ER Protein Quality Control and the Unfolded Protein Response in the Heart.

Cardiac myocytes are the cells responsible for the robust ability of the heart to pump blood throughout the circulatory system. Cardiac myocytes grow in response to a variety of physiological and pathological conditions; this growth challenges endoplasmic reticulum-protein quality control (ER-PQC), a major feature of which includes the unfolded protein response (UPR). ER-PQC and the UPR in cardiac myocytes growing under physiological conditions, including normal development, exercise, and pregnancy, are sufficient to support hypertrophic growth of each cardiac myocyte. However, the ER-PQC and UPR are insufficient to respond to the challenge of cardiac myocyte growth under pathological conditions, including myocardial infarction and heart failure. In part, this insufficiency is due to a continual decline in the expression levels of important adaptive UPR components as a function of age and during myocardial pathology. This chapter will discuss the physiological and pathological conditions unique to the heart that involves ER-PQC, and whether the UPR is adaptive or maladaptive under these circumstances.

Use of sensor-integrated pump therapy to reduce hypoglycaemia in people with Type 1 diabetes: a real-world study in the UK.

AIMS: To assess the efficacy of insulin pumps with automated insulin suspension systems in a real-world setting. METHODS: We analysed anonymized data uploaded to CareLink™ by people (n=920) with Type 1 diabetes using the MiniMed Paradigm Veo system and the MiniMed 640G system (Medtronic International Trading Sàrl, Tolochanez, Switzerland) with SmartGuard technology, with or without automated insulin suspension enabled, between February 2016 and June 2018. Users with ≥15 days of sensor data and ≥70% sensor-wear time were classified as sensor-augmented pump alone, sensor-integrated pump with low glucose suspend enabled or sensor-integrated pump with predictive low glucose management enabled. RESULTS: The median (25th -75th percentile) system use was 161 (58-348) days. The median time spent with sensor glucose values ≤3 mmol/l was 0.8 (0.3-1.7)% in the sensor-augmented pump group, 0.3 (0.1-0.7)% in the sensor-integrated pump with low glucose suspend group, and 0.3 (0.1-0.5)% in the sensor-integrated pump with predictive low glucose management group. In individuals switching from sensor-augmented pump to sensor-integrated pump with low glucose suspend (n=31), there were significant reductions in the monthly rate of hypoglycaemic events <3 mmol/l (rate ratio 0.63, 95% CI 0.45-0.89; P=0.009) and in the percentage of time with glucose values ≤3 mmol/l [sensor-augmented pump: 0.63% (95% CI 0.34-1.29), sensor-integrated pump with low glucose suspend: 0.33% (95% CI 0.16-0.64); P=0.001]. The monthly rate of hypoglycaemic events decreased further in individuals (n=139) switching from sensor-integrated pump with low glucose suspend to sensor-integrated pump with predictive low glucose management [rate ratio 0.82 (95% CI 0.69-0.98); P<0.0274]. Similar results were seen for events <3.9 mmol/l. There was no difference in median time spent in target glucose range. CONCLUSION: Real-world UK data show that increasing automation of insulin suspension reduces hypoglycaemia exposure in people with Type 1 diabetes.

The birthweight toll of mining pollution: evidence from the most contaminated mine site in the Andean region.

OBJECTIVE: To assess the effect of mining pollution on birthweight. DESIGN: A retrospective before-and-after study with an untreated comparison group. SETTING: La Oroya, a mining town in the Peruvian Andes, considered the most contaminated town in the Andean region. POPULATION: All pregnant women who delivered in the social security healthcare system in years 2005, 2006, 2008 and 2009. A total of 214 983 births records were used, 957 from La Oroya and 214 026 from the rest of the country. METHODS: A difference-in-difference estimation is used to assess the effect of mining pollution on birthweight before and after two business policy changes: a partial environmental improvement and a subsequent closure of smelter operations in La Oroya. Birthweight was compared with a group not affected by the environmental changes in La Oroya. MAIN OUTCOME MEASURES: Birthweight in grams. RESULTS: A steep reduction in mining pollution due to the closure of smelter operations in La Oroya showed an increased birthweight of 71.6 g after controlling for socio-economic and medical characteristics. None of the environmental improvements prior to the closure had a statistically significant effect on birthweight. CONCLUSIONS: Mining pollution in La Oroya had a negative impact on birthweight. Partial environmental improvements were not enough to improve birthweight. Only after the closure of all mining and smelter operations in La Oroya was a significant gain in birthweight shown. TWEETABLE ABSTRACT: The closure of the most contaminated mine site in the Andean region increased birthweight by 72 g.

Chlorophyll a Covalently Bonded to Organo-Modified Translucent Silica Xerogels: Optimizing Fluorescence and Maximum Loading.

Chlorophyll is a pyrrolic pigment with important optical properties, which is the reason it has been studied for many years. Recently, interest has been rising with respect to this molecule because of its outstanding physicochemical properties, particularly applicable to the design and development of luminescent materials, hybrid sensor systems, and photodynamic therapy devices for the treatment of cancer cells and bacteria. More recently, our research group has been finding evidence for the possibility of preserving these important properties of substrates containing chlorophyll covalently incorporated within solid pore matrices, such as SiO2, TiO2 or ZrO2 synthesized through the sol-gel process. In this work, we study the optical properties of silica xerogels organo-modified on their surface with allyl and phenyl groups and containing different concentrations of chlorophyll bonded to the pore walls, in order to optimize the fluorescence that these macrocyclic species displays in solution. The intention of this investigation was to determine the maximum chlorophyll a concentration at which this molecule can be trapped inside the pores of a given xerogel and to ascertain if this pigment remains trapped as a monomer, a dimer, or aggregate. Allyl and phenyl groups were deposited on the surface of xerogels in view of their important effects on the stability of the molecule, as well as over the fluorescence emission of chlorophyll; however, these organic groups allow the trapping of either chlorophyll a monomers or dimers. The determination of the above parameters allows finding the most adequate systems for subsequent in vitro or in vivo studies. The characterization of the obtained xerogels was performed through spectroscopic absorption, emission and excitation spectra. These hybrid systems can be employed as mimics of natural systems; the entrapment of chlorophyll inside pore matrices indicates that it is possible to exploit some of the most physicochemical properties of trapped chlorophyll for diverse technological applications. The data herein collected suggest the possibility of applying the developed methodology to other active, captive molecules in order to synthesize new hybrid materials with optimized properties, suitable to be applied in diverse technological fields.

Two new HLA-B35 subtypes characterized in Spaniards: HLA-B*35:270 and HLA-B*35:273.

Two new HLA-B*35 alleles, B*35:270 and B*35:273, were characterized in the Spanish population.

Routine use of continuous glucose monitoring in 10 501 people with diabetes mellitus.

AIMS: To analyse blood glucose control according to continuous glucose monitoring use in data from the CareLink database, and to identify factors associated with continuation of sensor use during sensor-augmented pump therapy. METHODS: The analysis used data from 10 501 people with Type 1 and 2 diabetes mellitus, of whom 7916 (61.7%) had used glucose sensors for ≥ 15 days during any 6-month period over a 2-year observation period. Data were analysed according to the extent of sensor use ( < 25%, 25-49%, 50-74% and ≥ 75% of the time). Time to discontinuation of sensor use was also analysed in new users of glucose sensors. RESULTS: Compared with patients in the lowest sensor usage group and non-users, the highest glucose sensor usage group had significantly (P < 0.0001) lower mean blood glucose and blood glucose sd, were more likely to achieve a mean blood glucose concentration < 8.6 mmol/l, (odds ratio 1.5, 95% CI 1.3-1.7; P < 0.0001), and had 50% fewer hypoglycaemic (blood glucose concentration < 2.8 mmol/l) episodes. Among new users, sensor use during the first month of therapy was an important predictor of subsequent discontinuation. Lack of full reimbursement was also significantly associated with early discontinuation, whereas measures of glycaemic control were predictive of discontinuation during long-term treatment. CONCLUSIONS: The use of continuous glucose monitoring was significantly associated with reductions in hypoglycaemia and improved metabolic control during insulin pump therapy. Sensor use during the first month was strongly associated with long-term adherence; patient education and training may be helpful in achieving this.

Differential partial activation phenotype and production of tumour necrosis factor-α by conventional dendritic cells in response to lipopolysaccharide in HIV+ viraemic subjects and HIV+ controllers.

HIV(+) subjects are reported to have increased soluble CD14 (sCD14) in plasma, an indicator of microbial translocation. We evaluated if microbial translocation has a differential impact on the activation and function of conventional dendritic cells (cDC) from viraemic HIV(+) subjects and HIV(+) controllers (CTs). The HIV(+) subjects were classified into two groups according to their plasma viral load (pVL): CT and viraemic. Subjects without HIV were included as controls (HIV(-) ). The frequencies and phenotypes of cDC from these subjects were evaluated by multi-parameter flow cytometry. In addition, peripheral blood mononuclear cells (PBMCs) were stimulated with lipopolysaccharide (LPS) or single-stranded RNA40 (ssRNA40), the phenotype of the cDC and the intracellular production of tumour necrosis factor (TNF)-α by the cDC were evaluated by flow cytometry. We observed a partial activation phenotype for the cDC in the viraemic subjects and CTs ex vivo and after LPS activation, which showed differences in the expression of CD40 and CD86. Furthermore, in response to LPS the cDC from the viraemic subjects produced more TNF-α compared to the cDC from CTs. Interestingly, the percentage of TNF-α(+) cDC was found to be correlated positively with the pVL. The partial activation of cDC and the over-production of TNF-α in response to LPS in viraemic HIV(+) subjects might be related to the increased chronic activation observed in these subjects. In contrast, cDC from CTs seem to have a regulated response to LPS, indicating that they respond differently to chronic immune activation. These results may have implications in the development of HIV therapies and vaccines using DC.

[Biodegradable catheters for fistula prevention in hypospadias. Experimental preliminary study]. / Sondas biodegradables para la prevención de las fístulas de hipospadias. Estudio preliminar experimental.

INTRODUCTION: Continuous technical innovations are not enough to resolve the high incidence of fistula after hypospadias repair. A urethral catheter-tutor made of reabsorbable polymeric biomaterial (RPB) which could be left in situ long enough could reduce the complications. TARGET: To investigate in an animal model differents RPB to be used in urology. METHODOLOGY: CRL Wistar rats, males, divided into 5 equal groups according to the used polymers: polylactide; lactic-coprolactone copolymer; lactic-glycolic copolymer; simulated; control silicones. Three individuals were sacrificed per group at 4th, 10th and 16th week. In all animals (exceptuating the simulated group), biomaterial was fixed to the bladder wall bylaparotomy. Animals remained in individual housing and kept under daily control of hematuria during the first 15 days and weekly weight and urine control for pH and lactate. After being slaughtered, remaining polymer was collected for chemical analysis and bladder tissue for hystologic study. RESULTS: There was no mortality, hematuria nor other clinical signs. The bladder wall showed a mild foreign body reaction. The values of lactate and pH in urine did not reach toxic levels. Lactic-glycolic was totally reabsorbed by the 10th week and had the lowest degree of calcification. Polylactide and lactic-coprolactone remained intact. CONCLUSION: The model of urinary bladder has proven useful for studying the degradation of bioresorbable polymers. The analyzed polymers have spent long time to be reabsorbed, so we will have to study new others.

Phototherapy for Prurigo Nodularis: Our Experience and a Review of the Literature. / Fototerapia en el prurigo nodular. Experiencia propia y revisión de la literatura.

BACKGROUND AND OBJECTIVE: Prurigo nodularis is a chronic inflammatory skin disease characterized by highly pruritic nodular lesions that cause constant itching and scratching and significant quality-of-life impairment. It has been described in a range of conditions, including skin diseases (mainly atopic dermatitis) and metabolic, neurological, and psychiatric disorders. The pathophysiological mechanisms are largely unknown. Various modalities of phototherapy have been described as appropriate and safe treatments for achieving clinical control and alleviating symptoms. In this article, we describe our experience with phototherapy in patients with prurigo nodularis. MATERIAL AND METHODS: Retrospective observational study of patients who received their first cycle of phototherapy to treat prurigo nodularis between March 2011 and October 2019. Information was collected on epidemiological and clinical characteristics, concomitant treatments, type and duration of phototherapy, maximum dose reached, and response to treatment. RESULTS: We studied 44 patients (30 women and 14 men) with a median age of 65.5years. The most common form of phototherapy used was narrowband UV-B phototherapy (34 cycles, 77.27%) followed by a combination of UV-B and UV-A phototherapy (8 cycles). Response to treatment was considered satisfactory (clearance rate of ≥75%) in 24 patients (55.4%). CONCLUSIONS: Phototherapy is a suitable treatment for prurigo nodularis in a considerable proportion of patients. It can be used as monotherapy or combined with other treatments.

Oral maribavir for treatment of refractory or resistant cytomegalovirus infections in transplant recipients.

BACKGROUND: Despite advances in cytomegalovirus (CMV) prophylaxis and therapy, some transplant recipients still develop refractory CMV infections. Maribavir (MBV), an investigational benzimidazole antiviral agent, acts by a mechanism different from that of existing anti-CMV drugs. Previous Phase I and II studies have demonstrated a favorable safety profile for MBV, but its utility in treatment of complex CMV syndromes is unknown. METHODS: Between June and December 2008, MBV was released for use under individual emergency investigational new drug applications requested by treating physicians and approved by the US Food and Drug Administration and local institutional review boards. Six patients (5 solid organ transplant recipients and 1 hematopoietic stem cell transplant recipient) who had failed to respond to other therapies and/or had known ganciclovir-resistant CMV were treated with MBV at a starting oral dose of 400 mg twice daily. RESULTS: Patients were treated for a median of 207 days (range, 15-376). Four of 6 patients had no detectable CMV DNAemia within 6 weeks of starting MBV therapy. One patient, who had an initial viral load of 1.8 million copies/mL, developed MBV resistance mutations. One patient, who had low serum levels of MBV, had persistent CMV DNAemia and viruria without developing genotypic or phenotypic resistance to MBV. One patient cleared CMV DNAemia, but died of pneumonia and multiorgan failure. No significant adverse effects attributable to MBV were observed. CONCLUSIONS: MBV deserves further systematic evaluation as treatment for CMV infection that is resistant and/or refractory to standard therapies, but its optimal dose, duration of therapy, and use in combinations versus as a single agent have yet to be determined.

[Child protection: Pediatricians' knowledge and practices in Brittany]. / Évaluation des connaissances et des pratiques des pédiatres de Bretagne concernant la protection de l'enfance.

BACKGROUND AND AIMS: On 5 March 2007, the law concerning the child protection system was reformed. Since then, child protection services have been responsible for the management of child abuse and neglect. Reporting and asking for child protection is now easier for every physician by submitting a "preoccupying information" form. A study conducted in 2014 in the general practitioners (GP) in the Ille-et-Vilaine department showed that they were quite unfamiliar with the child protection updates and that they needed special training. We wished to study the knowledge and practices of the pediatricians in Brittany and compare these results to the previous study. METHODS: An anonymous postal investigation was conducted between May and July 2014. The questionnaire was referred to the previous study so the results would be comparable. RESULTS: A total of 134 pediatricians (including 99 women) of the 316 pediatricians of Brittany answered our questionnaire regarding their activity and their knowledge about child abuse and neglect. These results were analyzed and compared to the data of GPs in Ille-et-Vilaine. Only 4.4 % of the pediatricians obtained more than 80 % correct answers and 12 % of the pediatricians obtained fewer than 50 % correct answers. Among the pediatricians, 41 % of them had not reported a single time since 2007. The pediatricians who obtained better results (P<0.001) had more training and were more often in contact with child abuse and neglect than the GPs. The most common reasons that clinicians gave for not reporting were lack of a return from social services after a report, lack of training and the fear of making a misdiagnosis. Indeed only 9 % had received feedback from social services. To make reporting easier, 92 % of the pediatricians would like training and 97 % found a simple practice guide on child abuse useful. CONCLUSION: Child protection is a neglected subject, including by pediatricians. To fight against professional denial and isolation, a substantial effort is still needed concerning caregivers' training as well as pediatric care organization.

Two new HLA class I alleles described in a Spanish individual, HLA-A*11:01:01:04 and HLA-B*35:330.

Two new HLA class I alleles, HLA-A*11:01:01:04 and HLA-B*35:330, were characterized in a Spanish patient.

Four new HLA class I alleles in Spaniards, HLA-A*32:01:23, HLA-B*18:01:24, HLA-B*18:72:02 and HLA-C*12:166.

Characterization of four new human leukocyte antigen (HLA) class I alleles, A*32:01:23, B*18:01:24, B*18:72:02 and C*12:166.

[Child protection system: Knowledge and role of the general practitioners in Ille-et-Vilaine]. / Protection de l'enfance : connaissance et place des médecins généralistes en Ille-et-Vilaine.

BACKGROUND AND AIMS: On 5 March 2007 the law concerning the child protection system was reformed. Since this date, child protection services are responsible for child abuse and neglect. Child protection services are now attempting to determine the rightful place for parents. Asking for child protection is now easier for the general practitioner (GP), who can submit a "preoccupying information (PI)" form. The aim of this study was to review GPs' knowledge on this issue 6 years after the passage of this new law. METHODS: Prospective postal investigation between 04/01/2013 and 06/01/2013. RESULTS: A total of 298 (113 women) of the 899 GPs of the Ille-et-Vilaine area in Brittany answered a few questions about their activity and their knowledge on child abuse and neglect. The sample's mean age, sex, and practice was representative of the GPs in this area. Only 25.5% of the GPs had any knowledge of this new law. The term "preoccupying information" was unfamiliar to 70.1% of the GPs and what to do with the PI was unknown to 77.2%. The GPs did not know which type of letter to send nor where to send it between legal child protection and social protection services. Only 5% of the GPs had child protection training on PI. The main problem informing the child protection services was the lack of training. Consequently, 91.9% of the GPs would like training. CONCLUSIONS: The GPs in the Ille-et-Vilaine area in Brittany are unfamiliar with the child protection updates and need special training.

Evaluation of Culture Conditions to Obtain Fatty Acids from Saline Microalgae Species: Dunaliella salina, Sinecosyfis sp., and Chroomonas sp.

The use of the saline microalgae, Dunaliella salina, Sinecosyfis sp., and Chroomonas sp., was explored as an alternative source for the production of fatty acids using fertilizer and glycerol as culture media. The nutrient medium used contained "Nutrifoliar," a commercial fertilizer, and/or glycerol, in natural sea water. The microalgae were placed in cultures with different conditions. The parameters that favored the largest production of fatty acids were 24 hours of agitation and illumination, 1620 L/day of air supply, 2.25 L of air/min, and a temperature of 32°C using "Nutrifoliar" as the culture media. Results indicated that, from 3 g of microalgae in wet base of Chroomonas sp., 54.43 mg of oil was produced. The chromatographic characterization of oil obtained revealed the presence of essential fatty acids such as 9,12,15-octadecatrienoic acid (omega-3) and 4,7,10-hexadecatrienoic acid (omega-6) from the species Dunaliella salina. On the other hand, 9,12-octadecadienoic acid (omega-6) and cis-11-eicosenoic acid (omega-9) were identified from the species Chroomonas sp. The temperature variations played an important role in the velocity of growth or the production of the algae biomass, the amount of oil, and the ability to produce fatty acids.

Stress urinary incontinence surgery with sling MiniArc: a 4-year results.

OBJETIVES: The aim of this publication is to describe retrospectively the results of the surgical technique of AMS MiniArc for the treatment of female urinary incontinence, evaluate its results at 4 years follow-up. MATERIAL AND METHODS: We present a retrospective cohort study of 135 patients, 110 (81.5%) had urinary incontinence and 25 (18.5%) mixed urinary incontinence. All these procedures were performed with local anesthesia and in "out patient surgery". Patients were monitored in the outpatient clinic at 6 months (control 1), one year (control 2) and annually (control 3, 4, and 5). During the following up, clinical history was made in every woman with ICIQ-SF questionnaire, that included a fourth question to evaluate the degree of satisfaction after surgery, as well as physical examination. We considered objective cure when negative stress with full bladder. We use the SPSS program (V19.0) for statistical analysis of the results. RESULTS: The mean follow-up was of 59 months (range from 33 to 72 months). When evaluating the success rate of anti-incontinence surgery, 86.7% of patients showed objective cured (80.8% with MUI and 89.2% with SUI). The ICIQ-SF decreased average of 12.7 points, 85.7% patients were very or fairly satisfied. CONCLUSION: The AMS MiniArc is an optim anti-incontinence procedure a medium term. But the results should be interpreted with caution given the limitations of the study.

Enhancement of fluorescence in thin-layer chromatography induced by the interaction between n-alkanes and an organic cation

Fluorescence enhancement of a broad variety of solutes has been used extensively in TLC although no thorough explanation has been proposed. In this work, we try to understand it and explore new applications to which it can be put. In this way, alkanes can be quantitatively determined by fluorescence scanning densitometry using silica gel plates impregnated with berberine sulfate. Molecular simulation and analysis of molecular orbitals allows this phenomenon to be explained in this case and lays the groundwork to explain fluorescence enhancements produced by other molecules. A ion-molecule interaction between alkanes and berberine sulfate is responsible for the enhancement of fluorescence produced by alkanes. Computational results suggest that the surrounding alkane molecules provide an apolar environment to the berberine cation, thus enhancing the intensity of the fluorescence signal. This proposed explanation has been tested by extending the fluorescence determination to other compounds. These include biologically interesting saturated and unsaturated fatty acids, steroids and derivatives, prostaglandins, ceramides, galactocerebrosides, as well as terpenes, and polypropylene glycols. In addition, according to the proposed explanation, the properties required for alternative impregnants to berberine are discussed.