Pathway-based integration of multi-omics data reveals lipidomics alterations validated in an Alzheimer's disease mouse model and risk loci carriers.

Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder. Despite increasing evidence of the importance of metabolic dysregulation in AD, the underlying metabolic changes that may impact amyloid plaque formation are not understood, particularly for late-onset AD. This study analyzed genome-wide association studies (GWAS), transcriptomics, and proteomics data obtained from several data repositories to obtain differentially expressed (DE) multi-omics elements in mouse models of AD. We characterized the metabolic modulation in these data sets using gene ontology, transcription factor, pathway, and cell-type enrichment analyses. A predicted lipid signature was extracted from genome-scale metabolic networks (GSMN) and subsequently validated in a lipidomic data set derived from cortical tissue of ABCA-7 null mice, a mouse model of one of the genes associated with late-onset AD. Moreover, a metabolome-wide association study (MWAS) was performed to further characterize the association between dysregulated lipid metabolism in human blood serum and genes associated with AD risk. We found 203 DE transcripts, 164 DE proteins, and 58 DE GWAS-derived mouse orthologs associated with significantly enriched metabolic biological processes. Lipid and bioenergetic metabolic pathways were significantly over-represented across the AD multi-omics data sets. Microglia and astrocytes were significantly enriched in the lipid-predominant AD-metabolic transcriptome. We also extracted a predicted lipid signature that was validated and robustly modeled class separation in the ABCA7 mice cortical lipidome, with 11 of these lipid species exhibiting statistically significant modulations. MWAS revealed 298 AD single nucleotide polymorphisms-metabolite associations, of which 70% corresponded to lipid classes. These results support the importance of lipid metabolism dysregulation in AD and highlight the suitability of mapping AD multi-omics data into GSMNs to identify metabolic alterations.

Somatic SNCA Copy Number Variants in Multiple System Atrophy are Related to Pathology and Inclusions.

BACKGROUND: Somatic α-synuclein (SNCA) copy number variants (CNVs, specifically gains) occur in multiple system atrophy (MSA) and Parkinson's disease brains. OBJECTIVE: The aim was to compare somatic SNCA CNVs in MSA subtypes (striatonigral degeneration [SND] and olivopontocerebellar atrophy [OPCA]) and correlate with inclusions. METHODS: We combined fluorescent in situ hybridization with immunofluorescence for α-synuclein and in some cases oligodendrocyte marker tubulin polymerization promoting protein (TPPP). RESULTS: We analyzed one to three brain regions from 24 MSA cases (13 SND, 11 OPCA). In a region preferentially affected in one subtype (putamen in SND, cerebellum in OPCA), mosaicism was higher in that subtype, and cells with CNVs were 4.2 times more likely to have inclusions. In the substantia nigra, nonpigmented cells with CNVs and TPPP were about six times more likely to have inclusions. CONCLUSIONS: The correlation between SNCA CNVs and pathology (at a regional level) and inclusions (at a single-cell level) suggests a role for somatic SNCA CNVs in MSA pathogenesis. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Serum Levels of MicroRNA-206 and Novel Mini-STR Assays for Carrier Detection in Duchenne Muscular Dystrophy.

Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disorder in which the detection of female carriers is of the utmost importance for genetic counseling. Haplotyping with polymorphic markers and quantitation of creatine kinase levels (CK) allow tracking of the at-risk haplotype and evidence muscle damage, respectively. Such approaches are useful for carrier detection in cases of unknown mutations. The lack of informative markers and the inaccuracy of CK affect carrier detection. Therefore, herein we designed novel mini-STR (Short Tandem Repeats) assays to amplify 10 loci within the DMD gene and estimated allele frequencies and the polymorphism information content among other parameters in 337 unrelated individuals from three Mexican populations. In addition, we tested the utility of the assays for carrier detection in three families. Moreover, given that serum levels of miR-206 discern between DMD patients and controls with a high area under the curve (AUC), the potential applicability for carrier detection was assessed. The serum levels of miR-206 of non-carriers (n = 24) and carriers (n = 23) were compared by relative quantitation using real-time PCR (p < 0.05), which resulted in an AUC = 0.80 in the Receiver Operating Characteristic curve analysis. In conclusion, miR-206 has potential as a "liquid biopsy" for carrier detection and genetic counseling in DMD.

Neurotrophin blood-based gene expression and social cognition analysis in patients with autism spectrum disorder.

Autism spectrum disorders (ASD) comprise neurodevelopmental disorders with clinical onset during the first years of life. The identification of peripheral biomarkers could significantly impact diagnosis and an individualized, early treatment. Although the aetiology of ASD remains poorly understood, there is increasing evidence that neurotrophins and their receptors represent a group of candidate genes for ASD pathophysiology and biomarker research. Total messenger RNA (mRNA) from whole blood was obtained from adolescents and adults diagnosed as ASD (n = 21) according to DSM-IV criteria and confirmed by the Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview-Revised (ADI-R) algorithms, as well as healthy controls (n = 10). The mRNA expression of neurotrophins (BDNF, NT3 and NT4) and their receptors (TrkA, TrkB and p75 (NTR) ) was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, social cognition abilities of ASD patients and controls were determined according to three Theory of Mind (ToM) tests (Reading the Mind in the Eyes, Faux pas, and Happé stories). The NT3 and NT4 mRNA expression in the whole blood was significantly lower in ASD compared to healthy controls, while p75(NTR) was higher (P < 0.005). In addition, lower scores in three of the ToM tests were observed in ASD subjects compared to controls. A significant (P < 0.005) ToM impairment in Happé stories test was demonstrated in ASD. Nevertheless, no correlations were observed between neurotrophins and their receptors expressions and measures of ToM. Given their potential as peripheral blood-based biomarkers, NT3, NT4 and p75 (NTR) mRNA expression patterns may be useful tools for a more personalized diagnostics and therapy in ASD. Further investigations with larger numbers of samples are needed to verify these results.

Comparison of mutation profiles in the Duchenne muscular dystrophy gene among populations: implications for potential molecular therapies.

Novel therapeutic approaches are emerging to restore dystrophin function in Duchenne Muscular Dystrophy (DMD), a severe neuromuscular disease characterized by progressive muscle wasting and weakness. Some of the molecular therapies, such as exon skipping, stop codon read-through and internal ribosome entry site-mediated translation rely on the type and location of mutations. Hence, their potential applicability worldwide depends on mutation frequencies within populations. In view of this, we compared the mutation profiles of the populations represented in the DMD Leiden Open-source Variation Database with original data from Mexican patients (n = 162) with clinical diagnosis of the disease. Our data confirm that applicability of exon 51 is high in most populations, but also show that differences in theoretical applicability of exon skipping may exist among populations; Mexico has the highest frequency of potential candidates for the skipping of exons 44 and 46, which is different from other populations (p < 0.001). To our knowledge, this is the first comprehensive comparison of theoretical applicability of exon skipping targets among specific populations.

Non-Invasive Biomarkers for Duchenne Muscular Dystrophy and Carrier Detection.

Non-invasive biological indicators of the absence/presence or progress of the disease that could be used to support diagnosis and to evaluate the effectiveness of treatment are of utmost importance in Duchenne Muscular Dystrophy (DMD). This neuromuscular disorder affects male children, causing weakness and disability, whereas female relatives are at risk of being carriers of the disease. A biomarker with both high sensitivity and specificity for accurate prediction is preferred. Until now creatine kinase (CK) levels have been used for DMD diagnosis but these fail to assess disease progression. Herein we examined the potential applicability of serum levels of matrix metalloproteinase 9 and matrix metalloproteinase 2, tissue inhibitor of metalloproteinases 1, myostatin (GDF-8) and follistatin (FSTN) as non-invasive biomarkers to distinguish between DMD steroid naïve patients and healthy controls of similar age and also for carrier detection. Our data suggest that serum levels of MMP-9, GDF-8 and FSTN are useful to discriminate DMD from controls (p < 0.05), to correlate with some neuromuscular assessments for DMD, and also to differentiate between Becker muscular dystrophy (BMD) and Limb-girdle muscular dystrophy (LGMD) patients. In DMD individuals under steroid treatment, GDF-8 levels increased as FSTN levels decreased, resembling the proportions of these proteins in healthy controls and also the baseline ratio of patients without steroids. GDF-8 and FSTN serum levels were also useful for carrier detection (p < 0.05). Longitudinal studies with larger cohorts are necessary to confirm that these molecules correlate with disease progression. The biomarkers presented herein could potentially outperform CK levels for carrier detection and also harbor potential for monitoring disease progression.

Altered peripheral BDNF mRNA expression and BDNF protein concentrations in blood of children and adolescents with autism spectrum disorder.

Findings from molecular genetic studies and analyses of postmortem and peripheral tissue led to the hypothesis that neurotrophins-as crucial moderators of neuroplasticity-impact on the pathophysiology of autism spectrum disorder (ASD). The study projects aimed to complement former results on the role of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family with fundamental impact on brain development and function. The purpose of this work was to investigate peripheral BDNF mRNA expression and BDNF protein concentrations in ASD as potential surrogates for the effects observed in the central nervous system. In a BDNF protein quantification study, serum concentrations were analyzed using Enzyme-Linked Immunosorbent Assays in 24 male patients with ASD, all with an IQ > 70 (age 13.9 ± 3.0 years) and 20 age- and gender-matched healthy control subjects (age 14.4 ± 2.1 years; p = 0.522). In a further independent project, a BDNF mRNA expression analysis, mRNA levels from total blood were assessed by quantitative real-time polymerase chain reaction in a sample of 16 male ASD patients (age 10.8 ± 2.2), 15 age- and gender-matched healthy controls (age 12.1 ± 2.2) and 15 patients with attention deficit hyperactivity disorder as a clinical control group (age 11.8 ± 2.2; p = 0.207). In the protein quantification project, significantly decreased BDNF serum concentrations were found in ASD cases compared to healthy control children (t = -2.123, df = 42, p < 0.05). Analysis of covariance (ANCOVA) revealed this result in accordance with significant reductions in BDNF mRNA expression in ASD, observed in the mRNA expression study (F = 3.65; df = 2.43; p < 0.05); neither age nor IQ confounded the result, as indicated by ANCOVA (F = 3.961; df = 2.41; p < 0.05, η (2) = 0.162). Our study projects supported the notion that neurotrophins are involved in the pathophysiology of ASD. Further studies may eventually contribute to the identification of distinct peripheral mRNA expression and protein concentration patterns possibly supporting diagnostic and therapeutic processes.

The Effect of the Season on the Time Dependent Changes in Colostrum Lactoferrin Level in Murciano-Granadina Goats in Intensive System Farming.

The aim of this research was to evaluate the effects of postpartum day and parity season on the lactoferrin (LF), immunoglobulin G (IgG), and chemical composition of Murciano-Granadina goat colostrum during the first 96 h after kidding, and the use of the Brix refractometer to estimate IgG content. A herd of 3500 intensively managed Murciano-Granadina dairy goats (45-50 kg body weight) was used. Colostrum samples were collected from days 1 to 4 postpartum in the winter, spring, summer, and autumn. The colostrum composition was assessed using an automated infrared method; the LF and IgG concentrations were measured using an ELISA, and for the Brix percentage, we used a digital refractometer. Colostrum taken on the first postpartum day showed the highest concentrations of LF, IgG, proteins and non-fat solids (NFSs). As the postpartum days progressed, a rapid decrease in the LF, IgG, protein, and NFS contents and the Brix value was observed. In contrast, the lactose content increased steadily until the fourth postpartum day (p < 0.001). The season influenced milk yield, LF, IgG, protein, fat, and somatic cell content (p < 0.05). LF contents were significantly higher in the spring season, IgG contents were higher in autumn colostrum, and fat components were higher in the winter season. The colostrum Brix value showed a positive correlation with the ELISA colostrum LF (r = 0.716, p < 0.001) and IgG (r = 0.894, p < 0.001) determination; a 20 mg IgG/mL colostrum concentration corresponded to 18 °Brix. Our results corroborate the importance of feeding colostrum to newborns on the first day after birth, not only because of its high level of IgG but also because of its greater presence of the other bioactive protein compounds such as lactoferrin.

Metabolic Control of Microglia.

Microglia, immune sentinels of the central nervous system (CNS), play a critical role in maintaining its health and integrity. This chapter delves into the concept of immunometabolism, exploring how microglial metabolism shapes their diverse immune functions. It examines the impact of cell metabolism on microglia during various CNS states, including homeostasis, development, aging, and inflammation. Particularly in CNS inflammation, the chapter discusses how metabolic rewiring in microglia can initiate, resolve, or perpetuate inflammatory responses. The potential of targeting microglial metabolism as a therapeutic strategy for chronic CNS disorders with prominent innate immune cell activation is also explored.

Integrated multi-omics analysis reveals molecular changes associated with chronic lipid accumulation following contusive spinal cord injury.

Functional and pathological recovery after spinal cord injury (SCI) is often incomplete due to the limited regenerative capacity of the central nervous system (CNS), which is further impaired by several mechanisms that sustain tissue damage. Among these, the chronic activation of immune cells can cause a persistent state of local CNS inflammation and damage. However, the mechanisms that sustain this persistent maladaptive immune response in SCI have not been fully clarified yet. In this study, we integrated histological analyses with proteomic, lipidomic, transcriptomic, and epitranscriptomic approaches to study the pathological and molecular alterations that develop in a mouse model of cervical spinal cord hemicontusion. We found significant pathological alterations of the lesion rim with myelin damage and axonal loss that persisted throughout the late chronic phase of SCI. This was coupled by a progressive lipid accumulation in myeloid cells, including resident microglia and infiltrating monocyte-derived macrophages. At tissue level, we found significant changes of proteins indicative of glycolytic, tricarboxylic acid cycle (TCA), and fatty acid metabolic pathways with an accumulation of triacylglycerides with C16:0 fatty acyl chains in chronic SCI. Following transcriptomic, proteomic, and epitranscriptomic studies identified an increase of cholesterol and m6A methylation in lipid-droplet-accumulating myeloid cells as a core feature of chronic SCI. By characterizing the multiple metabolic pathways altered in SCI, our work highlights a key role of lipid metabolism in the chronic response of the immune and central nervous system to damage.

SUMOtherapeutics for Ischemic Stroke.

The small, ubiquitin-like modifier (SUMO) is a post-translational modifier with a profound influence on several key biological processes, including the mammalian stress response. Of particular interest are its neuroprotective effects, first recognized in the 13-lined ground squirrel (Ictidomys tridecemlineatus), in the context of hibernation torpor. Although the full scope of the SUMO pathway is yet to be elucidated, observations of its importance in managing neuronal responses to ischemia, maintaining ion gradients, and the preconditioning of neural stem cells make it a promising therapeutic target for acute cerebral ischemia. Recent advances in high-throughput screening have enabled the identification of small molecules that can upregulate SUMOylation, some of which have been validated in pertinent preclinical models of cerebral ischemia. Accordingly, the present review aims to summarize current knowledge and highlight the translational potential of the SUMOylation pathway in brain ischemia.

Integrative transcriptomic and metabolic analyses of the mammalian hibernating brain identifies a key role for succinate dehydrogenase in ischemic tolerance.

Ischemic stroke results in a loss of tissue homeostasis and integrity, the underlying pathobiology of which stems primarily from the depletion of cellular energy stores and perturbation of available metabolites 1 . Hibernation in thirteen-lined ground squirrels (TLGS), Ictidomys tridecemlineatus , provides a natural model of ischemic tolerance as these mammals undergo prolonged periods of critically low cerebral blood flow without evidence of central nervous system (CNS) damage 2 . Studying the complex interplay of genes and metabolites that unfolds during hibernation may provide novel insights into key regulators of cellular homeostasis during brain ischemia. Herein, we interrogated the molecular profiles of TLGS brains at different time points within the hibernation cycle via RNA sequencing coupled with untargeted metabolomics. We demonstrate that hibernation in TLGS leads to major changes in the expression of genes involved in oxidative phosphorylation and this is correlated with an accumulation of the tricarboxylic acid (TCA) cycle intermediates citrate, cis-aconitate, and α-ketoglutarate-αKG. Integration of the gene expression and metabolomics datasets led to the identification of succinate dehydrogenase (SDH) as the critical enzyme during hibernation, uncovering a break in the TCA cycle at that level. Accordingly, the SDH inhibitor dimethyl malonate (DMM) was able to rescue the effects of hypoxia on human neuronal cells in vitro and in mice subjected to permanent ischemic stroke in vivo . Our findings indicate that studying the regulation of the controlled metabolic depression that occurs in hibernating mammals may lead to novel therapeutic approaches capable of increasing ischemic tolerance in the CNS.

UTP affects the Schwannoma cell line proteome through P2Y receptors leading to cytoskeletal reorganisation.

Glial cells in the peripheral nervous system, such as Schwann cells, respond to nucleotides, which play an important role in axonal regeneration and myelination. Metabotropic P2Y receptor agonists are promising therapeutic molecules for peripheral neuropathies. Nevertheless, the proteomic mechanisms involved in nucleotide action on Schwann cells remain unknown. Here, we studied intracellular protein changes in RT4-D6P2T Schwann cells after treatment with nucleotides and Nucleo CMP Forte (CMPF), a nucleotide-based drug. After treatment with CMPF, 2-D DIGE revealed 11 differential gel spots, which were all upregulated. Among these, six different proteins were identified by MS. Some of these proteins are involved in actin remodelling (actin-related protein, Arp3), membrane vesicle transport (Rab GDP dissociation inhibitor ß, Rab GDI), and the endoplasmic reticulum stress response (protein disulfide isomerase A3, PDI), which are hallmarks of a possible P2Y receptor signalling pathway. Expression of P2Y receptors in RT4-D6P2T cells was demonstrated by RT-PCR and a transient elevation of intracellular calcium measured in response to UTP. Actin reorganisation was visualized after UTP treatment using phalloidin-FITC staining and was blocked by the P2Y antagonist suramin, which also inhibited Arp3, Rab GDI, and PDI protein upregulation. Our data indicate that extracellular UTP interacts with Schwann P2Y receptors and activates molecular machinery that induces changes in the glial cell cytoskeleton.

[Takayasu arteritis. Therapeutic alternatives and long term outcomes]. / Arteritis de Takayasu. Alternativas terapéuticas y pronóstico a largo plazo.

The aim of this study was to describe the long term prognosis of 34 patients with Takayasu arteritis and the results of surgical and endovascular treatment. A total of 5 central surgeries and 53 endovascular procedures were performed including 18 bypass surgeries (33.8%) and 35 angioplasties (66.2%). The median follow-up was 7.5 years, interquartile range [IQR] 2.6-12.5. Among the 18 bypass surgeries 6 (33.3%) had events, while in the 35 patients with endovascular treatment there were 16 events (45.7%). The overall 1-, 3-, 5-, and 10-year death and arterial complication-free survival rates were 80% (95% CI between 74 and 89%), 68% (95% CI between 58 and 79%), 65% (95% CI between 54 and 76%) and 47% (95% CI between 41 and 62%). Both revascularization techniques were initially successful. In long term follow-up there was a high restenosis recurrence rate with endovascular treatment requiring repeated revascularization to the same vessel in 41% of the cases. Surgery had higher mortality in patients with aortic and ascending aortic valve disease, combined coronary artery disease and carotid disease. In long term follow up Takayasu arteritis frequently requires revascularization and restenosis or new lesions are common. Surgical treatment had better results with less restenosis than angioplasty.

Se analizaron los resultados del tratamiento quirúrgico y endovascular a 7.5 años, rango intercuartilo (RIC) entre 2.6 y 12.5 años de seguimiento en 34 pacientes con arteritis de Takayasu. Se realizaron en total 5 cirugías cardíacas centrales y 53 procedimientos vasculares,18 cirugías de bypass (33.9%) y 35 angioplastías (66.1%). Entre los 18 procedimientos quirúrgicos realizados, 6 (33.3%) presentaron eventos, mientras que en los 35 con intervención percutánea hubo 16 eventos (45.7%). La supervivencia actuarial y otras complicaciones vasculares (método de Kaplan y Meier) a 1,3,5 y 10 años fue: 80% (IC 95% entre 74 y 89%), 68% (IC 95% entre 58 y 79%), 65% (IC 95% entre 54 y 76%) y 47% (IC 95% entre 41 y 62%).Tanto la revascularización endovascular como la quirúrgica fueron inicialmente exitosas. En el seguimiento del tratamiento endovascular hubo una alta tasa de eventos con necesidad de revascularización repetida a un mismo vaso en el 41% de los casos. La cirugía tuvo mayor mortalidad en pacientes con valvulopatía aórtica, de aorta ascendente y enfermedad coronaria y carotidea combinada. La arteritis de Takayasu requiere frecuentemente revascularización debido a reestenosis y lesiones de novo. En su evolución alejada, el procedimiento quirúrgico ofreció mejores resultados con menor reestenosis.

Comprehensive short and long read sequencing analysis for the Gaucher and Parkinson's disease-associated GBA gene.

GBA variants carriers are at increased risk of Parkinson's disease (PD) and Lewy body dementia (LBD). The presence of pseudogene GBAP1 predisposes to structural variants, complicating genetic analysis. We present two methods to resolve recombinant alleles and other variants in GBA: Gauchian, a tool for short-read, whole-genome sequencing data analysis, and Oxford Nanopore sequencing after PCR enrichment. Both methods were concordant for 42 samples carrying a range of recombinants and GBAP1-related mutations, and Gauchian outperformed the GATK Best Practices pipeline. Applying Gauchian to sequencing of over 10,000 individuals shows that copy number variants (CNVs) spanning GBAP1 are relatively common in Africans. CNV frequencies in PD and LBD are similar to controls. Gains may coexist with other mutations in patients, and a modifying effect cannot be excluded. Gauchian detects more GBA variants in LBD than PD, especially severe ones. These findings highlight the importance of accurate GBA analysis in these patients.

Is Ankyrin a genetic risk factor for psychiatric phenotypes?

BACKGROUND: Genome wide association studies reported two single nucleotide polymorphisms in ANK3 (rs9804190 and rs10994336) as independent genetic risk factors for bipolar disorder. Another SNP in ANK3 (rs10761482) was associated with schizophrenia in a large European sample. Within the debate on common susceptibility genes for schizophrenia and bipolar disorder, we tried to investigate common findings by analyzing association of ANK3 with schizophrenia, bipolar disorder and unipolar depression. METHODS: We genotyped three single nucleotide polymorphisms (SNPs) in ANK3 (rs9804190, rs10994336, and rs10761482) in a case-control sample of German descent including 920 patients with schizophrenia, 400 with bipolar affective disorder, 220 patients with unipolar depression according to ICD 10 and 480 healthy controls. Sample was further differentiated according to Leonhard's classification featuring disease entities with specific combination of bipolar and psychotic syndromes. RESULTS: We found no association of rs9804190 and rs10994336 with bipolar disorder, unipolar depression or schizophrenia. In contrast to previous findings rs10761482 was associated with bipolar disorder (p = 0.015) but not with schizophrenia or unipolar depression. We observed no association with disease entities according to Leonhard's classification. CONCLUSION: Our results support a specific genetic contribution of ANK3 to bipolar disorder though we failed to replicate findings for schizophrenia. We cannot confirm ANK3 as a common risk factor for different diseases.

[Population analysis by area of health of changes in consumption, price and expenditure of cardiovascular drugs in eight autonomous communities, Spain, 2005]. / Análisis poblacional por áreas de salud de las variaciones en consumo, precio y gasto de medicamentos cardiovasculares en 8 comunidades autónomas, españa, 2005.

BACKGROUND: Variability in cardiovascular drugs is of great interest because of its high population use, its high expenditure and the availability of strong evidence supporting its use. The aim of this study is to describe variation in dispensation, price and pharmaceutical expenditure for 11 subgroups of cardiovascular drugs by healthcare areas. METHODS: This was a population study describing dispensation for 11 subgroups of cardiovascular drugs among healthcare areas in 2005. POPULATION: 93 healthcare areas of the 8 participant Autonomous Regions. ANALYSIS: Descriptive analysis of dispensation (Defined Daily Dose (DDD) per 1,000 pensioners and day (DDD/1000P/Day), average price (euros per DDD), pharmaceutical expenditure (euros per 100 pensioners) and standardized consumption ratios. Small-area variation analysis was used to analyze observed variability. RESULTS: Consumption of cardiovascular drugs oscillated between 324 DDD/1000p/Day for drugs with action on the renin-angiotensin system, and 6.5 DDD/1000p/Day for anti-aldosterone diuretics. Variation in consumption for areas in the 5th and 95th percentiles went from 1.8 times (digitalics) to 17.2 times (flavonoids), although most of the groups showed an extremal quotient of around 5. Variation in average prices was lower than in consumption (1.1 times for doxazosin and 3.7 for flavonoids) and variations in pharmaceutical expenditure was similar to variation in consumption (from 2.0 timesfor digitalics to 13.0 times for flavonoids). CONCLUSIONS: Major variations in the consumption of cardiovascular drugs between healthcare areas, together with discreet variations in price mean there are big differences in pharmaceutical expenditure from one population to another.

Effect of Parity on Reproductive Performance and Composition of Sow Colostrum during First 24 h Postpartum.

The aim of this study is to assess the effects of parity number on sow reproductive performance and the chemical and immunological composition of colostrum and immunoglobin concentrations in the sera of the sows. Colostrum samples were collected at 0, 6 and 24 h after the births of the first piglets from 56 sows with different numbers of parturitions (ranging 1-6). The piglets born alive to primiparous sows had lower birth weights (p < 0.05) than piglets from second and fourth parturition sows. The colostrum composition was influenced (p < 0.05) by parity number: primiparous sows had higher concentrations of dry matter, fat, lactose and non-fat-solids. No parity-dependent differences were found concerning total protein amount. Colostrum composition was drastically affected (p < 0.001) by sampling time-the highest concentrations of dry matter and protein and lowest concentrations of fat and lactose were found immediately after parturition (0 h). The study revealed no effect of parity (p ≥ 0.05) on the concentrations of immunoglobulins in colostrum. The immunoglobulin with the highest level in sow serum at day 110 of gestation was IgG, while IgA showed the lowest values and greater variability with respect to parity from an immunological point of view. Regarding the relationship between serum Ig levels at the end of gestation and colostrum Ig, serum IgG showed a strong correlation with colostrum IgG and IgM, while colostrum IgG was strongly related with colostrum IgM, but not with IgA. IgA did not correlate with any other immunoglobulin. The different behaviors of the immunoglobins in colostrum were probably due to IgG coming almost exclusively from the sows' sera, whereas IgA is mainly synthetized by the mammary gland.