Silicone breast implant materials.
This opinion article has been written on request because of the recent public controversy over silicone breast implants produced by a now-defunct company, Poly Implant Prosthese (PIP) in France. More than 300,000 PIP devices have been implanted. The purposes of my article are to (1.) provide a general overview of silicone breast implant materials, (2.) to describe the general safety of these materials as reported to date, and (3.) to summarise current publicly available information about these aspects of the PIP prostheses. The materials covered are the silicone rubber from which the implant shells are made and the silicone gel used to fill the shell. The materials safety issues are biocompatibility (especially of the gel) and biodurability of the shell. The literature reviewed indicates that biocompatibility is not an issue with other current generation implants. However, biodurability is. A rough estimate of implant shell rupture rate is ~10+% at 10 years. Information is still emerging about the PIP implants. Initial regulatory disclosures suggest the PIP implants may have both biocompatibility and biodurability problems. They also suggest that PIP implants may have been produced using silicone materials not certified as medical grade. Governmental health and regulatory agencies are just now in the process of deciding what actions should be taken to protect patients.


Nephrolithiasis Among Middle Aged and Elderly Urban Chinese: A Report from Prospective Cohort Studies in Shanghai.
Kidney stone risk factors are understudied among Asians. Our study objective was to investigate associations of obesity and other chronic diseases with incident kidney stones among the urban Chinese. Included in this study are two prospective cohorts: the Shanghai Women's Health Study (N = 69,166) and Shanghai Men's Health Study (N = 58,054). Incident kidney stones were determined by self-report in 2004 and 2008. Cox regression models were used to evaluate the associations of study variables with stone risk with adjustment of demographics, medical history, and dietary intakes. There were 2653 incident stones over 1,007,958 person-years of follow-up. Overall incidence rates (per 1000 person-years, 95% confidence interval [CI]) were 2.10 (1.99, 2.21) among women and 3.80 (3.59, 4.02) among men. Higher body mass index (BMI) was associated with risk (BMI ≥25 vs 18.5-24.9 kg/m2, women: hazard ratio [HR] = 1.14 [95% CI 1.01, 1.28]; men: HR = 1.17 [1.03, 1.32]). High waist-hip ratio (≥0.80 and ≥0.90 for women and men, respectively) was associated with risk (HR 1.13, 95% CI 1.01, 1.27 for women; HR 1.19, 95% CI 1.05, 1.35 for men). Coronary heart disease or stroke history was associated with risk in women only (HR 1.31, 95% CI 1.10, 1.56). Hypertension history was associated with risk in men only (HR 1.27, 95% CI 1.11, 1.45). No significant association with diabetes mellitus was observed. Among the Chinese, kidney stone incidence in men is almost twice that of women. Obesity is a shared risk factor. Hypertension history is associated with risk in men, whereas history of coronary heart disease or stroke is associated with risk in women.


The interruptive effect of pain in a multitask environment: an experimental investigation.
Daily life is characterized by the need to stop, start, repeat, and switch between multiple tasks. Here, we experimentally investigate the effects of pain, and its anticipation, in a multitask environment. Using a task-switching paradigm, participants repeated and switched between 3 tasks, of which 1 predicted the possible occurrence of pain. Half of the participants received low intensity pain (N = 30), and half high intensity pain (N = 30). Results showed that pain interferes with the performance of a simultaneous task, independent of the pain intensity. Furthermore, pain interferes with the performance on a subsequent task. These effects are stronger with high intensity pain than with low intensity pain. Finally, and of particular importance in this study, interference of pain on a subsequent task was larger when participants switched to another task than when participants repeated the same task. This article is concerned with the interruptive effect of pain on people's task performance by using an adapted task-switching paradigm. This adapted paradigm may offer unique possibilities to investigate how pain interferes with task performance while people repeat and switch between multiple tasks in a multitask environment.


[Current approach to gastrointestinal diagnosis. With special reference to sonography and whole-body computer tomography].
In the last 10 years the diagnostic approach to gastrointestinal diseases has changed markedly. A new tactic, based upon modern diagnostic methods, is outlined. 1. Endoscopy has won a dominant position in diagnostic evaluation of the upper gastrointestinal tract and the colon, while routine x-ray plays a much reduced role. 2. In the diagnosis of liver, pancreatic and bile tract disease ultrasonography has largely replaced many of the previous procedures, particularly cholangiography, laparoscopy, scintigraphy, angiography and ERCP. 3. The diagnostic accuracy of ultrasonography appears to be equivalent to computer tomography in diseases of liver, pancreas and bile tract, and is less costly. 4. Ultrasonography has, however, its limits, which relate in part to the technic and still more to the technician. Its diagnostic accuracy is particularly limited in diffuse parenchymatous diseases of liver and pancreas.


Predicting treatment initiation in a family-based adolescent overweight and obesity intervention.
Little is known about factors associated with treatment initiation in overweight and obese adolescents. This study investigated parent-reported adolescent demographic, adolescent health, and parent motivation factors associated with initiation of a family-based adolescent overweight and obesity intervention. A telephone survey was completed by 349 parents calling to register their interest in participating in a cognitive behavioral lifestyle intervention for adolescent overweight and obesity. A total of 172 families (49.3%) returned their consent form to initiate treatment. A binomial logistic regression, with predictors entered in three blocks: (i) adolescent demographic (adolescent age, gender, adolescent BMI-for-age z-score, parent BMI); (ii) adolescent health (perceived adolescent physical and mental health, presence of an adolescent physical health problem or mental health problem, medication intake); and (iii) parent motivation (perceived adolescent weight category, concern about adolescent weight, importance of adolescent weight, confidence in adolescent capacity to change weight, priority of adolescent weight loss, discrepancy between adolescent current and ideal weight, previous weight loss attempts), was significant (χ2 (16) = 35.19, P = 0.004) accounting for 12.4-16.5% (95% confidence interval) of treatment initiation variance. Parent-reported adolescent physical health problem, parent perception of adolescent weight category, parent priority of adolescent weight loss, and parent perception of discrepancy between adolescent current and ideal weight were significant in the model. These findings indicate that data collected at intake are associated with treatment initiation and highlight the role of assessing and enhancing treatment motivation from initial contact.


Methyl alcohol poisoning: an autopsy study of 28 cases.
Twenty eight fatal cases out of the 97 cases of methyl alcohol (MA) poisoning admitted to K. E. M. Hospital in August 1988 during a single outbreak were studied. The latent period between consumption of the drink and development of symptoms was variable (range 7 1/2 hours to 60 hours). CNS symptoms were predominant (75% of cases) and shock either at admission or as a late event was seen in 89% of the cases. Blurring of vision was seen in 42.8% and blindness in 10.7% of cases. Minimum fatal period was 7 1/2 hours and maximum was 12 days. Methanol levels in blood and viscera were variable (average 155.8 mg%, max. 420.4 mg%). In 4 cases, significant amount of MA was detected in stomach contents 5-12 days after consumption of MA, raising the question of resecretion of MA in stomach. Shrinkage and degeneration of neurons in the parietal cortex was seen in 85.7% of cases. Putamental degeneration and necrosis was seen in 7.14%. Haemorrhage (3.5%) and sponginess (7.14%) was observed in the optic chiasma. Severe renal tubular degeneration and patchy necrosis was seen in all cases. Fatty changes (67.8%) and microvesicular fat (42.5%) were seen in the hepatocytes.


Snow depth variability in the Northern Hemisphere mountains observed from space.
Accurate snow depth observations are critical to assess water resources. More than a billion people rely on water from snow, most of which originates in the Northern Hemisphere mountain ranges. Yet, remote sensing observations of mountain snow depth are still lacking at the large scale. Here, we show the ability of Sentinel-1 to map snow depth in the Northern Hemisphere mountains at 1 km² resolution using an empirical change detection approach. An evaluation with measurements from ~4000 sites and reanalysis data demonstrates that the Sentinel-1 retrievals capture the spatial variability between and within mountain ranges, as well as their inter-annual differences. This is showcased with the contrasting snow depths between 2017 and 2018 in the US Sierra Nevada and European Alps. With Sentinel-1 continuity ensured until 2030 and likely beyond, these findings lay a foundation for quantifying the long-term vulnerability of mountain snow-water resources to climate change.


Synergy between the Mos/mitogen-activated protein kinase pathway and loss of p53 function in transformation and chromosome instability.
Constitutive activation of mitogen-activated protein kinase (MAPK) is a property common to many oncoproteins, including Mos, Ras, and Raf, and is essential for their transforming activities. We have shown that high levels of expression of the Mos/MAPK pathway in Swiss 3T3 fibroblast cause cells in S phase to undergo apoptosis, while cells in G1 irreversibly growth arrest. Interestingly, cells in G2 and M phases also arrest at a G1-like checkpoint after proceeding through mitosis. These cells fail to undergo cytokinesis and are binucleated. Thus, constitutive overexpression of Mos and MAPK cannot be tolerated, and fibroblasts transformed by Mos express only low levels of the mos oncogene product. Here, we show that p53 plays a key role in preventing oncogene-mediated activation of MAPK. In the absence of p53 (p53-/-), the growth arrest normally observed in wild-type p53 (p53+/+) mouse embryo fibroblasts (MEFs) is markedly reduced. The mos transformation efficiency in p53-/- MEFs is two to three orders of magnitude higher than that in p53+/+ cells, and p53-/- cells tolerate > 10-fold higher levels of both Mos and activated MAPK. Moreover, we show that, like Mos, both v-ras and v-raf oncogene products induce apoptosis in p53+/+ MEFs. These oncogenes also display a high transforming activity in p53-/- MEFs, as does a gain-of-function MAPK kinase mutant (MEK*). Thus, the p53-dependent checkpoint pathway is responsive to oncogene-mediated MAPK activation in inducing irreversible G1 growth arrest and apoptosis. Moreover, we show that the chromosome instability induced by the loss of p53 is greatly enhanced by the constitutive activation of the Mos/MAPK pathway.


[The microcirculation of patients with arterial ischemia of the lower extremities during laser therapy].
Microcirculation in the patient's foot skin with different stages of arterial ischemia, was examined with the aid of TV-capillaroscopy, laser dopplerography, polarography of transcutaneous oxygen tension. The effect of semiconductor laser (wave length 0.98 mcm) on microcirculation system was studied. The dependence of capillary blood flow on the transcutaneous oxygen tension was determined. The laser therapy proved to be successful in the patients with the II and III stages of arterial ischemia.


The Human Immunodeficiency Virus Continuum of Care in European Union Countries in 2013: Data and Challenges.
The Joint United Nations Programme on HIV/AIDS (UNAIDS) has set a "90-90-90" target to curb the human immunodeficiency virus (HIV) epidemic by 2020, but methods used to assess whether countries have reached this target are not standardized, hindering comparisons. Through a collaboration formed by the European Centre for Disease Prevention and Control (ECDC) with European HIV cohorts and surveillance agencies, we constructed a standardized, 4-stage continuum of HIV care for 11 European Union countries for 2013. Stages were defined as (1) number of people living with HIV in the country by end of 2013; (2) proportion of stage 1 ever diagnosed; (3) proportion of stage 2 that ever initiated ART; and (4) proportion of stage 3 who became virally suppressed (≤200 copies/mL). Case surveillance data were used primarily to derive stages 1 (using back-calculation models) and 2, and cohort data for stages 3 and 4. In 2013, 674500 people in the 11 countries were estimated to be living with HIV, ranging from 5500 to 153400 in each country. Overall HIV prevalence was 0.22% (range, 0.09%-0.36%). Overall proportions of each previous stage were 84% diagnosed, 84% on ART, and 85% virally suppressed (60% of people living with HIV). Two countries achieved ≥90% for all stages, and more than half had reached ≥90% for at least 1 stage. European Union countries are nearing the 90-90-90 target. Reducing the proportion undiagnosed remains the greatest barrier to achieving this target, suggesting that further efforts are needed to improve HIV testing rates. Standardizing methods to derive comparable continuums of care remains a challenge.


A polyclonal model for B cell tolerance. I. Fc-dependent and Fc-independent induction of nonresponsiveness by pretreatment of normal splenic B cells with anti-Ig.
We have developed a simple and adaptable, polyclonal model for B cell nonresponsiveness that is based on the inhibitory activity of anti-Ig as a surrogate for Ag. In our system the induction phase (treatment with anti-Ig) is separated from the challenge phase (Ag or mitogen), so that the critical events in each phase can be evaluated. Our results show that T cell-depleted B cells precultured for 18 to 24 h with rabbit anti-Ig reagents are rendered unresponsive to challenge with either Ag, fluorescein coupled to Brucella abortus (FL-BA), or mitogen (LPS). This state of nonresponsiveness (anergy) is reflected by an inhibition of a prototype response to the fluorescein hapten, as well as total Ig and IgG synthesis, but no reduction in proliferation to LPS. Interestingly, mitogen-induced polyclonal antibody formation was consistently reduced by 90% by treatment with either F(ab')2 or intact IgG anti-Ig. In contrast, the Ag-driven (FL-BA) response of pretreated B cells was inhibited by only 50 to 70%. Moreover, the latter effect usually required pretreatment with intact IgG anti-Ig, a result that suggests the importance of an Fc-dependent negative signal affecting the B cell's response to FL-BA. Furthermore, pretreatment and coculture of B cells with IL-4 blocked the Fc-dependent inhibition of the FL-BA responsiveness. These results, as well as kinetics experiments establishing a 4-h latent period, suggest that simple blocking of surface Ig receptor on target B cells is not responsible for the induction of anergy. Pretreated B cells displayed unique phenotypic changes after treatment with anti-Ig, including a diminution of Thy-1 expression in response to LPS + IL-4, as well as a reduction in membrane IgM and J11d expression (i.e., they were IgMlo, IgDmed, and J11dlo, as recently reported for anergic B cells in transgenic mice). These results suggest that B cell anergy can be induced in mature B cells by both Fc-dependent and Fc-independent processes that lead to unique phenotypic changes and may reflect egress from G0 in the absence of T cell help. The significance of these changes to tolerance mechanisms is discussed.


[Access to research data: a light at the end of the tunnel?].
The recent update of a systematic review conducted by a group of researchers from the Cochrane Collaboration showed modest effectiveness of neuraminidase inhibitors in reducing hospitalizations in patients with influenza, and an even smaller impact of these drugs on overall mortality. However, the relevance of this systematic review mainly relies on the revolutionary methodology with which it was performed, as it included among the evidence considered findings from unpublished clinical study reports submitted by pharmaceutical companies to regulatory agencies. The paper by Jefferson et al. published in the BMJ as well as the campaigns supported by the same journal open a new phase that should bring greater transparency in the relationship between researchers, industry and government to the benefit of citizens.


Detection and Treatment of Long-Chain Omega-3 Fatty Acid Deficiency in Adolescents with SSRI-Resistant Major Depressive Disorder.
Residual depressive symptoms are commonly observed in adolescents with major depressive disorder (MDD) following treatment with selective serotonin reuptake inhibitors (SSRIs). This study combined a case-control analysis and an open-label fish oil (FO) trial to investigate the relationship between long-chain omega-3 (LCn-3) fatty acid status and residual depressive symptoms in SSRI-resistant adolescent MDD patients. Baseline erythrocyte docosahexaenoic acid (DHA)(-28%, p=0.0003), but not eicosapentaenoic acid (EPA)(-18%, p=0.2), was significantly lower in patients (n=20) compared with healthy controls (n=20). Patients receiving 10-week low-dose (2.4 g/d, n=7) and high-dose (16.2 g/d, n=7) FO exhibited significant increases in erythrocyte EPA and DHA composition. In the intent-to-treat sample, depressive symptoms decreased significantly in the high-dose group (n=7, -40%, p<0.0001), and there was a trend in the low-dose group (n=10, -20%, p=0.06). Symptom remission was observed in 40% of patients in the low-dose group and 100% of patients in the high-dose group. There were no significant changes in vital signs and adverse events were rated as mild or moderate in severity. These preliminary findings demonstrate that adolescents with SSRI-resistant depression exhibit robust DHA deficits, and suggest that adjunctive FO supplementation is well-tolerated and effective for increasing LCn-3 fatty acid status and augmenting SSRI antidepressant effects.


Contrast Dispersion on Epidurography May Be Associated with Clinical Outcomes After Percutaneous Epidural Neuroplasty Using an Inflatable Balloon Catheter.
Contrast dispersion pattern on epidurography may be associated with clinical improvement after epidural neuroplasty. However, insufficient evidence supports this theory. The current study aims to evaluate the relevance of contrast dispersion and clinical improvement after percutaneous epidural neuroplasty using an inflatable balloon catheter. One hundred patients with lumbar spinal stenosis who underwent combined balloon decompression and epidural adhesiolysis between March 2015 to December 2015 participated in the present study. Participants were divided into two groups by contrast dispersion pattern on postprocedural epidurography: the complete contrast dispersion (CCD) and incomplete contrast dispersion (ICCD) groups. The numeric rating scale (NRS), Oswestry Disability Index (ODI), and global perceived effects (GPE) were each assessed before and one, three, six, nine, and 12 months after the intervention. After combined balloon decompression and adhesiolysis, significant pain reduction and functional improvement were maintained up to 12 months in patients with lumbar spinal stenosis. NRS and GPE in the CCD group were significantly lower than in the ICCD group from six to 12 months after the intervention. The ODI in the CCD group was also significantly lower compared with that in the ICCD group from one to 12 months after the intervention. Combined balloon decompression and adhesiolysis with the inflatable balloon catheter can provide noteworthy pain reduction and improvement of physical function for a long-term period in patients with lumbar spinal stenosis. Because CCD showed better clinical improvement compared with ICCD, a contrast dispersion pattern may be associated with an improved clinical outcome.


[Laparoscopic left partial nephrectomy for renal cell carcinoma associated with ITP with platelet count of 10,000/μL].
A 58-year-old man from Brazil was followed as an outpatient with asymptomatic macroglobulinemia and idiopathic thrombocytopenic purpura (ITP). Abdominal enhanced computed tomographic (CT) scan for elevated liver enzymes revealed a left renal tumor. The tumor was in the middle outer left kidney, measured 18 mm in diameter, was discovered in its early phase, and appeared half exophytic. After investigations, the patient was diagnosed with left renal cell carcinoma associated with ITP. His preoperative platelet count was 10,000/μl ; five days of intravenous gamma globulin therapy with high-dose dexamethasone increased the platelet count to 76,000/μl just before operation. Laparoscopic left partial nephrectomy was performed successfully using the retroperitoneal approach. The renal artery was clamped and the tumor excised with an adequate margin. Renal parenchymal repair was completed using running sutures. Ischemia time was 16 minutes. There was no severe oozing of blood intraoperatively. The platelet count decreased to 15,000/μl on postoperative day three (POD 3), and there was oozing of blood around the retroperitoneal drain tube. The bleeding stopped after administration of platelet transfusion. The patient was discharged on POD 9. The histopathological diagnosis was clear cell carcinoma, and surgical margins were negative.


Validation of the Italian version of the UNESP-Botucatu unidimensional composite pain scale for the assessment of postoperative pain in cattle.
The aim of this study was to validate the Italian version of the UNESP-Botucatu Unidimensional Composite Pain Scale (UCPS-IV) for assessing postoperative pain in cattle. Video analysis and psychometric testing. A total of 40 Nellore cattle, age 2-3 years, weighing 365±51 kg. An English version of the scale was translated to Italian and back translated to English to ensure semantic equivalence. A total of four Italian observers and the researcher who developed the original scale (considered as the gold standard) analysed videos of 40 cattle previously subjected to orchiectomy (recorded for each cattle at four predetermined timepoints during the perioperative period) unaware of the videos' timepoint. They assigned a pain score [ranging from no pain (0) to severe pain (10)] using the Italian version of the scale and verified the need for analgesic treatment for each animal. The obtained scores were subjected to psychometric validity, responsiveness and reliability tests. The factor analysis of the scale resulted in a one-factor solution. Significant changes in pain scores in response to surgery and analgesics confirmed not only the content and construct validity, but also responsiveness. The agreement between the researcher who developed the original scale and the blinded observers and the correlation between the pain scores determined by the scale and those determined by three classical unidimensional pain scales confirmed criterion and concurrent validity. Internal consistency of the scale was excellent. Inter- and intrarater reliability ranged from moderate to good and from moderate to very good for all scale items, respectively, supporting reproducibility and stability. The cut-off point for rescue analgesia calculated by the receiver operating characteristic curve was > 3. The results confirm that the UNESP-Botucatu UCPS-IV appears to be a valid and reliable tool for the assessment of postorchiectomy pain in the bovine species. The determination of a cut-off point for rescue analgesia is also helpful for guiding analgesic therapy.


A history of uraemic toxicity and of the European Uraemic Toxin Work Group (EUTox).
The uraemic syndrome is a complex clinical picture developing in the advanced stages of chronic kidney disease, resulting in a myriad of complications and a high early mortality. This picture is to a significant extent defined by retention of metabolites and peptides that with a preserved kidney function are excreted or degraded by the kidneys. In as far as those solutes have a negative biological/biochemical impact, they are called uraemic toxins. Here, we describe the historical evolution of the scientific knowledge about uraemic toxins and the role played in this process by the European Uraemic Toxin Work Group (EUTox) during the last two decades. The earliest knowledge about a uraemic toxin goes back to the early 17th century when the existence of what would later be named as urea was recognized. It took about two further centuries to better define the role of urea and its link to kidney failure, and one more century to identify the relevance of post-translational modifications caused by urea such as carbamoylation. The knowledge progressively extended, especially from 1980 on, by the identification of more and more toxins and their adverse biological/biochemical impact. Progress of knowledge was paralleled and impacted by evolution of dialysis strategies. The last two decades, when insights grew exponentially, coincide with the foundation and activity of EUTox. In the final section, we summarize the role and accomplishments of EUTox and the part it is likely to play in future action, which should be organized around focus points like biomarker and potential target identification, intestinal generation, toxicity mechanisms and their correction, kidney and extracorporeal removal, patient-oriented outcomes and toxin characteristics in acute kidney injury and transplantation.


Nickel(II) and iron(III) selective off-on-type fluorescence probes based on perylene tetracarboxylic diimide.
Two novel "turn-on" fluorescent probes with perylene tetracarboxylic diimide (PDI) as the fluorophore and two different di-(2-picolyl)-amine (DPA) groups as the metal ion receptor (PDI-1 and PDI-2) were successfully synthesized with satisfactory yields. PDI-1 exhibited high selectivity toward Ni(2+) in the presence of various other metal cations including Zn(2+), Cd(2+) and Cu(2+) which were expected to interfere significantly. A 1 : 2 stoichiometry was found for the complex formed by PDI-1 and Ni(2+) by a Job's plot and by non-linear least square fitting of the fluorescence titration curves. By introducing an extra diamino ethylene group between DPA and the phenyl bridge, the receptor was modified and the high selectivity of the sensor toward Ni(2+) shifted to Fe(3+). The enhancement factor of the fluorescence response of PDI-2 to Fe(3+) was as high as 138. The binding behavior of the receptors in these two compounds is affected significantly by the PDI fluorophores. Most interestingly, both Ni(2+) and Fe(3+) are paramagnetic metal ions, which are known as fluorescence quenchers and are rarely targeted with "turn-on" fluorescence probes. This result suggests that PDIs are favorable fluorophores for a "turn-on" fluorescence probe for paramagnetic transition metal ions because of their high oxidation potential.


Muscle Strength, But Not Muscle Oxidative Capacity, Varies Between the Morning and the Afternoon in Patients with Multiple Sclerosis: A Pilot Study.
Despite frequent muscle strength or muscle oxidative capacity (based on exercise-onset oxygen uptake [VO2] kinetics) assessments in patients with multiple sclerosis, the impact of time of day on these parameters is often not taken into account. Based on observations in healthy subjects, it remains to be studied whether muscle strength, and/or exercise-onset VO2 kinetics, varies between the morning and the afternoon in patients with multiple sclerosis. In this prospective observational pilot study, walking capacity, exercise-onset VO2 kinetics, isometric knee extension/flexion strength (dynamometry), and self-reported fatigue were measured in 11 patients with multiple sclerosis (age, 51.8 ± 9.3 yrs; body mass index, 24.7 ± 5.1 kg/m; Expanded Disability Status Scale, 3.5 ± 1.4; 3 men) in the morning and 5 hrs later (afternoon). In the afternoon, self-reported fatigue (1.9 ± 0.9 cm) and muscle strength (knee extension peak torque at 45 degrees, 84 ± 26 Nm) were significantly different (P < 0.05), than in the morning (self-reported fatigue, 1.2 ± 0.9 cm; knee extension peak torque at 45 degrees, 93 ± 32 Nm), but walking capacity and exercise-onset VO2 kinetics were similar at these two time points (P > 0.05). Consistent with observations in healthy subjects, muscle strength varies between the morning and the afternoon in patients with multiple sclerosis, under the conditions of the present study. These findings suggest that muscle strength assessments should be conducted at similar or nearly similar times of the day to minimize diurnal variation in these measures and hence insure correct interpretation.


Generation of Defined Genomic Modifications Using CRISPR-CAS9 in Human Pluripotent Stem Cells.
Human pluripotent stem cells offer a powerful system to study gene function and model specific mutations relevant to disease. The generation of precise heterozygous genetic modifications is challenging due to CRISPR-CAS9 mediated indel formation in the second allele. Here, we demonstrate a protocol to help overcome this difficulty by using two repair templates in which only one expresses the desired sequence change, while both templates contain silent mutations to prevent re-cutting and indel formation. This methodology is most advantageous for gene editing coding regions of DNA to generate isogenic control and mutant human stem cell lines for studying human disease and biology. In addition, optimization of transfection and screening methodologies have been performed to reduce labor and cost of a gene editing experiment. Overall, this protocol is widely applicable to many genome editing projects utilizing the human pluripotent stem cell model.


A decision tree for rapid quality assurance and control of rifampicin-containing oral dosage forms for global distribution for tuberculosis treatment.
For centuries tuberculosis remained as a complex socioeconomic problem impeding human development. Directly observed treatment short-course and fixed dose combinations were implemented in tuberculosis therapy for maximum success of treatment. However, drug shortages primarily hindered the expansion of directly observed treatment short-course, which lead to development of the global tuberculosis drug facility. Since large geographical area is covered by the global tuberculosis drug facility for global drug supply for tuberculosis eradication programs, a rapid quality control and assurance has become necessary to ensure the quality and performance of supplied antituberculosis drugs. In this manuscript a decision tree is proposed for facilitating rapid quality control (in vitro and in vivo) of antituberculosis formulations procured by the global tuberculosis drug facility. This decision tree also predicted to be applicable at every stages of anti tuberculosis drug product development, especially in identification of poor quality products and monitoring batch-to-batch variability. Further, it provides opportunity for effective quality control in resource poor settings and the gained knowledge is anticipated to be applicable for development and evaluation of antimalarial and antiAIDS fixed dose combinations.


Impella for the Management of Ventricular Septal Defect Complicating Acute Myocardial Infarction: A European Multicenter Registry.
Ventricular septal defect (VSD) is a rare but severe complication of myocardial infarction (MI). Temporary mechanical circulatory support (MCS) can be used as a bridge to VSD closure, heart transplantation, or ventricular assist device. We describe the use of Impella device in this context based on a multicenter European retrospective registry (17 centers responded). Twenty-eight post-MI VSD patients were included (Impella device were 2.5 for 1 patient, CP for 20, 5.0 for 5, and unknown for 2). All patients were in cardiogenic shock with multiple organ failure (SAPS II 41 [interquantile range {IQR} = 27-53], lactate 4.0 ± 3.5 mmol/L) and catecholamine support (dobutamine 55% and norepinephrine 96%). Additional temporary MCS was used in 14 patients (50%), mainly extracorporeal life support (ECLS) (n = 9, 32%). Severe bleedings were frequent (50%). In-hospital and 1 year mortalities were 75%. Ventricular septal defect management was surgical for 36% of patients, percutaneous for 21%, and conservative for 43%. Only surgically managed patients survived (70% in-hospital survival). Type and combination of temporary MCS used were not associated with mortality (Impella alone or in combination with intra-aortic balloon pump [IABP] or ECLS, p = 0.84). Impella use in patients with post-MI VSD is feasible but larger prospective registries are necessary to further elucidate potential benefits of left ventricular unloading in this setting.


Prognosis associated with cutaneous melanoma metastases.
Information on the prognosis for patients with regional cutaneous melanoma metastases has been sparse and difficult to establish. In 2009 the American Joint Committee on Cancer (AJCC) melanoma staging has for the first time provided survival rates for patients who manifest intralymphatic metastases. We sought to validate the new staging system in this contemporary, prospectively collected cohort of patients following the development of cutaneous metastases as the first evidence of metastatic disease and explored the factors that influenced their prognosis. The Victorian Melanoma Service database was searched to identify all patients with cutaneous melanoma metastases. Patients who were found to have lymph node or visceral metastases at the time they were diagnosed with cutaneous metastatic disease were excluded. Survival curves were generated and univariate and multivariate assessments of prognostic factors associated with survival were performed. In total, 72 patients presented with cutaneous metastases as the first evidence of metastatic disease. The median melanoma-specific survival of patients with only regional cutaneous metastases (n = 56) was 5.07 years and their 5-year survival rate was 52%. Distant cutaneous metastases and thickness of the primary melanoma were found to be significant negative predictors of survival. We were able to validate the new AJCC melanoma staging system survival for patients with cutaneous metastatic disease. Patients presenting with regional cutaneous metastases have a much better prognosis than those with distant cutaneous metastases.


Small-for-size grafts in living-related liver transplantation.
The problems associated with small-for-size grafts in living-related liver transplantation are not fully understood. A consecutive series of 79 patients underwent 80 living-related liver transplantation procedures, including one retransplant, at the University of Tokyo from January 1996 to January 2000. They were divided into two groups by graft size: graft weight/recipient standard liver volume ratios of 40% or less (n = 24), and more than 40% (n = 56). Preoperative status, mortality, morbidity, duration of hospital stay, and postoperative graft function were examined and compared between the groups. The rate of patients who were restricted to the intensive care unit preoperatively was comparable between the groups (33% versus 21%, p = 0.27). The mean standard liver volume ratios were 37% in the small graft group and 84% in the large group. Survival rates were 80% (5 of 24) for the small graft group, which was significantly lower than that for the large group (96%, 54 of 56, p = 0.02). The rate of acute rejection was comparable between the groups (33% versus 43%, p = 0.47). Vascular complication was observed in 17% of the small graft group patients and 23% of the large group (p = 0.77). No difference was observed in the frequency of bile leakage or bile duct stenosis (25% versus 21%, p=0.77). Hyper-bilirubinemia and elongation of prothrombin time persisted longer in the small graft group than in the large group (p < 0.0001 for both). Our surgical results may suggest that a graft weight ratio of 40% or less provides a lower chance of survival after living-related liver transplantation.


Effects of nonthyroidal illness on thyroid function.
Despite the absence of thyroid disease, patients with nonthyroidal illness frequently have changes in serum thyroid hormone measurements that may suggest either hypothyroidism or hyperthyroidism. Serum T3 levels are frequently decreased mainly because of a decrease in the rate of T3 production from T4. The free T3 concentration may be either normal or reduced as well. The binding of T4 and T3 by the serum-binding proteins is almost always impaired, resulting in an increase in the dialyzable fraction (free) fraction. This is due to a decrease in the concentration of thyroxine-binding proteins and the presence of circulating inhibitors of binding. If serum T4 concentration remains within the normal range, the free T4 concentration can be increased. However, serum T4 is frequently decreased in patients with chronic and/or severe illness. The decrease in serum T4 in these patients, combined with an increase in the dialyzable fraction, results in normal free T4. In patients who are critically ill, none of the available methods for measurement of free T4 may give results that accurately reflect the euthyroid state. Since T3 is the major active thyroid hormone, it is surprising that patients with decreased serum T3 do not appear hypothyroid. The decrease in serum T3 is probably an adaptive change to nonthyroidal illness, which at least enables the sick patient to conserve protein. The clinical impression of euthyroidism is supported by the finding of a normal serum TSH level in most patients. Although TSH regulation may not be entirely normal in patients with nonthyroidal disease, it is likely that serum TSH will be increased in most sick patients who also have significant thyroid failure. The normal clinical findings in patients with decreased serum T3 may result from an augmentation of those biologic responses associated with the clinical manifestations of the euthyroid state. Several animal models of nonthyroidal disease or starvation show that cells have the ability to modulate some biologic responses to thyroid hormone. Further study should elucidate the mechanisms underlying these changes. This article has emphasized that no single laboratory measurement may reliably predict the thyroid state in patients with nonthyroidal disease. This fact emphasizes the need for careful clinical evaluation of these patients and judicious use of laboratory tests. Because the changes in thyroid hormone metabolism that occur in nonthyroidal disease probably represent adaptive changes to the illness, treatment with L-thyroxine to restore serum thyroid concentrations to the normal range is not indicated.


S2k guidelines for the treatment of psoriasis in children and adolescents - Short version part 1.
The present guidelines are aimed at residents and board-certified physicians in the fields of dermatology, pediatrics, pediatric dermatology and pediatric rheumatology as well as policymakers and insurance funds. They were developed by dermatologists and pediatric dermatologists in collaboration with pediatric rheumatologists using a formal consensus process (S2k). The guidelines highlight topics such as disease severity, quality of life, treatment goals as well as problems associated with off-label drug therapy in children. Trigger factors and diagnostic aspects are discussed. The primary focus is on the various topical, systemic and UV-based treatment options available and includes recommendations for use and treatment algorithms. Other aspects addressed herein include vaccinations in children and adolescents with psoriasis as well as various disease subtypes such as guttate psoriasis, diaper psoriasis, pustular psoriasis and psoriatic arthritis. Finally, we also provide recommendations for imaging studies and the diagnostic workup to rule out tuberculosis prior to initiating systemic treatment. Note: This article constitutes part 1 of the Sk2 guidelines for the treatment of psoriasis in children and adolescents. Part 2 will be published in the next issue. It contains chapters on UV therapy, systemic treatment, tonsillectomy and antibiotics, vaccinations, guttate psoriasis, psoriatic arthritis, complementary medicine, as well as imaging studies and diagnostic workup to rule out tuberculosis prior to systemic treatment.


The antifungal action mode of the rice endophyte Streptomyces hygroscopicus OsiSh-2 as a potential biocontrol agent against the rice blast pathogen.
Microbial antagonists and their bioactive metabolites provide one of the best alternatives to chemical pesticides to control crop disease for sustainable agriculture and global food security. The rice endophyte Streptomyces hygroscopicus OsiSh-2, with remarkable antagonistic activity towards the rice blast fungus Magnaporthe oryzae, was reported in our previous study. The present study deciphered the possible direct interaction mode of OsiSh-2 against M. oryzae. An in vitro antibiotic assay for OsiSh-2 culture filtrate revealed strong suppression of mycelial growth, conidial germination and appressorial formation of M. oryzae. Meanwhile, severe morphological and internal abnormalities in M. oryzae hyphae were observed under a scanning electron microscope and transmission electron microscope. Foliar treatment of rice seedlings by OsiSh-2 culture filtrate in the greenhouse and in the field showed 23.5% and 28.3% disease reduction, respectively. Correspondingly, OsiSh-2 culture filtrate could induce disorganized chitin deposition in the cell wall and lowered ergosterol content in the cell membrane of M. oryzae. Additionally, cell wall integrity pathway activation, large cell electrolytes release, reactive oxygen species accumulation and tricarboxylic acid cycle-related enzyme activity changes were found in M. oryzae. All these results suggested that the direct antagonistic activity of OsiSh-2 against M. oryzae may be attributed to damaging the integrity of the cell wall and membrane and disrupting mitochondrial function in the pathogen.


Enabling enrichment analysis with the Human Disease Ontology.
Advanced statistical methods used to analyze high-throughput data such as gene-expression assays result in long lists of "significant genes." One way to gain insight into the significance of altered expression levels is to determine whether Gene Ontology (GO) terms associated with a particular biological process, molecular function, or cellular component are over- or under-represented in the set of genes deemed significant. This process, referred to as enrichment analysis, profiles a gene set, and is widely used to make sense of the results of high-throughput experiments. Our goal is to develop and apply general enrichment analysis methods to profile other sets of interest, such as patient cohorts from the electronic medical record, using a variety of ontologies including SNOMED CT, MedDRA, RxNorm, and others. Although it is possible to perform enrichment analysis using ontologies other than the GO, a key pre-requisite is the availability of a background set of annotations to enable the enrichment calculation. In the case of the GO, this background set is provided by the Gene Ontology Annotations. In the current work, we describe: (i) a general method that uses hand-curated GO annotations as a starting point for creating background datasets for enrichment analysis using other ontologies; and (ii) a gene-disease background annotation set - that enables disease-based enrichment - to demonstrate feasibility of our method.


Cumulative sum analysis of learning curve for video-assisted mini-laparotomy partial nephrectomy in renal cell carcinoma.
Video-assisted mini-laparotomy surgery (VAMS), a hybrid of open and laparoscopic surgical techniques, is an important surgical approach in the field of partial nephrectomy. The learning curve for VAMS partial nephrectomy has not been studied to date; we therefore, evaluated this learning curve.We prospectively evaluated 20 consecutive patients who underwent VAMS partial nephrectomy performed by a single surgeon (YEY) between March 2015 and December 2016. The learning curve was evaluated using the cumulative sum method. The measure of surgical performance was composed of 3 parameters (total operation time [Op time], warm ischemic time [WIT], and estimated blood loss [EBL]).Among the 20 patients who underwent VAMS partial nephrectomy, the mean age was 54.6 years. The mean Op time and WIT were 172.5 and 28.8 minutes, respectively. The learning curve for the Op time, WIT, and EBL consisted of 3 unique phases: phase 1 (the first 7 cases), phase 2 (the next 5 to 7 cases), and phase 3 (all subsequent cases). Phase 1 represents the initial learning curve, and the phase 2 plateau represents the period of expert competency. Phase 3 represents when one is competent in VAMS partial nephrectomy.The learning curve for VAMS partial nephrectomy is relatively short and after a learning curve of approximately 7 cases, the surgeon became familiar with VAMS partial nephrectomy; after 12 to 14 cases, the surgeon became competent in this procedure.


Targeted next generation sequencing of clinically significant gene mutations and translocations in leukemia.
Leukemias are currently subclassified based on the presence of recurrent cytogenetic abnormalities and gene mutations. These molecular findings are the basis for risk-adapted therapy; however, such data are generally obtained by disparate methods in the clinical laboratory, and often rely on low-resolution techniques such as fluorescent in situ hybridization. Using targeted next generation sequencing, we demonstrate that the full spectrum of prognostically significant gene mutations including translocations, single nucleotide variants (SNVs), and insertions/deletions (indels) can be identified simultaneously in multiplexed sequence data. As proof of concept, we performed hybrid capture using a panel of 20 genes implicated in leukemia prognosis (covering a total of 1 Mbp) from five leukemia cell lines including K562, NB4, OCI-AML3, kasumi-1, and MV4-11. Captured DNA was then sequenced in multiplex on an Illumina HiSeq. Using an analysis pipeline based on freely available software we correctly identified DNA-level translocations in three of the three cell lines where translocations were covered by our capture probes. Furthermore, we found all published gene mutations in commonly tested genes including NPM1, FLT3, and KIT. The same methodology was applied to DNA extracted from the bone marrow of a patient with acute myeloid leukemia, and identified a t(9;11) translocation with single base accuracy as well other gene mutations. These results indicate that targeted next generation sequencing can be successfully applied in the clinical laboratory to identify a full spectrum of DNA mutations ranging from SNVs and indels to translocations. Such methods have the potential to both greatly streamline and improve the accuracy of DNA-based diagnostics.


SIGMA: a set-cover-based inexact graph matching algorithm.
Network querying is a growing domain with vast applications ranging from screening compounds against a database of known molecules to matching sub-networks across species. Graph indexing is a powerful method for searching a large database of graphs. Most graph indexing methods to date tackle the exact matching (isomorphism) problem, limiting their applicability to specific instances in which such matches exist. Here we provide a novel graph indexing method to cope with the more general, inexact matching problem. Our method, SIGMA, builds on approximating a variant of the set-cover problem that concerns overlapping multi-sets. We extensively test our method and compare it to a baseline method and to the state-of-the-art Grafil. We show that SIGMA outperforms both, providing higher pruning power in all the tested scenarios.


Pure laparoscopic hepatectomy as repeat surgery and repeat hepatectomy.
To assess clinical outcomes of laparoscopic hepatectomy (LH) in patients with a history of upper abdominal surgery and repeat hepatectomy. This study compared the perioperative courses of patients receiving LH at our institution that had or had not previously undergone upper abdominal surgery. Of the 80 patients who underwent LH, 22 had prior abdominal surgeries, including hepatectomy (n = 12), pancreatectomy (n = 3), cholecystectomy and common bile duct excision (n = 1), splenectomy (n = 1), total gastrectomy (n = 1), colectomy with the involvement of transverse colon (n = 3), and extended hysterectomy with extensive lymph-node dissection up to the upper abdomen (n = 1). Clinical indicators including operating time, blood loss, hospital stay, and morbidity were compared among the groups. Eighteen of the 22 patients who had undergone previous surgery had severe adhesions in the area around the liver. However, there were no conversions to laparotomy in this group. In the 58 patients without a history of upper abdominal surgery, the median operative time was 301 min and blood loss was 150 mL. In patients with upper abdominal surgical history or repeat hepatectomy, the operative times were 351 and 301 min, and blood loss was 100 and 50 mL, respectively. The median postoperative stay was 17, 13 and 12 d for patients with no history of upper abdominal surgery, patients with a history, and patients with repeat hepatectomy, respectively. There were five cases with complications in the group with no surgical history, compared to only one case in the group with a prior history. There were no statistically significant differences in the perioperative results between the groups with and without upper abdominal surgical history, or with repeat hepatectomy. LH is feasible and safe in patients with a history of upper abdominal surgery or repeat hepatectomy.


The Evaluation of Building Fire Emergency Response Capability Based on the CMM.
The construction of smart cities is a theme of urban development, and building fires greatly threaten public safety and urban environmental governance, in which fire emergency management is one of the key factors. However, most studies on the evaluation of emergency response capacity ignore the process of improvement, as well as the intelligence and practicality of the results. The evaluation system of building fire emergency response capability maturity (FE-CMM) was innovatively proposed based on the capability maturity model (CMM), including the evaluation index, evaluation grade, evaluation method, and evaluation process. At the same time, a plug-in for evaluating fire emergency response capability was developed based on the building information modeling (BIM) platform. Finally, an empirical study was carried out in combination with the case of a district fire center. The research demonstrates that the evaluation system can effectively judge the maturity of fire emergency response capability, and the established plug-in can preliminarily realize the intelligent evaluation of building fire emergency response capability, which improves the practice and intelligence of the fire emergency response capability evaluation system when fully considering the process of improvement. It has guiding significance for ex ante control and refined management of building fires, thus providing support for urban public safety and environmental governance.


[The reliability of computer tomography in the diagnosis of recurrent symptoms after lumbar disc operations].
In 67 patients with recurrent complaints after operations of herniated lumbar disks, the CT findings were compared with the results of the subsequent second operation. Postoperative complications as haemorrhages or inflammations appear as localised or diffuse densities within the spinal canal in the operated segment and can be diagnosed without difficulty. The differentiation between a true recurrent herniation and scar formation is difficult, mainly within the first 4 weeks after operation. Even with the administration of iv. contrast medium, the diagnostic accuracy is not higher than 70%. In addition to the enhancement effect, which is not always reliable, the shape, position and density of a suspected structure can be used as diagnostic criteria.


The effect of upper-limb motion on lower-limb muscle synchrony. Implications for anterior cruciate ligament injury.
A high prevalence of rupture of the anterior cruciate ligament is associated with activities that incorporate both abrupt deceleration and catching a ball. In the present study, we examined whether the upper-limb motion involved in catching a ball affected the synchrony of the lower-limb muscles during tasks known to stress the anterior cruciate ligament-namely, abrupt decelerative landings. Seven male and eleven female subjects decelerated abruptly to land in single-limb stance after catching a chest-height pass and after no catching. Ground-reaction force and electromyographic data for six lower-limb muscles were sampled while the subjects' landing technique was filmed. The joint-reaction forces and the sagittal planar net moments for the knee then were calculated to derive the tibiofemoral shear forces. The muscle onsets and peak muscle activities were temporally analyzed with respect to the time of initial foot-ground contact, the peak resultant ground-reaction force, and the peak tibiofemoral shear force. When catching a pass, the subjects demonstrated significantly (p < 0.05) earlier rectus femoris onset relative to the timing of the initial foot-ground contact and of the peak tibiofemoral shear force, and they showed delayed biceps femoris onset relative to the timing of the peak tibiofemoral shear force compared with the findings in the trials without catching. We concluded that catching a ball during an abrupt landing could increase the potential for an anterior cruciate ligament injury by limiting the time available for the hamstring muscles to generate posterior tibial-drawer force before the onset of the quadriceps-induced anterior tibial translation. The integrity of the anterior cruciate ligament during landing relies on the proper coordination of the lower-limb muscles, particularly the quadriceps and the hamstrings. The present study demonstrated that motion of the upper-limbs may interfere with recruitment of these muscles, thereby predisposing the anterior cruciate ligament to injury.


Exploring quality of life in the eating disorders.
The present study aimed to investigate the impact of Body Mass Index (BMI), duration of illness and severity of illness on quality of life within a sample of individuals in treatment for an eating disorder. In addition this study explored differences in specific areas of quality of life (Psychological, Physical/Cognitive, Work/School and Financial) according to specific eating disorder diagnoses. Participants (N = 156) were adults currently receiving treatment for an eating disorder. Eating disorder symptomatology and quality of life were assessed using self-report questionnaires. BMI, duration of illness and eating disorder diagnosis was obtained during a clinical interview. Severity of the eating disorder and BMI were predictors of low quality of life. Duration of illness, contrary to clinical expectations was not a significant predictor of poor quality of life. In terms of differences across diagnostic groups, individuals with a diagnosis of anorexia nervosa in this sample were found to have lower psychological and physical/cognitive quality of life than those with an EDNOS or BN diagnoses.


Treponemycin, a nitrile antibiotic active against Treponema hyodysenteriae.
Two strains of Streptomyces sp. (isolates 275 and 124) were isolated from soil samples collected from the fields around Lewiston, Idaho. Based on their cellular morphology and physiology, the two isolates were identified as Streptomyces albovinaceous. Both isolates produced an antibiotic when grown in liquid culture medium containing homogenized oats. The antibiotic (treponemycin) was isolated from the culture broth by solvent extraction and purified by silica gel column and preparative thin-layer chromatographies. Treponemycin is a crystalline light-yellow compound with an mp of 93 to 95 degrees C, levorotatory, and soluble in most organic solvents. It is sparingly soluble in water but insoluble in petroleum ether. On the basis of elemental analysis and mass spectral data, the molecular formula of the antibiotic was deduced to be C28H43O6N. The infrared spectrum of the antibiotic indicated the presence of unsaturation, nitrile, lactone, or ester or all three functions, and carbonyl functions in the molecule. A sharp infrared absorption band for nitrile at 2,220 cm-1 and the presence of an unsaturated group indicated that the nitrile function may be attached to an unsaturated carbon atom. The presence of dienenitrile functions was further supported by the UV absorption spectrum of the antibiotic, which gave a UVmax at 257 nm. The proton magnetic resonance spectrum of the antibiotic did not give any peak which could be exchanged with deuterated water, which is an indication of the absence of carboxylic and hydroxyl functions in the molecule. All of the functional groupings indicated by the infrared and UV spectra of the molecule were further confirmed by the 13C-magnetic resonance spectrum of the compound. A brief hydrogenation of the antibiotic yielded a biologically active tetrahydro derivative, whereas extended hydrogenation produced an inactive primary amine. Mild alkaline hydrolysis and subsequent esterification of the antibiotic with diazomethane produced an inactive dimethyl ester. Apparently both the nitrile and the lactone functions are essential for the treponomycin molecule to show antimicrobial activity. The antibiotic showed inhibitory activity against several species of bacteria, especially Treponema hyodysenteriae, the causative agent of swine dysentery. In view of the oral 50% lethal dose of 400 mg/g and its low MIC against four stains of T.hyodysenteriae, the antibiotic may have value as a swine dysentery therapeutic.


Interaction analysis through proteomic phage display.
Phage display is a powerful technique for profiling specificities of peptide binding domains. The method is suited for the identification of high-affinity ligands with inhibitor potential when using highly diverse combinatorial peptide phage libraries. Such experiments further provide consensus motifs for genome-wide scanning of ligands of potential biological relevance. A complementary but considerably less explored approach is to display expression products of genomic DNA, cDNA, open reading frames (ORFs), or oligonucleotide libraries designed to encode defined regions of a target proteome on phage particles. One of the main applications of such proteomic libraries has been the elucidation of antibody epitopes. This review is focused on the use of proteomic phage display to uncover protein-protein interactions of potential relevance for cellular function. The method is particularly suited for the discovery of interactions between peptide binding domains and their targets. We discuss the largely unexplored potential of this method in the discovery of domain-motif interactions of potential biological relevance.


Association of serum VEGF levels with prefrontal cortex volume in schizophrenia.
A large body of evidence indicates alterations in brain regional cellular energy metabolism and blood flow in schizophrenia. Among the different molecules regulating blood flow, vascular endothelial growth factor (VEGF) is generally accepted as the major factor involved in the process of angiogenesis. In the present study, we examined whether peripheral VEGF levels correlate with changes in the prefrontal cortex (PFC) volume in patients with schizophrenia and in healthy controls. Whole-blood samples were obtained from 96 people with schizophrenia or schizoaffective disorder and 83 healthy controls. Serum VEGF protein levels were analyzed by enzyme-linked immunosorbent assay, whereas quantitative PCR was performed to measure interleukin-6 (IL-6, a pro-inflammatory marker implicated in schizophrenia) mRNA levels in the blood samples. Structural magnetic resonance imaging scans were obtained using a 3T Achieva scanner on a subset of 59 people with schizophrenia or schizoaffective disorder and 65 healthy controls, and prefrontal volumes were obtained using FreeSurfer software. As compared with healthy controls, individuals with schizophrenia had a significant increase in log-transformed mean serum VEGF levels (t(177)=2.9, P=0.005). A significant inverse correlation (r=-0.40, P=0.002) between serum VEGF and total frontal pole volume was found in patients with schizophrenia/schizoaffective disorder. Moreover, we observed a significant positive association (r=0.24, P=0.03) between serum VEGF and IL-6 mRNA levels in patients with schizophrenia. These findings suggest an association between serum VEGF and inflammation, and that serum VEGF levels are related to structural abnormalities in the PFC of people with schizophrenia.


Variation of the clinical spectrum and genotype-phenotype associations in Coenzyme Q10 deficiency associated glomerulopathy.
Primary Coenzyme Q10 deficiency is a rare mitochondriopathy with a wide spectrum of organ involvement, including steroid-resistant nephrotic syndrome mainly associated with disease-causing variants in the genes COQ2, COQ6 or COQ8B. We performed a systematic literature review, PodoNet, mitoNET, and CCGKDD registries queries and an online survey, collecting comprehensive clinical and genetic data of 251 patients spanning 173 published (47 updated) and 78 new cases. Kidney disease was first diagnosed at median age 1.0, 1.2 and 9.8 years in individuals with disease-causing variants in COQ2, COQ6 and COQ8B, respectively. Isolated kidney involvement at diagnosis occurred in 34% of COQ2, 10.8% of COQ6 and 70.7% of COQ8B variant individuals. Classic infantile multiorgan involvement comprised 22% of the COQ2 variant cohort while 47% of them developed neurological symptoms at median age 2.7 years. The association of steroid-resistant nephrotic syndrome and sensorineural hearing loss was confirmed as the distinctive phenotype of COQ6 variants, with hearing impairment manifesting at average age three years. None of the patients with COQ8B variants, but 50% of patients with COQ2 and COQ6 variants progressed to kidney failure by age five. At adult age, kidney survival was equally poor (20-25%) across all disorders. A number of sequence variants, including putative local founder mutations, had divergent clinical presentations, in terms of onset age, kidney and non-kidney manifestations and kidney survival. Milder kidney phenotype was present in those with biallelic truncating variants within the COQ8B variant cohort. Thus, significant intra- and inter-familial phenotype variability was observed, suggesting both genetic and non-genetic modifiers of disease severity.


Prospective surveillance for surgical site infection in St. Petersburg, Russian Federation.
To assess the risk-adjusted incidence and predictors of surgical site infections (SSIs). Prospective, multicenter, observational cohort study. Seven surgical departments at 3 urban academic hospitals in St. Petersburg, Russian Federation. All patients had surgery performed between January 15 and May 12, 2000. A total of 1,453 surgical procedures were followed up. Medical records were unavailable for less than 3% of all patients; patients were not excluded for any other reason. The mean patient age was 49.3 years, 61% were female, and 34% had an American Society of Anesthesiologists physical status classification (hereafter, "ASA classification") of at least 3. Surgery for 45% of the patients was emergent. In all, 138 patients (9.5%) developed SSI, for a rate that was approximately 3.5 times the risk-stratified rates in the United States. Male sex (odds ratio [OR], 1.54), ASA classifications of 3 (OR, 3.7) or 4 (OR, 5.0), longer duration of surgery (OR, 2.2), and wound classes of 3 (OR, 5.5) or 4 (OR, 14.3) were associated with increased SSI risk in multivariate analysis. Endoscopic surgery was associated with a lower risk of SSI (OR, 0.23). Antibiotic prophylaxis was used in 0%-33% of operations, and 69% of uninfected patients received antibiotics after the operation. The SSI rates are significantly higher than previously reported. Although this finding may be attributable to inadequate antibiotic prophylaxis, local infection control and surgical practices may also be contributors. Use of antibiotic prophylaxis should be encouraged and the effect of local practices further investigated. Active SSI surveillance should be expanded to other parts of the Russian Federation.


Effect of a pH-Balanced Vaginal Gel on Dyspareunia and Sexual Function in Breast Cancer Survivors Who Were Premenopausal at Diagnosis: A Randomized Controlled Trial.
To assess whether a pH-balanced vaginal gel containing lactic acid is more effective than a placebo (lactate-free gel) in improving dyspareunia and sexual function among breast cancer survivors who were premenopausal at diagnosis and had dyspareunia after adjuvant chemotherapy. In a single-center, double-blind, randomized trial, a pH-balanced gel or placebo was administered three times per week at bedtime as well as during sexual intercourse for 8 weeks. The primary outcome was the improvement of dyspareunia measured by pain score of the Female Sexual Function Index after the treatment. Secondary outcomes included the total and individual domains of Female Sexual Function Index score, sexual dysfunction (a total Female Sexual Function Index score less than 25.0), vaginal pH, vaginal maturation index, and adverse events related to the intervention. A sample size of 47 per group was planned to achieve 80% power to detect a 19% difference in the primary outcome. From October 2009 and March 2013, 167 women were screened and 136 were randomized: 69 to a pH-balanced gel and 67 to placebo. Baseline characteristics were similar in both groups. Although there was no difference between the two groups, both experienced a significant improvement of dyspareunia. The increase in median pain score from baseline was 1.2 in both groups (median [interquartile range] from 2.8 [2.0-4.0] to 4.0 [2.8-4.8] in the pH-balanced group and from 3.2 [2.0-4.0] to 4.4 [3.2-4.8] in the placebo group; all P<.01). Overall Female Sexual Function Index score and the frequency of sexual dysfunction also did not differ between the two groups although there was a significant improvement. On the other hand, vaginal pH and vaginal maturation index were slightly but significantly improved only in the pH-balanced group. There were no severe adverse events in either group. The pH-balanced vaginal gel is not superior to the placebo in improving dyspareunia and overall sexual function. ClinicalTrials.gov, https://www.clinicaltrials.gov, NCT00981305.


[Use of pension records for occupational health surveillance: example of record-linkage with hospital discharge records to study the association between work and the incidence of leukaemias, lung and bladder cancer, and miscarriage].
Epidemiologic surveillance of occupational health based on routinely collected data allows groups of workers to be studied, whose type of work (e.g. small enterprises, self-employed workers, artisans) makes it difficult to use a traditional cohort study design. To evaluate the validity of a study design based on the record-linkage between hospital discharge records and INPS social security records (National Institute for Social Security), in order to investigate the association between past employment in an economic sector and occurrence of diseases with a low fraction attributable to occupation and a high frequency in the population, where it is too costly to perform retrospective interviews to gather data from each recruited subject. A case-control study design was used in which hospital discharge records from 1995 in the Piedmont Region represented the source of subjects enrolled. Four series of cases were identified: males aged 40-75 years, with first hospital admission for leukaemia, lung or bladder cancer; and women aged 18-39 years, admitted for miscarriage. The controls were a random sample of patients admitted in the same year and matched by sex and age. The exposure variable was the prevalent economic sector in the occupational history of the subjects enrolled, as inferred from INPS social security records. No economic sector examined showed a significant excess of incidence of bladder cancer or leukaemia. There was a significant excess of lung cancer in subjects with longest employment in the building industry, in metal working, and in the "foundries, heat pressing, forging, and rolling mills" sector. A significant excess of miscarriages was present only in women working in commerce. The results demonstrated overall a low consistency compared with those obtained via other surveillance systems of occupational morbidity and mortality, as well as by means of analytical studies. The results appear more plausible for the sectors characterized by a low number of job tasks, or by a more homogenous exposure to risk factors among workers in different jobs. Among the limitations of this study the lack of a complete occupational history, the absence of information on potential confounders like smoking and alcohol consumption, and the probable non-differential misclassification of the longest held job need to be stressed


Intracerebral Administration of BDNF Protects Rat Brain Against Oxidative Stress Induced by Ouabain in an Animal Model of Mania.
Several studies have suggested that alterations in brain-derived neurotrophic factor (BDNF) and increased oxidative stress have a central role in bipolar disorder (BD). Intracerebroventricular (ICV) injection of ouabain (OUA) in rats alters oxidative stress parameters and decreases BDNF levels in the brain. In this context, the present study aims to investigate the effects of BDNF ICV administration on BDNF levels and oxidative stress parameters in brains of rats submitted to animal model of mania induced by OUA. Wistar rats received an ICV injection of OUA, artificial cerebrospinal fluid (ACSF), OUA plus BDNF, or ACSF plus BDNF. Locomotor activity and risk-taking behavior in the rats were measured using the open-field test. In addition, we analyzed the BDNF levels and oxidative stress parameters (TBARS, Carbonyl, CAT, SOD, GR, and GPx) in the frontal cortex and hippocampus of rats. The BDNF was unable to reverse the ouabain-induced hyperactivity and risk-taking behavior. Nevertheless, BDNF treatment increased BDNF levels, modulated the antioxidant enzymes, and protected the OUA-induced oxidative damage in the brain of rats. These results suggest that BDNF alteration observed in BD patients may be associated with oxidative damage, both seen in this disorder.


Autophagy fights disease through cellular self-digestion.
Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.


Long-term outcomes in mothers diagnosed with gestational diabetes mellitus and their offspring.
Mothers with gestational diabetes mellitus (GDM) are at high lifetime risk of developing type 2 diabetes mellitus. The magnitude of risk for cardiovascular disease after GDM is less well established. Recently, intervention trials using lifestyle modification or medications used to treat type 2 DM have successfully prevented/delayed development of DM in women after GDM. Offspring of mothers with GDM are at risk for development of obesity and abnormal glucose metabolism during childhood, adolescence, and adulthood. Factors responsible for these risks are not fully understood. Having fetal hyperinsulinism is a risk factor for development of both obesity and abnormal glucose metabolism, and might be implicated in pathophysiology. It remains to be established whether the long-term effects of exposure to diabetes mellitus during intrauterine development can be prevented.


Comparative effectiveness research in practice and policy for radiation oncology.
Interest in comparative effectiveness research (CER) has increased dramatically over the past decade, yet perceptions about what comprises CER varies. CER has several attributes relevant to practice and policy: (1) The goal of CER is to inform decisions about health care. (2) Literature synthesis is used in addition to primary research. (3) CER evaluates not only overall outcomes for the population but also evaluates subgroups that may have heterogeneous outcomes. (4) Research places an emphasis on outcomes in the "real-world" settings. (5) Outcomes studied should be relevant to patients. In radiation oncology, where many of the traditional clinical trials are comparative in nature, the line between CER and "traditional" research may be blurred, but an increased emphasis on CER can help to bridge the research enterprise and clinical practice, helping to inform decision making at the patient, clinician, and policy levels.


The Anti-Biofilm Efficacy of Caffeic Acid Phenethyl Ester (CAPE) In Vitro and a Murine Model of Oral Candidiasis.
Candida albicans is the main fungal species associated with the development of oral candidiasis. Currently, therapeutic options for these infections are limited by the adverse effects of antifungal drugs and by the emergence of drug resistant strains. Thus, the development of new antifungal agents is needed for the prevention and treatment of oral Candida infections. Caffeic acid phenethyl ester (CAPE) is a natural compound from propolis polyphenolic groups that exhibits many pharmacological properties. In this study, we investigated whether CAPE can have antifungal and immunomodulatory effects on oral candidiasis. Preliminary tests to assess the antifungal activity of CAPE were performed using the Minimum Inhibitory Concentration (MIC) assay that demonstrated inhibition in a range from 16 to 32 μg/mL, confirming its antifungal activity on several C. albicans strains isolated from the oral cavity. Subsequently, we analyzed Candida spp biofilms formed in vitro, in which CAPE treatment at 5 x MIC caused a reduction of 68.5% in the total biomass and ~2.60 Log in the viable cell count (CFU/mL) in relation to the untreated biofilm (p<0.0001). Next, RNA was extracted from untreated and CAPE-treated biofilms and analyzed by real-time qPCR. A series of genes analyzed (ALS1, ECE1, EPA1, HWP1, YWP1, BCR1, BGR1, CPH1, EFG1, NDT80, ROB1, TEC1, UME6, SAP2, SAP5, PBL2, and LIP9) were downregulated by CAPE compared to the untreated control group (p<0.0001). In in vivo studies using Galleria mellonella, the treatment with CAPE prolonged survival of larvae infected by C. albicans by 44.5% (p < 0.05) and accompanied by a 2.07-fold increase in the number of hemocytes. Flow cytometry revealed the most prominent increases were in types P2 and P3 hemocytes, granular cells, which phagocytize pathogens. In addition, CAPE treatment decreased the fungal load in the hemolymph and stimulated the expression of antifungal peptide genes such as galiomicin and gallerimycin. The antifungal and immunomodulatory activities observed in G. mellonella were extended to a murine model of oral candidiasis, in which CAPE decreased the levels of C. albicans colonization (~2 log CFU/mL) in relation to the untreated control group. In addition, CAPE treatment significantly reduced pseudomembranous lesions, invasion of hyphae on epithelium surfaces, tissue damage and inflammatory infiltrate (p < 0.05). CAPE was also able to increase the expression of β-defensin 3 compared to the infected and untreated group by 3.91-fold (p < 0.0001). Taken together, these results show that CAPE has both antifungal and immunomodulatory effects, making it a promising natural antifungal agent for the treatment and prevention of candidiasis and shows impact to oral candidiasis.


Retina Is Protected by Neuroserpin from Ischemic/Reperfusion-Induced Injury Independent of Tissue-Type Plasminogen Activator.
The purpose of the present study was to investigate the potential neuroprotective effect of neuroserpin (NSP) on acute retinal ischemic/reperfusion-induced (IR) injury. An IR injury model was established by elevating intraocular pressure (IOP) for 60 minutes in wild type and tPA-deficient (tPA-/-) mice. Prior to IR injury, 1 μL of 20 μmol/L NSP or an equal volume of bovine serum albumin (BSA) was intravitreally administered. Retinal function was evaluated by electroretinograph (ERG) and the number of apoptotic neurons was determined via TUNEL labeling. Caspase-3, -8, -9,poly (ADP-ribose) polymerase (PARP)and their cleaved forms were subsequently analyzed. It was found that IR injury significantly damaged retinal function, inducing apoptosis in the retina, while NSP attenuated the loss of retinal function and significantly reduced the number of apoptotic neurons in both wild type and tPA-/- mice. The levels of cleaved caspase-3, cleaved PARP (the substrate of caspase-3) and caspase-9 (the modulator of the caspase-3), which had increased following IR injury, were significantly inhibited by NSP in both wild type and tPA-/- mice. NSP increased ischemic tolerance in the retina at least partially by inhibiting the intrinsic cell death signaling pathway of caspase-3. It was therefore concluded that the protective effect of neuroserpin maybe independent from its canonical interaction with a tissue-type plasminogen activator.


Hemin control of heme biosynthesis in mouse Friend virus-transformed erythroleukemia cells in culture.
Hemin treatment of mouse Friend virus-transformed cells in cultured caused a dose-dependent increase in hemoglobin synthesis. By the addition of radioactively labeled hemin and by the analysis of the radioactive heme in hemoglobin, only 60 to 70% of heme in the newly synthesized hemoglobin was accounted for by the exogenously added hemin. In keeping with this finding, hemin treatment increased the activity of two enzymes in the heme biosynthetic activity, i.e. delta-aminolevulinate (ALA) dehydratase and uroporphyrinogen-I (URO) synthase in these cells. Incorporation of [2(-14C)]glycine, [14C]ALA, and 59Fe into heme was also significantly increased in the cells treated with hemin, suggesting that essentially all enzyme activities in the heme biosynethetic pathway were increased after hemin treatment. These results indicate that heme in the newly synthesized hemoglobin in hemin-treated Friend cells derives both from hemin added to the culture and from heme synthesized intracellularly. In addition, these results suggest that the stimulation of heme biosynthesis by hemin in Friend virus-transformed cells is in contrast to the hemin repression of heme biosynthesis in liver cells.


How does food-cue exposure lead to larger meal sizes?
Exposure to the sight and smell of food influences our momentary desire to consume it. This study explored the process by which cue exposure promotes greater consumption of food. Three hypotheses were explored, cue exposure: (i) increases the planned consumption of food; (ii) increases tolerance of larger portion sizes; (iii) arrests the development of satiety. Female participants (n 50) were each tested in two conditions. In a 'cue condition' they were exposed to the sight and smell of pizza for 60 s. Before and after this period they provided information about prospective and maximum tolerated portion sizes and their desire to eat pizza and other non-cued foods. Participants then consumed a fixed portion of pizza, rated their hunger and were finally offered ad libitum access to pizza. In the 'no-cue condition', cue exposure was replaced with a cognitive task. Cueing had little effect on tolerance of larger portion sizes or on hunger after consuming the fixed portion. Instead, it increased prospective pizza portion size and subsequent intake of pizza. Together, these results suggest that cueing increases the amount of food that people actively plan to eat. This plan is then executed, leading to greater intake. Pizza cueing also increased prospective portion size of other foods. Thus, contrary to previous reports, effects of exposure may generalize to other foods. Finally, we found evidence that restrained eaters are less 'cue reactive' than unrestrained eaters. In future, our approach might be adapted to consider whether heightened 'cue reactivity' represents a risk factor for obesity.


Marketing, financial goals play into CCRC refund plan.
An entry fee refund is the marketing tool for continuing care retirement communities (CCRCs) with the most easily assessed financial effects. The financial results of refund schedules can be measured in terms of a CCRC's ability to generate pools of cash and withdraw cash from these pools to fund operations. A CCRC's choice of refund schedule also will affect net present value of an investment in retirement housing.


Light- and nucleotide-dependent binding of phosphodiesterase to rod disk membranes: correlation with light-scattering changes and vesicle aggregation.
Under conditions in which large guanosine cyclic 3',5'-phosphate (cGMP)- and phosphodiesterase (PDE)-dependent changes in near-infrared transmission and vesicle aggregation and disaggregation occur, we have observed a striking change in the binding of PDE to rod disk membranes. The change in PDE binding is nucleotide and light dependent as are the light-scattering changes. The cGMP- and PDE-dependent light-scattering signal can be produced by a 500-nm light flash which bleaches 1/(1 X 10(7] rhodopsin molecules. Mg ions are an essential cofactor for the nucleotide-dependent PDE binding and light-scattering changes. 3-Isobutyl-1-methylxanthine and other competitive inhibitors of PDE hydrolytic activity support increased PDE binding to the disk membrane, vesicle aggregation, and the light-scattering signal. However, treatments which block GTP-dependent activation of PDE hydrolytic activity (colchicine, GDP, or ethylenediaminetetraacetic acid) also block these phenomena. Thus, GTP-dependent activation of PDE rather than its hydrolytic activity appears to be correlated with the light-scattering signal.


Fractional derivative method for anomalous aquitard flow in a leaky aquifer system with depth-decaying aquitard hydraulic conductivity.
Aquitards significantly affect groundwater flow in multi-aquifer systems through adjacent aquifer leakage. Despite this, studies focusing on their heterogeneity and the non-conventional diffusion patterns of their flow are still limited. In this study, a factional derivative approach was first extended to explore the time-dependent behavior of flow transport in the aquitard. Two analytical solutions were derived for specific discharges in independent aquitards under different boundary conditions. The findings revealed that aquitard flow exhibits obvious anomalous diffusion behaviors, characterized by slower decay and heavy-tailed specific discharge data. The fractional derivative model provided a more accurate representation of this behavior than traditional models, as evidenced by its superior agreement with experimental data. Moreover, a transient model for pumping tests in a leaky aquifer system was developed, incorporating the memory effect of anomalous flow and vertical heterogeneity in aquitards. Relevant semi-analytical solutions were derived to explore the impacts of memory factor β and decay exponent of aquitard hydraulic conductivity (K) on the leakage aquifer system. Theoretical results demonstrated that stronger memory effect reduces drawdowns in the aquitard and confined aquifer during mid-to-late times. A larger dimensionless decay exponent (Ad) decreases aquitard drawdown and increases aquifer drawdown at late times. Sensitivity analysis showed aquitard drawdown experiences two peaks in sensitivity to β and Ad at early- or mid-times, affected by memory effect and decay exponent of aquitard K, signifying maximal impact at these specific intervals. This study provides a practical model to effectively manage groundwater resources by accurately reflecting aquitard memory and heterogeneity effects.


Exome-wide somatic mutation characterization of small bowel adenocarcinoma.
Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (AI) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.


[Structural changes in the liposomes and the lamellar packing of liposomal lipids exposed to glycerin].
Glycerol-induced structural changes in multilamellar liposomes (ML) were studied by light and thin-section electron microscopy. It is shown that high concentrations of glycerol induce non-bilayer rearrangements of liposomal lipids in ML. The data obtained are discussed regarding the possible mechanisms of cryoprotector effects on natural (biological) and artificial (liposomal) membranes.


Covalent organic framework nanomedicines: Biocompatibility for advanced nanocarriers and cancer theranostics applications.
Nanomedicines for drug delivery and imaging-guided cancer therapy is a rapidly growing research area. The unique properties of nanomedicines have a massive potential in solving longstanding challenges of existing cancer drugs, such as poor localization at the tumor site, high drug doses and toxicity, recurrence, and poor immune response. However, inadequate biocompatibility restricts their potential in clinical translation. Therefore, advanced nanomaterials with high biocompatibility and enhanced therapeutic efficiency are highly desired to fast-track the clinical translation of nanomedicines. Intrinsic properties of nanoscale covalent organic frameworks (nCOFs), such as suitable size, modular pore geometry and porosity, and straightforward post-synthetic modification via simple organic transformations, make them incredibly attractive for future nanomedicines. The ability of COFs to disintegrate in a slightly acidic tumor microenvironment also gives them a competitive advantage in targeted delivery. This review summarizes recently published applications of COFs in drug delivery, photo-immuno therapy, sonodynamic therapy, photothermal therapy, chemotherapy, pyroptosis, and combination therapy. Herein we mainly focused on modifications of COFs to enhance their biocompatibility, efficacy and potential clinical translation. This review will provide the fundamental knowledge in designing biocompatible nCOFs-based nanomedicines and will help in the rapid development of cancer drug carriers and theranostics.


Models of Heart Failure Based on the Cardiotoxicity of Anticancer Drugs.
Heart failure (HF) is a complication of oncological treatments that may have dramatic clinical impact. It may acutely worsen a patient's condition or it may present with delayed onset, even years after treatment, when cancer has been cured or is in stable remission. Several studies have addressed the mechanisms of cancer therapy-related HF and some have led to the definition of disease models that hold valid for other and more common types of HF. Here, we review these models of HF based on the cardiotoxicity of antineoplastic drugs and classify them in cardiomyocyte-intrinsic, paracrine, or potentially secondary to effects on cardiac progenitor cells. The first group includes HF resulting from the combination of oxidative stress, mitochondrial dysfunction, and activation of the DNA damage response, which is typically caused by anthracyclines, and HF resulting from deranged myocardial energetics, such as that triggered by anthracyclines and sunitinib. Blockade of the neuregulin-1/ErbB4/ErbB2, vascular endothelial growth factor/vascular endothelial growth factor receptor and platelet-derived growth factor /platelet-derived growth factor receptor pathways by trastuzumab, sorafenib and sunitinib is proposed as paradigm of cancer therapy-related HF associated with alterations of myocardial paracrine pathways. Finally, anthracyclines and trastuzumab are also presented as examples of antitumor agents that induce HF by affecting the cardiac progenitor cell population.


Captopril-induced proteinuria in hypertensive psoriatic patients.
We have previously reported on a high prevalence of high renin essential hypertension in psoriasis. Since angiotensin-converting enzyme (ACE) was also reported to be increased in some psoriatics, we found it rational to treat 10 patients with hypertension and diffuse psoriasis with captopril at a dose of 25 mg t.i.d. Five patients had high PRA levels and in 1 of them serum ACE was also increased. Serum creatinine, BUN and urinalysis were normal in all of them. SPB fell from 163 +/- 3 to 138 +/- 3 and DBP from 107 +/- 3 to 86 +/- 2 mm Hg after 1 month of captopril treatment. A surprising clinical improvement of the cutaneous lesions occurred in 3 patients previously resistant to every local or systemic treatment. Unfortunately, however, 3 patients developed heavy proteinuria (greater than 2 g/day) which disappeared after captopril discontinuation. The unexpected incidence of reversible proteinuria induced by low doses of captopril in our patients recommends a careful monitoring of the renal function every time this drug is employed in the treatment of hypertension in a psoriatic.


Access to healthcare for undocumented migrants in France: a critical examination of State Medical Assistance.
In France in 2012, of the total population of 65.2 million, 8.7 % were migrants. After being the third principal host country, France is now the 6th highest host country in the OECD. Since the 1980's numerous Acts have been passed by parliament on immigration issues. In 2000 the Universal Health Cover (Couverture Maladie Universelle) was created as health coverage for all residents of France. At the same time the State Medical Assistance (Aide Médicale de l'Etat) was created as health protection for undocumented migrants. Since the creation of this scheme, it has been the object of many political debates which call it into question, on account of its cost, perceived fraud, and the legitimacy of a social protection for undocumented migrants. Recently, access to State Medical Assistance has been made difficult by introducing conditions of residence and financial contributions. After a reports' analysis on institutional, associative, research studies and European recommendations, we note that all reports converge on the necessity of health protection for undocumented migrants. The major reasons are humanitarian, respect of European and International conventions, for public health, and financial. Moreover, fraud allegations have proved to be unfounded. Finally, State Medical Assistance is underused: in 2014 data from Médecins du Monde shows that only 10.2 % of undocumented migrant patients in their health facilities have access to this scheme. We conclude that the political debate concerning the State Medical Assistance should be about its under-utilisation, its improvement, its merger with the Universal Health Cover, and not its elimination. Moreover, the current debates regarding this scheme stigmatize this population, which is already precarious, making it more difficult for migrants to access healthcare, and generally, weaken national social cohesion.


Optimum Angle of Force Production Temporarily Changes Due to Growth in Male Adolescence.
The peak increase in lean mass in adolescents is delayed from peak height velocity (PHV), and muscle flexibility temporarily decreases as bones grow. If the decrease in muscle flexibility is caused by muscle elongation, the relationship between the exerted torque and the joint angle could change in adolescents. The purpose of this study was to investigate the change in the optimum angle of force production due to growth. Eighty-eight healthy boys were recruited for this study. Isokinetic knee extension muscle strength of the dominant leg was recorded. The outcome variable was the knee flexion angle when maximal knee extension torque was produced (optimum angle). The age at which PHV occurred was estimated from subjects' height history. We calculated the difference between the age at measurement and the expected age of PHV (growth age). A regression analysis was performed with the optimal angle of force exertion as the dependent variable and the growth age as the independent variable. Then, a polynomial formula with the lowest p-value was obtained. A significant cubic regression was obtained between optimum angle and growth age. The results suggest that the optimum angle of force production temporarily changes in male adolescence.


Recent advances in the pathobiology and clinical management of lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a rare systemic disease that occurs almost exclusively in women. In the last few years, our understanding of disease pathobiology has improved substantially; in addition, a guideline document has recently been developed that provides recommendations for the diagnosis and clinical management of patients with LAM. Yet, significant gaps in knowledge remain. Groundbreaking insights into the cellular biochemistry of LAM have led to the reclassification of the disease as a low-grade, destructive, metastasizing neoplasm. In addition, recent data confirm the potential of next-generation sequencing to detect low-prevalence mutations in tuberous sclerosis (TSC) genes in sporadic LAM. A randomized, double-blind, multicentre trial has confirmed the efficacy of sirolimus in stabilizing lung function, improving functional performance and quality of life, and reducing lymphatic manifestations in patients with LAM. Accordingly, recent guidelines issued by the American Thoracic Society and the Japanese Respiratory Society recommend sirolimus treatment for patients with LAM and reduced lung function. Uncertainty remains, however, with regard to patient selection, and timing of initiation, duration and dosing of treatment. Significant advances have been made in the diagnosis and clinical management of patients with LAM. However, additional studies are needed to assess long-term safety and efficacy of sirolimus therapy, and to identify predictors of disease behaviour and response to treatment.


Implementing patient safety interventions in your hospital: what to try and what to avoid.
Hospitalists play an important role in improving patient safety through clinical expertise and leadership in hospital quality improvement activities. The evidence base in patient safety remains incomplete, despite an increasing body of published research in recent years. Thus, physicians must consider other factors in addition to the strength of evidence supporting a practice when deciding which patient safety interventions to implement. These factors include the prevalence of the safety problem targeted, the potential for unintended consequences of the intervention, the costs and complexity of implementing the intervention, and the potential of the intervention to generate momentum for further safety initiatives. In this article, the authors define a framework for evaluating patient safety interventions and discuss specific interventions hospitalists should consider.