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BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominantly inherited cerebral small vessel disease caused by Neurogenic locus notch homolog protein 3 (NOTCH3) gene mutations. The main clinical features include migraine with aura, recurrent ischemic strokes and dementia. Brain MRI typically shows multiple small lacunar infarcts and severe, diffuse, symmetrical white matter hyperintensities (WMHs), with characteristic involvement of the anterior temporal pole, external capsule, and superior frontal gyrus. Reports of twins with CADASIL are scarce. Herein we describe a pair of monozygotic twins with peculiar CADASIL phenotype, carrying a new NOTCH3 variant. CASE PRESENTATION: Twin A was a 45-year-old male suffering from migraine, obesity, arterial hypertension, and polycythemia (with negative genetic analysis), who complained of a transient, short-lasting (~ 5 minutes) episode of speech difficulties. Brain MRI showed diffuse, symmetrical, confluent periventricular WMHs involving frontal, parietal, and temporal lobes and external capsules, with sparing of anterior temporal poles. Genetic analysis of NOTCH3 gene demonstrated the presence of missense c.3329G>A, p.(Cys1110Tyr) variant, confirming CADASIL diagnosis. Twin B, affected by migraine and polycythemia, as well as his monozygotic twin, presented with a 2-month history of trigeminal neuralgia. Brain MRI demonstrated diffuse WMHs with a pattern of distribution like his twin. Genetic analysis revealed the same NOTCH3 pathogenic variant. CONCLUSIONS: Our monozygotic twins have a strikingly similar neuroimaging picture with sparing of anterior temporal poles. They also have a peculiar phenotype, both presenting polycythemia without genetically confirmed cause. Twin B had trigeminal neuralgia, that is unusual in CADASIL. The possible association of the peculiar findings with the newly reported NOTCH3 variant needs to be confirmed with further observations.
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CADASIL , Transtornos de Enxaqueca , Policitemia , Neuralgia do Trigêmeo , Masculino , Humanos , Pessoa de Meia-Idade , Gêmeos Monozigóticos/genética , CADASIL/diagnóstico por imagem , CADASIL/genética , Receptor Notch3/genéticaRESUMO
Introduction: childhood obesity is associated with an increased risk of chronic diseases. We aimed to examine the relation between serum levels of 25-hydroxyvitamin D (25[OH]D) and blood pressure in obese schoolchildren. Material and methods: a cross-sectional study in school-age children with obesity. The serum levels of 25(OH)D were measured and classified as sufficient or insufficient/deficient. Blood pressure was measured. Normal values were considered < 90th percentile, elevated blood pressure ≥ 90th to < 95th percentiles, and hypertension ≥ 95th percentile, according to blood pressure reference tables specific for age, sex, and height. A Pearson correlation was performed. Results: a total of 256 obese schoolchildren (123 [48.0 %] females and 133 [51.9 %] males) were evaluated. The prevalence rates of vitamin D deficiency, insufficiency, and sufficiency were 23.4 %, 52.3 %, and 24.2 %, respectively. Normal blood pressure was observed in 101 (39.4 %) children; the frequencies of elevated blood pressure and hypertension were 10.9 % and 49.6 %, respectively. A moderate inverse correlation of 25(OH)D levels with systolic blood pressure levels (r = -0.54, p = 0.03) was observed. When analyzed by sex, a significantly high inverse correlation between 25(OH)D levels and systolic blood pressure was observed in males (r = -0.85 and p ≤ 0.001). No significant correlation was found in females (systolic r = -0.16 and p = 0.67; diastolic r = -0.15 and p = 0.812). When performing the multiple regression analysis, the 25(OH)D levels and BMI were the significant predictors for systolic blood pressure. Conclusions: we identified an inverse correlation between 25[OH]D levels and systolic blood pressure in male schoolchildren with obesity (AU)
Introducción: la obesidad infantil se asocia con un mayor riesgo de desarrollar enfermedades crónicas. El objetivo fue analizar la relación entre los niveles séricos de 25-hidroxivitamina D (25[OH]D) y la presión arterial (PA) en escolares obesos. Material y métodos: estudio transversal en niños en edad escolar con obesidad. Los niveles séricos de 25(OH)D se clasificaron como suficientes e insuficientes/deficientes. Los valores de PA se clasificaron como normales si < percentil 90, presión elevada entre los percentiles ≥ 90 y < 95, e hipertensión si ≥ percentil 95, de acuerdo con las tablas de referencia de la PA, específicas para cada edad, sexo y altura. Se realizaron una correlación de Pearson y una regresión múltiple. Resultados: se evaluaron 256 escolares obesos (123 [48,0 %] mujeres y 133 [51,9 %] hombres). La frecuencia de la deficiencia, insuficiencia y suficiencia de vitamina D fue del 23,4 %, 52,3 % y 24,2 %, respectivamente. Se observó una PA normal en 101 (39,4 %) niños; las frecuencias de la PA elevada y la hipertensión fueron del 10,9 % y 49,6 %, respectivamente. Se observó una correlación inversa moderada de los niveles de 25(OH)D con los niveles de presión arterial sistólica (PAS) (r = -0,54; p = 0,03). Cuando se analizó por sexos, se observó una correlación inversa entre los niveles de 25(OH)D y la PAS en los niños (r = -0,85; p ≤ 0,001). No se encontró ninguna correlación significativa en las niñas (sistólica, r = -0,16; p = 0,67; diastólica, r = -0,15; p = 0,812). Al realizar el análisis de regresión múltiple, los niveles de 25(OH)D y el IMC fueron predictores significativos de la PAS. Conclusiones: identificamos una correlación inversa entre los niveles de 25[OH]D y la PAS en niños escolares con obesidad (AU)
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Humanos , Masculino , Feminino , Criança , Hipertensão/complicações , Obesidade Infantil/complicações , Deficiência de Vitamina D/complicações , Vitamina D/análogos & derivados , Hipertensão/epidemiologia , Obesidade Infantil/epidemiologia , Deficiência de Vitamina D/epidemiologia , Índice de Massa Corporal , Estudos Transversais , Fatores de Risco , Vitamina D/administração & dosagem , México/epidemiologiaRESUMO
OBJECTIVE: Sporadic cerebral amyloid angiopathy (CAA) is a degenerative brain small vessel disease of ageing resulting from progressive amyloid deposition in small arteries and arterioles of the cortex and leptomeninges. CAA may be diagnosed by the mean of Boston criteria, particularly with the use of the blood-sensitive T2* MRI sequences (GRE and SWI). Epileptic seizures have rarely been reported in CAA. PATIENTS AND METHODS: We describe two patients with late-onset unprovoked seizures due to CAA. A short literature review on this topic is presented. RESULTS: In our two patients with late-onset unprovoked seizures as the first manifestation of CAA, only GRE and SWI sequences lead to a correct diagnosis. In literature, only 15 patients with CAA presenting with seizures have been reported. In these subjects, data on seizures semiology and prognosis are scarce. CONCLUSIONS: Our report highlights the importance to perform blood-sensitive sequences in all subjects with LOE of otherwise unknown etiology, not to miss a diagnosis of CAA.
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Angiopatia Amiloide Cerebral , Epilepsia , Angiopatia Amiloide Cerebral/complicações , Córtex Cerebral , Epilepsia/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Convulsões/diagnóstico por imagem , Convulsões/etiologiaRESUMO
This work discusses a jellium scheme, built within the framework of the multicomponent Ornstein-Zernike (OZ) equation, which is capable of describing the collective structure of suspensions of highly charged colloids with added salt, even in the presence of finite-size multivalent microions. This approach uses a suitable approximation to decouple the microion-microion correlations from the macroion-microion profiles, which in combination with the methodology from the dressed ion theory (DIT) gives a full account of the electrostatic effective potential among the colloids. The main advantages of the present contribution reside in its ability to manage the short-range potentials and non-linear correlations among the microions, as well as its realistic characterization of the ionic clouds surrounding each macroion. The structure factors predicted by this jellium scheme are contrasted with previously reported experimental results for microgel suspensions with monovalent salts (2019Phys. Rev. E100032602), thus validating its high accuracy in these situations. The present theoretical analysis is then extended to microgel suspensions with multivalent salts, which reveals the prominent influence of the counterion valence on the makeup of the effective potentials. Although the induced differences may be difficult to identify through the mesoscopic structure, our results suggest that the microgel collapsing transition may be used to enhance these distinct effects, thus giving a feasible experimental probe for these phenomena.
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Recent experimental studies have demonstrated the huge influence that the volume phase transition (VPT) has on the collective structure of highly charged thermo-responsive microgels in aqueous solution with low concentrations of added monovalent salt, thus opening a promising new route for controlling the overall properties of practical colloidal suspensions. We present here an analysis of this structure based on the effective electrostatic potential obtained with the exact methodology of the dressed ion theory (DIT). Starting with a description at the primitive model level, we determine the correlations among the components of our model system (macroions plus monovalent anions and cations) by utilizing the two-density integral equation theory, thus allowing us to consider realistic values for the microgel charges. The resulting microgel structure factors show a good agreement with the reported light scattering measurements, whereas the microscopic pair distributions reveal that in this regime the shrunken states promote an enhanced counterion absorption into the microgels. This packing of counterions inside the microgels induces strongly non-linear correlations among the microions, and in turn provokes a substantial weakening of the microgel-microgel correlations. The ensuing effective interactions are then obtained by contracting the description to the level in which only the macroions are present. We find not only that the magnitude and reach of the corresponding pair potentials are markedly inhibited in the shrunken states, but also that their general form diverges from the conventional screened Coulomb shape. This makes it necessary to rethink the concepts of effective charge and screening length.
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Anthropogenic and natural changes are threatening pond ecological integrity in Patagonia and tools for bioassessment are required. Macrophytes are good candidates to determine the conservation status of ponds; nevertheless, metric selection procedures should be founded on an adequate knowledge of plant ecological responses. We assessed the main environmental constraints driving variation in macrophyte assemblages, and trophic status at 29 ponds located at the continental and insular Patagonia region. We screened 20 potential macrophyte metrics as indicators of pond condition that included origin (native, endemic, exotic), lifeforms (annual/biannual, perennial), functional groups (submersed, emergent, floating-leaved, landforms), and community attributes. A set of 106 taxa were recorded, and richness per site (10 species) was unexpectedly high for a cold temperate area, reinforcing the value of isolated ponds as habitat for macrophytes in the Patagonian landscape. Natives dominated most assemblages; exotics were present at 24 ponds, contributing with high cover (>45%) at 15% of them. Macrophyte assemblages were driven by natural factors over anthropogenic ones, with temperature, rainfall, pH, conductivity and nutrients explaining most variation in patterns. However, pond eutrophication symptoms (high phosphorous concentration and chlorophyll a) were associated with extensive cattle grazing (manure and trampling) and urbanization (runoff). Generalized linear models captured natural variables (temperature, alkalinity) as most powerful explaining richness measures. Models also indicated that both richness of emergent and endemics were negatively affected by total phosphorous increases. Land cover factors: grasses/herbaceous, mallín and trees (%) in 100 m buffer around ponds appeared as additional ecological drivers of macrophyte patterns, particularly of submersed (>50%) and native richness (36%). Natural and anthropogenic gradients were overlapped, making it difficult to generalize our conclusions. Further studies are needed to test the performance of the macrophyte metrics selected here, which are a vital tool for the conservation of the most austral ponds in South America.
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Clorofila A , Lagoas , Animais , Argentina , Benchmarking , Bovinos , Ecossistema , América do SulRESUMO
Forensic identification tests often need recourse to markers that can successfully type highly degraded DNA, and binary single nucleotide polymorphisms (SNPs) have become the variants of choice for such analyses because of their short amplified fragment lengths. The two main drawbacks of SNPs are their reduced power of discrimination per marker compared with mainstream forensic STRs and an inability to robustly detect mixed DNA-particularly using capillary electrophoresis genotyping systems such as SNaPshot™, where the dye signals are much more imbalanced than those of STR profiles. This study compiled a compact set of multiple-allele SNPs consisting of loci that had three or four nucleotide variants at the same site in order to address the lack of mixture detection capability with binary SNP tests, as well as improving levels of polymorphism per SNP by transitioning to a maximum of six or ten genotypes per locus. We report the development and optimisation of a SNaPshot-based forensic test comprising 27 tri-allelic and 2 tetra-allelic SNPs, which we named MASTiFF: a multiple-allele SNP test for forensics. Assessments of the MASTiFF panel's levels of discrimination power in the five main population groups indicate random match probabilities ranging from 10-15 down to 10-20-improving the levels possible from an equivalent number of binary SNPs. The SNaPshot test was able to detect simple mixtures successfully with more than two alleles observed in 30% of SNPs. From allele frequency data, it is estimated that more than two alleles will be present in at least one MASTiFF SNP in 99.8% of two-person mixtures, making this panel an ideal supplementary test when SNPs are chosen for the analysis of degraded forensic DNA.
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Alelos , DNA/análise , Genética Forense/métodos , Frequência do Gene , Genótipo , Técnicas de Genotipagem/métodos , Polimorfismo de Nucleotídeo Único , Degradação Necrótica do DNA , Impressões Digitais de DNA , Etnicidade/genética , Humanos , Mudanças Depois da Morte , Grupos Raciais/genéticaRESUMO
We introduce a theoretical approach to describe structural correlations among charged permeable spheres at finite particle concentrations. This theory explicitly accounts for correlations among microions and between microions and macroions and allows for the proposal of an effective interaction among macroions that successfully captures structural correlations observed in poly-N-isopropyl acrylamide microgel systems. In our description the bare charge is fixed and independent of the microgel size, the microgel concentration, and the ionic strength, which contrasts with results obtained using linear response approximations, where the bare charge needs to be adapted to properly account for microgel correlations obtained at different conditions.
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BACKGROUND: Chronic pain is a major therapeutic problem in kidney transplant patients owing to nephrotoxicity associated with nonsteroidal antiiflammatory drugs. Benefits in chronic pain treatment with cannabidiol (CBD) have been reported. This study assesses the effect, safety, and possible drug interactions in kidney transplant patients treated with CBD for chronic pain. METHODS: We assessed patients who asked to receive CBD for pain treatment. Doses were increased from 50 to 150 mg twice a day for 3 weeks. Creatinine, blood count, liver function, liver enzymes, and drug levels were determined every 48 hours the first week and then once a week thereafter. RESULTS: We assessed 7 patients with a mean age of 64.5 years (range, 58-75 years). CBD initial dose was 100 mg/d, CBD dose reduction to 50 mg/d has been done on day 4 to patient 1 for persistent nausea. Tacrolimus dose reduction in patient 3 was undertaken on days 4, 7, and 21 owing to persisting elevated levels (even before CBD) and itching, and on day 21 in patient 5. Tacrolimus levels decreased in patient 2 but were normal in the control 1 week later. Patients on cyclosporine were stable. Adverse effects were nausea, dry mouth, dizziness, drowsiness, and intermittent episodes of heat. CBD dose decrease was required in 2 patients. Two patients had total pain improvement, 4 had a partial response in the first 15 days, and in 1 there was no change. CONCLUSIONS: During this follow-up, CBD was well-tolerated, and there were no severe adverse effects. Plasma levels of tacrolimus were variable. Therefore, longer follow-up is required.
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Canabidiol/uso terapêutico , Dor Crônica/tratamento farmacológico , Transplante de Rim/efeitos adversos , Manejo da Dor/métodos , Idoso , Dor Crônica/etiologia , Ciclosporina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tacrolimo/uso terapêutico , Resultado do Tratamento , UruguaiRESUMO
PurposeThe goal was to develop a simple model for predicting the individual risk profile for age-related macular degeneration (AMD) on the basis of genetic information, disease family history, and smoking habits.Patients and methodsThe study enrolled 151 AMD patients following specific clinical and environmental inclusion criteria: age >55 years, positive family history for AMD, presence of at least one first-degree relative affected by AMD, and smoking habits. All of the samples were genotyped for rs1061170 (CFH) and rs10490924 (ARMS2) with a TaqMan assay, using a 7500 Fast Real Time PCR device. Statistical analysis was subsequently employed to calculate the real individual risk (OR) based on the genetic data (ORgn), family history (ORf), and smoking habits (ORsm).Results and conclusionThe combination of ORgn, ORf, and ORsm allowed the calculation of the Ort that represented the realistic individual risk for developing AMD. In this report, we present a computational model for the estimation of the individual risk for AMD. Moreover, we show that the average distribution of risk alleles in the general population and the knowledge of parents' genotype can be decisive to assess the real disease risk. In this contest, genetic counseling is crucial to provide the patients with an understanding of their individual risk and the availability for preventive actions.
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Aconselhamento Genético , Testes Genéticos , Degeneração Macular/etiologia , Anamnese , Idoso , Alelos , Feminino , Humanos , Degeneração Macular/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco , Fumar/efeitos adversosRESUMO
BACKGROUND: The Institute of Nephrology and Urology (INU) has performed 75% of kidney transplantations (KT) in Uruguay during its 35 years of activity, with 90.6% from cadaveric donors. We investigated the risk factors (RF) for delayed graft function (DGF) and patient and graft survival (SV). METHODS: We analyzed retrospectively the characteristics and evolution of 1500 KT performed by INU until December 2014. The incidence of DGF and RF for patient and graft SV were analyzed in 4 eras, according to the year that KT was performed. RESULTS: The number of KT per year has progressively increased until reaching 40 KT per million population in 2006, with a decrease of the living donor KT (LDKT) rate. The age of the donors (D) and recipients (R) as well as the time on dialysis (TOD) have progressively increased over the different eras. Five hundred twenty-five R (35%) presented with DGF. The RF for DGF were the age of the R and the D, the TOD, the DDKT, and the warm ischemia time (WIT). In the DDKT group, the cold ischemia time and "died of stroke" were added factors. The death-censored graft SV at 1, 5, 10, and 15 years were 90%, 76%, 62%, and 49%, respectively. They improved as from era I, the patient SV being 92%, 83%, and 75% at 1, 5, and 10 years, in era I; 98%, 93%, and 86% in era II; 98%, 92%, and 83% in era III; and 95% and 90% at 1 and 5 years in era IV (P < .001). The graft SV over the same periods was 76%, 58%, and 40% in era I; 88%, 68%, and 52% in era II; 93%, 81%, and 70% in era III; and 93% and 85% at 1 and 5 years in era IV (P < .0001). The RF for patient SV were diabetes mellitus, era I, lower albuminemia, older age or TOD, and DGF. For kidney SV, the era, the age of the R, TOD, DGF, and D older than 60 years were RF associated with a worse evolution. In DDKT, the RF for the graft SV were the era, younger age of the R, and DGF. The group with the worst graft SV was the one made up of children and adolescents. CONCLUSIONS: Our results relating to patient and graft SV are acceptable and comparable to those mentioned on large records such as the OPNT/SRTR and the Collaborative Transplant Study. This has been the case, even though we have transplanted increasingly aged patients, with increasingly aged donors, or donors with associated pathology. The risk factors that we found both for DGF and SV have also been pointed out by other authors. The validity of some findings has the limitation of being from a retrospective analysis; hence, they should be corroborated by a prospective study.
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Transplante de Rim/estatística & dados numéricos , Academias e Institutos/estatística & dados numéricos , Adolescente , Adulto , Distribuição por Idade , Idoso , Cadáver , Criança , Função Retardada do Enxerto/mortalidade , Feminino , Sobrevivência de Enxerto/fisiologia , Humanos , Incidência , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Nefrologia/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Doadores de Tecidos/estatística & dados numéricos , Urologia/estatística & dados numéricos , Uruguai/epidemiologia , Adulto JovemRESUMO
A 31-plex SNaPshot assay, named 'Global AIMs Nano', has been developed by reassembling the most differentiated markers of the EUROFORGEN Global AIM-SNP set. The SNPs include three tri-allelic loci and were selected with the goal of maintaining a balanced differentiation of: Africans, Europeans, East Asians, Oceanians and Native Americans. The Global AIMs Nano SNP set provides higher divergence between each of the five continental population groups than previous small-scale AIM sets developed for forensic ancestry analysis with SNaPshot. Both of these characteristics minimise potential bias when estimating co-ancestry proportions in individuals with admixed ancestry; more likely to be observed when using markers disproportionately informative for only certain population group comparisons. The optimised multiplex is designed to be easily implemented using standard capillary electrophoresis regimes and has been used to successfully genotype challenging forensic samples from highly degraded material with low level DNA. The ancestry predictive performance of the Global AIMs Nano set has been evaluated by the analysis of samples previously characterised with larger AIM sets.
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Genética Forense/métodos , Grupos Raciais/genética , DNA/genética , Genética Forense/normas , Frequência do Gene , Variação Genética , Genética Populacional/métodos , Genótipo , Humanos , Reação em Cadeia da Polimerase Multiplex/métodos , Reação em Cadeia da Polimerase Multiplex/normas , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The first kidney transplantation (KT) in Uruguay was performed in 1969. We report the rates of KT and survival of patients and grafts up to December 2014. The country has a surface of 176,215 km(2) and a population of 3,286,314 inhabitants (18.6 inhabitants per km(2)). Till December 31, 2014, 1,940 KT have been performed in Uruguay (41.8 pmp that year); 90.4% of them were from cadaveric donors (CD). Median age of recipients (R) was 44 ± 14 years; R older than 55 years increased from 0 to 27% during the period. Our pre-emptive KT program started in 2007. Optimal donors (D) decreased from 65.2% to 35.5%, and D older than 45 years old increased from 9% to 37%. Trauma as cause of death decreased from 49% to 32% and stroke as cause of death increased from 25% to 39%. Patient survival rates at 1, 5, and 8 years were 93%, 87%, and 78%, respectively for KT performed between 1980 and 1989; they were 98%, 93%, and 89%, respectively, for KT performed between 1990 and1999; they were 97%, 91%, and 90%, respectively, for KT performed between 2000 and 2010. In December 2013, there were 1098 patients pmp in renal replacement therapy, 758 pmp in dialysis, and 340 pmp (30.9%) with a functioning graft. Our national KT program is mainly based (90.6%) on cadaveric donation. Epidemiological changes in the characteristics of R and D followed the changes in aging that occurred in the general population and the dialysis population. The survival rates from patients and kidneys are similar to those reported by the European and the American registries.
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Falência Renal Crônica/terapia , Transplante de Rim/estatística & dados numéricos , Desenvolvimento de Programas , Obtenção de Tecidos e Órgãos/organização & administração , Adulto , Feminino , Humanos , Falência Renal Crônica/epidemiologia , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia de Substituição Renal/estatística & dados numéricos , Taxa de Sobrevida , Doadores de Tecidos/estatística & dados numéricos , Uruguai/epidemiologiaRESUMO
Kidney transplantation is the best treatment for end-stage chronic renal disease. In Uruguay, the prevalence of patients on dialysis is 757 patients per millon inhabitants, plus 316 alive with a functioning renal graft. We install a preemptive renal transplantation program. Twenty-five patients received grafts without dialysis from 2004 to 2013, 5 receiving their 2nd transplantation and 17 from cadaveric donors, with 7.4 ± 7.7 months in the waiting list. At 24 months, patients' survival rate was 100% and the grafts' 97%, with a serum creatinine of 1.4 ± 0.6 mg%. The developed programs of dialysis and renal health care contributed install our preemptive kidney transplantation. Kidney transplantation should be proposed to selected patients with chronic renal failure as primary therapy of substitution of renal function.
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Falência Renal Crônica/cirurgia , Transplante de Rim , Adolescente , Adulto , Criança , Feminino , Sobrevivência de Enxerto , Humanos , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Diálise Renal , Taxa de Sobrevida , Resultado do Tratamento , Uruguai , Listas de Espera , Adulto JovemRESUMO
BACKGROUND: According to our experience, survival of cadaveric renal graft in 5 years increased from 63% as of the introduction of cyclosporine to 73% after azathioprine was substituted with mycophenolate mofetil (MMF) in 1997. Until 2003, the innovator mycophenolate mofetil (IMMF) (Cellcept; Roche) was used. In 2003, Laboratorios Clausen introduced in Uruguay a generic MMF (GMMF) (Suprimun/Micoflavin/Myclausen; Laboratorios Clausen) with previous bioequivalence studies. Since then, every health care provider administers one of these types of MMF available on the market to its renal transplant (RT) patients. METHODS: We compared the evolution of 2 groups of patients and their grafts, those treated with GMMF or with IMMF. This was a descriptive, retrospective, nonrandomized, comparative study that involved all transplant patients in a center from January 2005 to June 2010 from 2 different health care providers which administered GMMF or IMMF uninterruptedly. Patients were older than 18 years, underwent their first RT and received triple immunosuppressive regime with calcineurin inhibitor (CNI), corticoids, and MMF, and completed ≥6 months of post-RT evolution. RESULTS: The GMMF group included 29 patients and the IMMF group 23. Patients from both groups had no significant differences (NS) regarding age, sex, diabetes, hepatitis C virus (HCV), recipient hypertension, donor type (living or cadaveric, sex, age, cause of death), or mismatch degree. There were no material differences regarding antibody induction, CNI type, day of diuresis, or function recovery percentage. Statistically different results were reported for time in dialysis (6.1 ± 0.7 y in IMMF vs 3.8 ± 0.5 y in GMMF) and cadaveric donor cold ischemia time (989 ± 205 min vs 851 ± 219 min, respectively). For IMMF and GMMF, respectively, clinical acute rejection was 40.9% and 31% and creatinine over 3, 6, 12, 24, 36, and 48 months, respectively, was (mg%): 1.65 ± 0.12, 1.66 ± 0.15, 1.43 ± 0.10, 1.44 ± 0.12, 1.49 ± 0.18, and 1.41 ± 0.17 and 1.50 ± 0.08, 1.41 ± 0.07, 1.63 ± 0.26, 1.31 ± 0.08, 1.26 ± 0.09, and 1.21 ± 0.10, with 22/28, 22/28, 22/28, 22/26, 19/20, 17/11, and 15/9 patients under follow-up (NS). Patient survival over 3, 6, 12, and 18 months, respectively, was 94%, 94%, 94%, and 94% and 96%, 96%, 96%, and 96%, and graft survival was 94%, 89%, 89%, and 89% and 96%, 93%, 93%, and 93% for IMMF and GMMF, respectively (NS). Dosing adjustment frequency and substitution with mycophenolate sodium was similar for both groups. CONCLUSIONS: With the results of this preliminary study we can not reach any final conclusion regarding assistance practice. From both groups, which involved similar baseline variables except for time in dialysis and cold ischemia (both greater in IMMF), we could gather a similar graft and patient evolution. New prospective, randomized, double-blind studies involving an adequate number of patients will help to determine the efficacy of GMMF in renal transplantation.
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Medicamentos Genéricos/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Transplante de Rim , Ácido Micofenólico/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Sobrevivência de Enxerto , Humanos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Uruguai , Adulto JovemRESUMO
The suggestion of an anatomical and functional relationship between the basal ganglia and cerebellum is recent. Traditionally, these structures were considered as neuronal circuits working separately to organize and control goal-directed movements and cognitive functions. However, several studies in rodents and primates have described an anatomical interaction between cortico-basal and cortico-cerebellar networks. Most importantly, functional changes have been observed in one of these circuits when altering the other one. In this context, we aimed to accomplish an extensive description of cerebellar activation patterns using cFOS expression (cFOS-IR) after acute and chronic manipulation of dopaminergic activity. In the acute study, substantia nigra pars compacta (SNc) activity was stimulated or suppressed by intra cerebral administration of picrotoxin or lidocaine, respectively. In addition, we analyzed cerebellar activity after the induction of a parkinsonism model, the tremulous jaw movements. In this model, tremulous jaw movements were induced in male rats by IP chronic administration of the dopamine antagonist haloperidol (1.5mg/kg). Acute stimulation of SNc by picrotoxin increased cFOS-IR in the vermis and cerebellar hemispheres. However, lidocaine did not produce an effect. After 14days of haloperidol treatment, the vermis and cerebellar hemispheres showed an opposite regulation of cFOS expression. Chronic dopaminergic antagonism lessened cFOS expression in the vermis but up-regulated such expression in the cerebellar hemisphere. Overall, the present data indicate a very close functional relationship between the basal ganglia and the cerebellum and they may allow a better understanding of disorders in which there are dopamine alterations.
Assuntos
Cerebelo/metabolismo , Dopamina/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Substância Negra/fisiologia , Análise de Variância , Anestésicos Locais/farmacologia , Animais , Cerebelo/efeitos dos fármacos , Eletromiografia , Lateralidade Funcional , Antagonistas GABAérgicos/farmacologia , Arcada Osseodentária , Lidocaína/farmacologia , Masculino , Microinjeções , Movimento/efeitos dos fármacos , Vias Neurais/fisiologia , Picrotoxina/farmacologia , Ratos , Ratos Wistar , Tartaratos/farmacologiaRESUMO
OBJECTIVE. The relationship between metformin accumulation and lactate increase is still debated. This observational case series aims to evaluate the correlation of metformin plasma levels with the pH, lactate and creatinine levels, and with the mortality rate in selected patients with metformin accumulation confirmed through metformin plasma concentration detection at hospital admission. MATERIAL AND METHODS. All cases of lactic acidosis (pH, ≤ 7.35; arterial lactate, ≥ 5 mmol/L) related to metformin accumulation (plasma level ≥ 4 mcg/mL) from 2007 to 2011 were retrospectively reviewed. Erroneous ingestion and voluntary overdoses were excluded. Epidemiological, medical history, clinical and laboratory data were evaluated in all cases. RESULTS. Sixty-six patients were included. Thirty-one patients (47%) had contraindication to therapy with metformin. All patients showed severe lactic acidosis (pH, 6.91 ± 0.18; lactate, 14.36 ± 4.90 mmol/L) and acute renal failure (creatinine, 7.24 ± 3.29 mg/dL). The mean metformin plasma concentration was 40.68 ± 27.70 mcg/mL. Metformin plasma concentrations showed a correlation, statistically significant even if not strong, with creatinine (p = 0.002, R = 0.37), pH (p < 0.0001, R = - 0.43) and plasma lactate levels (p = 0.001, R = 0.41). Sixty-two (94%) underwent dialysis. Early mortality (before discharge from ICU) was 26% (17 cases). Lactate and metformin concentrations had mean levels not statistically different in surviving and deceased patients. CONCLUSIONS. Patients on chronic therapy with metformin may develop a mitochondrial-related toxicity that should be considered when patients present with lactic acidosis, renal failure, and frequently, a medical history of gastrointestinal manifestations during the days preceding the hospital admission. The correlation between metformin plasma concentrations and creatinine, pH, and lactate levels seems to be related to the mechanism of action (inhibition of complex I of the mitochondrial respiratory chain) and to the kinetic properties (high distribution volume and low protein binding) of the drug. The relevant early mortality seems not correlated with the levels of metformin or lactates: this could be due to the possible role of concurrent illness even if, such as for the relationships with lactate and creatinine, a more proper toxicological evaluation could be obtained by assessing metformin erythrocyte concentrations instead of the plasmatic ones.
Assuntos
Acidose Láctica/sangue , Metformina/sangue , Metformina/farmacocinética , Acidose Láctica/etiologia , Acidose Láctica/terapia , Injúria Renal Aguda/sangue , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Creatinina/sangue , Feminino , Humanos , Concentração de Íons de Hidrogênio , Ácido Láctico/sangue , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Pessoa de Meia-Idade , Diálise Renal , Estudos RetrospectivosRESUMO
CONTEXT: Pyrethroids are synthetic pyrethrin analogues that induce sodium-channel depolarization and hyperexcitation. Severe pyrethroid poisoning is manifested by a "Tremor Syndrome" (Type I cyano-agents) or a "Choreoathetosis/Salivation Syndrome" (Type II non cyano-agents). Very few reports of neurotoxic effects caused by Type I pyrethroids ingestion are available, and no human data concerning Type I pyrethroid blood levels in pediatric poisoning are reported in the medical literature. CASE DETAILS: A 19-month-old female patient presented with irritability and inconsolable crying that rapidly worsened to tonic-clonic seizures and coma (GCS 6). On admission vital signs including BP 110/70 mmHg, HR 110 beats/min, and SpO2 98% on room air were normal. Orotracheal intubation, oxygen administration, and midazolam infusion (4 µg/kg/min) were performed. Intravenous thiopental sodium, up to 18 mg/kg/hour, was administered to control convulsions. An inquiry revealed that 9 h before presentation the patient had ingested an unknown amount of an insecticide containing 7% piperonyl-butoxide and a mixture of the Type I pyrethroids bifenthrin (5%) and esbiothrin (3%). Consequently, gastric lavage was performed, followed by administration of activated charcoal and cathartics. On the subsequent 48 h, the patient returned progressively alert; she was extubated on day 4 and discharged asymptomatically 12 days after hospitalization. After 9, 48, and 72 h of ingestion, the plasma levels were 500, 95, and 40 ng/mL for bifenthrin and 1,640, 640, and 165 ng/mL for piperonyl-butoxide respectively. DISCUSSION: This pediatric case showed severe pyrethroid neurotoxicity associated with measurable plasma levels of bifenthrin and piperonyl-butoxide. In pediatric pyrethroid poisoning, coma and seizures may represent the main life-threatening features. First-aid therapy including airway maintenance and control of muscle fasciculation and seizures is of major importance. Benzodiazepines and high-dose thiopental sodium were effective treatments for convulsion.
Assuntos
Coma/induzido quimicamente , Epilepsia Tônico-Clônica/induzido quimicamente , Inseticidas/toxicidade , Piretrinas/toxicidade , Aletrinas/análogos & derivados , Aletrinas/sangue , Aletrinas/toxicidade , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Lactente , Inseticidas/sangue , Piretrinas/sangueRESUMO
Despite the current clinical use of boronophenylalanine-fructose (BPA-f), as radiosensitizer, in BNCT application for brain tumors, still remains to be determined the safety dose of this agent. We evaluated the potential risk of primary BPA-f toxicity before neutronic irradiation at different concentrations (0-100µgBeq/ml) after short- and long-term exposure (4-48h and 7-10 days), using a battery of tests (i.e. MTT assay, calcein-AM/Propidium Iodide staining, clonogenic test) in CNS cell models (D384 and SH-SY5Y), and non-neuronal primary human fibroblasts (F26). MTT data showed: (i) no cytotoxic effects after short-term exposure (4h) to any of BPA-f concentrations tested in all cell models; (ii) dose- and time-dependent mitochondrial activity impairment in D384 and SH-SY5Y cells only (with 60% and 40% cell death in D384 and SH-SY5Y, respectively, after 48h exposure to BPA-f 100µgBeq/ml). By Calcein-AM/PI staining, BPA-f treatment was specific toward SH-SY5Y cells only: a dose-dependent cell density reduction was observed, with a more pronounced effect after 48h exposure (15-40% at doses ranging 20-100µgBeq/ml). Clonogenic data revealed dose-dependent decrease of cell proliferative capacity in all cell lines, still the SH-SY5Y cells were the most sensitive ones: the lowest dose (20µgBeq/ml) produced 90% cell decrease. These results indicate dose- and time-dependent cytotoxic effects of BPA-f, with CNS cells showing a lower tolerance compared to fibroblasts. Long-term exposure to BPA-f compromised the proliferative capacity regardless of cell model type (cell sensitivity being SH-SY5Y>D384>F26). In short-time exposure, BPA-f exhibits a safe dosage up to 40µgBeq/ml for the viability of CNS cell lines.
Assuntos
Compostos de Boro/toxicidade , Terapia por Captura de Nêutron de Boro/métodos , Fibroblastos/efeitos dos fármacos , Frutose/análogos & derivados , Neurônios/efeitos dos fármacos , Radiossensibilizantes/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fibroblastos/patologia , Frutose/toxicidade , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Neurônios/patologia , Medição de Risco , Fatores de Tempo , Testes de ToxicidadeRESUMO
Cholinergic muscarinic receptors (MRs) and monoamine oxidase activity (MAO-B), expressed both in brain and blood cells, were investigated in animals and exposed subjects to assess (i) MeHg (0.5-1 mg/kg/day GD7-PD7) and/or PCB153 (20 mg/kg/day GD10-GD16) effects on cerebellar MAO-B and MRs, and lymphocyte MRs, in dams and offspring 21 days postpartum; (ii) MAO-B in platelets and MRs in lymphocytes of a Faroese 7-year-old children cohort, prenatally exposed to MeHg/PCBs. Animal Data. MAO-B was altered in male cerebellum by MeHg, PCB153, and their combination (35%, 45%, and 25% decrease, resp.). Cerebellar MRs were enhanced by MeHg alone in dams (87%) and male pups (27%). PCB153 alone and in mixture did not modify cerebellar MRs. Similarly to brain, lymphocyte MRs were enhanced in both dams and offspring by MeHg alone. All changes were caused by 1 MeHg mg/kg/day, the lower dose was ineffective. Human Data. Both biomarkers showed homogeneous distributions within the cohort (MRs, range 0.1-36.78 fmol/million cells; MAO-B, 0.95-14.95 nmol/mg protein/h). No correlation was found between the two biomarkers and neurotoxicant concentrations in blood (pre- and postnatally).