Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Risk in Patients with Chronic Kidney Disease without Previous Cardiac Pathology.

Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the clonal expansion of hematopoietic stem cells carrying certain genes associated with an increased risk of hematological malignancies. Our study analyzes the influence of CHIP on the risk of heart disease and cardiovascular events in a population with chronic kidney disease (CKD). A total of 128 patients were prospectively followed up for 18 months to detect major cardiovascular events (MACE). To detect the presence of silent heart disease, troponin I, NT-Pro-BNP, and coronary calcification were measured. A massive sequencing was performed to detect CHIP. A total of 24.2% of the patients presented CHIP, including that which was only pathogenic. The most frequently affected gene was TET2 (21.1%). Using multivariate logistic regression analysis, the presence of CHIP was not related to coronary calcification (OR 0.387, 95% CI 0.142-1.058, p = 0.387), nor was it related to troponin I or NT-Pro-BNP. A total of nine patients developed major cardiovascular events. Patients with CHIP did not have a higher risk of major cardiovascular events, although patients with DNMT3A did have a higher risk (HR 6.637, 95% CI 1.443-30.533, p = 0.015), independent of other variables. We did not find that CHIP was associated with a greater risk of silent heart disease or cardiovascular events, although those affected by DNMT3a, analyzed independently, were associated with a greater number of cardiovascular events.

Health and economic benefits of achieving contraceptive and maternal health targets in Small Island Developing States in the Pacific and Caribbean.

INTRODUCTION: Reducing unmet need for modern contraception and expanding access to quality maternal health (MH) services are priorities for improving women's health and economic empowerment. To support investment decisions, we estimated the additional cost and expected health and economic benefits of achieving the United Nations targets of zero unmet need for modern contraceptive choices and 95% coverage of MH services by 2030 in select Small Island Developing States. METHODS: Five Pacific (Kiribati, Samoa, Solomon Islands, Tonga and Vanuatu) and four Caribbean (Barbados, Guyana, Jamaica and Saint Lucia) countries were considered based on population survey data availability. For each country, the Lives Saved Tool was used to model costs, health outcomes and economic benefits for two scenarios: business-as-usual (BAU) (coverage maintained) and coverage-targets-achieved, which scaled linearly from 2022 (following COVID-19 disruptions) coverage of evidence-based family planning and MH interventions to reach United Nations targets, including modern contraceptive methods and access to complete antenatal, delivery and emergency care. Unintended pregnancies, maternal deaths, stillbirths and newborn deaths averted by the coverage-targets-achieved scenario were converted to workforce, education and social economic benefits; and benefit-cost ratios were calculated. RESULTS: The coverage-targets-achieved scenario required an additional US$12.6M (US$10.8M-US$15.9M) over 2020-2030 for the five Pacific countries (15% more than US$82.4M to maintain BAU). This additional investment was estimated to avert 126 000 (40%) unintended pregnancies, 2200 (28%) stillbirths and 121 (29%) maternal deaths and lead to a 15-fold economic benefit of US$190.6M (US$67.0M-US$304.5M) by 2050. For the four Caribbean countries, an additional US$17.8M (US$15.3M-US$22.4M) was needed to reach the targets (4% more than US$405.4M to maintain BAU). This was estimated to avert 127 000 (23%) unintended pregnancies, 3600 (23%) stillbirths and 221 (25%) maternal deaths and lead to a 24-fold economic benefit of US$426.2M (US$138.6M-US$745.7M) by 2050. CONCLUSION: Achieving full coverage of contraceptive and MH services in the Pacific and Caribbean is likely to have a high return on investment.

Suitability of Goat Colostrum to Produce a Fermented Yogurt-Type Product.

The aim of this study was to investigate the potential use of goat colostrum to produce a yogurt-type product as a novel functional dairy food. Four batches of fermented goat colostrum (GCY) were produced using fermented goat milk (GMY) as a reference. Physicochemical, mechanical, and microbial characteristics of cold storage fermented products were evaluated in a weekly basis for 28 days. Sensory analysis was applied to detect potential differences between products and to evaluate the acceptance of GCY by consumers. Results indicate that colostrum showed higher coagulation times than goat milk (480 vs. 350 min to reach pH 4.6). In general, GCY showed a higher protein and fat content and similar features than GMY for most quality parameters, which were highly stable along time. Sensory evaluation led to significant differences between products related to their color and taste. The consumer acceptance test, using a 5 point-Likert scale, showed an overall acceptance of 3.90 ± 0.79 for GCY, with aroma and consistency being the sensory attributes having highest ratings (4.30 ± 0.80 and 4.20 ± 0.96, respectively). Therefore, fermenting goat colostrum with yogurt specific starters could be an interesting alternative to make use of surplus colostrum on farms, allowing for the diversification of commercial goat milk products with potential health benefits for the consumer.

Exchange of cellular components between platelets and tumor cells: impact on tumor cells behavior.

Background: Platelets are active players in tumorigenesis, although the exact interactive mechanisms and their direct impact on tumor cells remain largely unknown. Methods: Bidirectional transference of lipids, proteins and RNA between platelets and tumor cells and its impact on tumor cell behavior and tumor process are analyzed in this work. Phenotypic, genetic and functional modifications induced by platelets were analyzed both in tumor cell lines and in circulating tumor cells (CTCs). Results: Data from these assays showed that platelets transferred structural components to tumor cells with higher efficiency than tumor cells to platelets (p = 0.001). This biological interplay occurred by direct contact, internalization or via extracellular vesicles. As a result, tumor cells acquired platelet markers (CD61 and CD42), showed decreased EpCAM, expressed epithelial-to-mesenchymal transition markers, and increased proliferation rates. Moreover, we were able to detect CD61 in CTCs from early and advanced prostate cancer. Conclusions: Our results demonstrated, for the first time, that platelets educate tumor cells by highly efficient transference of lipids, proteins and RNA through different mechanisms. These results suggest that tumor cells and CTCs might acquire highly dynamic and aggressive phenotypes due to platelets interaction including EMT, stem-like phenotype and high proliferative rates.

Albendazole residues in goat's milk: Interferences in microbial inhibitor tests used to detect antibiotics in milk.

Albendazole (ABZ) residues in goat's milk and their effect on the response of microbial inhibitor tests used for screening antibiotics were evaluated. A total of 18 Murciano-Granadina goats were treated with ABZ and individually milked once a day over a 7-day period. ABZ quantification was performed by high performance liquid chromatography. The ABZ parent drug was not detected. The maximum concentration of its metabolites (ABZ sulfoxide, ABZ sulfone, and ABZ 2-aminosulfone) was reached on the 1st day post treatment (260.0 ± 70.1 µg/kg, 112.8 ± 28.7 µg/kg, 152.0 ± 23.6 µg/kg, respectively), decreasing to lower than the maximum residue limit (MRL, 100 µg/kg) on the 3rd day post treatment. Milk samples were also analyzed by microbial tests [Brilliant Black Reduction Test (BRT) MRL, Delvotest SP-NT MCS and Eclipse 100], and only one positive result was found for Delvotest SP-NT MCS and Eclipse 100. However, a high occurrence of positive outcomes was obtained for BRT MRL during 6 days post treatment, whereas ABZ residues were not detected from the 4th day post administration, suggesting that factors other than the antiparasitic agent might affect the microbial test response.

Interferences on microbial inhibitor tests related to ivermectin treatment in lactating dairy goats.

This Research Communication reports interferences related to the administration of ivermectin in lactating dairy goats on the response of microbial tests for screening antibiotics in milk. Twenty-eight Murciano-Granadina goats, naturally infested with Sarcoptes scabiei var. caprae, were treated with a subcutaneous injection of ivermectin (200 µg/kg b.w.). To prevent re-infestation, a second dose was applied 7 d later. Individual milk samples were collected, daily, up to 15 d post-treatment. Milk samples were analysed by microbial inhibitor tests (BRT MRL, Delvotest SP-NT MCS and Eclipse 100) and ivermectin residues were quantified by HPLC. A large number of positive results were obtained for all microbial tests, especially on the first day after treatment (BRT MRL = 46·4%; Delvotest SP-NT MCS = 14·3%; and Eclipse 100 = 17·8%). However, the highest concentration of drug residues in milk (24·3 ng/ml) was detected on the tenth day after treatment, when positive outcomes were relatively lower (BRT MRL = 17·8%; Delvotest SP-NT MCS = 10·7%; and Eclipse 100 = 7·4%). Results herein suggest that factors related to the ivermectin treatment other than drug residues in milk, or alterations produced by the parasitic disease itself affecting the immune response of animals, could be the cause of false-positive results in microbial tests. It can be concluded that the application of ivermectin in dairy goats infested with sarcoptes mange during lactation produces persistent drug residues in milk, and could also cause false-positive results in microbial inhibitor tests for screening antibiotics.

Composition, proteolysis indices and coagulating properties of ewe milk as affected by bulk tank somatic cell count.

The aim of this study was to assess the effect of ovine bulk tank somatic cell count (BTSCC) on composition, proteose-peptone (p-p) content and casein fractions as indicating parameters for proteolysis and coagulating properties of milk. A total of 97 samples of bulk tank milk from Manchega breed ewe flocks were grouped according to somatic cell count (SCC) into four classes: fewer than 500,000 cells/ml, from 500,000 to 10,00000 cells/ml, from 10,00000 to 15,00000 and more than 15,00000 cells/ml. The casein : protein ratio and lactose content decreased with BTSCC. Proteolysis increased with BTSCC, causing a drop in ß-casein and an increase in the γ-caseins from a concentration of 500,000 cells/ml. Regarding coagulation behaviour, the rennet clotting time (RCT) and firming time (k20) rose from 10,00000-15,00000 cells/ml of milk. The results showed that the impairment of milk quality and milk ability to make cheese as affected by intramammary infection (IMI) can be inferred from the bulk tank milk of flocks with poor udder health.

Detection of antibiotics in goat's milk: effect of detergents on the response of microbial inhibitor tests.

The aim of the study was to evaluate the interference of acid and alkaline detergents employed in the cleaning of milking equipment of caprine dairy farms on the performance of microbial tests used in antibiotic control (BRT MRL, Delvotest MCS, and Eclipse 100). Eight concentrations of commercial detergents, five acid (0-0.25%) and five alkaline (0-1%) were add to antimicrobial-free goat's milk to evaluate the detergent effect on the response of microbial inhibitor tests. To evaluate the effect of detergents on the detection capability of microbial tests two detergents at 0.5 ml/l (one acid and one basic) and eight concentrations of four ß-lactam antibiotics (ampicillin, amoxicillin, cloxacillin and benzylpenicillin) were used. Milk without detergents was used as control. The spiked samples were analysed twelve times by three microbial tests. The results showed that the presence of acid detergents did not affect the response of microbial tests for any of the concentrations tested. However, at concentrations equal to or greater than 2 ml/l alkaline detergents positive results were found in microbial tests (16.7-100%). The detection limits of the screening tests for penicillins were not modified substantially by the presence of detergents. In general, the presence of acid and alkaline detergents in goat's milk did not produce a great interference in the microbial tests, only high concentrations of detergents could cause non-compliant results, but these concentrations are difficult to find in practice if proper cleaning procedures are applied in goat dairy farms.

Asesoramiento genético en enfermedades con herencia mendeliana / Genetic counseling in mendelian inherited diseases

El asesoramiento genético es el proceso de comunicación por el que un profesional con preparación adecuada (genetista) informa al paciente (familia) sobre un diagnóstico genético y sus repercusiones físicas y psíquicas en el individuo y sus familiares, incluyendo el riesgo de recurrencia, opciones reproductivas, posibilidades de tratamiento y/o prevención y apoyo en la toma de decisiones. El cálculo del riesgo reproductivo se basa principalmente en el tipo de herencia de la enfermedad y en el caso de las enfermedades mendelianas suele ser de gran fiabilidad si el estudio genético ha confirmado el diagnóstico de sospecha (AU)

Genetic counselling is a communication process in which a profesional with the required competences (geneticist) explains the genetic condition to the patient, its physical and physiological consequences, the recurrence risk, the reproductive options and the therapeutic and preventive possibilities available, helping the consultant thorough the decision-taking-process. Recurrence risk calculation depends mainly on the mode of inheritance of the disease and, in the case of mendelian conditions is highly reliable if the diagnosis has been confirmed by the genetic test (AU)

Mutaciones de Splicing / Splicing Mutations

El splicing o maduración del pre-mRNA es un mecanismo que está adquiriendo gran relevancia no sólo por las posibilidades que ofrece de expansión del proteoma, sino también por su implicación en la patofisiología de las enfermedades humanas. Las mutaciones de splicing alteran el procesamiento del mRNA al afectar a las secuencias del pre-mRNA (mutaciones en cis) o a las proteínas que intervienen en el splicing (mutaciones en trans). Las secuencias que pueden verse alteradas son: las limitantes de exones e intrones, la zona de ramificación, la zona rica en pirimidinas y también otros elementos reguladores que incrementan o suprimen la selección de un exón. La comprensión en profundidad del efecto de las mutaciones sobre el splicing puede abrir la puerta a su tratamiento mediante terapia moléculas (AU)

Splicing or maturation of pre-mRNA is a mechanism that is becoming more relevant not only for its potential expansion of the proteome, but also for its involvement in the physiopathology of human diseases. Splicing mutations after the processing of mRNA by affecting pre-mRNA sequences (mutations in cis) or proteins involved in splicing (mutations in trans). The sequences that can be altered are: the limiting areas between exons and interns, the branch site, the polypirimidine tract and, finally, other regulatory elements that enhance or suppress the selection of an exon. The whole understanding of the effect of mutations on the splicing processes will help to design molecular therapy targets to correct these defects (AU)

Complejo Sandifer en un paciente con Síndrome Cornelia de Lange y mutación en el gen SMC1A / Sandifer Complex in a patient with Cornelia de Lange Syndrome and mutation in the gene SMC1A

El síndrome Cornelia de Lange es un trastorno del desarrollo hereditario de transmisión dominante que se caracteriza por un fenotipo facial distintivo, anomalías en las extremidades superiores y retraso de crecimiento y psicomotor. Clínicamente se distinguen tres fenotipos: grave, moderado y leve. En la actualidad se conocen tres genes causales del síndrome: NIPBL, SMC1A y SMC3 que codifican proteínas relacionadas con el complejo de cohesinas. Las manifestaciones clínicas más graves suele asociarse a mutaciones en el gen NIPBL, mientras que las mutaciones en los genes SMC1A y SMC3 cursan con cuadros leves y predominio de retraso mental. En este trabajo se describe un paciente con SCdL y mutación en el gen SMC1A que cursa con un fenotipo grave en el que destaca la presencia de un complejo Sandifer y la ausencia de habla (AU)

Cornelia de Lange Syndrome is a dominant inherited developmental disorder characterized by distinctive dysmorphic craniofacial features, limb malformations and growth and cognitive impairment. Clinically, three phenotypes can be distinguished: severe, moderate, and mild. To date, three genes are associated to the disease: NIPBL, SMC1A and SMC3, which encode proteins related with the cohesion complex. The more severe clinical manifestations are seen in patients with mutations in the gene NIPBL, whereas mutations in the genes SMC1A or SMC3 cause mild phenotypes although with cognitive impairment. In this work we reported a patient with mild physical phenotype of CdLS who carries a mutation in SMC1A and has severe clinical manifestations including the Sandifer complex and absence of speech (AU)

Una mutación en el gen SOS1 causa un Fenotipo clásico en el Síndrome de Noonan / A mutation in gene SOS1 causes a classic Phenotype in Noonan Syndrome

El Síndrome de Noonan (SN) (OMIM 16395950) es un trastorno genético autosómico dominante caracterizado por un fenotipo dismórfico (similar al síndrome de Turner), talla baja y cardiopatía congénita. La incidencia del SN se estima entre 1/1000 y 1/2500 de recién nacidos vivos. El fenotipo se caracteriza por unos rasgos faciales peculiares que incluyen ptosis palpebral, hipertelorismo ocular, fisuras palpebrales inclinadas hacia abajo, y orejas de implantación baja. Otros hallazgos frecuentes son talla baja, pectus excavatum retraso mental de grado variable, defectos cardíacos y criptorquidia en varones. En la actualidad existen 4 genes relacionados con el SN, PTPN11, KRAS, SOS1, y RAF1, Y todos ellos codifican proteínas que participan en la vía de señalización Ras/MAPK (AU)

Noon syndrome (NS) (OMIM 16350) is an autosomal dominant genetic syndrome echaracterized by a dysmorphic phenotype (with similarities to Turner syndrome), short stature and congenital heart disease. Its prevalence is estimated in 1/1000 y 1/2500 live newborns. Common physical findings include a distinctive facial appearance with ptosis, ocular hypertelorism, downslanting palpebral fissures and low set ears. Other frequent manifestations include short stature pectus excavatum, psychomotor/mental delay, congenital heart disease and cryptorchidism in males. Currently, four genes are associated to NS: PTPN11, KRAS, SOS1 y RAF1, and all of them codify proteins involved in the Ras/MAPK signaling pathway (AU)

Evaluation of a Microbiological Multi-Residue System on the detection of antibacterial substances in ewe milk.

To protect both, public health and the dairy industry, from the presence of antibiotic residues in milk, control programmes have been established, which include the needed screening tests. This work focuses on the application of a Microbiological Multi-Residue System in ewe milk, a method based on the use of six different plates, each seeded with one of the following bacteria: Geobacillus stearothermophilus var. calidolactis (beta-lactams), Bacillus subtilis at pH 8.0 (aminoglycosides), Kocuria rhizophila (macrolides), Escherichia coli (quinolones), B. cereus (tetracyclines) and B. subtilis at pH 7.0 (sulphonamides), respectively. Twenty-three antimicrobial substances were analysed and a logistic regression was established for each substance assayed to relate the antibiotic concentration and the zone of microbial growth inhibition. Great linearity in the response was observed (regression coefficients of over 0.97). This fact suggests the possibility of establishing a decision level of antibiotic concentrations near to the Maximum Residue Limits (MRL). Zones of inhibition were suggested as proposed action levels for the different antimicrobial groups (diameters of inhibition of 18 mm for the aminoglycoside, beta-lactam and sulphonamide plates; 19 mm for the tetracycline plate, 21 mm for the macrolide plate, and 24 mm for the quinolone plate). Specificity and cross-reactivity were also assayed.

Síndrome X Frágil / Fragile X Syndrome

El Síndrome X Frágil (SXF) es la principal causa de retraso mental hereditario, con una incidencia aproximada de ¼.000 varones y 1/8.000 mujeres en la población general. Se hereda de forma dominante ligada al sexo. Clínicamente se caracteriza por retrasomental, fenotipo peculiar con cara alargada y pabellones auriculares grandes y despegados, hiperlaxitud articular y macroorquidismo tras la pubertad. En las mujeres afectadas las manifestaciones clínicas suelen ser menos evidentes. El mecanismo etiológico es una expansión excesiva (>200) del trinucleótido CGG en el extremo 5´ del gen FMR1, que además está metilado, dando lugar a la ausencia de la proteína FMRP (AU)

Fragile X syndrome (FXS) is considered the most common known cause of inherited mental retardation, with a frequency of approximately 1:4.000 males and 1:8.000 females in the general population. It is an X-linked dominant disorder. Characteristic clinical features included mental retardation, distinctive phenotype with long face and large prominent ears, joint laxity and macroorchidism after puberty. Affected females usually show a less severe phenotype. In the vast majority of the cases, FXS is caused by an abnormal expansion (>200) of a CGG trinucleotide repeat in the 5´- untranslated region of the FMR1 gene, which is methylated, leading to the absence of the FMRP protein (AU)

Bases Moleculares del syndrome Cornelia de Lange / Molecular Basis of Cornelia de Lange Syndrome

El Síndrome de Cornelia de Lange (SCdL) es un trastorno del desarrollo hereditario caracterizado por un fenotipo facial distintivo, malformaciones en extremidades superiores y retrasado de crecimiento y psicomotor. La prevalencia oscila entre 1:45.000 y 1:62.000 nacimientos. Hasta la fecha, se han encontrado mutaciones en tres genes que codifican subunidades reguladoras o estructurales del Complejo de Cohesinas: NIPBL (5p13), SMC1A (Xp11) y SMC3 (10q25), y que afectan alrededor de un 55% de los pacientes. Clínicamente se distinguen tres fenotipos: grave, moderado y leve. El fenotipo grave sólo ha sido descrito en pacientes con mutaciones del gen NIPBL. Las bases patogénicas del síndrome no están aún aclaradas, pero parecen relacionarse con problemas de regulación de la expresión génico y/o de la cohesión cromosómica (AU)

Cornelia de Lange Syndorme (CDLS) is a congenital hereditary developmental disorder characterized by a distinctive craniofacial phenotype, upper limb malformations, and growth and developmental delay. The estimated prevalence range from 1:45.000 to 1:62.000 livebirths. Up to date, there genes that encode structural or regulator subunits of Cohesin Complex: NIPBL (5p13), SMC1A (Xp11), and SMC3 (10q25), have been found to bear mutations in approximately 55% of affected patients. Three phenotypes can be distinguished clinically: severe, moderate and mild. The severe one has been only seen in patients carrying mutations in the NIPBL gene. Although the pathogenic bases of the syndrome remain unclear, it has been hypothesized that CdLS is related to anomalies in gene expression regulations and /or chromosome cohesion (AU)

Natural immunity to human African trypanosomiasis: trypanosome lytic factors and the blood incubation infectivity test.

This review focuses on the epidemiology of human African trypanosomiasis: why it occurs in humans, the current methods of surveillance, and the drugs available to treat it. Emphasis is placed on the identification of human-infective trypanosomes by the blood incubation infectivity test. This test distinguishes between trypanosomes that are non-infective for humans and those that are potentially infective. Currently the test requires incubation of parasites with human serum before injection into mice; any surviving parasites are considered human-infective. The factors in serum that kill all non-human-infective parasites are known as trypanosome lytic factors. The paper details the biochemistry of these factors and recommends standardization of the test based on current knowledge. This test can be used to screen animals with trypanosomiasis, in order to evaluate their role during endemic and epidemic human African trypanosomiasis.