The Molecular Chaperone Hsc70 Interacts with Tyrosine Hydroxylase to Regulate Enzyme Activity and Synaptic Vesicle Localization.

We previously reported that the vesicular monoamine transporter 2 (VMAT2) is physically and functionally coupled with Hsc70 as well as with the dopamine synthesis enzymes tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase, providing a novel mechanism for dopamine homeostasis regulation. Here we expand those findings to demonstrate that Hsc70 physically and functionally interacts with TH to regulate the enzyme activity and synaptic vesicle targeting. Co-immunoprecipitation assays performed in brain tissue and heterologous cells demonstrated that Hsc70 interacts with TH and aromatic amino acid decarboxylase. Furthermore, in vitro binding assays showed that TH directly binds the substrate binding and carboxyl-terminal domains of Hsc70. Immunocytochemical studies indicated that Hsc70 and TH co-localize in midbrain dopaminergic neurons. The functional significance of the Hsc70-TH interaction was then investigated using TH activity assays. In both dopaminergic MN9D cells and mouse brain synaptic vesicles, purified Hsc70 facilitated an increase in TH activity. Neither the closely related protein Hsp70 nor the unrelated Hsp60 altered TH activity, confirming the specificity of the Hsc70 effect. Overexpression of Hsc70 in dopaminergic MN9D cells consistently resulted in increased TH activity whereas knockdown of Hsc70 by short hairpin RNA resulted in decreased TH activity and dopamine levels. Finally, in cells with reduced levels of Hsc70, the amount of TH associated with synaptic vesicles was decreased. This effect was rescued by addition of purified Hsc70. Together, these data demonstrate a novel interaction between Hsc70 and TH that regulates the activity and localization of the enzyme to synaptic vesicles, suggesting an important role for Hsc70 in dopamine homeostasis.

Breast cancer trends in Chile: Incidence and mortality rates (2007-2018).

Breast cancer (BC) is one of the most common cancers in women worldwide and in Chile. Due to the lack of a Chilean national cancer registry, there is partial information on the status of BC in the country. We aim to estimate BC incidence and mortality rates by health care providers and regions for Chilean women. We used two public anonymized databases provided by the Ministry of Health: the national death and hospital discharges datasets. We considered a cohort of 58,254 and 16,615 BC hospital discharges and deaths for the period 2007-2018. New BC cases increased by 43.6%, from 3,785 in 2007 to 5,435 in 2018. Total BC deaths increased by 33.6% from 1,158 to 1,547 during the same period. Age-adjusted incidence rates were stable over time, with an average rate of 44.0 cases/100,000 women (SD 2.2). There were considerable differences in age-adjusted incidence rates among regions, with no clear geographical trend. Women affiliated to a private provider (ISAPRE) have an average age-adjusted incidence rate of 60.6 compared to 38.8 (both cases/100,000 women) for women affiliated with the public provider (FONASA). Age-adjusted mortality rates have an average of 10.5 cases/100,000 women (SD 0.4). This study shows important differences in incidence rates between private and publicly insured women, with no significant differences in mortality rates. Such differences may be associated with women's lifestyles, dietary compositions, comorbidities, and differences in healthcare systems. These hypotheses should be studied in greater depth. Additionally, differences in BC incidence found in this study compared to incidences reported from other estimations reinforce the need of a national cancer registry that should lead to more accurate indicators regarding BC in Chile.

Relationship between serum uric acid, nocturnal hypertension and risk for preeclampsia in high-risk pregnancies.

To analyze the possible association between serum uric acid (SUA) and nocturnal hypertension and to evaluate the ability of these variables (alone or in combination) to predict preeclampsia (PE) we conducted a historical cohort study in 532 high-risk pregnancies. Women were divided according to SUA values and nocturnal blood pressure (BP) into four groups: 1- normal SUA and nocturnal normotension; 2- high SUA and nocturnal normotension; 3- normal SUA and nocturnal hypertension and 4- high SUA and nocturnal hypertension. High SUA was defined by the top quartile values and nocturnal hypertension as BP ≥ 120/70 mmHg, using ambulatory blood pressure monitoring (ABPM), during nocturnal rest. Risks for PE were compared using logistic regression. SUA had a weak but significant correlation with daytime systolic ABPM (r = 0.11, p = 0.014), daytime diastolic ABPM (r = 0.13, p = 0.004), nighttime systolic ABPM (r = 0.16, p < 0.001) and nighttime diastolic ABPM (r = 0.18, p < 0.001). Also, all ABPM values were higher in women with high SUA. The absolute risk of PE increased through groups: 6.5%, 13.1%, 31.2%, and 47.9% for groups 1, 2, 3, and 4, respectively, p < 0.001. Compared with Group 1, Group 3 (OR 6.29 95%CI 3.41-11.60), but not Group 2 (OR 2.15 95%CI 0.88-5.24), had statistically significant higher risk for PE. Group 4 (women with both, high SUA and nocturnal hypertension) had the highest risk (OR 13.11 95%CI 6.69-25.70). Risks remained statistically significant after the adjustment for relevant variables. In conclusion, the combination of SUA > 4 mg/dL and nocturnal BP > 120/70 mmHg implies a very high risk to developed PE.

An updated estimation approach for SEIR models with stochastic perturbations: Application to COVID-19 data in Bogotá.

This paper studies the updated estimation method for estimating the transmission rate changes over time. The models for the population dynamics under SEIR epidemic models with stochastic perturbations are analysed the dynamics of the COVID-19 pandemic in Bogotá, Colombia. We performed computational experiments to interpret COVID-19 dynamics using actual data for the proposed models. We estimate the model parameters and updated their estimates for reported infected and recovered data.

Meteorological, PM2.5 and PM10 factors on SARS-COV-2 transmission: The case of southern regions in Chile.

There are several determinants of a population's health, including meteorological factors and air pollution. For example, it is well known that low temperatures and air pollution increase mortality rates in infant and elderly populations. With the emergence of SARS-COV-2, it is important to understand what factors contribute to its mitigation and control. There is some research in this area which shows scientific evidence on the virus's behavior in the face of these variables. This research aims to quantify the impact of climatic factors and environmental pollution on SARS-COV-2 specifically the effect on the number of new infections in different areas of Chile. At the local level, historical information available from the Department of Statistics and Health Information, the Chilean National Air Quality Information System, the Chilean Meteorological Directorate, and other databases will allow the generation of panel data suitable for the analysis. The results show the significant effect of pollution and climate variables measured in lags and will allow us to explain the behavior of the pandemic by identifying the relevant factors affecting health, using heteroskedastic models, which in turn will serve as a contribution to the generation of more effective and timely public policies for the control of the pandemic.

Hypertension arising after 20 weeks of gestation: gestational hypertension or masked chronic hypertension?

The objectives of this study were 1-to evaluate the prevalence of masked chronic hypertension in pregnant women classified as gestational hypertension 2-to compare the risks of developing preeclampsia in true gestational hypertension vs those women classified as having gestational hypertension but who had had masked hypertension in the first half of pregnancy. We conducted a cohort study in consecutive high-risk pregnancies who were evaluated before 20 weeks of gestation. Women who developed gestational hypertension (normotension in the office before 20 weeks of gestation and office BP ≥ 140/90 mmHg and/or antihypertensive treatment in the second half of gestation) were divided, according to an ABPM performed before 20 weeks of pregnancy, in two subgroups: subgroup 1-if their ABPM was normal, and subgroup 2-if they had masked chronic hypertension. Risks for preeclampsia (PE) were estimated and compared with normotensive women. Before 20 weeks of gestation, 227 women were evaluated (age 32 ± 6 years, median gestation age 15 weeks); 67 had chronic hypertension (29.5%). Of the remaining 160, 39 developed gestational hypertension (16 in subgroup 1 and 23 insubgroup 2. Compared with normotensive pregnant women, subgroup 1 of women with gestational hypertension did not increase the risk of developing PE (OR = 0.76, 95% CI = 0.16-6.65). Conversely, subgroup 2 of gestational hypertension increased the risk of PE more than 4 times (0R = 4.47 CI = 1.16-12.63). Risk estimation did not change substantially after the adjustment for multiple possible confounders. In conclusion, the59% of women initially diagnosed as gestational hypertensive according to current recommendations had masked chronic hypertension and a very high risk of developing PE.

Uncontrolled and masked uncontrolled blood pressure in treated pregnant women with chronic hypertension and risk for preeclampsia/eclampsia.

To analyze the relationship between the level of BP achieved with treatment and the risk for development of preeclampsia/eclampsia (PE), we conducted a historical cohort study on 149 consecutive pregnant women with treated chronic hypertension, evaluated between January 1, 2016, and November 31, 2022. According to office BP readings and ambulatory blood pressure monitoring (ABPM) performed after 20 weeks of gestation, the cohort was classified in controlled hypertension, white-coat uncontrolled hypertension, masked uncontrolled hypertension and sustained hypertension. Risks for the development of PE were estimated using logistic regression. One hundred and twenty-four pregnant women with a control BP evaluation were included in this analysis. The rates of PE were 19.4%, 27.3%, 44.8% and 47.1% for controlled, white-coat uncontrolled, masked uncontrolled and sustained uncontrolled hypertension, respectively. Compared with women with controlled hypertension, the relative risk for PE increased markedly in women with sustained uncontrolled (OR 3.69, 95% CI, 1.19-11.45) and masked uncontrolled (OR 3.38, 95% CI, 1.30-11.45) hypertension, but not in those with white-coat uncontrolled (OR 1.56 95% CI, 0.36-6.70); adjustment for covariates did not modify the results. Each mmHg higher of systolic and diastolic daytime ABPM increased the relative risk for PE ~4% and ~5%, respectively. Each mmHg higher of systolic and diastolic nocturnal BP increased the risk ~5% and ~6%, respectively. When these risks were adjusted for ABPM values in opposite periods of the day, only nocturnal ABPM remained as a significant predictor. In conclusion, masked uncontrolled hypertension implies a substantial risk for the development of PE, comparable to those of sustained uncontrolled. The presence of nocturnal hypertension seems important.

COVID-19: A Comparative Study of Contagions Peaks in Cities from Europe and the Americas.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a group of viruses that provoke illnesses ranging from the common cold to more serious illnesses such as pneumonia. COVID-19 started in China and spread rapidly from a single city to an entire country in just 30 days and to the rest of the world in no more than 3 months. Several studies have tried to model the behavior of COVID-19 in diverse regions, based on differential equations of the SIR and stochastic SIR type, and their extensions. In this article, a statistical analysis of daily confirmed COVID-19 cases reported in eleven different cities in Europe and America is conducted. Log-linear models are proposed to model the rise or drop in the number of positive cases reported daily. A classification analysis of the estimated slopes is performed, allowing a comparison of the eleven cities at different epidemic peaks. By rescaling the curves, similar behaviors among rises and drops in different cities are found, independent of socioeconomic conditions, type of quarantine measures taken, whether more or less restrictive. The log-linear model appears to be suitable for modeling the incidence of COVID-19 both in rises and drops.

How far are we from predicting multi-drug interactions during treatment for COVID-19 infection?

Seriously ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and hospitalized in intensive care units (ICUs) are commonly given a combination of drugs, a process known as multi-drug treatment. After extracting data on drug-drug interactions with clinical relevance from available online platforms, we hypothesize that an overall interaction map can be generated for all drugs administered. Furthermore, by combining this approach with simulations of cellular biochemical pathways, we may be able to explain the general clinical outcome. Finally, we postulate that by applying this strategy retrospectively to a cohort of patients hospitalized in ICU, a prediction of the timing of developing acute kidney injury (AKI) could be made. Whether or not this approach can be extended to other diseases is uncertain. Still, we believe it represents a valuable pharmacological insight to help improve clinical outcomes for severely ill patients.

Studies on the basic reproduction number in stochastic epidemic models with random perturbations.

In this paper, we discuss the basic reproduction number of stochastic epidemic models with random perturbations. We define the basic reproduction number in epidemic models by using the integral of a function or survival function. We study the systems of stochastic differential equations for SIR, SIS, and SEIR models and their stability analysis. Some results on deterministic epidemic models are also obtained. We give the numerical conditions for which the disease-free equilibrium point is asymptotically stable.

Nocturnal hypertension and risk of developing early-onset preeclampsia in high-risk pregnancies.

To test the hypothesis that nocturnal hypertension identifies risk for early-onset preeclampsia/eclampsia (PE), we conducted an historical cohort study of consecutive high-risk pregnancies between 1st January 2016 and 31st March 2020. Office blood pressure (BP) measurements and ambulatory blood pressure monitoring (ABPM) were performed. The cohort was divided into patients without PE or with early- or late-onset PE (<34 and ≥34 weeks of gestation, respectively). The relative risks of office and ABPM hypertension for the development of late- or early-onset PE were estimated with multinomial logistic regression using no PE as a reference category. Four hundred and seventy-seven women (mean age 30 ± 7 years, with 23 ± 7 weeks of gestation at the time of the BP measurements) were analyzed; 113 (23.7%) developed PE, 69 (14.5%) developed late-onset PE, 44 (9.2%) developed early-onset PE. Office and ambulatory BP increased between the groups, and women who developed early-onset PE had significantly higher office and ambulatory BP values than those with late-onset PE or without PE. Hypertension prevalence increased across groups, with the highest values in early-onset PE. Nocturnal hypertension was the most prevalent finding and was highly prevalent in women who developed early-onset PE (88.6%); only 1.6% of women without nocturnal hypertension developed early-onset PE. Additionally, nocturnal hypertension was a stronger predictor for early-onset PE than for late-onset PE (adjusted OR, 5.26 95%CI 1.67-16.60) vs. 2.06, 95%CI 1.26-4.55, respectively). In conclusion, nocturnal hypertension was the most frequent BP abnormality and a significant predictor of early-onset PE in high-risk pregnancies.

In situ roughness measurements for the solar cell industry using an atomic force microscope.

Areal roughness parameters always need to be under control in the thin film solar cell industry because of their close relationship with the electrical efficiency of the cells. In this work, these parameters are evaluated for measurements carried out in a typical fabrication area for this industry. Measurements are made using a portable atomic force microscope on the CNC diamond cutting machine where an initial sample of transparent conductive oxide is cut into four pieces. The method is validated by making a comparison between the parameters obtained in this process and in the laboratory under optimal conditions. Areal roughness parameters and Fourier Spectral Analysis of the data show good compatibility and open the possibility to use this type of measurement instrument to perform in situ quality control. This procedure gives a sample for evaluation without destroying any of the transparent conductive oxide; in this way 100% of the production can be tested, so improving the measurement time and rate of production.

Non-BRCA1/2 Variants Detected in a High-Risk Chilean Cohort With a History of Breast and/or Ovarian Cancer.

METHODS: Data were retrospectively collected from the registry of the High-Risk Breast and Ovarian Cancer Program at Clínica Las Condes, Santiago, Chile. Data captured included index case diagnosis, ancestry, family history, and genetic test results. RESULTS: Three hundred fifteen individuals underwent genetic testing during the study period. The frequency of germline pathogenic and likely pathogenic variants in a breast or ovarian cancer predisposition gene was 20.3%. Of those patients who underwent testing with a panel of both high- and moderate-penetrance genes, 10.5% were found to have pathogenic or likely pathogenic variants in non-BRCA1/2 genes. CONCLUSION: Testing for non-BRCA1 and -2 mutations may be clinically relevant for individuals who are suspected to have a hereditary breast or ovarian cancer syndrome in Chile. Comprehensive genetic testing of individuals who are at high risk is necessary to further characterize the genetic susceptibility to cancer in Chile.

Nocturnal hypertension in high-risk mid-pregnancies predict the development of preeclampsia/eclampsia.

OBJECTIVE: The aim of this study was to test if hypertension detected by ambulatory blood pressure monitoring (ABPM) performed at mid-pregnancy, is a useful predictor for preeclampsia/eclampsia (PEEC). METHODS: The study was performed in women coursing high-risk mid-pregnancies. Office blood pressure (BP) was estimated as the mean of three values, taken by a specialized nurse after a 15-min interview, and office hypertension defined as at least 140/90 mmHg. Immediately after, an ABPM was started. Diurnal hypertension was defined as ABPM at least 135/85 mmHg during daily activities, nocturnal hypertension as ABPM at least 120/70 mmHg during night rest. The adjusted risk of PEEC was estimated using logistic regression. RESULTS: Eighty-seven women (mean age 31 ±â€Š7 years) with 23 ±â€Š2 weeks of pregnancy were included. The prevalence of office and ABPM hypertension was 13.8 and 40.2%, respectively. The concordance between both hypertension diagnosis was low (κ = 0.170, P = 0.044). Nocturnal hypertension (35.6%) was more frequent than diurnal hypertension (26.4%). Nocturnal hypertension markedly increased the relative risk of PEEC (OR 5.32, 95% CI 1.48-19.10). The risk of PEEC attributed to diurnal hypertension did not reach statistical significance; and when both, diurnal and nocturnal hypertension were included in the same model, only the second one was a significant predictor (P = 0.012). The relative risk associated with nocturnal hypertension increased for women not taking acetylsalicylic acid (ASA); (OR 11.40, 95% CI 2.35-55.25). CONCLUSION: Nocturnal hypertension at high-risk mid-pregnancy is a frequent condition and a strong predictor for PEEC; the risk doubled for women not taking ASA.

Office blood pressure values and the necessity of out-of-office measurements in high-risk pregnancies.

OBJECTIVES: To determine if there is an office blood pressure (BP) value below which out-of-office measurements are unnecessary in high-risk pregnant women. METHODS: We conducted a prospective cohort study in women in the second half of high-risk pregnancies. Office BP measurements and ambulatory blood pressure monitoring (ABPM) was performed. The cohort was divided according to quartiles of office BP and in normotension, white-coat hypertension, masked hypertension and sustained hypertension. The risks for preeclampsia/eclampsia for each category were estimated. RESULTS: Three hundred seventy-three women (30 ±â€Š7 years with 32 ±â€Š4 weeks of gestation) were included; 69 women (18.5%) developed preeclampsia/eclampsia. Risk for preeclampsia/eclampsia increased in a stepwise manner through quartiles of systolic office BP (8.8, 13.4, 19.6 and 32.3%, P < 0.001) and diastolic office BP (6.5, 13.7, 19.6 and 34,4%, P < 0.001). OR increased significantly through quartiles of systolic (P = 0.004) and diastolic (P < 0.001) office BP; the significance becomes evident between the second and third quartile, the cut-off point between these was 125/76 mmHg. Prevalence of white-coat and masked hypertension were 3.8 and 24.7%, respectively. Using ABPM, 14/61 office hypertensive women were reclassified as white-coat hypertension but 92/312 normotensive women as masked hypertension. OR for preeclampsia/eclampsia increased significantly in women with masked hypertension. Absolute risk for preeclampsia/eclampsia in women with office BP less than 125/75 mmHg was similar than that in women with normal ABPM, 7.2 and 7.1%, respectively. CONCLUSION: Masked hypertension was a prevalent and high-risk condition. Office BP at least 125/75 mmHg in the second half of gestation seems appropriate to indicate out-of-office measurements in high-risk pregnancies.

Principles: mechanisms and modeling of synergism in cellular responses.

Cells can be considered as integrators of simultaneous stimuli, in which cross-talk between transduction pathways can eventually produce responses that are significantly different from simply additive responses. Synergism represents an efficient means of increasing the amplitude of cellular responses induced by low levels of stimulation. Recently, several kinetic and physicochemical models have been developed to describe and predict synergistic responses. In this article, the mechanisms that control the magnitude and timing of cellular synergism are discussed. We suggest that the analysis of theoretical models could enable a general prediction of synergism despite the presence of signal-specific synergistic responses. In addition, application of the proposed concepts should aid understanding of the wide occurrence of synergism induced by interacting transduction pathways in multi-drug clinical treatment.

Liderazgo en enfermería desde la perspectiva de sus seguidores / Care of the person with motor disabilities

Analizar el perfil de liderazgo de los directivos en enfermería desde la perspectiva de sus seguidores.

Breast cancer management in middle-resource countries (MRCs): consensus statement from the Breast Health Global Initiative.

In middle resource countries (MRCs), cancer control programs are becoming a priority as the pattern of disease shifts from infectious diseases to non-communicable diseases such as breast cancer, the most common cancer among women in MRCs. The Middle Resource Scenarios Working Group of the BHGI 2010 Global Summit met to identify common issues and obstacles to breast cancer detection, diagnosis and treatment in MRCs. They concluded that breast cancer early detection programs continue to be important, should include clinical breast examination (CBE) with or without mammography, and should be coupled with active awareness programs. Mammographic screening is usually opportunistic and early detection programs are often hampered by logistical and financial problems, as well as socio-cultural barriers, despite improved public educational efforts. Although multidisciplinary services for treatment are available, geographical and economic limitations to these services can lead to an inequity in health care access. Without adequate health insurance coverage, limited personal finances can be a significant barrier to care for many patients. Despite the improved availability of services (surgery, pathology, radiology and radiotherapy), quality assurance programs remain a challenge. Better access to anticancer drugs is needed to improve outcomes, as are rehabilitation programs for survivors. Focused and sustained government health care financing in MRCs is needed to improve early detection and treatment of breast cancer.

Primer caso en Uruguay de tuberculosis asociada a terapia con agentes biológicos: reporte de un caso clínico / Tuberculosis associated with biological therapeutic agents: first case in Uruguay

Las terapias biológicas con anticuerpos monoclonales antifactor de necrosis tumoral alfa (TNF- ) revolucionaron el tratamiento de la artritis reumatoide. Su uso implica un riesgo elevado para el desarrollo de tuberculosis pulmonar por lo que exige una evaluación exhaustiva, tanto al inicio del tratamiento como en el seguimiento del paciente, descartando infección latente o tuberculosis activa. Se presenta el primer caso clínico descripto en Uruguay de tuberculosis pulmonar asociada a terapia con agentes biológicos (adalimumab).

Biologic therapies with anti-tumor necrosis factor alpha (TNF- ) monoclonal antibodies were a revolution in the treatment of rheumatoid arthritis. The use of antibodies implies a high risk of developing pulmonary tuberculosisand thus a thorough assessment is necessary, both upon the initiation of treatment and during patient follow up, to rule out a latent infection or active tuberculosis. The study presents the first clinical case of pulmonary tuberculosis associated with biologic therapydescribed in Uruguay (adalimumab).

As terapias biológicas com anticorpos monoclonais antifator de necrose tumoral alfa (TNF- ) revolucionaramo tratamento da artrite reumatoide. Seu uso implica um risco elevado para o surgimento de tuberculose pulmonarrazão pela qual é imprecindível a avaliação exaustiva, tanto no inicio do tratamento como durante o seguimentodo paciente para descartar infecção latente ou tuberculose ativa. Apresentamos o primeiro caso clínicodescrito no Uruguai de tuberculose pulmonar associada à terapia com agentes biológicos (adalimumab).

Cancer care in Chile.

Cancer is responsible for 22% of deaths in Chile and this proportion is increasing every year. After years of comparative neglect, the Chilean government is now attempting to implement a systematic anticancer policy rooted in evidence-based medicine. Major reform of the national health system promises to guarantee healthcare for those affected by "catastrophic" illnesses. However, budgetary constraints mean that only some cancers will count as catastrophic. This Reportage considers how cancer care has evolved in Chile over recent years and examines the rationale behind the allocation of scarce resources.