Perspectives of people with HIV and HIV clinicians on characteristics of antiretroviral treatment and HIV-related symptoms.

OBJECTIVES: We aimed to assess HIV symptoms from the perspective of both patients and HIV specialists and the impact of discontinuing antiretroviral treatment (ART) on symptomology. We gathered opinions from HIV specialists and people living with HIV about ideal ART parameters and treatment satisfaction. METHODS: Ex post-facto cross-sectional surveys were administered to 502 people living with HIV and 101 HIV clinicians in Spain (18 sites). RESULTS: The median age of participants with HIV was 43.2 years, 74.5% were male, and 91.6% had an undetectable viral load. The mean time since initiation of ART was 10.2 years. Between 54% and 67% of people living with HIV reported experiencing nervousness or anxiety, sadness, fatigue, sleep problems, or muscle/joint pain during the preceding 4 weeks. However, only 22%-27% of specialists acknowledged the presence of these symptoms. The most bothersome symptoms were related to mental health or the central nervous system. There were significant differences between the burden of symptoms reported by people living with HIV and those acknowledged by specialists. The symptoms that more frequently caused ART discontinuation were depression, dizziness, and sleep problems. Both people living with HIV and specialists prioritized ART efficacy and low toxicity, but their importance ratings differed for 5 of the 11 ART characteristics assessed. People living with HIV rated their satisfaction with ART at a mean (± standard deviation) of 8.9 ± 1.5 out of 10, whereas HIV specialists rated it lower, at 8.3 ± 0.7 (p < 0.001). CONCLUSIONS: Despite advances in HIV care and treatment, a large proportion of patients still experience symptoms. HIV specialists may not be fully aware of these. People living with HIV and HIV specialists are, overall, satisfied with ART. However, the importance they place on different ART characteristics may vary.

Obesity status and obesity-associated gut dysbiosis effects on hypothalamic structural covariance.

BACKGROUND: Functional connectivity alterations in the lateral and medial hypothalamic networks have been associated with the development and maintenance of obesity, but the possible impact on the structural properties of these networks remains largely unexplored. Also, obesity-related gut dysbiosis may delineate specific hypothalamic alterations within obese conditions. We aim to assess the effects of obesity, and obesity and gut-dysbiosis on the structural covariance differences in hypothalamic networks, executive functioning, and depressive symptoms. METHODS: Medial (MH) and lateral (LH) hypothalamic structural covariance alterations were identified in 57 subjects with obesity compared to 47 subjects without obesity. Gut dysbiosis in the subjects with obesity was defined by the presence of high (n = 28) and low (n = 29) values in a BMI-associated microbial signature, and posthoc comparisons between these groups were used as a proxy to explore the role of obesity-related gut dysbiosis on the hypothalamic measurements, executive function, and depressive symptoms. RESULTS: Structural covariance alterations between the MH and the striatum, lateral prefrontal, cingulate, insula, and temporal cortices are congruent with previously functional connectivity disruptions in obesity conditions. MH structural covariance decreases encompassed postcentral parietal cortices in the subjects with obesity and gut-dysbiosis, but increases with subcortical nuclei involved in the coding food-related hedonic information in the subjects with obesity without gut-dysbiosis. Alterations for the structural covariance of the LH in the subjects with obesity and gut-dysbiosis encompassed increases with frontolimbic networks, but decreases with the lateral orbitofrontal cortex in the subjects with obesity without gut-dysbiosis. Subjects with obesity and gut dysbiosis showed higher executive dysfunction and depressive symptoms. CONCLUSIONS: Obesity-related gut dysbiosis is linked to specific structural covariance alterations in hypothalamic networks relevant to the integration of somatic-visceral information, and emotion regulation.

Polypharmacy, functional outcome and treatment effect of intravenous alteplase for acute ischaemic stroke.

BACKGROUND AND PURPOSE: Polypharmacy is an important challenge in clinical practice. Our aim was to determine the effect of polypharmacy on functional outcome and treatment effect of alteplase in acute ischaemic stroke. METHODS: This was a post hoc analysis of the randomized, placebo-controlled WAKE-UP trial of magnetic resonance imaging guided intravenous alteplase in unknown onset stroke. Polypharmacy was defined as an intake of five or more medications at baseline. Comorbidities were assessed by the Charlson Comorbidity Index (CCI). The primary efficacy variable was favourable outcome defined by a score of 0-1 on the modified Rankin Scale at 90 days. Logistic regression analysis was used to test for an association of polypharmacy with functional outcome, and for interaction of polypharmacy and the effect of thrombolysis. RESULTS: Polypharmacy was present in 133/503 (26%) patients. Patients with polypharmacy were older (mean age 70 vs. 64 years; p < 0.0001) and had a higher score on the National Institutes of Health Stroke Scale at baseline (median 7 vs. 5; p = 0.0007). A comorbidity load defined by a CCI score ≥ 2 was more frequent in patients with polypharmacy (48% vs. 8%; p < 0.001). Polypharmacy was associated with lower odds of favourable outcome (adjusted odds ratio 0.50, 95% confidence interval 0.30-0.85; p = 0.0099), whilst the CCI score was not. Treatment with alteplase was associated with higher odds of favourable outcome in both groups, with no heterogeneity of treatment effect (test for interaction of treatment and polypharmacy, p = 0.29). CONCLUSION: In stroke patients, polypharmacy is associated with worse functional outcome after intravenous thrombolysis independent of comorbidities. However, polypharmacy does not interact with the beneficial effect of alteplase.

Prognosis of status epilepticus in elderly patients.

PURPOSE: To evaluate the clinical features and prognosis of status epilepticus (SE) in patients above 70 years old. METHODS: Retrospective analysis of all patients ≥70 years old with SE registered prospectively during 4 years. Follow-up after discharge was performed. RESULTS: Ninety patients were evaluated. Acute symptomatic etiology was the most prevalent. The mean number of antiepileptic drugs (AEDs) used was 2.7 ± 1.2, and 21% of the patients required sedation. A poor outcome was considered when death (31.1%) or developing of new neurological impairment at discharge (32.2%) occurred. After multivariate analysis, four variables predicted a poor outcome: acute symptomatic etiology (OR: 6.320; 95% CI: 1.976-20.217; P = .002), focal motor SE type (OR: 9.089; 95% CI: 2.482-33.283; P = .001), level of consciousness (OR: 4.596; 95% CI: 1.903-11.098; P = .001), and SE duration >12 hours (OR: 3.763; 95% CI: 1.130-12.530; P = .031). Independent predictive factors of mortality were SE duration >12 hours (OR: 4.306; 95% CI: 1.044-17.757; P = .043), modified Status Epilepticus Severity Score (mSTESS) (OR: 2.216; 95% CI: 1.313-3.740; P = .003), and development of complications (OR: 3.334; 95% CI: 1.004-11.070, P = .049). Considering long-term mortality, age (HR 1.036; 95% CI 1.001-1.071; P = .044), a potentially fatal underlying cause (HR 2.609; 95% CI 1.497- 4.548; P = .001), and mSTESS score >4 (HR 1.485; 95% CI 1.158-1.903; P = .002) remained as predictive factors. There was no association between sedation and the number of AEDs used with outcome at discharge or long-term mortality (P > .05). CONCLUSIONS: SE above 70 years old has a high morbimortality. Prognosis is not related to treatment aggressiveness.

Outcome of cancer-related seizures in patients treated with lacosamide.

OBJECTIVES: Lacosamide is an antiepileptic drug (AED), which has proven to be effective to control seizures, including acute conditions such as status epilepticus. The aim of this study is to describe the clinical experience with lacosamide in neuro-oncological patients. MATERIALS AND METHODS: Multicenter retrospective study in patients with cancer-related seizures, who received lacosamide as an add-on therapy. RESULTS: Forty-eight patients with benign and malignant tumors, including primary brain tumors, lymphomas, systemic cancer with central nervous system involvement, or paraneoplastic encephalitis, were included. Lacosamide was effective in the control of chronic seizures in patients with either benign or malignant tumors. The success rate was greater in malignant tumors, and drug-resistant epilepsies were more likely associated with benign tumors. Adverse events occurred in nearly 70% of patients, particularly in acute conditions and associated with the concomitant use of radio-/chemotherapy. Lacosamide-related adverse events were more likely somnolence and dizziness, which usually resolved after dose adjustment. After starting lacosamide, nearly half of the patients discontinued one of the baseline AEDs and decreased or discontinued dexamethasone. Fifteen patients with status epilepticus were treated with intravenous lacosamide, and 73% of them had their condition resolved without serious drug-related adverse events. CONCLUSION: Lacosamide is an AED to consider in cases of cancer-related seizures. Lacosamide pharmacodynamics and pharmacokinetics allow the achievement of responder rates over 50% with no serious adverse effects, amelioration of side effects from other AEDs or radio-/chemotherapy, and no significant drug interactions. Furthermore, the intravenous formulation shows clear benefits in acute conditions such as status epilepticus.

Individualized lung recruitment maneuver guided by pulse-oximetry in anesthetized patients undergoing laparoscopy: a feasibility study.

BACKGROUND: We conducted this study to test whether pulse-oximetry hemoglobin saturation (SpO2 ) can personalize the implementation of an open-lung approach during laparoscopy. Thirty patients with SpO2  ≥ 97% on room-air before anesthesia were studied. After anesthesia and capnoperitoneum the FIO2 was reduced to 0.21. Those patients whose SpO2 decreased below 97% - an indication of shunt related to atelectasis - completed the following phases: (1) First recruitment maneuver (RM), until reaching lung's opening pressure, defined as the inspiratory pressure level yielding a SpO2 ≥ 97%; (2) decremental positive end-expiratory (PEEP) titration trial until reaching lung's closing pressure defined as the PEEP level yielding a SpO2  < 97%; (3) second RM and, (4) ongoing ventilation with PEEP adjusted above the detected closing pressure. RESULTS: When breathing air, in 24 of 30 patients SpO2 was < 97%, PaO2 /FIO2  Ë‚ 53.3 kPa and negative end-expiratory transpulmonary pressure (PTP-EE ). The mean (SD) opening pressures were found at 40 (5) and 33 (4) cmH2 O during the first and second RM, respectively (P < 0.001; 95% CI: 3.2-7.7). The closing pressure was found at 11 (5) cmH2 O. This SpO2 -guided approach increased PTP-EE (from -6.4 to 1.2 cmH2 O, P < 0.001) and PaO2 /FIO2 (from 30.3 to 58.1 kPa, P < 0.001) while decreased driving pressure (from 18 to 10 cmH2 O, P < 0.001). SpO2 discriminated the lung's opening and closing pressures with accuracy taking the reference parameter PTP-EE (area under the receiver-operating-curve of 0.89, 95% CI: 0.80-0.99). CONCLUSION: The non-invasive SpO2 monitoring can help to individualize an open-lung approach, including all involved steps, from the identification of those patients who can benefit from recruitment, the identification of opening and closing pressures to the subsequent monitoring of an open-lung condition.

Variable endothelial cell function restoration after initiation of two antiretroviral regimens in HIV-infected individuals.

Background: The effect of ART on endothelial cell function is incompletely characterized. Methods: We performed a 24 week prospective, case-control and comparative pilot study of ART-naive HIV-infected patients who started a darunavir- or rilpivirine-based regimen, matched with non-HIV-infected volunteers, to compare changes at week 24 from baseline in levels of circulating endothelial cells (CECs), endothelial progenitor cells (EPCs) and circulating angiogenic cells, as well as changes in immune-activation markers. Results: The study population comprised 24 HIV-infected patients and 24 non-infected volunteers. Both HIV groups completely suppressed viraemia. HIV-infected patients had higher levels of activation markers than the control group in CD8 T cells at baseline; these decreased after 24 weeks of treatment, but without reaching the levels of the control group. No statistical differences in immune activation were seen between the darunavir and rilpivirine groups. Levels of CECs were higher and levels of EPCs and circulating angiogenic cells were lower in HIV-infected patients than in the control group, although these parameters were similar between the darunavir group and the control group, but not the rilpivirine group, at week 24. An unfavourable association was observed between rilpivirine, age and increased number of CECs. Conclusions: Restoration of circulating levels of EPCs and CECs in darunavir-treated patients was greater than in those treated with rilpivirine, suggesting ongoing endothelial repair mechanisms.

Neuroinflammation in obesity: circulating lipopolysaccharide-binding protein associates with brain structure and cognitive performance.

BACKGROUND/OBJECTIVES: Growing evidence implicates neuroinflammation in the pathogenesis of diet-induced obesity and cognitive dysfunction in rodent models. Obesity is associated with reduced white matter integrity and cognitive decline. Circulating lipopolysaccharide binding protein (LBP) concentration is known to be increased in patients with obesity. Here, we aimed to evaluate whether circulating LBP is associated longitudinally with white matter structure and cognitive performance according to obesity status. SUBJECTS/METHODS: This longitudinal study analyzed circulating LBP (ELISA), DTI-metrics (axial diffusivity (L1), fractional anisotropy (FA) and radial diffusivity (RD)) in specific regions of the white matter of 24 consecutive middle-aged obese subjects (13 women) and 20 healthy volunteers (10 women) at baseline and two years later. Digit Span Test (DST) was used as a measure of working memory/short-term verbal memory. RESULTS: Circulating LBP concentration was associated with FA and L1 values of several white matter regions both at baseline and follow-up. The associations remained significant after controlling for age, BMI, fat mass and plasma high sensitivity C-reactive protein. Importantly, the increase in LBP over time impacted negatively on FA and L1 values and on DST performance. CONCLUSIONS: Circulating LBP associates with brain white matter integrity and working memory/short-term verbal memory in both obese and non-obese subjects.

Significant improvement in triglyceride levels after switching from ritonavir to cobicistat in suppressed HIV-1-infected subjects with dyslipidaemia.

OBJECTIVES: Cobicistat seems to have a low rate of adverse events compared with ritonavir. METHODS: This restrospective observational study to evaluated changes in lipid parameters and the percentage of subjects with dyslipidemia in virologically suppressed HIV-infected patients who were receiving a regimen containing darunavir/ritonavir and were then switched from ritonavir to cobicistat, carried out from December 2015 to May 2016, included 299 HIV-1-infected patients who were on stable antiretroviral treatment including darunavir/ritonavir (monotherapy, bitherapy or triple therapy for at least 6 months) and were then switched from ritonavir to cobicistat. Lipid parameters, as well as plasma HIV-1 RNA and CD4 cell counts, were recorded at baseline just before the switch, and 24 weeks after the switch. Patients were stratified according to the presence of hypercholesterolaemia [baseline total cholesterol > 200 mg/dL and/or low-density lipoprotein (LDL) cholesterol > 130 mg/dL] or hypertriglyceridaemia (baseline triglyceride levels > 200 mg/dL). RESULTS: Two hundred and ninety-nine patients were enrolled in the study. Fifty-two per cent of the total study population showed dyslipidaemia at baseline. All patients maintained HIV-1 RNA ≤ 50 HIV-1 RNA copies/mL at week 24. No statistically significant changes were seen in CD4 T-cell count from baseline to week 24 [654 (298) to 643 (313) cells/µL; P = 0.173]. When patients were stratified according to the presence of hypercholesterolaemia at baseline (n = 124), significant changes were observed in total cholesterol (P < 0.001), LDL cholesterol (P = 0.047), high-density lipoprotein (HDL) cholesterol (P = 0.002) and triglyceride levels (P = 0.025), and when they were stratified according to the presence of hypertriglyceridaemia at baseline (n = 64), changes from baseline to week 24 in triglyceride level were statistically significant [median (interquartile range) 352 (223, 389) mg/dL at baseline and 229 (131, 279) mg/dL at week 24; P < 0.001]. CONCLUSIONS: Cobicistat as a booster of darunavir in HIV-infected subjects had a beneficial effect on the lipid profile in patients with hypercholesterolaemia or hypertrigliceridaemia at baseline.

Controlling the generation of bilayer and multilayer vesicles in block copolymer/epoxy blends by a slow photopolymerization process.

Vesicles are a highly attractive morphology to achieve in micellar dispersions of block copolymers (BCP) in epoxy thermosets due to the fact that small amounts can affect a large volume fraction of the matrix, a fact that is important for toughening purposes. However, generating vesicles in epoxy matrices requires operating in a narrow range of formulations and processing conditions. In this report, we show that block-copolymer vesicles dispersed in an epoxy matrix could be obtained through a sphere-to-cylinder-to-vesicle micellar transition induced by visible-light photopolymerization at room temperature. A 10 wt% colloidal solution of poly(ethylene-co-butene)-block-poly(ethylene oxide) (PEB-b-PEO) block copolymer (BCP) in an epoxy monomer (DGEBA) self-assembled into spherical micelles as shown by small-angle X-ray scattering (SAXS). During a slow photopolymerization of the epoxy monomer carried out at room temperature, a sphere-to-cylinder-to-vesicle transition took place as revealed by in situ SAXS and TEM images. This was driven by the tendency of the system to reduce the local interfacial curvature as a response to a decrease in the miscibility of PEO blocks in the polymerizing epoxy matrix. When the BCP concentration was increased from 10 to 20 and 40 wt%, the final structure evolved from bilayer vesicles to multilayer vesicles and to lamellae, respectively. In particular, for 20 wt% PEB-b-PEO, transient structures such as partially fused multilayered vesicles were observed by TEM, giving insight into the growth mechanism of multilayer vesicles. On the contrary, when a relatively fast thermal polymerization was performed at 80 °C, the final morphology consisted of kinetically trapped spherical and cylindrical micelles. Hopefully, this study will lead to new protocols for the preparation of vesicles dispersed in epoxy matrices in a controlled way.

Myoclonic epilepsy in Down syndrome and Alzheimer disease. / Epilepsia mioclónica en el síndrome de Down y en la enfermedad de Alzheimer.

INTRODUCTION: Patients with Down syndrome (DS) who exhibit Alzheimer disease (AD) are associated with age. Both diseases with a common neuropathological basis have been associated with late-onset myoclonic epilepsy (LOMEDS). This entity presents electroencephalogram features as generalized polyspike-wave discharges. METHOD: We present a series of 11 patients with the diagnosis of DS or AD who developed myoclonic seizures or generalized tonic-clonic seizures. In all cases, clinical and neuroimaging studies and polygraph EEG monitoring was performed. RESULTS: In all cases, cognitive impairment progressed quickly after the onset of epilepsy causing an increase in the degree of dependence. The most common finding in the EEG was a slowing of brain activity with theta and delta rhythms, plus intercritical generalized polyspike-waves were objectified in eight patients. In neuroimaging studies was found cerebral cortical atrophy. The most effective drug in this series was the levetiracetam. CONCLUSIONS: The association of generalized epilepsy with elderly DS represents an epiphenomenon in evolution which is associated with a progressive deterioration of cognitive and motor functions. This epilepsy has some electroclinical characteristics and behaves as progressive myoclonic epilepsy, which is probably related to the structural changes that characterize the evolutionary similarity of DS with AD. Recognition of this syndrome is important, since it has prognostic implications and requires proper treatment.

Reduced circulating levels of sTWEAK are associated with NAFLD and may affect hepatocyte triglyceride accumulation.

CONTEXT: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is strongly associated with obesity, dyslipidaemia and altered glucose regulation. Previous data demonstrated that low circulating levels of tumour necrosis factor weak inducer of apoptosis (sTWEAK) were associated with obesity, diabetes and insulin resistance, all traits associated with an increased risk of NALFD. Circulating sTWEAK levels are expected to be reduced in the presence of NAFLD. OBJECTIVE: We aimed to explore the relationship between NAFLD and circulating sTWEAK levels in obese patients, and to evaluate the effect of sTWEAK on hepatocyte triglyceride accumulation.Design setting and patients:This is an observational case-control study performed in n=112 severely obese patients evaluated for NAFLD by abdominal ultrasound and n=32 non-obese patients without steatosis. Serum sTWEAK concentrations were measured by ELISA. Multivariable analyses were performed to determine the independent predictors of NAFLD. We analysed TWEAK and Fn14 protein expression in liver biopsies by western blotting and immunohistochemistry. An immortalized primary human hepatocyte cell line (HHL) was used to evaluate the effect of sTWEAK on triglyceride accumulation. RESULTS: We observed a reduction in serum circulating sTWEAK concentrations with the presence of liver steatosis. On multivariable analysis, lower sTWEAK concentrations were independently associated with the presence of NAFLD (odds ratio (OR)=0.023; 95% confidence interval: 0.001-0.579; P<0.022). In human hepatocytes, sTWEAK administration reduced fat accumulation as demonstrated by the reduction in palmitic acid-induced accumulation of triglyceride and the decreased expression of cluster of differentiation 36 (CD36) and perilipin 1 and 2 (PLIN1 and PLIN2) genes. CONCLUSIONS: Decreased sTWEAK concentrations are independently associated with the presence of NAFLD. This is concordant with the observation that TWEAK reduces lipid accumulation in human liver cells.

A new clinical score for the prognosis of status epilepticus in adults.

BACKGROUND AND PURPOSE: The severity of status epilepticus (SE) has an important impact in clinical outcomes. The Status Epilepticus Severity Score (STESS) is a score for predicting mortality in SE at admission. The baseline modified Rankin Scale (mRS) might be a prognostic factor for assessing the short-tem outcomes of SE. Therefore, our aim was to evaluate the effectiveness of mRS and whether its addition to the STESS improves the prediction of mortality. METHODS: Consecutive patients with SE and aged >16 years were recruited during 3 years. Receiver operating characteristic curves and a logistic regression model were developed to estimate the scores of the new score, designated as modified STESS (mSTESS), and it was subsequently compared with the STESS. RESULTS: In all, 136 patients were included. Mean age was 62.01 ± 17.62 (19-95) years, and 54% were male. The capacity of the STESS to predict mortality was 74.3% (95% confidence interval 63.8%-81.8%), whilst the capacity of the mRS to predict mortality was 65.2% (95% confidence interval 54.2%-76.2%). The logistic regression model and receiver operating characteristic curves enabled the classification of mRS as follows: 0, mRS = 0; 1, mRS = 1-3; and 2, mRS > 3. These values, when added to the other items of the STESS, resulted in the mSTESS with scores between 0 and 8 points. The capacity of the mSTESS to predict mortality was 80.1%. An mSTESS > 4 established an overall accuracy of 81.8% for predicting mortality, which was considerably higher than the overall accuracy of STESS ≥ 3 (59.6%). CONCLUSIONS: The baseline mRS was associated with high mortality risk. It is proposed to use mSTESS to improve the prediction of mortality risk in SE.

A master dynamic flow diagram for the shear thickening transition in micellar solutions.

The shear thickening behavior of dilute micellar solutions of hexadecyltrimethylammonium-type surfactants with different counterions (tosylate, 3- and 4-fluorobenzoate, vinylbenzoate and salicylate) and of n-alkyltetradecylammonium bromide (CnTAB), with n = 14, 16 and 18, is examined here. These solutions undergo a shear thickening transition due to the formation of shear-induced structures (SISs) in the shear range studied. Here we report a relationship between the shear thickening intensity and the differences in the hydrophobicity of counterions according to the Hofmeister-like anion series, which leads to a master flow diagram. This master flow diagram is produced by plotting a normalized shear thickening intensity (Iη - 1)/(Imax - 1) versus CD/CD,max, where Iη is the shear-thickening intensity, defined as the largest viscosity obtained in the shear-thickening transition (STT) at a given surfactant concentration CD divided by the Newtonian viscosity η0, and Imax is the largest intensity value obtained in the STT at a surfactant concentration CD,max. The master flow diagram is built using several cetyltrimethylammonium-type surfactants with different counterions, according to a Hofmeister-like series, and by n-alkyltetradecylammonium bromide surfactants with different alkyl chain lengths.

Comparison of two different strategies of treatment with zoledronate in HIV-infected patients with low bone mineral density: single dose versus two doses in 2 years.

OBJECTIVES: Given the need for easily managed treatment of osteoporosis in HIV-infected patients, we evaluated the efficacy and tolerability of two doses of zoledronate, by comparing three groups of patients: those with annual administration, those with biennial administration (one dose in 2 years) and a control group with no administration of zoledronate. METHODS: We randomized (2:1) 31 patients on antiretroviral therapy with low bone mineral density (BMD) to zoledronate (5 mg administered intravenously; 21 patients) plus diet counselling and to a control group (diet counselling; 10 patients). At week 48, patients treated with zoledronate were randomized again to receive a second dose (two-dose group; n = 12) or to continue with diet counselling only (single-dose group; n = 9). Changes in lumbar spine and hip BMD and bone turnover markers were compared. RESULTS: The median percentage change from baseline to week 96 in L1-L4 BMD was -1.74% [interquartile range (IQR) -2.56, 3.60%], 7.90% (IQR 4.20, 16.57%) and 5.22% (IQR 2.02, 7.28%) in the control, two-dose and single-dose groups, respectively (P < 0.01, control vs. two doses; P = 0.02, control vs. single dose; P = 0.18, two doses vs. single dose). Hip BMD changed by a median of 2.12% (IQR -0.12, 3.08%), 5.16% (IQR 3.06, 6.74%) and 4.47% (IQR 1, 5.58%), respectively (P = 0.04, control vs. two doses; P = 0.34, two doses vs. single dose). No differences between the two-dose and single-dose groups were detected in bone markers at week 96. CONCLUSIONS: The benefits for BMD of a single dose of zoledronate in 2 years may be comparable to those obtained with two doses of the drug after 96 weeks, although this study is insufficiently powered to exclude a real difference. Future studies should explore whether biennial administration of zoledronate is a useful alternative in the treatment of osteoporosis in HIV-infected patients.

Hypoxanthine deregulates genes involved in early neuronal development. Implications in Lesch-Nyhan disease pathogenesis.

Neurological manifestations in Lesch-Nyhan disease (LND) are attributed to the effect of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency on the nervous system development. HPRT deficiency causes the excretion of increased amounts of hypoxanthine into the extracellular medium and we hypothesized that HPRT deficiency related to hypoxanthine excess may then lead, directly or indirectly, to transcriptional aberrations in a variety of genes essential for the function and development of striatal progenitor cells. We have examined the effect of hypoxanthine excess on the differentiation of neurons in the well-established human NTERA-2 cl.D1 (NT2/D1) embryonic carcinoma neurogenesis model. NT2/D1 cells differentiate along neuroectodermal lineages after exposure to retinoic acid (RA). Hypoxanthine effects on RA-differentiation were examined by the changes on the expression of various transcription factor genes essential to neuronal differentiation and by the changes in tyrosine hydroxylase (TH), dopamine, adenosine and serotonin receptors (DRD, ADORA, HTR). We report that hypoxanthine excess deregulate WNT4, from Wnt/ß-catenin pathway, and engrailed homeobox 1 gene and increased TH and dopamine DRD1, adenosine ADORA2A and serotonin HTR7 receptors, whose over expression characterize early neuro-developmental processes.

Low-dose sodium valproate in the treatment of idiopathic generalized epilepsies.

OBJECTIVE: Most patients with idiopathic generalized epilepsies (IGEs) have good seizure control when on antiepileptic drugs. To analyze prospectively the response to low-dose sodium valproate (VPA) treatment (<1000 mg/day) together with plasma VPA levels in a cohort of patients with IGE. METHODS: Patients with IGE were selected and followed for almost 2 years. In patients on VPA with no seizures in the last year, VPA dose was lowered to <1000 mg/day. Newly diagnosed patients with IGE started treatment on VPA directly on this low dose. RESULTS: Fifty-four patients were included, with juvenile myoclonic epilepsy (JME) in 23 (42.6%), juvenile absence epilepsy (JAE) in 17 (31.5%), and generalized tonic-clonic seizures only (GTCS only) in 14 (25.9%). VPA at low dose was administered to 38 (70%) patients. Mean plasma VPA level was 44.21 mg/l (18-78; SD 15.18). Seizure relapse during the 2-year follow-up was observed in 8 (21%). A reduction in adverse events was observed (P < 0.048). The only factor related to efficacy of VPA at low dose was syndromic diagnosis. Low-dose VPA controlled 92.9% (13) of patients with GTCS only, 78.3% (18) of those with JME, and 29.5% (5) of those with JAE. CONCLUSIONS: Low-dose VPA was a highly effective treatment for the majority of those with JME and GTCS only. The seizures in JAE tended to be more resistant to treatment, usually requiring higher doses of VPA or polytherapy.

A randomized clinical trial to determine the effect of angiotensin inhibitors reduction on creatinine clearance and haemoglobin in heart failure patients with chronic kidney disease and anaemia.

BACKGROUND: Chronic kidney disease is a common comorbidity in elderly patients with heart failure. Evidence supports the use of angiotensin inhibitors for patients with heart failure. However, there is little evidence with which to assess the risk and benefits of this treatment in elderly patients with renal dysfunction. OBJECTIVE: To determine the efficacy and safety of angiotensin inhibitor reduction in patients with heart failure, chronic kidney disease and anaemia. STUDY DESIGN: Open randomized controlled clinical trial. SETTING: Complexo Hospitalario Universitario A Coruña (Spain). PATIENTS: Patients ≥ 50 years old, with heart failure, haemoglobin (Hb) < 12 mg/dl and creatinine clearance <60 ml/min/1.73 m(2) admitted to hospital, in treatment with angiotensin inhibitors. Informed consent and Ethical Review Board approval were obtained. INTERVENTION: A 50% reduction of angiotensin inhibitor dose of the basal treatment on admission (n = 30) in the intervention group. Control group (n = 16) with the standard basal dose. MAIN OUTCOME MEASURE: Primary outcome was difference in Hb (gr/dl), creatinine clearance (ml/min/1.73 m(2) ) and protein C (mg/dl) between admission and 1-3 months after discharge. Secondary outcome was survival at 6-12 months after discharge. RESULTS: Patients in the intervention group experienced an improvement in Hb (10.62-11.47 g/dl), creatinine clearance (32.5 ml/min/1.73 m(2) to 42.9 ml/min/1.73 m(2) ), and a decrease in creatinine levels (1.98-1.68 mg/dl) and protein C (3.23 mg/dl to 1.37 mg/dl). There were no significant differences in these variables in the control group. Survival at 6 and 12 months in the intervention and control group was 86.7% vs. 75% and 69.3% vs. 50%, respectively. CONCLUSION: The reduction of the dose of angiotensin inhibitors in the intervention group resulted in an improvement in anaemia and kidney function, decreased protein C and an increased survival rate. TRIAL REGISTRATION: EudraCT: 2008-008480-10.

Surfing along the root ground tissue gene network.

Organization of tissues in Arabidopsis thaliana root is made of, from outside in, epidermis, cortex, middle cortex, endodermis, pericycle and vascular tissues. Cortex, middle cortex and endodermis form the ground tissue (GT) system. Functional and molecular characterization of GT patterning mutants' properties has greatly increased our understanding of fundamental processes of plant root development. These studies have demonstrated GT is an elegant model that can be used to study how different cell types and cell fates are specified. This review analyzes GT mutants to provide a detailed account of the molecular network that regulates GT formation in A. thaliana. The most recent results indicate an unexpectedly complex network of transcription factors, epigenetic and hormonal controls that play crucial roles in GT development. Major differences exist between GT formation in dicots and monocots, particularly in the model plant rice, opening the way for evo-devo of GT formation in angiosperm. In rice, adaptation to submergence relies on a multilayered cortex. Moreover, variation in the number of cortex cell layers is also observed between the five root types. A mechanism of control for cortical cell number should then exist in rice and it remains to be determined if any of the Arabidopsis thaliana identified GT network members are also involved in this process in rice. Alternatively, a totally different network may have been invented. However, first available results suggest functional conservation in rice of at least two transcription factors, SHORT ROOT (SHR) and SCARECROW (SCR), involved in ground tissue formation in Arabidopsis.

First-Pass Effect in M1-Occlusion Stroke Patients Treated with Combined Stent-Retriever/Large-Bore Distal Aspiration Catheter Thrombectomy.

INTRODUCTION: Combined stent-retriever/large-bore distal aspiration catheter (LB-DAC) thrombectomy was recently introduced to treat large-vessel occlusion; however, it is unclear whether larger inner diameters improve outcomes. We compared angiographic and clinical outcomes in patients with occlusions of the M1 segment of the middle cerebral artery treated with mechanical thrombectomy using extra-LB-DAC versus LB-DAC in combination with stent-retrievers. METHODS: We analyzed consecutive patients with M1 occlusion included in the ROSSETTI registry treated with non-balloon guide catheter combined LB-DAC/stent-retriever thrombectomy between June 2019 and April 2022. We compared demographics, baseline clinical variables, procedural variables, angiographic outcomes, and clinical outcomes [National Institute of Health Stroke Scale score at 24 h (24h-NIHSS) and modified Rankin scale score at 3 months] between patients treated with extra-LB-DAC (Sofia Plus, MIVI Q6, Catalyst7; inner diameter, 0.068″-0.070″) versus LB-DAC (Sofia 5F, MIVI Q5, Catalyst 6; inner diameter, 0.055″-0.064″). Primary outcome was the first-pass effect (FPE) rate, defined as near-complete/complete reperfusion (mTICI 2c-3) after a single pass of the device. RESULTS: We included 324 patients (extra-LB-DAC, 185, 57.1% patients). Demographics, clinical data, and clinical outcomes were similar between the two groups; however, there was a trend towards improvement in National Institute of Health Stroke Scale score at 24 h (24h-NIHSS) in the cohort treated with extra-LB-DAC 9 points (IQR 4;16 points) vs. 12 points (IQR 4;18 points, P = 0.083). Patients treated with extra-LB-DAC had higher FPE rate (47% vs. 30.9%; P = 0.003) and higher modified FPE (mTICI ≥ 2b after a single pass) rate (65.9% vs 46.8%; P = 0.001). The use of extra-LB-DAC was an independent factor in predicting FPE (odds ratio 1.982, 95% confidence interval 1.250-3.143, P = 0.004). CONCLUSION: Our results suggest that in combined LB-DAC/stent-retriever thrombectomy, a larger aspiration catheter inner diameter is associated with higher rates of FPE and mFPE.