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1.
J Clin Sleep Med ; 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32003737

RESUMO

STUDY OBJECTIVES: To determine whether an intensive weight-loss program (IWLP) is effective for reducing weight, the severity of sleep apnea syndrome (OSA) and metabolic variables in patients with obesity and severe OSA undergoing continuous positive airway pressure treatment. METHODS: 42 patients were randomized to the control (CG,n=20) or the intervention group (IG,n=22), who followed a 12-month IWLP. The primary outcome was a reduction in the apnea-hypopnea index (AHI) as measured at 3 and 12 months by full polysomnography. Metabolic variables, blood pressure, body fat composition by bioimpedance, carotid intima media thickness and visceral fat by computed tomography scan were also assessed. RESULTS: Mean age was 49(6.7) years, body mass index 35(2.7) kg/m² and AHI 69(20) events/h. Weight reduction was higher for the IG than the CG at 3 and 12 months, -10.5 vs -2.3 kg (p<0.001), and -8.2 vs -0.1 kg (p<0.001), respectively, as was loss of visceral fat at 12 months. AHI decreased more in the IG at 3 months (-23.72 events/h vs -9 events/h) but the difference was not significant at 12 months, though 28% of patients from the IG had an AHI <30 events/h compared to none in the CG (p=0.046). At 12 months, the IG showed a reduction in C-reactive protein (p=0.013), glycated hemoglobin (p=0.031) and an increase in high density lipoprotein cholesterol (p=0.027). CONCLUSIONS: An IWLP in patients with obesity and severe OSA is effective for reducing weight and OSA severity. It also results in an improvement in lipid profiles, glycemic control and inflammatory markers.

2.
Curr Eye Res ; : 1-8, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32011181

RESUMO

Objectives: To evaluate the acute effect of caffeine consumption on the accuracy and variability of accommodation, as well as its impact on pupil size and perceived levels of activation.Methods: 22 university students (21.68 ± 3.67 years old) ingested a capsule of caffeine (4 mg/kg) or placebo (300 mg of corn-starch) in two different days and counterbalanced order. After 30 min of capsule ingestion, we objectively measured the accuracy and variability of accommodation, and pupil size using the WAM-5500 binocular open-field autorefractometer for 2 min at each of the six viewing distances (5 m, 50 cm, 40 cm, 33 cm, 25 cm, and 20 cm). Subjective levels of activation to check the effectiveness of caffeine/placebo manipulation were also reported.Results: We found that after 30 min of caffeine/placebo ingestion, participant perceived higher levels of activation in the caffeine condition (p = .047, Cohen´s d = 0.48). Caffeine consumption induced a statistically significant dilator effect on pupil size (p = .011, η2 = 0.271), and reduced variability of accommodative response (p = .027, η2 = 0.211). However, no differences were obtained for the accuracy of accommodation (p = .321).Conclusions: Our data suggest that caffeine consumption reduced the variability of accommodative response and induced pupil dilation. Nevertheless, the accuracy of accommodation was insensitive to caffeine intake. These findings may be explained by the bidirectional relationship between ocular functioning and the nervous system´s state of activation.

3.
Curr Probl Cancer ; : 100551, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-32057462

RESUMO

PURPOSE: To investigate whether there are differences in diversity, taxonomic composition, and predicted functional pathways of the gut microbiome between Island Hispanic Puerto Ricans (HPR) and mainland non-Hispanic whites (NHW) measured before and at the end of chemo-radiation (CRT) for Rectal Cancer. METHODS: Fifty-six stool samples of newly diagnosed rectal cancer patients (25 HPR and 31 NHW) were amplicon-sequenced during chemo-radiotherapy. 16S rRNA gene data was analyzed using QIIME2, phyloseq, and LEfSe. RESULTS: We observed similar within-sample alpha diversity for HPR and NHW participants during CRT. However, at the end of CRT, several taxa were present at significantly different abundances across both groups. Taxa enriched in the gut of HPR compared to NHW included Muribaculaceae, Prevotella 2 and 7, Gemella, Bacillales Family XI, Catenibacterium, Sutterella, Pasteurellales, and Pasteurellaceae genera, whereas over-represented taxa in NHW participants were Turicibacter and Eubacteriaceae. Significant differences in predicted HPR microbiota functions included pathways for synthesis of L-methionine and degradation of phenylethylamine and phenylacetate. CONCLUSION: In this pilot study, taxonomic analyses and functional predictions of the gut microbiomes suggest greater inflammatory potential in gut microbial functions among HPR rectal cancer patients undergoing CRT compared to that of NHW participants.

4.
Sci Rep ; 10(1): 1902, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024974

RESUMO

Elite controllers (EC) represent a small subset of HIV-1-infected people that spontaneously control viral replication. However, natural virological suppression and absence of immune dysfunction are not always long-term sustained. We define exceptional EC (EEC) as HIV-1 subjects who maintain the EC characteristics without disease progression for more than 25 years. We analyzed three EEC, diagnosed between 1988 and 1992, who never showed signs of clinical disease progression in absence of any antiretroviral treatment. A comprehensive clinical, virological, and immunological study was performed. The individuals simultaneously exhibited ≥3 described host protective alleles, low levels of total HIV-1 DNA (<20 copies/106 CD4+ T-cells) without evidence of replication-competent viruses (<0.025 IUPM), consistent with high levels of defective genomes, strong cellular HIV-1-specific immune response, and a high poly-functionality index (>0.50). Inflammation levels of EEC were similar to HIV-1 negative donors. Remarkably, they showed an exceptional lack of viral evolution and 8-fold lower genetic diversity (<0.01 s/n) in env gene than other EC. We postulate that these EEC represent cases of spontaneous functional HIV-1 cure. A non-functional and non-genetically evolving viral reservoir along with an HIV-1-specific immune response seems to be key for the spontaneous functional cure.

5.
Lancet Respir Med ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32043986

RESUMO

BACKGROUND: There is no proven specific pharmacological treatment for patients with the acute respiratory distress syndrome (ARDS). The efficacy of corticosteroids in ARDS remains controversial. We aimed to assess the effects of dexamethasone in ARDS, which might change pulmonary and systemic inflammation and result in a decrease in duration of mechanical ventilation and mortality. METHODS: We did a multicentre, randomised controlled trial in a network of 17 intensive care units (ICUs) in teaching hospitals across Spain in patients with established moderate-to-severe ARDS (defined by a ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen of 200 mm Hg or less assessed with a positive end-expiratory pressure of 10 cm H2O or more and FiO2 of 0·5 or more at 24 h after ARDS onset). Patients with brain death, terminal-stage disease, or receiving corticosteroids or immunosuppressive drugs were excluded. Eligible patients were randomly assigned based on balanced treatment assignments with a computerised randomisation allocation sequence using blocks of 10 opaque, sealed envelopes to receive immediate treatment with dexamethasone or continued routine intensive care (control group). Patients in the dexamethasone group received an intravenous dose of 20 mg once daily from day 1 to day 5, which was reduced to 10 mg once daily from day 6 to day 10. Patients in both groups were ventilated with lung-protective mechanical ventilation. Allocation concealment was maintained at all sites during the trial. Primary outcome was the number of ventilator-free days at 28 days, defined as the number of days alive and free from mechanical ventilation from day of randomisation to day 28. Secondary outcome was all-cause mortality 60 days after randomisation. All analyses were done according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT01731795. FINDINGS: Between March 28, 2013, and Dec 31, 2018, we enrolled 277 patients and randomly assigned 139 patients to the dexamethasone group and 138 to the control group. The trial was stopped by the data safety monitoring board due to low enrolment rate after enrolling more than 88% (277/314) of the planned sample size. The mean number of ventilator-free days was higher in the dexamethasone group than in the control group (between-group difference 4·8 days [95% CI 2·57 to 7·03]; p<0·0001). At 60 days, 29 (21%) patients in the dexamethasone group and 50 (36%) patients in the control group had died (between-group difference -15·3% [-25·9 to -4·9]; p=0·0047). The proportion of adverse events did not differ significantly between the dexamethasone group and control group. The most common adverse events were hyperglycaemia in the ICU (105 [76%] patients in the dexamethasone group vs 97 [70%] patients in the control group), new infections in the ICU (eg, pneumonia or sepsis; 33 [24%] vs 35 [25%]), and barotrauma (14 [10%] vs 10 [7%]). INTERPRETATION: Early administration of dexamethasone could reduce duration of mechanical ventilation and overall mortality in patients with established moderate-to-severe ARDS. FUNDING: Fundación Mutua Madrileña, Instituto de Salud Carlos III, The European Regional Development's Funds, Asociación Científica Pulmón y Ventilación Mecánica.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32030406

RESUMO

OBJECTIVES: We report the results of the reverse transcriptase (RT)/protease (PR) transmitted drug resistance (TDR) prevalence study in 2018, focusing on doravirine resistance-associated mutations and the differences observed when Stanford or French National Agency for AIDS Research (ANRS)/Spanish Network of AIDS Research (RIS)/IAS-USA resistance interpretation algorithms are used to describe clinically relevant resistance. METHODS: We used the WHO 2009 list to investigate the prevalence of NNRTI, NRTI and PI TDR, in treatment-naive HIV-1-infected patients, adding mutations E138A/G/K/Q/R, V106I, V108I, V179L, G190Q, H221Y, F227C/L/V, M230IDR, L234I, P236L and Y318F in RT. The prevalence of doravirine resistance-associated mutations, as described by Soulie et al. in 2019, was evaluated. Clinically relevant TDR was investigated using the latest versions of ANRS, RIS, IAS-USA and Stanford algorithms. RESULTS: NNRTI mutations were detected in 82 of 606 (13.5%) patients. We found 18 patients (3.0%) with NRTI mutations and 5 patients (0.8%) with PI mutations. We detected 11 patients harbouring doravirine resistance-associated mutations (prevalence of 1.8%). Furthermore, we observed important differences in clinically relevant resistance to doravirine when ANRS/RIS (0.7%), IAS-USA (0.5%) or Stanford algorithms (5.0%) were used. V106I, which was detected in 3.8% of the patients, was the main mutation driving these differences. V106I detection was not associated with any of the clinical, demographic or virological characteristics of the patients. CONCLUSIONS: The prevalence of NRTI and PI TDR remains constant in Spain. Doravirine TDR is very infrequent by RIS/ANRS/IAS-USA algorithms, in contrast with results using the Stanford algorithm. Further genotype-phenotype studies are necessary to elucidate the role of V106I in doravirine resistance.

7.
Oncologist ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32045052

RESUMO

BACKGROUND: Data on the incidence, etiology, and prognosis of non-ventilator-associated pneumonia in hospitalized patients with solid tumors are scarce. We aimed to study the characteristics of non-ventilator-associated pneumonia in hospitalized patients with solid tumors. MATERIALS AND METHODS: This was a prospective noninterventional cohort study of pneumonia in patients hospitalized in an oncology ward in a tertiary teaching hospital. Pneumonia was defined according to the American Thoracic Society criteria. Patients were followed for 1 month after diagnosis or until discharge. Survivors were compared with nonsurvivors. RESULTS: A total of 132 episodes of pneumonia were diagnosed over 1 year (9.8% of admissions to the oncology ward). They were health care-related (67.4%) or hospital-acquired pneumonia (31.8%). Lung cancer was the most common malignancy. An etiology was established in 48/132 episodes (36.4%). Knowing the etiology led to changes in antimicrobial therapy in 58.3%. Subsequent intensive care unit admission was required in 10.6% and was linked to inappropriate empirical therapy. Ten-day mortality was 24.2% and was significantly associated with hypoxia (odds ratio [OR], 2.1). Thirty-day mortality was 46.2%. The independent risk factors for 30-day mortality were hypoxia (OR, 3.3), hospital acquisition (OR, 3.1), and a performance status >1 (OR, 2.6). Only 40% of patients who died within 30 days were terminally ill. CONCLUSION: Pneumonia is a highly prevalent condition in hospitalized patients with solid tumors, even with nonterminal disease. Etiology is diverse, and poor outcome is linked to inappropriate empirical therapy. Efforts to get the empirical therapy right and reach an etiological diagnosis to subsequently de-escalate are warranted. IMPLICATIONS FOR PRACTICE: The present study shows that pneumonia is a prevalent infectious complication in patients admitted to oncology wards, with a very high mortality, even in non-terminally ill patients. Etiology is diverse, and etiological diagnosis is reached in fewer than 40% of cases in nonintubated patients. Intensive care unit admission, a marker of poor outcome, is associated with inappropriate empirical therapy. These results suggest that, to improve prognosis, a more precise and appropriate antimicrobial empirical therapy for pneumonia in patients with solid tumors is necessary, together with an effort to reach an etiological diagnosis to facilitate subsequent de-escalation.

8.
PLoS One ; 15(1): e0227535, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31999701

RESUMO

BACKGROUND: Campylobacter jejuni is the most common bacterial cause of human infectious intestinal disease. METHODS: We genome sequenced 601 human C. jejuni isolates, obtained from two large prospective studies of infectious intestinal disease (IID1 [isolates from 1993-1996; n = 293] and IID2 [isolates from 2008-2009; n = 93]), the INTEGRATE project [isolates from 2016-2017; n = 52] and the ENIGMA project [isolates from 2017; n = 163]. RESULTS: There was a significant increase in the prevalence of the T86I mutation conferring resistance to fluoroquinolone between each of the three later studies (IID2, INTEGRATE and ENIGMA) and IID1. Although the distribution of major multilocus sequence types (STs) was similar between the studies, there were changes in both the abundance of minority STs associated with the T86I mutation, and the abundance of clones within single STs associated with the T86I mutation. DISCUSSION: Four population-based studies of community diarrhoea over a 25 year period revealed an increase over time in the prevalence of the T86I amongst isolates of C. jejuni associated with human gastrointestinal disease in the UK. Although associated with many STs, much of the increase is due to the expansion of clones associated with the resistance mutation.

9.
Anal Chim Acta ; 1093: 28-34, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31735212

RESUMO

Alzheimer's disease is one of the most common causes of dementia nowadays, and its prevalence increases over time. Because of this and the difficulty of its diagnosis, accurate methods for the analysis of specific biomarkers for an early diagnosis of this disease are much needed. Recently, the levels of unfolded isoform of the multifunctional protein p53 in plasma have been proved to increase selectively in Alzheimer's Disease patients in comparison with healthy subjects, thus entering the list of biomarkers that can be used for the diagnosis of this illness. We present here the development of an electrochemical immunosensor based on nanostructured screen-printed carbon electrodes for the quantification of unfolded p53 in plasma samples. The sensor shows a suitable linear range (from 2 to 50 nM) for its application in real blood samples and a very low limit of detection (0.05 nM). The concentration of unfolded p53 has been accurately detected in plasma of elderly people in healthy conditions, subjects with mild cognitive impairment (MCI) and Alzheimer's Disease (AD) subjects, obtaining results with no significant differences to those provided by an ELISA assay. These results support the possibility of measuring unfolded p53 levels with a cheap, simple and miniaturized device with a promising future for point-of-care applications in the early diagnosis of Alzheimer's dementia.

10.
BMC Cancer ; 19(1): 1163, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783816

RESUMO

BACKGROUND: Patients with metastatic spinal cord compression (MSCC) and favorable survival prognoses can benefit from radiation doses greater than 30Gy in 10 fractions in terms of improved local progression-free survival (LPFS) and overall survival (OS). METHODS/DESIGN: This prospective study mainly investigates LPFS after precision radiotherapy (volumetric modulated arc therapy or stereotactic body radiotherapy) with 18 × 2.33Gy in 3.5 weeks. LPFS is defined as freedom from progression of motor deficits during radiotherapy and an in-field recurrence of MSCC following radiotherapy. The maximum relative dose allowed to the spinal cord is 101.5% of the prescribed dose, resulting in an equivalent dose in 2Gy-fractions (EQD2) for radiation myelopathy is 45.5Gy, which is below the tolerance dose of 50Gy according to the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC). The EQD2 of this regimen for tumor cell kill is 43.1Gy, which is 33% higher than for 30Gy in 10 fractions (EQD2 = 32.5Gy). Primary endpoint is LPFS at 12 months after radiotherapy. Secondary endpoints include the effect of 18 × 2.33Gy on motor function, ambulatory status, sensory function, sphincter dysfunction, LPFS at other follow-up times, overall survival, pain relief, relief of distress and toxicity. Follow-up visits for all endpoints will be performed directly and at 1, 3, 6, 9 and 12 months after radiotherapy. A total of 65 patients are required for the prospective part of the study. These patients will be compared to a historical control group of at least 235 patients receiving conventional radiotherapy with 10x3Gy in 2 weeks. DISCUSSION: If precision radiotherapy with 18 × 2.33Gy results in significantly better LPFS than 10x3Gy of conventional radiotherapy, this regimen should be strongly considered for patients with MSCC and favorable survival prognoses. TRIAL REGISTRATION: Clinicaltrials.gov NCT04043156. Registered 30-07-2019.

11.
Arch Bronconeumol ; 2019 Nov 26.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31784347

RESUMO

INTRODUCTION: It is unclear whether low-risk patients with acute symptomatic pulmonary embolism (PE) should undergo echocardiogram. METHODS: We performed a meta-analysis of studies that enrolled patients with acute low-risk PE to assess the prognostic value of echocardiographic diagnosis of right ventricular (RV) dysfunction for the primary outcome of short-term all-cause mortality, and the secondary outcome of short-term PE-related mortality. We used a random-effects model to pool study results, a Begg rank correlation method to evaluate for publication bias, and I2 testing to assess heterogeneity. RESULTS: The meta-analysis included a total of 11 studies 1,868 patients with low-risk PE. Ten of the 447 (2.2%; 1.1%-4.1%) low-risk patients with echocardiographic RV dysfunction died soon after the diagnosis of PE compared with 10 of 1,421 (0.7%; 0.3-1.3%) patients without RV dysfunction. RV dysfunction was not significantly associated with short-term all-cause mortality (odds ratio 2.0; 95% confidence interval, 0.8-5.1, p=.14; I2=8%). RV dysfunction was significantly associated with short-term PE-related mortality (odds ratio 5.2; 95% confidence interval, 1.7-16, p <.01; I2=0%). CONCLUSIONS: In patients with low-risk PE, echocardiographic RV dysfunction is not associated with all-cause mortality, but identifies patients with an increased risk for short-term PE-related mortality.

12.
Horm Behav ; 119: 104653, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31816282

RESUMO

E2 and its alpha receptor (ERα) have an essential role in the regulation of maternal behavior. In dwarf hamster (Phodopus campbelli), E2 facilitates the display of paternal care, and it is possible that ERα is part of the neuroendocrine mechanisms that regulate this behavior. The aim of this study was to analyze the influence of copulation, cohabitation with the pregnant mate and the presence of the pups on paternal behavior, circulating E2 levels and the presence of ERα in the medial preoptic area (mPOA) and medial amygdala (MeA) in dwarf hamsters. Eight males were mated with intact females (IFs), 8 with tubally ligated females (TLFs) and 8 with ovariectomized females (OFs). In males mated with IFs, paternal behavior tests were performed after copulation, halfway through pregnancy and 24 h after the birth of their pups. Males mated with TLFs were subjected to paternal behavior tests at equivalent periods as the males mated with IFs. In males mated with OFs, paternal behavior tests were performed on days 1, 5 and 10 of cohabitation. After the last paternal behavior tests, blood samples were taken for quantification of E2 by radioimmunoassay (RIA), and the brains were dissected to determine ERα immunoreactivity (ir) in the mPOA and MeA. Fathers mated with IFs had higher serum E2 concentrations and more ERα-ir cells in the mPOA than those of males mated with TLFs and OFs. These results suggest that E2 and its ERα may be associated with paternity in the dwarf hamster.

13.
Int J Mol Sci ; 20(24)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842432

RESUMO

The four member family of "Cyclin and Cystathionine ß-synthase (CBS) domain divalent metal cation transport mediators", CNNMs, are the least-studied mammalian magnesium transport mediators. CNNM4 is abundant in the brain and the intestinal tract, and its abnormal activity causes Jalili Syndrome. Recent findings show that suppression of CNNM4 in mice promotes malignant progression of intestinal polyps and is linked to infertility. The association of CNNM4 with phosphatases of the regenerating liver, PRLs, abrogates its Mg2+-efflux capacity, thus resulting in an increased intracellular Mg2+ concentration that favors tumor growth. Here we present the crystal structures of the two independent intracellular domains of human CNNM4, i.e., the Bateman module and the cyclic nucleotide binding-like domain (cNMP). We also derive a model structure for the full intracellular region in the absence and presence of MgATP and the oncogenic interacting partner, PRL-1. We find that only the Bateman module interacts with ATP and Mg2+, at non-overlapping sites facilitating their positive cooperativity. Furthermore, both domains dimerize autonomously, where the cNMP domain dimer forms a rigid cleft to restrict the Mg2+ induced sliding of the inserting CBS1 motives of the Bateman module, from a twisted to a flat disk shaped dimer.

15.
PLoS One ; 14(11): e0224990, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31774846

RESUMO

The aim of our study was to understand how male partners of women diagnosed with fibromyalgia syndrome perceive sexuality. Gadamerian hermeneutic phenomenology and the Roy Adaptation Model provided the overall framework for this research study. Eighteen participants were recruited through convenience and purposive sampling. Data collection was conducted between February and July of 2017 and included a focus group and twelve in-depth interviews. Two main themes were extracted: "facing a new sex life" and "resisting the loss of the couple's sexuality". Fibromyalgia syndrome compromises the couple's sex life. Enhancing intimacy, skin-to-skin contact (during acute FMS outbreaks), finding new positions, non-coital sex and use of sex toys can increase female desire and help coping.

16.
Am J Crit Care ; 28(6): 471-476, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31676522

RESUMO

BACKGROUND: Post-intensive care syndrome-family (PICS-F) refers to acute and chronic psychological effects of critical care on family members of patients in intensive care units (ICUs). Evidence suggests that increased distress during the ICU stay increases risk of PICS-F. Sensation Awareness Focused Training (SAF-T) is a new, promising stress management intervention, but the feasibility of such training during the ICU stay for family caregivers who are acting as the surrogate decision-maker for patients who are undergoing mechanical ventilation is unknown. OBJECTIVES: To assess feasibility and acceptability of SAF-T to inform a future larger randomized controlled trial. METHODS: This randomized controlled trial of SAF-T (n = 5) versus a control (n = 5) group was conducted at a level 1 trauma center. Participants assigned to SAF-T completed 1 session daily for 3 days. Measures included enrollment rate, data completion rate, acceptability of SAF-T, and symptoms of PICS-F. Scales used included Perceived Stress, Hospital Anxiety and Depression, Impact of Event, and National Institutes of Health Toolbox Emotion Battery. RESULTS: Mean age was 58 (SD, 12) years; 70% of participants were female. Predetermined feasibility criteria were met in enrollment rate (67%), outcome measures completion rate (> 90%), and SAF-T acceptability (100% of doses completed during the ICU stay) without adverse events. Stress scores after SAF-T were significantly lower than scores before SAF-T (z = -3.5, P = .01). CONCLUSIONS: SAF-T intervention during the ICU stay is feasible, acceptable, and may improve family caregivers' post-ICU outcomes. Larger clinical trial to assess the effectiveness of SAF-T in preventing PICS-F seem warranted.

17.
Int J Mol Sci ; 20(21)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694170

RESUMO

In higher organisms, epithelia separate compartments in order to guarantee their proper function. Such structures are able to seal but also to allow substances to pass. Within the paracellular pathway, a supramolecular structure, the tight junction transport is largely controlled by the temporospatial regulation of its major protein family called claudins. Besides the fact that the expression of claudins has been identified in different forms of human diseases like cancer, clearly defined mutations in the corresponding claudin genes have been shown to cause distinct human disorders. Such disorders comprise the skin and its adjacent structures, liver, kidney, the inner ear, and the eye. From the phenotype analysis, it has also become clear that different claudins can cause a complex phenotype when expressed in different organs. To gain deeper insights into the physiology and pathophysiology of claudin-associated disorders, several mouse models have been generated. In order to model human disorders in detail, they have been designed either as full knockouts, knock-downs or knock-ins by a variety of techniques. Here, we review human disorders caused by CLDN mutations and their corresponding mouse models that have been generated thus far and assess their usefulness as a model for the corresponding human disorder.

18.
Fungal Biol ; 123(12): 905-912, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31733733

RESUMO

The diversity of the fungal community associated with adults of Dryocosmus kuriphilus following emergence was examined using HTS analysis. Ascomycota dominated the fungal core-biome community. The functional guilds of the 90 taxa forming the core-biome were assessed, demonstrating three main groups: saprotrophs, plant pathogens and entomopathogens. Twenty-nine OTUs out of 90 were resolved to species level identifying 26 different fungal species. Among these species, many were cosmopolitan or previously recorded in Europe. Ten taxa were previously recorded on chestnut, including some recognized plant pathogens associated with foliage and green tissues such as Epicoccum nigrum, Gnomoniopsis castanea, Colletotrichum acutatum, Stromatoseptoria castaneicola, Ramularia endophylla. Beauveria bassiana; within the core microbiome, Fusarium larvarum represented the most abundant entomopathogenic species. Some of these species are known to impact directly or indirectly the vitality of the insects in the galls. The chestnut blight pathogen, Cryphonectria parasitica, was never found associated with D. kuriphilus. Based on the present study, an active role for D. kuriphilus as a vector of chestnut fungal endophyte/pathogens cannot be demonstrated but neither ruled out.

19.
J Biomed Sci ; 26(1): 83, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31640710

RESUMO

BACKGROUND: Most of the circulating Vitamin D (VitD) is transported bound to vitamin D-binding protein (DBP), and several DBP single nucleotide polymorphisms (SNPs) have been related to circulating VitD concentration and disease. In this study, we evaluated the association among DBP SNPs and AIDS progression in antiretroviral treatment (ART)-naïve-HIV-infected patients. METHODS: We performed a retrospective study in 667 patients who were classified according to their pattern of AIDS progression (183 long-term non-progressors (LTNPs), 334 moderate progressors (MPs), and 150 rapid progressors (RPs)) and 113 healthy blood donors (HIV, HCV, and HBV negative subjects). We genotyped seven DBP SNPs (rs16846876, rs12512631, rs2070741, rs2282679, rs7041, rs1155563, rs2298849) using Agena Bioscience's MassARRAY platform. The genetic association was evaluated by Generalized Linear Models adjusted by age at the moment of HIV diagnosis, gender, risk group, and VDR rs2228570 SNP. Multiple testing correction was performed by the false discovery rate (Benjamini and Hochberg procedure; q-value). RESULTS: All SNPs were in HWE (p > 0.05) and had similar genotypic frequencies for DBP SNPs in healthy-controls and HIV-infected patients. In unadjusted GLMs, we only found significant association with AIDS progression in rs16846876 and rs12512631 SNPs. In adjusted GLMs, DBP rs16846876 SNP showed significant association under the recessive inheritance model [LTNPs vs. RPs (adjusted odds ratio (aOR) = 3.53; q-value = 0.044) and LTNPs vs. MPs (aOR = 3.28; q-value = 0.030)] and codominant [LTNPs vs. RPs (aOR = 4.92; q-value = 0.030) and LTNPs vs. MPs (aOR = 3.15; q-value = 0.030)]. Also, we found DBP rs12512631 SNP showed significant association in the inheritance model dominant [LTNPs vs. RPs (aOR = 0.49; q-value = 0.031) and LTNPs vs. MPs (aOR = 0.6; q-value = 0.047)], additive [LTNPs vs. RPs (aOR = 0.61; q-value = 0.031)], overdominant [LTNPs vs. MPs (aOR = 0.55; q-value = 0.032)], and codominant [LTNPs vs. RPs (aOR = 0.52; q-value = 0.036) and LTNPs vs. MPs (aOR = 0.55; q-value = 0.032)]. Additionally, we found a significant association between DBP haplotypes (composed by rs16846876 and rs12512631) and AIDS progression (LTNPs vs RPs): DBP haplotype AC (aOR = 0.63; q-value = 0.028) and the DBP haplotype TT (aOR = 1.64; q-value = 0.028). CONCLUSIONS: DBP rs16846876 and rs12512631 SNPs are related to the patterns of clinical AIDS progression (LTNP, MP, and RP) in ART-naïve HIV-infected patients. Our findings provide new knowledge about AIDS progression that may be relevant to understanding the pathogenesis of HIV infection.

20.
BMC Infect Dis ; 19(1): 883, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646969

RESUMO

BACKGROUND: Penicillin G Benzathine (PGB) is the cornerstone of syphilis treatment. However, its intramuscular (IM) administration is associated with pain at the site of injection. The dilution of PGB with local anesthetics is recommended in some guidelines, but the evidence that supports it, particularly in adults and in HIV infection, is scarce. Preliminary clinical experience also suggests that the IM administration of PGB through increased needle gauges might improve its tolerability. The aim of the study to identify less painful ways of administering IM PGB in the treatment of syphilis in adults. METHODS: Multicenter, randomized, double-blinded clinical trial in patients diagnosed with primary syphilis that required a single IM injection of PGB 2400,00 IU. Patients were randomized to receive PGB diluted with 0.5 mL mepivacaine 1% (MV) or PGB alone, and both groups either with a long 19G or short 21G IM needle. The primary objective was the effect on local pain immediately after the administration through a visual scale questionnaire on pain (0 to 10). RESULTS: One hundred eight patients were included, 27 in each group. Ninety-four (94.4%) were male, and 41.7% were also HIV-infected. Mean age 36.6 years (SD 11). Significant differences in immediate pain intensity were observed when comparing the long 19G group with anesthesia (mean pain intensity, [MPI] 2.92 [CI 95% 1.08-4.07]) vs long 19G without anesthesia (MPI 5.56 [CI 95% 4.39-6.73), p < 0.001; and also between short 21G group with anesthesia (MPI 3.36 [CI 95% 2.22-4.50]) vs short 21G without anesthesia (MPI 5.06 [CI 95% 3.93-6.19]), p = 0.015). No significant differences in immediate pain were observed between 19G and 21G in the presence or absence of anesthesia (p = 1.0 in both cases). No differences were found between study arms after 6 and 24 h. CONCLUSIONS: The IM administration of 1% mepivacaine-diluted PGB induces significantly less immediate local pain as compared to PGB alone. The needle gauge did not have any effect on the pain. Based on these results, we suggest anesthetic-diluted IM PGB as the standard treatment for primary syphilis. TRIAL REGISTRATION: EudraCT 2014-003969-24 (Date of registration 18/09/2014).


Assuntos
Anestésicos Locais/uso terapêutico , Mepivacaína/uso terapêutico , Dor/tratamento farmacológico , Penicilina G Benzatina/uso terapêutico , Sífilis/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Adolescente , Adulto , Anestésicos Locais/administração & dosagem , Anestésicos Locais/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Infecções por HIV/microbiologia , Humanos , Injeções Intramusculares/instrumentação , Masculino , Mepivacaína/administração & dosagem , Mepivacaína/efeitos adversos , Agulhas , Penicilina G Benzatina/administração & dosagem , Penicilina G Benzatina/efeitos adversos
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