Safety of Low-Dose Oral Minoxidil in Patients With Hypertension and Arrhythmia: A Multicenter Study of 264 Patients.

BACKGROUND AND OBJECTIVE: Systemic adverse effects (AE) are a major concern of low-dose oral minoxidil (LDOM) treatment, especially in patients with arterial hypertension or arrhythmia. The objective of this study was to evaluate the safety of LDOM in patients with hypertension or arrhythmia. PATIENTS AND METHODS: Retrospective multicenter study of patients with hypertension or arrhythmia treated with LDOM for any type of alopecia. RESULTS: A total of 254 patients with hypertension [176 women (69.3%) and 78 men (30.7%)] with a mean age of 56.9 years (range 19-82) were included. From them, the dose of LDOM was titrated in 128 patients, allowing the analysis of 382 doses. Patients were receiving a mean of 1.45 (range 0-5) antihypertensive drugs. Systemic AE were detected in 26 cases (6.8%) and included lightheadedness (3.1%), fluid retention (2.6%), general malaise (0.8%), tachycardia (0.8%) and headache (0.5%), leading to LDOM discontinuation in 6 cases (1.5%). Prior treatment with doxazosin (P<0.001), or with three or more antihypertensive drugs (P=0.012) was associated with a higher risk of discontinuation of LDOM. CONCLUSIONS: LDOM treatment showed a favorable safety profile in patients with hypertension or arrhythmia, similar to general population.

Safety of Low-Dose Oral Minoxidil in Patients With Hypertension and Arrhythmia: A Multicenter Study of 264 Patients. / [Artíulo traducido] Seguridad de minoxidil oral a dosis bajas en pacientes con hipertensión o arritmias: estudio multicéntrico de 264 pacientes.

BACKGROUND AND OBJECTIVE: Systemic adverse effects (AE) are a major concern of low-dose oral minoxidil (LDOM) treatment, especially in patients with arterial hypertension or arrhythmia. The objective of this study was to evaluate the safety of LDOM in patients with hypertension or arrhythmia. PATIENTS AND METHODS: Retrospective multicenter study of patients with hypertension or arrhythmia treated with LDOM for any type of alopecia. RESULTS: A total of 254 patients with hypertension [176 women (69.3%) and 78 men (30.7%)] with a mean age of 56.9 years (range 19-82) were included. From them, the dose of LDOM was titrated in 128 patients, allowing the analysis of 382 doses. Patients were receiving a mean of 1.45 (range 0-5) antihypertensive drugs. Systemic AE were detected in 26 cases (6.8%) and included lightheadedness (3.1%), fluid retention (2.6%), general malaise (0.8%), tachycardia (0.8%) and headache (0.5%), leading to LDOM discontinuation in 6 cases (1.5%). Prior treatment with doxazosin (P<0.001), or with three or more antihypertensive drugs (P=0.012) was associated with a higher risk of discontinuation of LDOM. CONCLUSIONS: LDOM treatment showed a favorable safety profile in patients with hypertension or arrhythmia, similar to general population.

A 1.8-Mb-reduced Streptomyces clavuligerus genome: relevance for secondary metabolism and differentiation.

A large part (21%) of the wild-type Streptomyces clavuligerus genome is located in a 1.8-Mb megaplasmid that greatly influences secondary metabolites biosynthesis even if the secondary metabolites are chromosomally encoded. The megaplasmid copy number may change depending on the nutritional and environmental conditions. The S. clavuligerus oppA2::aph mutant described by Lorenzana et al. (2004) does not form aerial mycelium, spores, and clavulanic acid, but overproduces holomycin. Transcriptomic studies, polymerase chain reactions (PCR), qPCR, and RT-qPCR analysis showed that S. clavuligerus oppA2::aph has a drastically reduced number of copies (about 25,000-fold lower than the parental strain) of plasmids pSCL1 (10.5 kb), pSCL2 (149.4 kb), and the megaplasmid pSCL4 (1.8 Mb). To clarify the role of the linear plasmids and the function of OppA2 in S. clavuligerus oppA2::aph we constructed oppA2 mutants which contained: (1) a normal copy number of the linear plasmids, (2) completely lack of the linear plasmids, and (3) a parA-parB pSCL4 mutant that resulted in lack of pSCL4. In addition, a strain with a functional oppA2 gene was constructed lacking the megaplasmid pSCL4. The results confirmed that the oppA2 gene is essential for clavulanic acid production, independently of the presence or absence of linear plasmids, but oppA2 has little relevance on differentiation. We demonstrated that the lack of sporulation of S. clavuligerus oppA2::aph is due to the absence of linear plasmids (particularly pSCL4) and the holomycin overproduction is largely due to the lack of pSCL4 and is stimulated by the oppA2 mutation.

Expression of the endogenous and heterologous clavulanic acid cluster in Streptomyces flavogriseus: why a silent cluster is sleeping.

Clusters for clavulanic acid (CA) biosynthesis are present in the actinomycetes Streptomyces flavogriseus ATCC 33331 and Saccharomonospora viridis DSM 43017. These clusters, which are silent, contain blocks of conserved genes in the same order as those of the Streptomyces clavuligerus CA cluster but assembled in a different organization. S. flavogriseus was grown in nine different media, but clavulanic acid production was undetectable using bioassays or by high-performance liquid chromatography analyses. Reverse-transcriptase polymerase chain reaction (RT-PCR) of S. flavogriseus CA biosynthesis genes showed that the regulatory genes ccaR and claR and some biosynthetic genes were expressed whereas expression of cyp, orf12, orf13, and oppA2 was undetectable. The ccaR gene of S. clavuligerus was unable to switch on CA production in S. flavogriseus::[Pfur-ccaR C], but insertion of a cosmid carrying the S. clavuligerus CA cluster (not including the ccaR gene) conferred clavulanic acid production on S. flavogriseus::[SCos-CA] particularly in TBO and YEME media; these results suggests that some of the S. flavogriseus CA genes are inactive. The known heptameric sequences recognized by CcaR in S. clavuligerus are poorly or not conserved in S. flavogriseus. Quantitative RT-PCR analysis of the CA gene clusters of S. clavuligerus and S. flavogriseus showed that the average expression value of the expressed genes in the former strain was in the order of 1.68-fold higher than in the later. The absence of CA production by S. flavogriseus can be traced to the lack of expression of the essential genes cyp, orf12, orf13, orf14, and oppA2. Heterologous expression of S. clavuligerus CA gene cluster in S. flavogriseus::[SCos-CA] was 11- to 14-fold lower than in the parental strain, suggesting that the genetic background of the host strain is important for optimal production of CA in Streptomyces.

Theta/gamma Co-modulation Disruption After NMDAr Blockade by MK-801 Is Associated with Spatial Working Memory Deficits in Mice.

Abnormal N-methyl-D-aspartate receptor (NMDAr) function has been linked to oscillopathies, psychosis, and cognitive dysfunction in schizophrenia (SCZ). Here, we investigate the role of NMDAr hypofunction in pathological oscillations and behavior. We implanted mice with tetrodes in the dorsal/intermediate hippocampus and medial prefrontal cortex (mPFC), administered the NMDAr antagonist MK-801, and recorded oscillations during spontaneous exploration in an open field and in the y-maze spatial working memory test. Our results show that NMDAr blockade disrupted the correlation between oscillations and speed of movement, crucial for internal representations of distance. In the hippocampus, MK-801 increased gamma oscillations and disrupted theta/gamma coupling during spatial working memory. In the mPFC, MK-801 increased the power of theta and gamma, generated high-frequency oscillations (HFO 155-185 Hz), and disrupted theta/gamma coupling. Moreover, the performance of mice in the spatial working memory version of the y-maze was strongly correlated with CA1-PFC theta/gamma co-modulation. Thus, theta/gamma mediated by NMDAr function might explain several of SCZ's cognitive symptoms and might be crucial to explaining hippocampal-PFC interaction.

Characterization of DNA-binding sequences for CcaR in the cephamycin-clavulanic acid supercluster of Streptomyces clavuligerus.

RT-PCR analysis of the genes in the clavulanic acid cluster revealed three transcriptional polycistronic units that comprised the ceaS2-bls2-pah2-cas2, cyp-fd-orf12-orf13 and oppA2-orf16 genes, whereas oat2, car, oppA1, claR, orf14, gcaS and pbpA were expressed as monocistronic transcripts. Quantitative RT-PCR of Streptomyces clavuligerus ATCC 27064 and the mutant S. clavuligerus ccaR::aph showed that, in the mutant, there was a 1000- to 10,000-fold lower transcript level for the ceaS2 to cas2 polycistronic transcript that encoded CeaS2, the first enzyme of the clavulanic acid pathway that commits arginine to clavulanic acid biosynthesis. Smaller decreases in expression were observed in the ccaR mutant for other genes in the cluster. Two-dimensional electrophoresis and MALDI-TOF analysis confirmed the absence in the mutant strain of proteins CeaS2, Bls2, Pah2 and Car that are required for clavulanic acid biosynthesis, and CefF and IPNS that are required for cephamycin biosynthesis. Gel shift electrophoresis using recombinant r-CcaR protein showed that it bound to the ceaS2 and claR promoter regions in the clavulanic acid cluster, and to the lat, cefF, cefD-cmcI and ccaR promoter regions in the cephamycin C gene cluster. Footprinting experiments indicated that triple heptameric conserved sequences were protected by r-CcaR, and allowed identification of heptameric sequences as CcaR binding sites.

The impact of silent vascular brain burden in cognitive impairment in Parkinson's disease.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) detected by magnetic resonance imaging (MRI) of the brain are associated with dementia and cognitive impairment in the general population and in Alzheimer's disease. Their effect in cognitive decline and dementia associated with Parkinson's disease (PD) is still unclear. METHODS: We studied the relationship between WMHs and cognitive state in 111 patients with PD classified as cognitively normal (n = 39), with a mild cognitive impairment (MCI) (n = 46) or dementia (n = 26), in a cross-sectional and follow-up study. Cognitive state was evaluated with a comprehensive neuropsychological battery, and WMHs were identified in FLAIR and T2-weighted MRI. The burden of WMHs was rated using the Scheltens scale. RESULTS: No differences in WMHs were found between the three groups in the cross-sectional study. A negative correlation was observed between semantic fluency and the subscore for WMHs in the frontal lobe. Of the 36 non-demented patients re-evaluated after a mean follow-up of 30 months, three patients converted into MCI and 5 into dementia. Progression of periventricular WMHs was associated with an increased conversion to dementia. A marginal association between the increase in total WMHs burden and worsening in the Mini Mental State Examination was encountered. CONCLUSIONS: White matter hyperintensities do not influence the cognitive status of patients with PD. Frontal WMHs have a negative impact on semantic fluency. Brain vascular burden may have an effect on cognitive impairment in patients with PD as WMHs increase overtime might increase the risk of conversion to dementia. This finding needs further confirmation in larger prospective studies.

Safety of Low-Dose Oral Minoxidil in Patients With Hypertension and Arrhythmia: A Multicenter Study of 264 Patients / Seguridad de minoxidil oral a dosis bajas en pacientes con hipertensión o arritmias: estudio multicéntrico de 264 pacientes

Background and objective Systemic adverse effects (AE) are a major concern of low-dose oral minoxidil (LDOM) treatment, especially in patients with arterial hypertension or arrhythmia. The objective of this study was to evaluate the safety of LDOM in patients with hypertension or arrhythmia. Patients and methods Retrospective multicenter study of patients with hypertension or arrhythmia treated with LDOM for any type of alopecia. Results A total of 254 patients with hypertension [176 women (69.3%) and 78 men (30.7%)] with a mean age of 56.9 years (range 19–82) were included. From them, the dose of LDOM was titrated in 128 patients, allowing the analysis of 382 doses. Patients were receiving a mean of 1.45 (range 0–5) antihypertensive drugs. Systemic AE were detected in 26 cases (6.8%) and included lightheadedness (3.1%), fluid retention (2.6%), general malaise (0.8%), tachycardia (0.8%) and headache (0.5%), leading to LDOM discontinuation in 6 cases (1.5%). Prior treatment with doxazosin (P<0.001), or with three or more antihypertensive drugs (P=0.012) was associated with a higher risk of discontinuation of LDOM. Conclusions LDOM treatment showed a favorable safety profile in patients with hypertension or arrhythmia, similar to general population (AU)

Antecedentes y objetivo Los efectos adversos sistémicos son una de las principales limitaciones del uso de minoxidil oral a dosis bajas (MODB), especialmente en pacientes con hipertensión arterial o arritmias. El objetivo de este estudio fue evaluar la seguridad de MODB en estos pacientes. Material y método Estudio retrospectivo multicéntrico con pacientes con antecedentes de hipertensión o arritmias tratados con MODB para cualquier tipo de alopecia. Resultados Se incluyó un total de 254 pacientes con hipertensión (176 mujeres [69,3%] y 78 hombres [30,7%]) con una edad media de 56,9 años (rango 19 – 82). La dosis de MODB se incrementó gradualmente en 128 pacientes, obteniendo un total de 382 dosis analizadas. Los sujetos estaban tomando de media 1,45 fármacos antihipertensivos (rango 0 – 5). Se detectaron EA sistémicos en 26 casos (6,8%), incluyendo mareo (3,1%), retención de líquidos (2,6%), malestar general (0,8%), taquicardia (0,8%) y cefalea (0,5%), requiriendo suspensión del MODB en seis casos (1,5%). Los pacientes en tratamiento con doxazosina (p < 0,001) o con tres o más antihipertensivos (p = 0,012) presentaron mayor riesgo de suspensión de MODB. Conclusión El tratamiento con MODB mostró un perfil de seguridad favorable en pacientes con hipertensión o arritmias, similar al de la población general (AU)

[Artíulo traducido] Seguridad de minoxidil oral a dosis bajas en pacientes con hipertensión o arritmias: estudio multicéntrico de 264 pacientes / Safety of Low-Dose Oral Minoxidil in Patients With Hypertension and Arrhythmia: A Multicenter Study of 264 Patients

Antecedentes y objetivo Los efectos adversos sistémicos son una de las principales limitaciones del uso de minoxidil oral a dosis bajas (MODB), especialmente en pacientes con hipertensión arterial o arritmias. El objetivo de este estudio fue evaluar la seguridad de MODB en estos pacientes. Material y método Estudio retrospectivo multicéntrico con pacientes con antecedentes de hipertensión o arritmias tratados con MODB para cualquier tipo de alopecia. Resultados Se incluyó un total de 254 pacientes con hipertensión (176 mujeres [69,3%] y 78 hombres [30,7%]) con una edad media de 56,9 años (rango 19 – 82). La dosis de MODB se incrementó gradualmente en 128 pacientes, obteniendo un total de 382 dosis analizadas. Los sujetos estaban tomando de media 1,45 fármacos antihipertensivos (rango 0 – 5). Se detectaron EA sistémicos en 26 casos (6,8%), incluyendo mareo (3,1%), retención de líquidos (2,6%), malestar general (0,8%), taquicardia (0,8%) y cefalea (0,5%), requiriendo suspensión del MODB en seis casos (1,5%). Los pacientes en tratamiento con doxazosina (p < 0,001) o con tres o más antihipertensivos (p = 0,012) presentaron mayor riesgo de suspensión de MODB. Conclusión El tratamiento con MODB mostró un perfil de seguridad favorable en pacientes con hipertensión o arritmias, similar al de la población general (AU)

Background and objective Systemic adverse effects (AE) are a major concern of low-dose oral minoxidil (LDOM) treatment, especially in patients with arterial hypertension or arrhythmia. The objective of this study was to evaluate the safety of LDOM in patients with hypertension or arrhythmia. Patients and methods Retrospective multicenter study of patients with hypertension or arrhythmia treated with LDOM for any type of alopecia. Results A total of 254 patients with hypertension [176 women (69.3%) and 78 men (30.7%)] with a mean age of 56.9 years (range 19–82) were included. From them, the dose of LDOM was titrated in 128 patients, allowing the analysis of 382 doses. Patients were receiving a mean of 1.45 (range 0–5) antihypertensive drugs. Systemic AE were detected in 26 cases (6.8%) and included lightheadedness (3.1%), fluid retention (2.6%), general malaise (0.8%), tachycardia (0.8%) and headache (0.5%), leading to LDOM discontinuation in 6 cases (1.5%). Prior treatment with doxazosin (P<0.001), or with three or more antihypertensive drugs (P=0.012) was associated with a higher risk of discontinuation of LDOM. Conclusions LDOM treatment showed a favorable safety profile in patients with hypertension or arrhythmia, similar to general population (AU)

Randomised clinical trial: a leucine-metformin-sildenafil combination (NS-0200) vs placebo in patients with non-alcoholic fatty liver disease.

BACKGROUND: Sirtuin 1 (Sirt1) is suppressed in non-alcoholic fatty liver disease (NAFLD), while its' stimulation or overexpression results in reduced disease severity in pre-clinical NAFLD models. Leucine allosterically activates Sirt1 and synergise with other Sirt/AMPK/NO pathway activators. We developed a triple combination of leucine, metformin and sildenafil (NS-0200), which was effective in a mouse model of non-alcoholic steatohepatitis (NASH). AIM: To report the results from a Phase 2, randomised clinical trial of of NS-0200 in 91 subjects with NAFLD (liver fat ≥15% by magnetic resonance imaging-proton-density fat fraction (MRI-PDFF)). METHODS: Subjects were randomised to placebo, low-dose (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil) or high-dose NS-0200 (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) b.d. for 16 weeks; change in hepatic fat was assessed via MRI-PDFF, and lipid metabolism was assessed via changes in the lipidomic signature. Seventy subjects completed the trial and met a priori compliance criteria. Analyses were conducted on the full cohort and on those with alanine aminotransferase (ALT) values above median (50 U/L; n = 35). RESULTS: In the full cohort, active treatments did not separate from placebo. High dose NS-0200 reduced hepatic fat by 15.7% (relative change from baseline) in the high ALT group (P < 0.005) while low dose NS-0200 and placebo did not significantly change hepatic fat. Lipidomic analysis showed dose-responsive treatment effects in both overall and high ALT cohorts, with significant decreases in metabolically active lipids and up-regulation of fatty acid oxidation. CONCLUSION: These data support further evaluation of high-dose NS-0200 for treating NASH, especially in those with elevated ALT (NCT 02546609).

Use of Clarus Video System® in expected difficult airway in a patient with Rett syndrome. / Uso del Clarus Video System® en una vía aérea difícil en paciente con síndrome de Rett.

Difficult airway management remains one of the key points in our specialty, as the difficulty or impossibility of tracheal intubation is the main cause of morbidity/mortality attributable to anaesthesia. Rett syndrome is a severe and incapacitating neurological disease. We present the case of a 21-year-old girl affected by this syndrome, with significant psychomotor retardation and difficult airway predictors, who was scheduled to have a laparoscopic cholecystectomy under general anaesthesia. We decided on one attempt of Clarus Video System® fiberoptic intubation as primary intervention. Intubation was successfully performed with the help of this optical stylet. The use of optical stylets is gaining prominence and finding a place in the latest algorithms of difficult airway management. We highlight the growing role these devices play in managing difficult airway, therefore we review the current situation of videolaryngoscopes in the management of the predicted difficult airway.

SEOM clinical guideline in ovarian cancer (2020)

Despite remarkable advances in the knowledge of molecular biology and treatment, ovarian cancer remains the leading cause of death from gynecologic cancer. In the last decade, there have been important advances both in systemic and surgical treatment. However, there is no doubt that the incorporation of PARP inhibitors as maintenance after the response to platinum-based chemotherapy, first in recurrent disease and recently also in first line, will change the natural history of the disease. The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of ovarian cancer, and to provide evidence-based recommendations for clinical practice (AU)

Genotyping of infectious bursal disease virus strains by restriction fragment length polymorphism analysis of the VP1, VP2, and VP3 genes.

SUMMARY. This study aimed to genotype infectious bursal disease virus (IBDV) isolates from the Minas Gerais state poultry industry. RNA was extracted from bursae obtained from field cases without passage or commercial vaccines. Genetic subtyping of IBDV isolates and vaccine strains was carried out by the reverse transcriptase-polymerase chain reaction (RT-PCR) and restriction fragment length polymorphism (RFLP) analysis. A 588-bp fragment in the VP1 gene, an 847-bp fragment in the VP2 gene, and a 320-bp fragment in the VP3 gene were amplified by PCR and digested with restriction enzymes PstI and ScaI (VP1); BamHI, BstEII, and PstI (VP2); and NcoI, ScaI, and XbaI (VP3). Our work shows that complementing the clinical history of the outbreaks with RT-PCR followed by RFLP analysis using PstI for VP1, BamHI for VP2, and XbaI for VP3 allowed an accurate classification of a causative agent as a very virulent IBDV.

Influence of tree canopy on N2 fixation by pasture legumes and soil rhizobial abundance in Mediterranean oak woodlands.

Symbiotic N2 fixation is of primordial significance in sustainable agro-forestry management as it allows reducing the use of mineral N in the production of mixed stands and by protecting the soils from degradation. Thereby, on a 2-year basis, N2 fixation was evaluated in four oak woodlands under Mediterranean conditions using a split-plot design and three replicates. (15)N technique was used for determination of N2 fixation rate. Variations in environmental conditions (temperature, rainfall, radiation) by the cork tree canopy as well as the age of stands and pasture management can cause great differences in vegetation growth, legume N2 fixation, and soil rhizobial abundance. In the present study, non-legumes dominated the swards, in particular beneath the tree canopy, and legumes represented only 42% of total herbage. A 2-fold biomass reduction was observed in the oldest sown pasture in relation to the medium-age sward (6 t DW ha(-1)yr(-1)). Overall, competition of pasture growth for light was negligible, but soil rhizobial abundance and symbiotic N2 fixation capacity were highly favored by this environmental factor in the spring and outside the influence of tree canopy. Nitrogen derived from the atmosphere was moderate to high (54-72%) in unsown and sown swards. Inputs of fixed N2 increased from winter to spring due to more favorable climatic conditions (temperature and light intensity) for both rhizobia and vegetation growths. Assuming a constant fixation rate at each seasonal period, N2 fixation capacity increased from about 0.10 kg N ha(-1) per day in the autumn-winter period to 0.15 kg N ha(-1) per day in spring. Belowground plant material contributed to 11% of accumulated N in pasture legumes and was not affected by canopy. Size of soil fixing bacteria contributed little to explain pasture legumes N.