and maternal responsiveness and psychological control. Mothers of youth with T1D seem at risk to practice overprotective parenting and clinicians could play an important role in making mothers aware of this risk. However, the absence of group differences for the maladaptive parenting dimension of psychological control and adaptive dimension of responsiveness are reassuring and testify to the resilient nature of youth with T1D and their families. Additionally, there is accumulating evidence that T1D could interfere with engaging in supportive friendships.


Involvement of multiple transcription factors for metal-induced spy gene expression in Escherichia coli.
Bacteria are directly exposed to metals in environment. To maintain the intracellular metal homeostasis, Escherichia coli contain a number of gene regulation systems, each for response to a specific metal. A periplasmic protein Spy of E. coli was found to be induced upon short-exposure to copper ion in CpxAR-dependent manner. Transcription of the spy gene was also induced by long-exposure to zinc ion. This induction, however, depended on another two-component system BaeSR. Using DNase-I footprinting assay, we identified two BaeR-binding regions on the spy promoter with a direct repeat of the BaeR-box sequence, TCTNCANAA. The zinc-responsive BaeR-binding sites were separated from copper-responsive CpxR-binding site, implying that the spy promoter responds to two species of metal independently through different using sensor-response regulator systems. Since BaeSR-dependent zinc response requires longer time, the induction of spy gene transcription by external zinc may include multiple steps such as through sensing the zinc-induced envelope disorder by BaeSR.


Irradiation and stenting.
Intravascular irradiation by both gamma and beta sources has been shown to prevent neointimal proliferation after balloon injury in the overstretch pig coronary model. A number of clinical studies are underway that involve brachytherapy from gamma sources in vessels that have been stented. The purpose of this review is to analyse the physical nature of the interaction of various forms of radiation with stent materials and to summarize the available experimental information for relevant clinical correlates of these effects. The ultimate use of vascular radiation in the presence of metallic stents will require knowledge of the possible dose alterations, and where possible, techniques to compensate for these effects.


Hydrothermal C-C bond formation and disproportionation of acetaldehyde with formic acid.
Reaction pathways and kinetics of C2 (carbon-two) aldehyde, acetaldehyde (CH3CHO), and formic acid HCOOH or HOCHO, are studied in neutral and acidic subcritical water at 200-250 degrees C. Acetaldehyde is found to exhibit (i) the acid-catalyzed C-C bond formation between acetaldehyde and formic acid, which generates lactic acid (CH3CH(OH)COOH), (ii) the cross-disproportionation, where formic acid reduces acetaldehyde into ethanol, and (iii) the aldol condensation. The lactic acid formation is a green C-C bond formation, proceeding without any organic solvents or metal catalysts. The new C-C bond formation takes place between formic acid and aldehydes irrespective of the presence of alpha-hydrogens. The hydrothermal cross-disproportionation produces ethanol without base catalysts and proceeds even in acidic condition, in sharp contrast to the classical base-catalyzed Cannizzaro reaction. The rate constants of the reactions (i)-(iii) and the equilibrium constant of the lactic acid formation are determined in the temperature range of 200-250 degrees C and at HCl concentrations of 0.2-0.6 M (mol/dm(3)). The reaction pathways are controlled so that the lactic acid or ethanol yield may be maximized by tuning the reactant concentrations and the temperature. A high lactic acid yield of 68% is achieved when acetaldehyde and formic acid are mixed in hot water, respectively, at 0.01 and 2.0 M in the presence of 0.6 M HCl at 225 degrees C. The ethanol yield attained 75% by the disproportionation of acetaldehyde (0.3 M) and formic acid (2.0 M) at 225 degrees C in the absence of added HCl.