The influence of physical activity on alcohol consumption among heavy drinkers participating in an alcohol treatment intervention.
Researchers have hypothesized that physical activity may be beneficial for individuals attempting to reduce their alcohol consumption, although few studies have actually tested this relationship. The purpose of the present study was to describe the physical activity of 620 male veterans enrolled in a treatment intervention study for heavy drinkers, and to determine whether greater involvement in physical activity was associated with greater reductions in alcohol consumption. Participants endorsed moderate physical activity at the baseline visit (median=1.65 kcal/kg/day expended from physical activity), although physical activity declined during over time, p=.011. The most frequently endorsed activities included walking, gardening/yardwork, calisthenics, biking, swimming, weight lifting, golfing, and dancing. Regression analyses revealed no significant relationships between energy expenditure from physical activity and reductions in alcohol consumption at the six- and 12-month visits. Findings suggest that engaging in physical activity does not enhance treatment outcomes within interventions that do not specifically aim to increase physical activity. However, commonly endorsed activities may be easily incorporated into interventions in which physical activity is a desired component.


Molecular mechanisms for the control of translation by insulin.
Insulin acutely stimulates protein synthesis in mammalian cells, and this involves activation of the process of mRNA translation. mRNA translation is a complex multi-step process mediated by proteins termed translation factors. Several translation factors are regulated in response to insulin, often as a consequence of changes in their states of phosphorylation. The initiation factor eIF4E binds to the cap structure at the 5'-end of the mRNA and mediates assembly of an initiation-factor complex termed eIF4F. Assembly of this complex can be regulated by eIF4E-binding proteins (4E-BPs), which inhibit eIF4F complex assembly. Insulin induces phosphorylation of the 4E-BPs, resulting in alleviation of the inhibition. This regulatory mechanism is likely to be especially important for the control of the translation of specific mRNAs whose 5'-untranslated regions (5'-UTRs) are rich in secondary structure. Translation of another class of mRNAs, those with 5'-UTRs containing polypyrimidine tracts is also activated by insulin and this, like phosphorylation of the 4E-BPs, appears to involve the rapamycin-sensitive signalling pathway which leads to activation of the 70 kDa ribosomal protein S6 kinase (p70 S6 kinase) and the phosphorylation of the ribosomal protein S6. Overall stimulation of translation may involve activation of initiation factor eIF2B, which is required for all initiation events. This effect is dependent upon phosphatidylinositol 3-kinase and may involve the inactivation of glycogen synthase kinase-3 and consequent dephosphorylation of eIF2B, leading to its activation. Peptide-chain elongation can also be activated by insulin, and this is associated with the dephosphorylation and activation of elongation factor eEF2, probably as a consequence of the insulin-induced reduction in eEF2 kinase activity. Thus multiple signalling pathways acting on different steps in translation are involved in the activation of this process by insulin and lead both to general activation of translation and to the selective regulation of specific mRNAs.


Identification and characterization of the single-stranded DNA-binding protein of bacteriophage P1.
The genome of bacteriophage P1 harbors a gene coding for a 162-amino-acid protein which shows 66% amino acid sequence identity to the Escherichia coli single-stranded DNA-binding protein (SSB). The expression of the P1 gene is tightly regulated by P1 immunity proteins. It is completely repressed during lysogenic growth and only weakly expressed during lytic growth, as assayed by an ssb-P1/lacZ fusion construct. When cloned on an intermediate-copy-number plasmid, the P1 gene is able to suppress the temperature-sensitive defect of an E. coli ssb mutant, indicating that the two proteins are functionally interchangeable. Many bacteriophages and conjugative plasmids do not rely on the SSB protein provided by their host organism but code for their own SSB proteins. However, the close relationship between SSB-P1 and the SSB protein of the P1 host, E. coli, raises questions about the functional significance of the phage protein.


Coexistence of two neurocutaneous syndromes: tuberous sclerosis and hypomelanosis of Ito.
Tuberous sclerosis complex (TSC) and hypomelanosis of Ito (HI) are two uncommon neurocutaneous syndromes and their coexistence is extremely rare. An epileptic child presented with progressively increasing multiple hypopigmented macules arranged in a linear and whorled pattern along the lines of Blaschko over the trunk and limbs, characteristic of HI. He also had facial angiofibromas, ash-leaf and confetti macules and shagreen patches. Magnetic resonance imaging of the brain showed cortical tubers and subependymal nodules; which are diagnostic of TSC. The TSC defining loci have been mapped to Chromosome 9q34 (TSC1) and 16 pl3.3 (TSC2). There is no common genetic background for HI, but mosaicism of 9q33 locus has been documented. As per our knowledge, this is the second case of association of TSC with HI in a four-year-old child.


Direct-to-consumer sales of genetic services on the Internet.
PURPOSE The increasing use of the Internet to obtain genetics information and to order medical services without a prescription, combined with a rise in direct-to-consumer marketing for genetic testing, suggests the potential for the Internet to be used to sell genetic services. METHODS A systematic World Wide Web search was conducted in May 2002 to assess the availability of genetic services sold directly to consumers on the Internet. RESULTS Out of 105 sites that offered genetic services directly, most offered non-health-related services, including parentage confirmation testing (83%), identity testing (56%), and DNA banking (24%); however, health-related genetic tests were offered through 14 sites (13%). The health-related genetic tests available ranged from standard tests, such as hemochromatosis and cystic fibrosis, to more unconventional tests related to nutrition, behavior, and aging. Of these 14 sites, 5 described risks associated with the genetic services and 6 described the availability of counseling. CONCLUSIONS The availability of direct sales of health-related genetic tests creates the potential for inadequate pretest decision making, misunderstanding test results, and access to tests of questionable clinical value.


Aggression in war veterans suffering from posttraumatic stress disorder with co-morbid alcoholism.
For thousands of years it has been known that aggression as a symptom appears in numerous psychiatric disorders and diseases. During the last decade the appearance of the aggressive behavior related to the posttraumatic stress disorder (PTSD) has been frequently investigated, often associated with war trauma. The goal of this study is to analyze the impact of alcoholism on a way war veterans suffering from chronic PTSD express and control aggression. The sample included 240 war veterans with chronic PTSD. The subjects were divided in two groups. PTSD group (n=147) and controlled group composed of those suffering from alcoholism in addition to PTSD (n=93). In this study, the following psychological instruments were used: The Harvard trauma questionnaire for PTSD diagnosis (HTQ); the questionnaire for self-evaluation of aggression (STAXI); The Profile Index Emotion (PIE); questionnaire for auto-diagnosis of alcoholism (CAGE). The obtained results indicate that subjects who have PTSD with co-morbid alcoholism are more deprived, aggressive (p < 0.001) and oppositional (p < 0.05) in comparison to subjects whose PTSD is not combined with alcoholism (PIE). The aggression is statistically more expressed in subjects with PTSD who have also been diagnosed with alcoholism on all subscales in comparison to subjects with PTDS who have not been diagnosed with alcoholism: the current state of aggression, the general state of aggression, aggression towards an unfair treatment, aggression directed inwards and outwards (p < 0.001); aggression towards nonspecific provocation and a general way of expressing aggression (p < 0.05) (STAXI). Subjects that had PTSD combined with alcoholism show a higher degree of aggression in comparison to subjects with PTDS who are not diagnosed with alcoholism.


All fiber-optic neural network using coupled SOA based ring lasers.
An all-optical neural network is presented that is based on coupled lasers. Each laser in the network lases at a distinct wavelength, representing one neuron. The network status is determined by the wavelength of the network's light output. Inputs to the network are in the optical power domain. The nonlinear threshold function required for neural-network operation is achieved optically by interaction between the lasers. The behavior of the coupled lasers is explained by a simple laser model developed in the paper. In particular, the winner take all (WTA) neural-network behavior of a system of many lasers is described. An experimental system is implemented using single mode fiber optic components at wavelengths near 1550 nm. A number of functions are implemented to demonstrate the practicality of the new network. The neural network is particularly robust against input wavelength variations.


How NICU design and infant and family-centered developmental care act synergistically to support babies and families.
Recommended NICU Design Standards and Infant and Family Centered Developmental Care standards have complementary goals. Design standards focus on environmental modifications necessary to enhance NICU baby and family experiences and outcomes. Infant and Family Developmental Care Standards focus on the functional aspects of babies' and families' experience, including the caregiving environment. When applied in the NICU environment of care, both complementary evidence-based standards can function synergistically to promote better outcomes for babies and families.


Memory Decline and Its Reversal in Aging and Neurodegeneration Involve miR-183/96/182 Biogenesis.
Aging is characterized by progressive memory decline that can lead to dementia when associated with neurodegeneration. Here, we show in mice that aging-related memory decline involves defective biogenesis of microRNAs (miRNAs), in particular miR-183/96/182 cluster, resulting from increased protein phosphatase 1 (PP1) and altered receptor SMAD (R-SMAD) signaling. Correction of the defect by miR-183/96/182 overexpression in hippocampus or by environmental enrichment that normalizes PP1 activity restores memory in aged animals. Regulation of miR-183/96/182 biogenesis is shown to involve the neurodegeneration-related RNA-binding proteins TDP-43 and FUS. Similar alterations in miR-183/96/182, PP1, and R-SMADs are observed in the brains of patients with amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration (FTLD), two neurodegenerative diseases with pathological aggregation of TDP-43. Overall, these results identify new mechanistic links between miR-183/96/182, PP1, TDP-43, and FUS in age-related memory deficits and their reversal.


Optimal time of surgical treatment for Kawasaki coronary artery disease.
The major complication of Kawasaki coronary disease is myocardial infarction caused by thrombus formation inside the aneurysm or by organic obstructive lesion following the regression of aneurysm, while the indications for surgical therapy remain controversial. We have adopted coronary artery bypass grafting (CABG) even in young children for giant coronary aneurysms (more than 8 mm diameter) with or without a stenotic region when myocardial ischemia is detected. We hypothesized that a shorter time-period from diagnosis of acute Kawasaki disease (KD) to CABG would lead to better postoperative results. To elucidate the validity of our strategy, we evaluated preoperative patient characteristics and long-term outcome. Twenty-one patients (mean age: 12.0 years old) with Kawasaki coronary disease had undergone CABG during the last 12 years. The mean age at the time of acute KD was 2.7 years and the mean time range from diagnosis of acute KD to CABG was 8.1 years. The incidence of preoperative reduced ventricular function was 10 per 21 patients (47.6%). A multivariate logistic regression analysis using patient characteristics showed that the time range from acute KD to CABG was the only predictor for ventricular functional deterioration (p=0.03, odds ratio 1.55. 95%CI: 1.033 approximately 2.325). Based on these results, we divided the patients into two groups of short time range (mean: 3.7 years; group S) and long time range (mean: 13.9 years; group L). Preoperative left ventricular functional deterioration was recognized more frequently in group L (9/9, 100%) than in group S (1/12, 8.3%)(p<0.01). Myocardial infarction was documented significantly higher in the group L (6/9, 66.7%) than group S (1/12, 8.3%)(p=0.04). There was no surgical mortality in either group. The arterial grafts demonstrated good potential for growth and graft patency was 96.9%. Moreover, seven of the giant aneurysms proximal to the graft anastomosis showed complete thrombotic occlusion after CABG without development of myocardial infarction. The cardiac events free rate of group L and group S was 66.7% and 100%, respectively, during the postoperative follow up periods of 5.5+/-1.1 years (group L) and 4.7+/-1.1 years (group S). We successfully applied CABG for Kawasaki coronary disease. Based on our experience, a short interval after acute KD appears to be ideal for surgical treatment of Kawasaki coronary disease.


Osteogenesis Is Improved by Low Tumor Necrosis Factor Alpha Concentration through the Modulation of Gs-Coupled Receptor Signals.
In the early phase of bone damage, low concentrations of the cytokine tumor necrosis factor alpha (TNF-α) favor osteoblast differentiation. In contrast, chronic high doses of the same cytokine contribute to bone loss, demonstrating opposite effects depending on its concentration and on the time of exposure. In the bone microenvironment, TNF-α modulates the expression/function of different G protein-coupled receptors (GPCRs) and of their regulatory proteins, GPCR-regulated kinases (GRKs), thus dictating their final biological outcome in controlling bone anabolic processes. Here, the effects of TNF-α were investigated on the expression/responsiveness of the A2B adenosine receptor (A2BAR), a Gs-coupled receptor that promotes mesenchymal stem cell (MSC) differentiation into osteoblasts. Low TNF-α concentrations exerted a prodifferentiating effect on MSCs, pushing them toward an osteoblast phenotype. By regulating GRK2 turnover and expression, the cytokine impaired A2BAR desensitization, accelerating receptor-mediated osteoblast differentiation. These data supported the anabolic effect of TNF-α submaximal concentration and demonstrated that the cytokine regulates GPCR responses by interfering with the receptor desensitization machinery, thereby enhancing the anabolic responses evoked by A2BAR ligands. Overall, these results indicated that GPCR desensitization plays a pivotal role in osteogenesis and that its manipulation is an effective strategy to favor bone remodeling.


Measuring the loss of consumer choice in mandatory health programmes using discrete choice experiments.
Economic evaluation of mandatory health programmes generally do not consider the utility impact of a loss of consumer choice upon implementation, despite evidence suggesting that consumers do value having the ability to choose. The primary aim of this study was to explore whether the utility impact of a loss of consumer choice from implementing mandatory health programmes can be measured using discrete choice experiments (DCEs). Three case studies were used to test the methodology: fortification of bread-making flour with folate, mandatory influenza vaccination of children, and the banning of trans-fats. Attributes and levels were developed from a review of the literature. An orthogonal, fractional factorial design was used to select the profiles presented to respondents to allow estimation of main effects. Overall, each DCE consisted of 64 profiles which were allocated to four versions of 16 profiles. Each choice task compared two profiles, one being voluntary and the other being mandatory, plus a 'no policy' option, thus each respondent was presented with eight choice tasks. For each choice task, respondents were asked which health policy they most preferred and least preferred. Data was analysed using a mixed logit model with correlated coefficients (200 Halton draws). The compensating variation required for introducing a programme on a mandatory basis (versus achieving the same health impacts with a voluntary programme) that holds utility constant was estimated. Responses were provided by 535 participants (a response rate of 83 %). For the influenza vaccination and folate fortification programmes, the results suggested that some level of compensation may be required for introducing the programme on a mandatory basis. Introducing a mandatory influenza vaccination programme required the highest compensation (Australian dollars [A$] 112.75, 95 % CI -60.89 to 286.39) compared with folate fortification (A$18.05, 95 % CI -3.71 to 39.80). No compensation was required for introducing the trans-fats programme (-A$0.22, 95 % CI -6.24 to 5.80) [year 2010 values]. In addition to the type of mandatory health programme, the compensation required was also found to be dependent on a number of other factors. In particular, the study found an association between the compensation required and stronger libertarian preferences. DCEs can be used to measure the utility impact of a loss of consumer choice. Excluding the utility impact of a loss of consumer choice from an economic evaluation taking a societal perspective may result in a sub-optimal, or incorrect, funding decision.


Comparing Repeatability and Agreement between Commonly Used Corneal Imaging Devices in Keratoconus.
Keratometry and pachymetry are important for diagnosis and monitoring of keratoconus. Many corneal imaging units exist, but comparison to determine repeatability and agreement is paramount for adequate keratoconus management in primary and secondary care. This study aimed to evaluate the repeatability and agreement of a Placido disc-based videokeratoscope (Melbourne, Victoria, Australia) used in primary care with spectral-domain optical coherence tomography (Optopol Technology, Zawiercie, Poland) and Scheimpflug corneal tomography (Oculus, Wetzlar, Germany) in secondary care. This was a prospective single-center study where one eye was randomized to have central corneal thickness;thinnest corneal thickness (TCT); and maximum, mean, steep, and flat keratometry (Kmax, Kmean, Ksteep, and Kflat, respectively), measured with all three devices. Three measurements were completed per device to assess intraobserver repeatability. A total of 110 eyes from 110 patients with keratoconus were analyzed. Repeatability was best with the Pentacam for central corneal thickness, Kmax, Kmean, Ksteep, and Kflat parameters (precision, 9.21, 0.8, 0.38, 0.52, and 0.58). The Medmont had better repeatability than the Revo with Kmax, Kmean, Ksteep, and Kflat (precision, 1.41,1.35,1.43, and 1.59). Revo had the best repeatability with TCT (precision, 3.81). The intraclass correlation coefficient was >0.94 for all parameters in all devices. Agreement was generally poor between devices. However, there was good agreement between Pentacam and Medmont Kflat measurements ( P > .05). Repeatability of keratometry parameters with the Pentacam and Medmont was greater than the Revo, suggesting a lower threshold for detecting change in anterior corneal parameters. The Revo had the greatest repeatability for TCT, suggesting a lower threshold for detecting thinning in disease progression and corneal-crosslinking safety. There was poor agreement between devices, and it is not recommended for them to be used interchangably.


Bilateral femur metastasis in endometrial adenocarcinoma.
Bone metastasis of endometrial carcinoma is uncommon, and bilateral femur metastasis is extremely rare. A 48-year-old woman with Federation International of Gynecology and Obstetrics stage IIB grade 2-3 endometrial adenocarcinoma underwent curative radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy followed by radiotherapy and chemotherapy. Twenty-two months after surgery, she suffered from progressive pain and then presented bilateral femur metastasis. She was administered the surgical excision of bony metastasis and adjuvant therapies including chemotherapy, palliative radiation, and hormone therapy. Three and a half years after treatment of bony metastasis, she remains clinically well. Bone metastasis of endometrial carcinoma may occur at some unusual sites, and bilateral femur metastasis should be considered in patients. Multimodal therapies are usually advocated for bone metastasis of endometrial carcinoma.


Biotin status: which are valid indicators and how do we know?
Although estimated average requirements for biotin have been proposed, the human requirements for biotin in specific populations and at various ages remain uncertain, in part because indicators of biotin status have not been validated. With the use of improved methods for measuring biotin and metabolites, a recent study indicated that decreased urinary excretion of biotin and bisnorbiotin is an early and sensitive indicator of biotin deficiency, but decreased serum concentration of biotin is not. Increased urinary excretion of 3-hydroxyisovaleric acid (3-HIA), a leucine metabolite that is excreted in increased quantities with deficiency of the biotin-dependent enzyme beta-methylcrotonyl-CoA carboxylase, is also an early and sensitive indicator of biotin deficiency. When these indicators were assessed longitudinally in 13 pregnant women, biotin excretion was not significantly decreased early in pregnancy but did decrease significantly from early to late pregnancy. Excretion of 3-HIA was abnormally increased in about three-fourths of the women studied in both early and late pregnancy. Thus, each indicator detected biotin deficiency late in pregnancy, but assessment of biotin status for the two indicators conflicted early in pregnancy. Preliminary results from a trial assessing response of 3-HIA excretion to biotin treatment indicate that biotin status is indeed impaired both early and late in pregnancy.


Retrospective comparison of Velcro® and twill tie outcomes following pediatric tracheotomy.
To compare the rates of skin-related complications and accidental decannulation in pediatric patients who received Velcro® ties versus twill ties during the early postoperative period following tracheotomy. The rates of skin-related complications and accidental decannulation in patients with Velcro® ties was hypothesized to differ from those in patients with twill ties. Medical records of 109 patients ≤18 years old who underwent elective tracheotomy were reviewed: 70 received twill ties and 39 received Velcro® ties. Patients were followed for the first seven postoperative days. The primary outcome was skin-related complications, which were further categorized into mild (irritation) and severe (breakdown). The secondary outcome was accidental decannulation. Rates of skin-related complication and accidental decannulation were compared across the two groups using chi-square analysis. Skin irritation occurred in 32 patients (45.7%) with twill ties and 10 patients (25.6%) with Velcro®. Skin breakdown occurred in 20 patients (28.6%) with twill ties and 6 patients (15.4%) with Velcro®. There were no accidental decannulation events. The use of Velcro® ties was associated with a decreased rate of skin irritation (OR: 0.41; 95% CI: 0.17-0.97; P = 0.039). The use of Velcro® ties was associated with a decrease in the rate of skin irritation. There were no accidental decannulation events. These findings support the use of Velcro® ties at the time of pediatric tracheotomy placement.


Improved herbicide discovery using physico-chemical rules refined by antimalarial library screening.
Herbicides have physico-chemical properties not unlike orally-delivered human drugs, but are known to diverge in their limits for proton donors, partition coefficients and molecular weight. To further refine rules specific for herbicides, we exploited the close evolutionary relationship between Plasmodium falciparum and plants by screening the entire Malaria Box, a chemical library of novel chemical scaffolds with activity against the blood stage of P. falciparum. Initial screening against Arabidopsis thaliana on agar media and subsequently on soil demonstrated the crucial nature of log P and formal charge are to active molecules. Using this information, a weighted scoring system was applied to a large chemical library of liver-stage effective antimalarial leads, and of the six top-scoring compounds, one had potency comparable to that of commercial herbicides. This novel compound, MMV1206386, has no close structural analogues among commercial herbicides. Physiological profiling suggested that MMV1206386 has a new mode of action and overall demonstrates how weighted rules can help during herbicide discovery programs.


Perspectives for analyzing non-linear photo-ionization spectra with deep neural networks trained with synthetic Hamilton matrices.
We have constructed deep neural networks, which can map fluctuating photo-electron spectra obtained from noisy pulses to spectra from noise-free pulses. The network is trained on spectra from noisy pulses in combination with random Hamilton matrices, representing systems which could exist but do not necessarily exist. In [Giri et al., Phys. Rev. Lett., 2020, 124, 113201] we performed a purification of fluctuating spectra, that is, mapping them to those from Fourier-limited Gaussian pulses. Here, we investigate the performance of such neural-network-based maps for predicting spectra of double pulses, pulses with a chirp and even partially-coherent pulses from fluctuating spectra generated by noisy pulses. Secondly, we demonstrate that along with purification of a fluctuating double-pulse spectrum, one can estimate the time-delay of the underlying double pulse, an attractive feature for single-shot spectra from SASE FELs. We demonstrate our approach with resonant two-photon ionization, a non-linear process, sensitive to details of the laser pulse.


Complete Protection from SARS-CoV-2 Lung Infection in Mice Through Combined Intranasal Delivery of PIKfyve Kinase and TMPRSS2 Protease Inhibitors.
Emerging variants of concern of SARS-CoV-2 can significantly reduce the prophylactic and therapeutic efficacy of vaccines and neutralizing antibodies due to mutations in the viral genome. Targeting cell host factors required for infection provides a complementary strategy to overcome this problem since the host genome is less susceptible to variation during the life span of infection. The enzymatic activities of the endosomal PIKfyve phosphoinositide kinase and the serine protease TMPRSS2 are essential to meditate infection in two complementary viral entry pathways. Simultaneous inhibition in cultured cells of their enzymatic activities with the small molecule inhibitors apilimod dimesylate and nafamostat mesylate synergistically prevent viral entry and infection of native SARS-CoV-2 and vesicular stomatitis virus (VSV)-SARS-CoV-2 chimeras expressing the SARS-CoV-2 surface spike (S) protein and of variants of concern. We now report prophylactic prevention of lung infection in mice intranasally infected with SARS-CoV-2 beta by combined intranasal delivery of very low doses of apilimod dimesylate and nafamostat mesylate, in a formulation that is stable for over 3 months at room temperature. Administration of these drugs up to 6 hours post infection did not inhibit infection of the lungs but substantially reduced death of infected airway epithelial cells. The efficiency and simplicity of formulation of the drug combination suggests its suitability as prophylactic or therapeutic treatment against SARS-CoV-2 infection in households, point of care facilities, and under conditions where refrigeration would not be readily available.


[Systemic antibiotic therapy of acne vulgaris].
Inflammatory, medium to severe acne vulgaris is treated with systemic antibiotics worldwide. The rationale is an effect on Propionibacterium acnes as well as the intrinsic anti-inflammatory properties of these antibiotics. Although there are no correlations between the number of P. acnes and the severity of the disease, associations between the degree of humoral and cellular immune-responses against P. acnes and the severity of acne have been reported. Exact data with respect to daily use of these compounds, such as differential effectiveness or side effects are unavailable. A summary of currently available studies is presented. The data of studies of systemic antibiotic therapy of acne vulgaris up to 1975, the summary of literature in English up to 1999, a systematic review of minocycline of the year 2002 as well as the data of randomized controlled studies published and listed in Medline thereafter were reviewed. Systemic tetracyclines [tetracycline 1 000 mg/d, doxycycline 100 (-200) mg/d, minocycline 100 (-200) mg/d, lymecycline 300 (-600) mg] and erythromycin 1 000 mg/d are significantly more effective than placebo in the systemic treatment of inflammatory acne. The data for tetracycline are best grounded. Similarly effective is clindamycin. Cotrimoxazole and trimethoprim are likely to be effective. Definite differences between the tetracyclines or between tetracycline and erythromycin cannot be ascertained. The data for the combination with topical treatments (topical benzoyl peroxide (BPO) or retinoids) suggest synergistic effects. Therefore systemic antibiotics should not be used as monotherapy. In case of similar efficacy, other criteria, such as pharmacokinetics (doxycycline, minocycline, lymecycline have longer half-life times than tetracyclines), the rate of side-effects (tetracycline: side effect-rate approximately 4 % mild side effects; erythromycin often gastrointestinal complaints; minocycline: rare, but potentially severe hypersensitivity reactions; doxycycline dose-dependent phototoxic reactions), the resistance-rate [percentage of resistant bacteria higher with erythromycin (approximately 50 %) than with tetracycline-therapy (approximately 20 %)], and the costs of therapy have to be taken into account. The systemic antibiotic therapy of widespread papulo-pustular acne not amenable to a topical therapy is effective and well-tolerated. In general therapy can be given for 3 months and should be combined with BPO to prevent resistance.


Lessons from a multidisciplinary partnership involving women parliamentarians to address the overuse of caesarean section in Italy.
The increase of caesarean sections (CS) represents a global concern. Interventions tested to reduce unnecessary caesareans have shown limited success to date, partly because they have focused on medical perspectives or on single faceted interventions targeting only one group of stakeholders. Limited attention has been given to examining multidisciplinary and advocacy activities that could reduce unnecessary CS by raising awareness and engaging the media, advocacy groups, healthcare professionals and politicians. In 2009 in Italy, the national CS rate was the highest in Europe and momentum was building for action. This case study includes a description of the activities conducted in Italy during 2009-2012 by a partnership that included the non-governmental organisation Osservatorio Nazionale sulla Salute della Donna, a bipartisan group of Italian women parliamentarians and the WHO. The objectives were to generate awareness about the increase and overuse of CS in Italy, to foster political actions to reverse this trend, to engage with the media and journalists and to better understand women's birth preferences and needs. A reduction of the CS rate has been observed in Italy following the activities of the initiative from 38.4% in 2009 to 34.2% in 2015 according to the Ministry of Health. Although we cannot infer a casual association between the Partnership and the CS decrease, it did contribute to political momentum and specific actions that should, in theory, have contributed to this reduction. These include the engagement of women parliamentarians for policy change, improved understanding of the local drivers of increases of CS including women's needs and preferences, raising awareness and working with the media to convey appropriate information and an inclusive strategy giving the opportunity to local stakeholders to make their voices heard. This partnership initiative illustrates a model for generating dialogue, reflection and action in countries showing signs of readiness to address escalating CS.


Articular contact pressures of meniscal repair techniques at various knee flexion angles.
Articular cartilage injury can occur after meniscal repair with biodegradable implants. Previous contact pressure analyses of the knee have been based on the tibial side of the meniscus at limited knee flexion angles. We investigated articular contact pressures on the posterior femoral condyle with different knee flexion angles and surgical repair techniques. Medial meniscus tears were repaired in 30 fresh bovine knees. Knees were mounted on a 6-degrees-of-freedom jig and statically loaded to 200 N at 45 degrees, 70 degrees, 90 degrees, and 110 degrees of knee flexion under 3 conditions: intact meniscus, torn meniscus, and meniscus after repair. For each repair, 3 sutures or biodegradable implants were used. A pressure sensor was used to determine the contact area and peak pressure. Peak pressures over each implant position were measured. Peak pressure increased significantly as knee flexion increased in normal, injured, and repaired knees. The change in peak pressure in knees with implant repairs was significantly higher than suture repairs at all knee flexion angles. Articular contact pressure on the posterior femoral condyle increased with knee flexion. Avoidance of deep knee flexion angles postoperatively may limit increases in articular contact pressures and potential chondral injury.


A critical analysis of the biological impacts of plasticizers on wildlife.
This review provides a critical analysis of the biological effects of the most widely used plasticizers, including dibutyl phthalate, diethylhexyl phthalate, dimethyl phthalate, butyl benzyl phthalate and bisphenol A (BPA), on wildlife, with a focus on annelids (both aquatic and terrestrial), molluscs, crustaceans, insects, fish and amphibians. Moreover, the paper provides novel data on the biological effects of some of these plasticizers in invertebrates, fish and amphibians. Phthalates and BPA have been shown to affect reproduction in all studied animal groups, to impair development in crustaceans and amphibians and to induce genetic aberrations. Molluscs, crustaceans and amphibians appear to be especially sensitive to these compounds, and biological effects are observed at environmentally relevant exposures in the low ng l(-1) to microg l(-1) range. In contrast, most effects in fish (except for disturbance in spermatogenesis) occur at higher concentrations. Most plasticizers appear to act by interfering with the functioning of various hormone systems, but some phthalates have wider pathways of disruption. Effect concentrations of plasticizers in laboratory experiments coincide with measured environmental concentrations, and thus there is a very real potential for effects of these chemicals on some wildlife populations. The most striking gaps in our current knowledge on the impacts of plasticizers on wildlife are the lack of data for long-term exposures to environmentally relevant concentrations and their ecotoxicity when part of complex mixtures. Furthermore, the hazard of plasticizers has been investigated in annelids, molluscs and arthropods only, and given the sensitivity of some invertebrates, effects assessments are warranted in other invertebrate phyla.


Reliability evaluation of the design space of the granulation process of mefenamic acid tablets using a bootstrap resampling technique.
The design space of the granulation process of mefenamic acid tablets, based on Box and Behnken design datasets, was described by a response surface method incorporating multivariate spline interpolation. The reliability of the optimal solutions and the acceptance ranges were evaluated by a bootstrap (BS) resampling technique. The distribution of the BS optimal solutions was almost symmetrical; however, several solutions, which were quite different from the original solution, were mixed. The reason for this problem was considered to be the mixing of the global and the local optima. Therefore, we applied self-organizing map (SOM) clustering for dividing data into several clusters and identified the cluster containing the global optima. The accuracy and reproducibility of the optimal solution in the cluster containing the optimal solution were quantitatively evaluated. In addition, the response surfaces modeled from all the BS datasets contained in the cluster were plotted into the same coordinates with the original response surface. The plots of BS optimal solutions were distributed around the original solution. Moreover, the average of all the BS response surfaces sufficiently corresponded with the original response surface. The conservative limits of the 95% confidence intervals of the acceptance ranges in three response variables could be calculated using the standard deviations of the BS response surfaces. Consequently, it was considered that a novel evaluation method based on BS resampling and SOM could be used for quantitatively evaluating the precision of the nonlinear response surface model.


Genes encoding conserved hypothetical proteins localized in the conjugative transfer region of plasmid pRet42a from Rhizobium etli CFN42 participate in modulating transfer and affect conjugation from different donors.
Among sequenced genomes, it is common to find a high proportion of genes encoding proteins that cannot be assigned a known function. In bacterial genomes, genes related to a similar function are often located in contiguous regions. The presence of genes encoding conserved hypothetical proteins (chp) in such a region may suggest that they are related to that particular function. Plasmid pRet42a from Rhizobium etli CFN42 is a conjugative plasmid containing a segment of approximately 30 Kb encoding genes involved in conjugative transfer. In addition to genes responsible for Dtr (DNA transfer and replication), Mpf (Mating pair formation) and regulation, it has two chp-encoding genes (RHE_PA00163 and RHE_PA00164) and a transcriptional regulator (RHE_PA00165). RHE_PA00163 encodes an uncharacterized protein conserved in bacteria that presents a COG4634 conserved domain, and RHE_PA00164 encodes an uncharacterized conserved protein with a DUF433 domain of unknown function. RHE_PA00165 presents a HTH_XRE domain, characteristic of DNA-binding proteins belonging to the xenobiotic response element family of transcriptional regulators. Interestingly, genes similar to these are also present in transfer regions of plasmids from other bacteria. To determine if these genes participate in conjugative transfer, we mutagenized them and analyzed their conjugative phenotype. A mutant in RHE_PA00163 showed a slight (10 times) but reproducible increase in transfer frequency from Rhizobium donors, while mutants in RHE_PA00164 and RHE_PA00165 lost their ability to transfer the plasmid from some Agrobacterium donors. Our results indicate that the chp-encoding genes located among conjugation genes are indeed related to this function. However, the participation of RHE_PA00164 and RHE_PA00165 is only revealed under very specific circumstances, and is not perceived when the plasmid is transferred from the original host. RHE_PA00163 seems to be a fine-tuning modulator for conjugative transfer.


Anti-TB polyynes from the roots of Angelica sinensis.
Following chemotaxonomic evidence, the PE and CHCl(3) extracts of the roots of the botanical Angelica sinensis (Oliv.) Diels (Dang Gui) were investigated for in vitro anti-TB activity, in parallel to studying their serotonergic and GABAergic potential. The activities were confirmed to overlap chemically with the neurotropic active principles present in medium lipophilic fractions. Phytochemical investigations led to the isolation of five polyynes: falcarindiol (1), 9Z,17-octadecadiene-12,14-diyne-1,11,16-triol,1-acetate (2), oplopandiol (3), heptadeca-1-ene-9,10-epoxy-4,6-diyne-3,8-diol (4) and the new polyyne 8-hydroxy-1-methoxy-(Z)-9-heptadecene-4,6-diyn-3-one (5), as characterized by spectroscopic techniques including 1D, 2D NMR and HR-MS. All compounds were tested against two pathogenic strains of Mycobacterium tuberculosis (H37Rv and Erdman) in vitro in a microplate Alamar Blue assay (MABA). The most potent anti-TB constituents were 1 and 2, exhibiting MIC values of 1.4-26.7 microg/mL; 3 showed moderate MICs (49.5 and 50.2 microg/mL, respectively) while 4 and 5 were weakly active (MIC > 60 microg/mL). Notably, none of the five compounds exhibited significant cytotoxicity against Vero cells. These findings not only reveal a new potential area of therapeutic value for A. sinensis, but also underline the role of polyynes as anti-TB active principles in ethnobotanical preparations, and as lead compounds.


Clinical, biomechanical, and physiological translational interpretations of human resting myofascial tone or tension.
Myofascial tissues generate integrated webs and networks of passive and active tensional forces that provide stabilizing support and that control movement in the body. Passive [central nervous system (CNS)-independent] resting myofascial tension is present in the body and provides a low-level stabilizing component to help maintain balanced postures. This property was recently called "human resting myofascial tone" (HRMT). The HRMT model evolved from electromyography (EMG) research in the 1950s that showed lumbar muscles usually to be EMG-silent in relaxed gravity-neutral upright postures. Biomechanical, clinical, and physiological studies were reviewed to interpret the passive stiffness properties of HRMT that help to stabilize various relaxed functions such as quiet balanced standing. Biomechanical analyses and experimental studies of the lumbar multifidus were reviewed to interpret its passive stiffness properties. The lumbar multifidus was illustrated as the major core stabilizing muscle of the spine, serving an important passive biomechanical role in the body. Research into muscle physiology suggests that passive resting tension (CNS-independent) is generated in sarcomeres by the molecular elasticity of low-level cycling cross-bridges between the actomyosin filaments. In turn, tension is complexly transmitted to intimately enveloping fascial matrix fibrils and other molecular elements in connective tissue, which, collectively, constitute the myofascial unit. Postural myofascial tonus varies with age and sex. Also, individuals in the population are proposed to vary in a polymorphism of postural HRMT. A few people are expected to have outlier degrees of innate postural hypotonicity or hypertonicity. Such biomechanical variations likely predispose to greater risk of related musculoskeletal disorders, a situation that deserves greater attention in clinical practice and research. Axial myofascial hypertonicity was hypothesized to predispose to ankylosing spondylitis. This often-progressive deforming condition of vertebrae and sacroiliac joints is characterized by stiffness features and particular localization of bony lesions at entheseal sites. Such unique features imply concentrations and transmissions of excessive force, leading to tissue micro-injury and maladaptive repair reactions. The HRMT model is now expanded and translated for clinical relevance to therapists. Its passive role in helping to maintain balanced postures is supported by biomechanical principles of myofascial elasticity, tension, stress, stiffness, and tensegrity. Further research is needed to determine the molecular basis of HRMT in sarcomeres, the transmission of tension by the enveloping fascial elements, and the means by which the myofascia helps to maintain efficient passive postural balance in the body. Significant deficiencies or excesses of postural HRMT may predispose to symptomatic or pathologic musculoskeletal disorders whose mechanisms are currently unexplained.


Lignins Isolated via Catalyst-Free Organosolv Pulping from Miscanthus x giganteus, M. sinensis, M. robustus and M. nagara: A Comparative Study.
As a low-input crop, Miscanthus offers numerous advantages that, in addition to agricultural applications, permits its exploitation for energy, fuel, and material production. Depending on the Miscanthus genotype, season, and harvest time as well as plant component (leaf versus stem), correlations between structure and properties of the corresponding isolated lignins differ. Here, a comparative study is presented between lignins isolated from M. x giganteus, M. sinensis, M. robustus and M. nagara using a catalyst-free organosolv pulping process. The lignins from different plant constituents are also compared regarding their similarities and differences regarding monolignol ratio and important linkages. Results showed that the plant genotype has the weakest influence on monolignol content and interunit linkages. In contrast, structural differences are more significant among lignins of different harvest time and/or season. Analyses were performed using fast and simple methods such as nuclear magnetic resonance (NMR) spectroscopy. Data was assigned to four different linkages (A: β-O-4 linkage, B: phenylcoumaran, C: resinol, D: β-unsaturated ester). In conclusion, A content is particularly high in leaf-derived lignins at just under 70% and significantly lower in stem and mixture lignins at around 60% and almost 65%. The second most common linkage pattern is D in all isolated lignins, the proportion of which is also strongly dependent on the crop portion. Both stem and mixture lignins, have a relatively high share of approximately 20% or more (maximum is M. sinensis Sin2 with over 30%). In the leaf-derived lignins, the proportions are significantly lower on average. Stem samples should be chosen if the highest possible lignin content is desired, specifically from the M. x giganteus genotype, which revealed lignin contents up to 27%. Due to the better frost resistance and higher stem stability, M. nagara offers some advantages compared to M. x giganteus. Miscanthus crops are shown to be very attractive lignocellulose feedstock (LCF) for second generation biorefineries and lignin generation in Europe.


[Development of a highly sensitive assay for serum thyroglobulin using avidin-biotin system and its clinical application].
The authors have developed a highly sensitive sandwich-type enzyme immunoassay (EIA) for serum thyroglobulin using the biotin-avidin system. The sensitivity of this EIA was 0.1 ng/ml. The intra- and inter-assay coefficient of variation was 4-15% and 4-11%, respectively. Human Tg in serum was detectable in 100% of 63 normal subjects, and the normal range was from 2.3 ng/ml to 47.4 ng/ml. The recovery rate was very good. Then we applied this EIA to the follow-up study of patients with thyroid cancer. Serum Tg levels were serially determined in 15 patients with thyroid cancer who had undergone thyroidectomy (n = 9 subtotal, n = 6 total) and were receiving thyroid hormone suppression therapy. It was found that there were three groups in regard to the relationship between serum TSH and Tg. The first group showed normal TSH and normal Tg levels (n = 4). The second group showed TSH levels that were lower than the lower limit of the assay, whereas Tg levels were within the normal limit (n = 5). The last group showed both TSH and Tg that were lower than the lower limit (n = 6). In one case in the last group, recurrence of thyroid cancer was forecast by the change of Tg levels (from below 0.1 ng/ml to 5.9 ng/ml). Therefore, it is important to suppress serum Tg and TSH levels as much as possible in order to obtain the best usefulness of serum Tg determination in the follow-up study of thyroid cancer in patients who have undergone subtotal thyroidectomy or have residual thyroid tissue. We also measured Tg levels in patients with untreated Graves' disease. Twelve patients were negative for anti-Tg antibody and 18 were positive for anti-Tg antibody. Even in the antibody positive cases, serum Tg could be detected and their levels could be calculated from the recovery studies. The mean serum Tg levels in antibody positive cases were lower than in negative cases. These studies showed that our sensitive EIA for serum Tg determination was useful in practice in patients with thyroid disease.


Expression of porcine prorelaxin in transgenic tobacco.
In vitro studies demonstrate that porcine relaxin may possess various therapeutic effects. In this study, we explore the possibility of expressing porcine relaxin in transgenic tobacco. Tobacco was selected because it is a non-food, non-feed crop, and recombinant protein production can readily be scaled up. The cDNA of porcine preprorelaxin was under the regulation of two different constitutive promoters. DNA analysis by polymerase chain reaction verified that all transgenic plants contained the correct size of gene insert. Preliminary studies showed the presence of putative prorelaxin bands in both silver-stained SDS-PAGE and western blot. The results also indicated that tobacco-produced prorelaxin may not be properly processed to yield the mature relaxin.


[Left-right shunt caused by anomalous implantation of the left coronary artery in the trunk of pulmonary artery. Detection by contrast echocardiography].
The authors describe a case of an anomalous left coronary artery arising from the main pulmonary artery in an 11 year old child suffering from chest pain on effort and with a continuous murmur in the second left intercostal space. Two dimensional echocardiography (2D E) showed dilatations of the first segment of the right coronary artery and the anomalous origin of the left main coronary artery. A peripheral injection of microbubbles showed a left-to-right shunt between the left coronary artery and the pulmonary artery. Semi-quantitative evaluation of LV regional wall motion showed abnormal contraction of the anterolateral walls. Haemodynamic, angiographic data and the operative findings confirmed the diagnosis. The abnormal coronary ostium was closed and a bypass graft from the aorta to the left anterior descending artery was performed. Clinical and echocardiographic follow-up 7 months after surgery was completely normal.


Cardiac expression of kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase inhibits glycolysis, promotes hypertrophy, impairs myocyte function, and reduces insulin sensitivity.
Glycolysis is important to cardiac metabolism and reduced glycolysis may contribute to diabetic cardiomyopathy. To understand its role independent of diabetes or hypoxic injury, we modulated glycolysis by cardiac-specific overexpression of kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (kd-PFK-2). PFK-2 controls the level of fructose 2,6-bisphosphate (Fru-2,6-P(2)), an important regulator of glycolysis. Transgenic mice had over 2-fold reduced levels of Fru-2,6-P(2). Heart weight/body weight ratio indicated mild hypertrophy. Sirius red staining for collagen was significantly increased. We observed a 2-fold elevation in glucose 6-phosphate and fructose 6-phosphate levels, whereas fructose 1,6-bisphosphate was reduced 2-fold. Pathways branching off of glycolysis above phosphofructokinase were activated as indicated by over 2-fold elevated UDP-N-acetylglucosamine and glycogen. The kd-PFK-2 transgene significantly inhibited glycolysis in perfused hearts. Insulin stimulation of metabolism and Akt phosphorylation were sharply reduced. In addition, contractility of isolated cardiomyocytes was impaired during basal and hypoxic incubations. The present study shows that cardiac overexpression of kinase-deficient PFK-2 reduces cardiac glycolysis that produced negative consequences to the heart including hypertrophy, fibrosis, and reduced cardiomyocyte function. In addition, metabolic and signaling responses to insulin were significantly decreased.


Nonradiative Recombination in Perovskite Solar Cells: The Role of Interfaces.
Perovskite solar cells combine high carrier mobilities with long carrier lifetimes and high radiative efficiencies. Despite this, full devices suffer from significant nonradiative recombination losses, limiting their VOC to values well below the Shockley-Queisser limit. Here, recent advances in understanding nonradiative recombination in perovskite solar cells from picoseconds to steady state are presented, with an emphasis on the interfaces between the perovskite absorber and the charge transport layers. Quantification of the quasi-Fermi level splitting in perovskite films with and without attached transport layers allows to identify the origin of nonradiative recombination, and to explain the VOC of operational devices. These measurements prove that in state-of-the-art solar cells, nonradiative recombination at the interfaces between the perovskite and the transport layers is more important than processes in the bulk or at grain boundaries. Optical pump-probe techniques give complementary access to the interfacial recombination pathways and provide quantitative information on transfer rates and recombination velocities. Promising optimization strategies are also highlighted, in particular in view of the role of energy level alignment and the importance of surface passivation. Recent record perovskite solar cells with low nonradiative losses are presented where interfacial recombination is effectively overcome-paving the way to the thermodynamic efficiency limit.


North Atlantic Ocean control on surface heat flux on multidecadal timescales.
Nearly 50 years ago Bjerknes suggested that the character of large-scale air-sea interaction over the mid-latitude North Atlantic Ocean differs with timescales: the atmosphere was thought to drive directly most short-term--interannual--sea surface temperature (SST) variability, and the ocean to contribute significantly to long-term--multidecadal--SST and potentially atmospheric variability. Although the conjecture for short timescales is well accepted, understanding Atlantic multidecadal variability (AMV) of SST remains a challenge as a result of limited ocean observations. AMV is nonetheless of major socio-economic importance because it is linked to important climate phenomena such as Atlantic hurricane activity and Sahel rainfall, and it hinders the detection of anthropogenic signals in the North Atlantic sector. Direct evidence of the oceanic influence of AMV can only be provided by surface heat fluxes, the language of ocean-atmosphere communication. Here we provide observational evidence that in the mid-latitude North Atlantic and on timescales longer than 10 years, surface turbulent heat fluxes are indeed driven by the ocean and may force the atmosphere, whereas on shorter timescales the converse is true, thereby confirming the Bjerknes conjecture. This result, although strongest in boreal winter, is found in all seasons. Our findings suggest that the predictability of mid-latitude North Atlantic air-sea interaction could extend beyond the ocean to the climate of surrounding continents.