Anti­CGRP monoclonal antibodies in resistant migraine: preliminary real-world effectiveness and clinical predictors of response at two years.

BACKGROUND: Monoclonal antibodies targeting calcitonin gene-related peptide (anti-CGRP mAbs) have shown clinical effectiveness and safety in randomized clinical studies. However, long-term studies in clinical practice remain limited. AIM: To assess the long-term effectiveness, clinical predictors and safety of three anti-CGRP mAbs (erenumab, galcanezumab, fremanezumab) in resistant migraine patients. METHOD: A single-center retrospective study was conducted from December 2019 to June 2023 involving 120 resistant migraine patients who received at least a month of anti-CGRP mAbs treatment. Patients completed a headache diary that included monthly acute medication intake (MAM), monthly migraine days (MMD), adverse events as well as completed Patient-Reported Outcome questionnaires (MIDAS [Migraine Disability Assessment] and Headache Impact Test 6 [HIT-6]). The number of patients achieving a ≥ 50% reduction in monthly migraine days was determined and classified as ≥ 50% responders, and baseline parameters and logistic regression between responders and non-responders were analyzed to identify potential predictors of response. Adverse events were registered in every follow-up. RESULTS: Treatment with anti-CGRP mAbs led to reductions in MIDAS, HIT-6, MMD and MAM from baseline to 6-24 months. At 6-12 months, responders (61% and 57%, respectively) exhibited lower baseline MMD and MAM. Medication overuse  was associated with non-responders from 6 to 24 months and it was identified as a negative predictor of treatment effectiveness (OR 0.23, 95% CI 0.07-0.74; p = 0.014). CONCLUSION: Anti-CGRP mAbs prove effectiveness and safety over a 24-month period in a RM population. Patients with no medication overuse and lower basal MMDs and MAM may respond better to anti-CGRP mAbs.

[Myths and evidence on the use of botulinum toxin: neuropharmacology and dystonia]. / Mitos y evidencias en el empleo de la toxina botulinica: neurofarmacologia y distonias.

INTRODUCTION: Botulinum toxin type A (BTA) is a bacterial endotoxin, whose therapeutic use has had a dramatic impact on different neurological disorders, such as dystonia and spasticity. AIM: To analyze and summarize different questions about the use of BTA in our clinical practice. DEVELOPMENT: A group of experts in neurology developed a list of topics related with the use of BTA. Two groups were considered: neuropharmacology and dystonia. A literature search at PubMed, mainly for English language articles published up to June 2016 was performed. The manuscript was structured as a questionnaire that includes those questions that, according to the panel opinion, could generate more controversy or doubt. The initial draft was reviewed by the expert panel members to allow modifications, and after subsequent revisions for achieving the highest degree of consensus, the final text was then validated. Different questions about diverse aspects of neuropharmacology, such as mechanism of action, bioequivalence of the different preparations, immunogenicity, etc. were included. Regarding dystonia, the document included questions about methods of evaluation, cervical dystonia, blepharospasm, etc. CONCLUSION: This review does not pretend to be a guide, but rather a tool for continuous training of residents and specialists in neurology, about different specific areas of the management of BTA.

TITLE: Mitos y evidencias en el empleo de la toxina botulinica: neurofarmacologia y distonias.Introduccion. La toxina botulinica de tipo A (TBA) ha supuesto una verdadera revolucion terapeutica en neurologia, y en la actualidad es el tratamiento rutinario en las distonias focales y la espasticidad. Objetivo. Plantear, revisar y responder cuestiones controvertidas en relacion con la neurofarmacologia de la TBA y su uso en las distonias en la practica clinica habitual. Desarrollo. Un grupo de expertos en trastornos del movimiento reviso una lista de temas controvertidos relacionados con la farmacologia de la TBA y su uso en las distonias. Revisamos la bibliografia e incluimos articulos relevantes especialmente en ingles, pero tambien, si su importancia lo merece, en castellano y en frances, hasta junio de 2016. El documento se estructuro como un cuestionario que incluyo las preguntas que podrian generar mayor controversia o duda. El borrador inicial del documento fue revisado por los miembros del panel y se realizaron las modificaciones necesarias hasta alcanzar el mayor grado de consenso. Incluimos preguntas sobre diferentes aspectos de la neurofarmacologia, especialmente el mecanismo de accion, la bioequivalencia de los diferentes preparados y la inmunogenicidad. En relacion con el subapartado de las distonias, se incluyeron aspectos sobre la evaluacion y el tratamiento de las distonias focales. Conclusiones. Esta revision no pretende ser una guia, sino una herramienta practica destinada a neurologos y medicos internos residentes interesados en esta area, dentro de diferentes ambitos especificos del manejo de la TBA.

Luminal contents from the gut of colicky infants induce visceral hypersensitivity in mice.

BACKGROUND: The pathophysiology of infantile colic is poorly understood, though various studies report gut microbiota dysbiosis in colicky infants. We aimed to test the hypothesis that colic-related dysbiosis is associated with visceral hypersensitivity triggered by an altered luminal milieu. METHODS: Fecal samples from seven colicky and seven non-colicky infants were studied. Fecal supernatants (FS) were infused into the colons of C57/Bl6 mice (n=10/specimen). Visceral sensitivity was subsequently assessed in the animals by recording their abdominal muscle response to colorectal distension (CRD) by electromyography (EMG). Serine and cysteine protease activities were assessed in FS with specific substrates. Infant fecal microbiota composition was analyzed by DNA extraction and 16S rRNA gene pyrosequencing. KEY RESULTS: FS from colicky infants triggered higher EMG activity than FS from non-colicky infants in response to both the largest CRD volumes and overall, as assessed by the area under the curve of the EMG across all CRD volumes. Infant crying time strongly correlated with mouse EMG activity. Microbiota richness and phylogenetic diversity were increased in the colicky group, without showing prominent microbial composition alterations. Only Bacteroides vulgatus and Bilophila wadsworthia were increased in the colicky group. Bacteroides vulgatus abundance positively correlated with visceral sensitivity. No differences were found in protease activities. CONCLUSIONS & INFERENCES: Luminal contents from colicky infants trigger visceral hypersensitivity, which may explain the excessive crying behavior of these infants. Additional studies are required to determine the nature of the compounds involved, their mechanism of action, and the potential implications of intestinal microbiota in their generation.

Quality of chilled and cold-stored (5 °C) canine spermatozoa submitted to different rapid cooling rates.

The aim of this study was to evaluate the sperm quality in chilled canine semen using different cooling rates from room temperature (23 °C) to 5 °C and subsequently cold-stored at 5 °C for up to 96 hours. In experiment 1, semen samples from five dogs were pooled, diluted in Tris-fructose-citrate extender with 20% egg yolk and split into four aliquots that were chilled to 5 °C using different cooling rates of 2.25, 0.9, 0.45, and 0.2 (control) °C/min. In experiment 2, semen from five dogs was processed individually as described above and split into two aliquots that were chilled to 5 °C using rates of either 2.25 °C/min or 0.2 °C/min. In both experiments, the sperm quality (i.e., sperm motility and viability) was evaluated before cooling and after 0, 24, 48, 72, and 96 hours of storage at 5 °C. The total motility, progressive motility, and quality of movement parameters were assessed using computer-assisted analysis system, and the percentage of viable spermatozoa was determined using flow cytometry (H-42/PI//FITC-PNA). The cooling rate did not influence the sperm quality parameters at any of the evaluation times. All evaluated males showed the same response to chilling semen at a rapid cooling rate. Storage time negatively influenced (P < 0.05) sperm motility, regardless of the cooling rate used. In conclusion, canine sperm could be chilled and stored for 96 hours at 5 °C in a Tris-fructose extender with 20% egg yolk using rapid cooling rates, with values for sperm quality similar to those from a conventional protocol.

The effects of hoechst 33342 staining and the male sample donor on the sorting efficiency of canine spermatozoa.

The aim of this study was to evaluate the influence of Hoechst 33342 (H-42) concentration and of the male donor on the efficiency of sex-sorting procedure in canine spermatozoa. Semen samples from six dogs (three ejaculates/dog) were diluted to 100 × 10(6) sperm/ml, split into four aliquots, stained with increasing H-42 concentrations (5, 7.5, 10 and 12.5 µl, respectively) and sorted by flow cytometry. The rates of non-viable (FDA+), oriented (OS) and selected spermatozoa (SS), as well as the average sorting rates (SR, sorted spermatozoa/s), were used to determine the sorting efficiency. The effects of the sorting procedure on the quality of sorted spermatozoa were evaluated in terms of total motility (TM), percentage of viable spermatozoa (spermatozoa with membrane and acrosomal integrity) and percentage of spermatozoa with reacted/damaged acrosomes. X- and Y-chromosome-bearing sperm populations were identified in all of the samples stained with 7.5, 10 and 12.5 µl of H-42, while these two populations were only identified in 77.5% of samples stained with 5 µl. The values of OS, SS and SR were influenced by the male donor (p < 0.01) but not by the H-42 concentration used. The quality of sorted sperm samples immediately after sorting was similar to that of fresh samples, while centrifugation resulted in significant reduction (p < 0.05) in TM and in the percentage of viable spermatozoa and a significant increase (p < 0.01) in the percentage of spermatozoa with damage/reacted acrosomes. In conclusion, the sex-sorting of canine spermatozoa by flow cytometry can be performed successfully using H-42 concentrations between 7.5 and 12.5 µl. The efficiency of the sorting procedure varies based on the dog from which the sperm sample derives.

Effect of a mixture of bovine milk oligosaccharides, Lactobacillus rhamnosus NCC4007 and long-chain polyunsaturated fatty acids on catch-up growth of intra-uterine growth-restricted rats.

AIM: To investigate the effect of a nutritional mixture (bovine milk oligosaccharides, Lactobacillus rhamnosus NCC4007, arachidonic and docosahexaenoic acid) on growth of intrauterine growth-restricted (IUGR) rats. METHODS: IUGR was induced by maternal food restriction. The offspring (males and females) were assigned to: REF (non-IUGR, no mixture), IUGRc (IUGR, no mixture), or IUGRmx (IUGR, mixture). The mixture was given from day 7 to day 58, when tissues and plasma from half of the animals were collected for hormones, metabolites and microarray analysis. The rest received a high-fat diet (HFD) until day 100. Glucose tolerance was measured at 56 and 98 days, and body fat content at 21, 52 and 97 days. RESULTS: IUGRmx had the greatest growth during lactation, but from day 22 to day 54, both IUGR groups gained less body weight than the REF (P < 0.05). In the short-term (58 days), IUGRmx tended to be longer (P = 0.06) and had less body fat (P = 0.03) than IUGRc. These differences were not seen after HFD. Microarray analysis of hepatic mRNA expression at 58 and 100 days revealed a gender-dependent treatment effect, and expression of genes related to lipid metabolism was the most affected. Twelve of these genes were selected for studying differences in DNA methylation in the promoter region, for some, we observed age- and gender-related differences but none because of treatment. CONCLUSION: The nutritional intervention promoted catch-up growth and normalized excessive adiposity in IUGR animals at short-term. The benefits did not extend after a period of HFD. IUGR and early diet had gender-dependent effects on hepatic gene expression.

Unusual systemic metastases of malignant seminoma in a dog.

Unilateral enlargement of left testicle and scrotum was detected in an 8-year-old West Highland White Terrier. The histopathological diagnosis after surgery was a seminoma (SEM) tumour, and a diagnosis of metastatic foci was also detected in vaginal tunic and scrotum. Two months later, new metastatic SEM foci in the skin were diagnosed. Twenty-two months after the initial orchiectomy new multiple cutaneous nodules and a swelling of periesophageal structures were observed. Finally, the necropsy revealed multiple malignant metastatic SEM focus. To the author's knowledge, this is the first description of a canine SEM with unusual widespread metastasis on the base of tongue, soft palate, trachea and pericardium.

[Vascular risk factors in HIV-infected patients in a penitentiary center]. / Factores de riesgo vascular en pacientes infectados por el VIH en un centro penitenciario.

OBJECTIVE: There is little data regarding vascular risk factors (VRF) in HIV-infected inmates. In this study, we have studied the prevalence of VRF in HIV-infected patients, analyzing the differences with a non-infected population. PATIENTS AND METHOD: HIV-infected inmates (n=80) and two non-HIV controls selected for each patient and matched for age and sex (n=160) were included in a descriptive cross-sectional study. We analyzed the VRF, and risk was assessed according to the SCORE, Framingham and REGICOR functions. RESULTS: In the studied population (mean age: 38.1 years; 92.5% men), HIV-infected patients had a significantly higher prevalence of cigarette smoking (97.5 vs 78.8%), diabetes (8.8 vs 1.3%), serum triglyceride s>150 mg/dl (43.8 vs 26.3%), low HDL-cholesterol levels (61.3 vs 40.6%), HCV infection (87.5 vs 22.5%), and cocaine consumption (77.5 vs 39.4%). The non-infected group had significantly higher prevalence of total cholesterol>200mg/dl and/or LDL-cholesterol >130 mg/dl (45.6 vs 28.8%), obesity (14.4 vs 2.5%), sedentary lifestyle (67.5 vs 42.5%) and increased waist circumference (14.4 vs 3.8%). All the evaluated inmates were considered to be at a low risk by SCORE and REGICOR, and 1.3% to be at a high risk by Framingham in both groups. CONCLUSION: The prevalence of VRF in HIV-infected patients of the studied prison was much higher to that of the HIV-negative subjects. However, the estimation of the cardiovascular risk was low.

Factores de riesgo vascular en pacientes infectados por el VIH en un centro penitenciario / Vascular risk factors in HIV-infected patients in a penitentiary center

Objetivo. Los factores de riesgo vascular (FRV) en pacientes penitenciarios infectados por el VIH (VIH+) no se conocen en toda su extensión. Hemos estudiado la prevalencia de estos factores en pacientes VIH+, en comparación con una población no infectada (VIH–). Pacientes y método. Estudio descriptivo transversal en el que se incluyeron pacientes VIH+ (n=80) de un centro penitenciario. Por cada paciente se analizaron dos internos VIH−, emparejados por edad y sexo (n=160). Se analizaron los FRV, y se estimó el riesgo vascular según las funciones de SCORE, Framingham y REGICOR. Resultados. Los 80 pacientes seleccionados (92,5% varones) tenían una edad media de 38,1 años. Los enfermos VIH+ presentaron una prevalencia significativamente mayor de tabaquismo (97,5 frente al 78,8%), infección por el VHC (87,5 frente al 22,5%), consumo de cocaína (77,5 frente al 39,4%), niveles bajos de colesterol-HDL (61,3 frente al 40,6%), triglicéridos elevados (43,8 frente al 26,3%), y diabetes mellitus (8,8 frente al 1,3%) que los internos VIH−. Entre los VIH− hubo significativamente más pacientes con niveles de colesterol total >200 mg/dl y/o colesterol-LDL >130 mg/dl (45,6 vs. 28,8%), con obesidad (14,4 vs. 2,5%), sedentarismo (67,5 vs. 42,5%) y con un perímetro abdominal de riesgo (14,4 vs. 3,8%). Todos los internos tuvieron una estimación de riesgo bajo según las ecuaciones SCORE y REGICOR, tan solo un 1,3%, según la ecuación de Framingham, mostraron un riesgo elevado. Conclusiones. La prevalencia de los FRV en los pacientes VIH+ del centro penitenciario estudiado fue muy superior a la de los sujetos VIH−. Sin embargo, la estimación del riesgo vascular fue reducida(AU)

Objective. There is little data regarding vascular risk factors (VRF) in HIV-infected inmates. In this study, we have studied the prevalence of VRF in HIV-infected patients, analyzing the differences with a non-infected population. Patients and method. HIV-infected inmates (n=80) and two non-HIV controls selected for each patient and matched for age and sex (n=160) were included in a descriptive cross-sectional study. We analyzed the VRF, and risk was assessed according to the SCORE, Framingham and REGICOR functions. Results. In the studied population (mean age: 38.1 years; 92.5% men), HIV-infected patients had a significantly higher prevalence of cigarette smoking (97.5 vs 78.8%), diabetes (8.8 vs 1.3%), serum triglycerides>150mg/dl (43.8 vs 26.3%), low HDL-cholesterol levels (61.3 vs 40.6%), HCV infection (87.5 vs 22.5%), and cocaine consumption (77.5 vs 39.4%). The non-infected group had significantly higher prevalence of total cholesterol>200mg/dl and/or LDL-cholesterol >130mg/dl (45.6 vs 28.8%), obesity (14.4 vs 2.5%), sedentary lifestyle (67.5 vs 42.5%) and increased waist circumference (14.4 vs 3.8%). All the evaluated inmates were considered to be at a low risk by SCORE and REGICOR, and 1.3% to be at a high risk by Framingham in both groups. Conclusion. The prevalence of VRF in HIV-infected patients of the studied prison was much higher to that of the HIV-negative subjects. However, the estimation of the cardiovascular risk was low(AU)

Antibiotic administration early in life impairs specific humoral responses to an oral antigen and increases intestinal mast cell numbers and mediator concentrations.

In this study, we assessed the effect of administering the antibiotic amoxicillin to rat pups on the immune response to orally fed ovalbumin (OVA). We first established that amoxicillin administration durably altered the gut microbiota of these animals. In parallel, we observed that the induction of the specific humoral response to ovalbumin was impaired when it occurred during antibiotic administration to the rat pups. We also examined the consequences of those observations on further allergic reactions. Amoxicillin administration had no significant impact on subsequent sensitization to OVA, as nonexacerbated systemic allergic responses were induced in antibiotic-treated animals. However, increased rat mast cell protease II levels and higher mast cell numbers were detected in their small intestines, independently of the antigen administration. Globally, our data suggest that antibiotic administration early in life negatively affects the specific immune response to a luminal antigen when it is first introduced during antibiotic administration. The increased mast cell numbers and mediator concentrations in the intestinal mucosae of the antibiotic-treated animals may testify to the early stages of an altered immune system homeostasis.

Conversion factors for external gamma dose derived from natural radionuclides in soils.

Field in situ gamma radiation exposure rates and laboratory measured radioactivity contents of 1500 Spanish soils were compared. The main objective was to determine if published theoretically derived conversion factors would yield accurate quantitative activity concentration (Bq kg(-1)) for the data carried out in different surveys developed by our laboratory during the last ten years. The in situ external gamma dose rate results were compared to laboratory gamma analysis of soils samples gathered from each site, considering the concentrations of seven radionuclides: 40K, 214Pb, 214Bi, 212Bi, 212Pb, 208Tl and 228Ac. The coefficient of correlation found between these variables indicate a good relationship. A discussion of the factors contributing to the uncertainties as well as measurement procedure are also given in this paper.

The digestion rate of protein is an independent regulating factor of postprandial protein retention.

To evaluate the importance of protein digestion rate on protein deposition, we characterized leucine kinetics after ingestion of "protein" meals of identical amino acid composition and nitrogen contents but of different digestion rates. Four groups of five or six young men received an L-[1-13C]leucine infusion and one of the following 30-g protein meals: a single meal of slowly digested casein (CAS), a single meal of free amino acid mimicking casein composition (AA), a single meal of rapidly digested whey proteins (WP), or repeated meals of whey proteins (RPT-WP) mimicking slow digestion rate. Comparisons were made between "fast" (AA, WP) and "slow" (CAS, RPT-WP) meals of identical amino acid composition (AA vs. CAS, and WP vs. RPT-WP). The fast meals induced a strong, rapid, and transient increase of aminoacidemia, leucine flux, and oxidation. After slow meals, these parameters increased moderately but durably. Postprandial leucine balance over 7 h was higher after the slow than after the fast meals (CAS: 38 +/- 13 vs. AA: -12 +/- 11, P < 0.01; RPT-WP: 87 +/- 25 vs. WP: 6 +/- 19 micromol/kg, P < 0.05). Protein digestion rate is an independent factor modulating postprandial protein deposition.

Neither glutamine nor arginine supplementation of diets increase glutamine body stores in healthy growing rats.

The aim of the work was to resolve whether glutamine and arginine supplemented diets affect plasma and tissue (muscle, liver and intestinal mucosa) glutamine concentrations, as well as glutaminase and glutamine synthetase specific activities. The trial was performed in growing rats fed 10% protein diets for 3 weeks. Protein sources were: whey proteins (W); whey proteins+free glutamine (WG); whey proteins+arginine (WA); and casein+wheat protein hydrolysate+acid whey (39:39:22), as source containing protein-bound glutamine (CGW). Rats fed the control diet (6.4% glutamine) (W) showed comparable glutamine body stores to those of rats fed the WG diet. In fact, glutamine sup- plementation down-regulated the hepatic glutamine synthetic capacity of growing rats (W/WG: 6.8+/-0.3 vs 6.0+/-0.2 nmol/min/mg protein). Arginine supplementation of the diet (up to 9% of the protein content) resulted in a decrease in plasma and tissue glutamine concentrations (W/WA: plasma, 1218+/-51 vs 1031+/-48 micromol/L; liver 7.5+/-0.4 vs 6.5+/-0.2 micromol/g; muscle: 5.7+/-0.2 vs 4.0+/-0.2 micromol/g). These data suggest that glutamine supplementation of the diet does not increase plasma and tissue glutamine concentrations in healthy growing rats, while the addition of arginine to the diet decreases glutamine body stores.

[30 cases of strongyloidiasis at a primary care center: characteristics and possible complications]. / Treinta casos de estrongiloidiasis en un centro de atención primaria: características y posibles complicaciones.

OBJECTIVE: To study the characteristics of the Strongyloides stercoralis infestation in our area. DESIGN: A 30-case series. Survey of workplace behaviour and hygienic conditions in the home. Review of clinical histories to check for factors putting subjects at risk of severe self-infection. SETTING: 21,000 inhabitants covered by the Oliva Health Centre. PATIENTS: All the cases diagnosed between January 1994 and June 1997. MEASUREMENTS AND INTERVENTIONS: The diagnosis was carried out by observing under the microscope both fresh Strongyloides stercoralis larvae and cultures of three serial faecal samples. RESULTS: We found 19 men (63.3%) and 11 women (36.7%), with an average age of 65 (SD, 11.5 years). 28 had been born in the area (93.4%). 15 had never travelled abroad (50%). Of the 19 men, 18 (94%) had done agricultural work barefoot, but none of the women. Clinically, 17 (56.6%) had chronic symptoms; cough was the most common, in 12 (40%). CONCLUSION: Incidence in our area of Strongyloidiasis, although diagnosed infrequently, has increased considerably with the systematic discarding of the infection in non-attributable cases of Eosinophilia.

Study of the occurrence of 222Rn and 226Ra in drinking water in Spain.

With the aim of determining the contribution of water to the background of natural radiation in Spain, the 222Rn concentration levels were measured in domestic drinking water from a large part of the country. The water analyzed, both surface and groundwater, was collected in two areas of very distinct geological characteristics, pre-selected for the likelihood of their containing high levels of 222Rn. This water was measured using a coaxial detector of high purity Ge. The overall results demonstrate a log-normal distribution of 222Rn levels, with a geometric and arithmetic means of 10 and 381 Bq L-1, respectively, and a range between detection limit of 2 Bq L-1 and a maximum of 31,000 Bq L-1. The 222Rn concentrations measured in surface water are generally below the detection limit. Significant differences have been found depending on the geological characteristics of the area of reference, although the very distinct concentration levels of 222Rn found in samples of similar lithology imply the influence of more complex factors in the solution of 222Rn in water. Due to the relationship between radon and 226Ra, the concentration of the latter was measured in the same water using radiochemical separation and a scintillation ZnS(Ag) detector. No significant correlation between 226Ra and 222Rn concentrations has been observed unless measurements carried out in a high background radiation region are considered separately.

Natural radioactivity in Spanish soils.

The program of studies and surveys of natural radiation and radioactivity in Spain organized by our research group at the end of the 1980s included a 4-y national survey to determine the concentrations of natural radionuclides in soil. Results obtained from measurements of soil samples collected nationwide at > 900 sampling sites are reported and discussed in this paper. Correlations between absorbed dose rates in air calculated from natural radionuclide concentrations in soil and terrestrial gamma dose rates measured experimentally outdoors are shown for the different autonomous regions of Spain. Assessment is also made of the dose to the Spanish population from outdoor exposure to terrestrial gamma rays.