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BACKGROUND: The purpose of this study was to identify and classify the anatomic variation of mandibular canal among Malaysians of three ethnicities. MATERIALS AND METHODS: The courses of the mandibular canal in 202 cone-beam computed tomography scanned images of healthy Malaysians were evaluated, and trifid mandibular canal (TMC) when present, were recorded and studied in detail by categorizing them to a new classification (comprising of 12 types). The diameter and length of canals were also measured, and their shape determined. RESULTS: Trifid mandibular canals were observed in 12 (5.9%) subjects or 16 (4.0%) hemi-mandibles. There were 10 obvious categories out the 12 types of TMCs listed. All TMCs (except one) were observed in patients older than 30 years. The prevalence according to ethnicity was 6 in Malays, 5 in Chinese and 1 in Indian. Four (33.3%) patients had bilateral TMCs, which was not seen in the Indian subject. More than half (56.3%) of the accessory canals were located above the main mandibular canal. Their mean diameter was 1.32 mm and 1.26 mm for the first and second accessory canal, and the corresponding lengths were 20.42 mm and 21.60 mm, respectively. Most (62.5%) canals had irregularly shaped lumen; there were more irregularly shaped canals in the second accessory canal than the first branch. None of the second accessory canal was oval (in shape). CONCLUSIONS: This new classification can be applied for the variations in the branching pattern, length and shape of TMCs for better clinical description.
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Canal Mandibular , Raíz del Diente , Humanos , Mandíbula/diagnóstico por imagen , Pueblo Asiatico , Tomografía Computarizada de Haz Cónico/métodosRESUMEN
OBJECTIVE: The diagnostic yield for congenital heart defects (CHD) with routine genetic testing is around 10%-20% when considering pathogenic CNVs or aneuploidies as positive findings. This is a pilot study to investigate the utility of genome sequencing (GS) for prenatal diagnosis of CHD. METHODS: Genome sequencing (GS, 30X) was performed on 13 trios with CHD for which karyotyping and/or chromosomal microarray results were non-diagnostic. RESULTS: Trio GS provided a diagnosis for 4/13 (30.8%) fetuses with complex CHDs and other structural anomalies. Findings included pathogenic or likely pathogenic variants in DNAH5, COL4A1, PTPN11, and KRAS. Of the nine cases without a genetic etiology by GS, we had outcome follow-up data on eight. For five of them (60%), the parents chose to keep the pregnancy. A balanced translocation [46,XX,t(14; 22)(q32.33; q13.31)mat] was detected in a trio with biallelic DNAH5 mutations, which together explained the recurrent fetal situs inversus and dextrocardia that was presumably due to de novo Phelan-McDermid syndrome. A secondary finding of a BRCA2 variant and carrier status of HBB, USH2A, HBA1/HBA2 were detected in the cohort. CONCLUSIONS: GS expands the diagnostic scope of mutation types over conventional testing, revealing the genetic etiology for fetal heart anomalies. Patients without a known genetic abnormality indicated by GS likely opted to keep pregnancy especially if the heart defect could be surgically repaired. We provide evidence to support the application of GS for fetuses with CHD.
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Enfermedades Fetales , Cardiopatías Congénitas , Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN , Femenino , Corazón Fetal , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/genética , Humanos , Proyectos Piloto , Embarazo , Diagnóstico Prenatal/métodosRESUMEN
AIMS: To utilize transgenic GMR-Aß42 Drosophila melanogaster as a model to evaluate potential Alzheimer's disease (AD)-reversal effects via the administration of lactic acid bacteria (LAB) strains, and associations of LAB with changes in gut microbiota profiles. METHODS AND RESULTS: Wild-type flies (Oregon-R) were crossed with glass multimer reporter-GAL4 (GMR-GAL4) to produce GMR-OreR (Control), while UAS-Aß42 (#33769) were crossed with GMR-GAL4 to produce transgenic Drosophila line that expressed Aß42 (GMR-Aß42). Feed containing seven different LAB strains (Lactobacillus paracasei 0291, Lactobacillus helveticus 1515, Lactobacillus reuteri 30242, L. reuteri 8513d, Lactobacillus fermentum 8312, Lactobacillus casei Y, Lactobacillus sakei Probio65) were given to GMR-Aß42 respectively, while feed without LAB strains were given to control and transgenic GMR-Aß42.nf Drosophila lines. The morphology of the eyes was viewed with scanning electron microscopy (SEM). The changes in gut microbiota profiles associated with LAB were analysed using 16s high throughput sequencing. Malformation of eye structures in transgenic GMR-Aß42 Drosophila were reversed upon the administration of LAB strains, with more prevalent effects from L. sakei Probio65 and L. paracasei 0291. The GMR-Aß42.nf group showed dominance of Wolbachia in the gut, a genus that was almost absent in the normal control group (P < 0·05). The administration of L. sakei Probio65 and L. paracasei 0291 reduced the abundance of Wolbachia accompanied by increased abundance of Stenotrophomonas and Acetobacter (P < 0·05), resembling the microbial profile of the control group. CONCLUSIONS: Lactobacillus sakei Probio65 and Lactobacillus paracasei 0291 have more prominent effects in reversing malformed eye of transgenic GMR-Aß42 Drosophila, and reducing the abundance of Wolbachia accompanied by an increased abundance of Stenotrophomonas and Acetobacter. SIGNIFICANCE AND IMPACT OF THE STUDY: Potentials of LAB to prevent and/or alleviate the onset and pathogenesis of neurodegenerative diseases such as AD, supporting brain health strategies along the gut-brain axis.
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Acetobacter , Enfermedad de Alzheimer , Microbioma Gastrointestinal , Lactobacillales , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Drosophila melanogaster/genética , Drosophila melanogaster/microbiologíaRESUMEN
INTRODUCTION: This study investigated the incidences of chromosomal abnormalities and the neurological outcomes according to the degree of fetal cerebral ventriculomegaly. METHODS: All women with antenatal ultrasound diagnosis of fetal cerebral ventriculomegaly were retrospectively identified from two maternal-fetal medicine units in Hong Kong from January 2014 to December 2018. Degrees of fetal ventriculomegaly were classified as mild (10-11.9 mm), moderate (12-14.9 mm), or severe (≥15 mm). Genetic investigation results were reviewed, including conventional karyotyping and chromosomal microarray analysis (CMA); correlations between chromosomal abnormalities and the degree of fetal ventriculomegaly were explored. The neurological outcomes of subsequent live births were analysed to identify factors associated with developmental delay. RESULTS: Of 84 cases (ie, pregnant women and their fetuses) included, 46 (54.8%) exhibited isolated fetal ventriculomegaly, 55 (65.5%) had mild cerebral ventriculomegaly, and 29 (34.5%) had moderate or severe cerebral ventriculomegaly. Overall, 20% (14/70) of cases had chromosomal abnormalities. Moreover, 12% (3/25) of mild isolated ventriculomegaly cases had abnormal karyotype or CMA results. The CMA provided an incremental diagnostic yield of 8.6% (6/70), compared with conventional karyotyping; 4.3% exhibited pathogenic variants and 4.3% exhibited variants of uncertain significance. Among the 53 live births in the cohort, fewer cases of mild isolated ventriculomegaly were associated with developmental delay than more severe isolated ventriculomegaly (9.7% vs 41.7%, P<0.03). CONCLUSIONS: Chromosomal microarray analysis testing should be offered to all women with fetal cerebral ventriculomegaly, including women with isolated mild ventriculomegaly. The incidence of developmental delay after birth increases with the degree of prenatal cerebral ventriculomegaly.
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Aberraciones Cromosómicas , Hidrocefalia , Estudios de Cohortes , Femenino , Humanos , Hidrocefalia/diagnóstico por imagen , Hidrocefalia/genética , Cariotipificación , Análisis por Micromatrices , Embarazo , Diagnóstico Prenatal , Estudios Retrospectivos , Ultrasonografía PrenatalRESUMEN
BACKGROUND: TB is the leading cause of death from a single infectious disease, particularly among people living with HIV (PLHIV). Molecular epidemiology provides information on prevalent genotypes of Mycobacterium tuberculosis and disease transmission dynamics, which aid in TB control. Identification of mutations that confer drug resistance is essential for the rapid diagnosis of drug-resistant TB, especially in high TB burden settings, like the Philippines.METHODS: This study aimed to determine mutations in M. tuberculosis drug resistance-conferring genes and circulating genotypes in PLHIV. MIRU-VNTR (mycobacterial interspersed repetitive unit-variable number of tandem repeats) typing using a set of 24-loci and sequencing of drug resistance-conferring genes were performed in 22 M. tuberculosis isolates from TB-HIV co-infected patients.RESULTS: The prevalence of resistance to any drug was 31.8%, 18.2% for isoniazid monoresistance, 4.5% for streptomycin monoresistance and 9.1% for multidrug resistance. The identified mutations in the katG, rpoB, pncA, rpsL and gyrA genes have been reported in the literature; none was found in the inhA and embB genes. All isolates belonged to the EAI2-Manila family and were grouped into four clusters based on their phenotypic drug resistance and mutation profiles.CONCLUSION: The use of 24-loci set may be used as a more discriminatory MIRU-VNTR typing in settings where the East African-Indian lineage is predominant, like the Philippines.
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Coinfección , Infecciones por VIH , Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Adulto , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Coinfección/tratamiento farmacológico , Coinfección/epidemiología , Farmacorresistencia Bacteriana Múltiple/genética , Genotipo , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Pruebas de Sensibilidad Microbiana , Epidemiología Molecular , Mutación , Mycobacterium tuberculosis/genética , Filipinas/epidemiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiologíaRESUMEN
PURPOSE: Angiogenesis plays an important role in the growth and metastatic spread of solid tumours and is characterised by the expression of integrins on the cell surface of endothelial cells. Radiolabelled RGD peptides specifically target angiogenesis-related αvß3 integrins, expressed on the activated endothelial cells of sprouting blood vessels. Here, we validated the feasibility of 68Ga[Ga]-DOTA-E-[c(RGDfK)]2 (68Ga-RGD) PET/CT to visualise angiogenesis in patients with oral squamous cell carcinoma (OSCC). METHODS: Ten patients with OSCC and scheduled for surgical resection including elective neck dissection received an intravenously administration of 68Ga-RGD (42 ± 8 µg; 214 ± 9 MBq). All patients subsequently underwent dynamic (n = 5) or static PET/CT imaging (n = 5) for 60 min or for 4 min/bed position at 30, 60 and 90 min after injection, respectively. Quantitative tracer uptake in tumour lesions was expressed as standardised uptake values (SUV). Additionally, tumour tissue was immunohistochemically stained for αvß3 integrin to assess the expression pattern. RESULTS: 68Ga-RGD tumour accumulation was observed in all patients. At 60 min post injection, tumour SUVmax ranged between 4.0 and 12.7. Tracer accumulation in tumour tissue plateaued at 10 min after injection. Uptake in background tissue did not change over time, resulting in tumour-to-muscle tissue of 6.4 ± 0.7 at 60 min post injection. CONCLUSIONS: 68Ga-RGD PET/CT of αvß3 integrin expression in OSCC patients is feasible with adequate tumour-to-background ratios. It will provide more insight in angiogenesis as a hallmark of the head and neck squamous cell carcinomas' tumour microenvironment. TRIAL REGISTRATION: https://eudract.ema.europa.eu no. 2015-000917-31.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Carcinoma de Células Escamosas/diagnóstico por imagen , Células Endoteliales , Radioisótopos de Galio , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Humanos , Integrina alfaVbeta3 , Neoplasias de la Boca/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Carcinoma de Células Escamosas de Cabeza y Cuello , Microambiente TumoralRESUMEN
Alzheimer's disease (AD) is a progressive disease and one of the most common forms of neurodegenerative disorders. Emerging evidence is supporting the use of various strategies that modulate gut microbiota to exert neurological and psychological changes. This includes the utilisation of probiotics as a natural and dietary intervention for brain health. Here, we showed the potential AD-reversal effects of Lactobacillus probiotics through feeding to our Drosophila melanogaster AD model. The administration of Lactobacillus strains was able to rescue the rough eye phenotype (REP) seen in AD-induced Drosophila, with a more prominent effect observed upon the administration of Lactobacillus plantarum DR7 (DR7). Furthermore, we analysed the gut microbiota of the AD-induced Drosophila and found elevated levels of Wolbachia. The administration of DR7 restored the gut microbiota diversity of AD-induced Drosophila with a significant reduction in Wolbachia's relative abundance, accompanied by an increase of Stenotrophomonas and Acetobacter. Through functional predictive analyses, Wolbachia was predicted to be positively correlated with neurodegenerative disorders, such as Parkinson's, Huntington's and Alzheimer's diseases, while Stenotrophomonas was negatively correlated with these neurodegenerative disorders. Altogether, our data exhibited DR7's ability to ameliorate the AD effects in our AD-induced Drosophila. Thus, we propose that Wolbachia be used as a potential biomarker for AD.
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Enfermedad de Alzheimer , Microbioma Gastrointestinal/efectos de los fármacos , Lactobacillus plantarum , Enfermedades Neurodegenerativas/microbiología , Probióticos/administración & dosificación , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/microbiología , Animales , Biomarcadores , Modelos Animales de Enfermedad , Drosophila melanogaster , Enfermedades Neurodegenerativas/tratamiento farmacológico , Probióticos/farmacología , Wolbachia/efectos de los fármacosRESUMEN
Prenatal substance exposure is a growing public health concern worldwide. Although the opioid crisis remains one of the most prevalent addiction problems in our society, abuse of cocaine, methamphetamines, and other illicit drugs, particularly amongst pregnant women, are nonetheless significant and widespread. Evidence demonstrates prenatal drug exposure can affect fetal brain development and thus can have long-lasting impact on neurobehavioral and cognitive performance later in life. In this review, we highlight research examining the most prevalent drugs of abuse and their effects on brain development with a focus on endoplasmic reticulum stress and oxidative stress signaling pathways. A thorough exploration of drug-induced cellular stress mechanisms during prenatal brain development may provide insight into therapeutic interventions to combat effects of prenatal drug exposure.
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BACKGROUND: BEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor of AKT isoforms 1-3, in combination with the first-line weekly paclitaxel for advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, and in a phosphoinositide 3-kinase, catalytic, alpha polypeptide mutation sub-population (PIK3CA+). PATIENTS AND METHODS: BEECH consisted of an open-label, phase Ib safety run-in (part A) in 38 patients with advanced breast cancer, and a randomised, placebo-controlled, double-blind, phase II expansion (part B) in 110 women with ER+/HER2- metastatic breast cancer. In part A, patients received paclitaxel 90 mg/m2 (days 1, 8 and 15 of a 28-day cycle) with capivasertib taken twice daily (b.i.d.) at two intermittent ascending dosing schedules. In part B, patients were randomly assigned, stratified by PIK3CA mutation status, to receive paclitaxel with either capivasertib or placebo. The primary end point for part A was safety to recommend a dose and schedule for part B; primary end points for part B were progression-free survival (PFS) in the overall and PIK3CA+ sub-population. RESULTS: Capivasertib was well tolerated, with a 400 mg b.i.d. 4 days on/3 days off treatment schedule selected in part A. In part B, median PFS in the overall population was 10.9 months with capivasertib versus 8.4 months with placebo [hazard ratio (HR) 0.80; P = 0.308]. In the PIK3CA+ sub-population, median PFS was 10.9 months with capivasertib versus 10.8 months with placebo (HR 1.11; P = 0.760). Based on the Common Terminology Criteria for Adverse Event v4.0, the most common grade ≥3 adverse events in the capivasertib group were diarrhoea, hyperglycaemia, neutropoenia and maculopapular rash. Dose intensity of paclitaxel was similar in both groups. CONCLUSIONS: Capivasertib had no apparent impact on the tolerability and dose intensity of paclitaxel. Adding capivasertib to weekly paclitaxel did not prolong PFS in the overall population or PIK3CA+ sub-population of ER+/HER2- advanced/metastatic breast cancer patients.ClinicalTrials.gov: NCT01625286.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Receptores de Estrógenos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Método Doble Ciego , Femenino , Humanos , Mutación , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirroles/administración & dosificación , Pirroles/efectos adversos , Tasa de SupervivenciaRESUMEN
Mucormycosis is a rare fungal infection and high mortality that commonly affects patients with the weakened immune system. We present an unusual case of tongue necrosis probably due to the healthcare-associated mucormycosis (HCM) in a diabetic patient. Although cannot be proved with certainty, we surmise that intubation as a risk factor in our case. The diagnosis was confirmed by histopathological examination (HPE) of the necrotic tissue specimen. The patient was responded well to lipid complex amphotericin B (250mg) regime after surgery. Subsequent follow up revealed that no signs of recurrence. Early, recognition, diagnosis, prompt treatment and awareness among clinician are representing the most effective way of managing the disease.
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Complicaciones de la Diabetes/microbiología , Mucormicosis/microbiología , Lengua/patología , Anfotericina B/administración & dosificación , Anfotericina B/uso terapéutico , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Desbridamiento , Complicaciones de la Diabetes/diagnóstico , Complicaciones de la Diabetes/tratamiento farmacológico , Complicaciones de la Diabetes/cirugía , Cetoacidosis Diabética/complicaciones , Femenino , Humanos , Huésped Inmunocomprometido , Intubación/efectos adversos , Malasia , Persona de Mediana Edad , Mucormicosis/complicaciones , Mucormicosis/tratamiento farmacológico , Mucormicosis/cirugía , Necrosis , Factores de Riesgo , Lengua/microbiología , Lengua/cirugía , Resultado del TratamientoRESUMEN
Drugs can affect the cardiovascular (CV) system either as an intended treatment or as an unwanted side effect. In both cases, drug-induced cardiotoxicities such as arrhythmia and unfavourable hemodynamic effects can occur, and be described using mathematical models; such a model informed approach can provide valuable information during drug development and can aid decision-making. However, in order to develop informative models, it is vital to understand CV physiology. The aims of this tutorial are to present (1) key background biological and medical aspects of the CV system, (2) CV electrophysiology, (3) CV safety concepts, (4) practical aspects of development of CV models and (5) regulatory expectations with a focus on using model informed and quantitative approaches to support nonclinical and clinical drug development. In addition, we share several case studies to provide practical information on project strategy (planning, key questions, assumptions setting, and experimental design) and mathematical models development that support decision-making during drug discovery and development.
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Enfermedades Cardiovasculares/inducido químicamente , Sistema Cardiovascular/efectos de los fármacos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Preparaciones Farmacéuticas/administración & dosificación , Animales , Presión Sanguínea/efectos de los fármacos , Perros , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Macaca mulatta , Conejos , RatasRESUMEN
BACKGROUND AND PURPOSE: Whole body physiologically based pharmacokinetic (PBPK) models have been increasingly applied in drug development to describe kinetic events of therapeutic agents in animals and humans. The advantage of such modelling is the ability to incorporate vast amounts of physiological information, such as organ blood flow and volume, to ensure that the model is as close to reality as possible. EXPERIMENTAL APPROACH: Previous PBPK model development of enantiomers of a series of seven racemic ß-blockers, namely, acebutolol, betaxolol, bisoprolol, metoprolol, oxprenolol, pindolol and propranolol, together with S-timolol in rat was based on tissue and blood concentration data at steady state. Compounds were administered in several cassettes with the composition mix and blood and tissue sampling times determined using a D-optimal design. KEY RESULTS: Closed-loop PBPK models were developed initially based on the application of open loop forcing function models to individual tissues and compounds. For the majority of compounds and tissues, distribution kinetics was adequately characterized by perfusion rate-limited models. For some compounds in the testes and gut, a permeability rate-limited distribution model was required to best fit the data. Parameter estimates of the tissue-to-blood partition coefficient through fitting of individual enantiomers and of racemic pair were generally in agreement and also concur with those from previous steady-state experiments. CONCLUSIONS AND IMPLICATIONS: PBPK modelling is a very powerful tool to aid drug discovery and development of therapeutic agents in animals and humans. However, careful consideration of the assumptions made during the modelling exercise is essential.
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Antagonistas Adrenérgicos beta/administración & dosificación , Antagonistas Adrenérgicos beta/metabolismo , Modelos Biológicos , Antagonistas Adrenérgicos beta/sangre , Animales , Inyecciones Intravenosas , Masculino , Ratas , Ratas Sprague-Dawley , Distribución Tisular/efectos de los fármacos , Distribución Tisular/fisiologíaRESUMEN
This document was developed to enable greater consistency in the practice, application, and documentation of Model-Informed Drug Discovery and Development (MID3) across the pharmaceutical industry. A collection of "good practice" recommendations are assembled here in order to minimize the heterogeneity in both the quality and content of MID3 implementation and documentation. The three major objectives of this white paper are to: i) inform company decision makers how the strategic integration of MID3 can benefit R&D efficiency; ii) provide MID3 analysts with sufficient material to enhance the planning, rigor, and consistency of the application of MID3; and iii) provide regulatory authorities with substrate to develop MID3 related and/or MID3 enabled guidelines.
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Guías como Asunto , Tecnología Farmacéutica/normas , Documentación , Diseño de Fármacos , Tecnología Farmacéutica/métodosRESUMEN
The objective of the present study was to evaluate the long-term outcomes of the surgical treatment of chronic suppurative otitis with cholesteatoma in terms of prevention of a residual disease and its relapses. The results of the postoperative observation of 149 patients during the period from 2009 till 2013 are presented. All the patients underwent sanation surgery with the obliteration of paratympanic spaces followed by the restoration of the posterior wall of the external auditory meatus and simultaneous tympanoplasty (closed-type surgery). The patients were examined one year after the treatment with the use of the MRI technology in the non-EPI DWI regime for the purpose of monitoring the residual disorders and relapses of cholesteatoma. The follow-up observation revealed 9 cases of residual cholesteatoma, no relapse of chronic suppurative otitis was documented.
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Colesteatoma del Oído Medio/cirugía , Otitis Media Supurativa/cirugía , Adolescente , Adulto , Anciano , Colesteatoma del Oído Medio/epidemiología , Enfermedad Crónica/terapia , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Otitis Media Supurativa/epidemiología , Resultado del Tratamiento , Adulto JovenRESUMEN
The objective of the present field study was to establish the beneficial effects of re-insemination of non-pregnant cows using ultrasonography 20 to 23 days after the artificial insemination. A total of 245 Japanese Black cows were artificially inseminated and early pregnancy diagnosis (EPD) was performed on 92 cows 20 days after insemination, using ultrasonography. The remaining 153 cows were considered as negative controls in which routine rectal palpation was performed for pregnancy diagnosis 45-50 days post-insemination. EPD revealed that eleven of the 92 cows (12%) were infertile due to ovarian abnormalities and were thus excluded from the rest of the study. Forty-eight (59%) of the remaining 81 cows were diagnosed as pregnant, while the other 33 (41%) were diagnosed as non-pregnant. Of these non-pregnant cows, 17 of them received a dose of an analogue of the gonadotropin-releasing hormone (GnRH analogue) and were then timed-inseminated, while the other 16 were observed for estrus signs, and 13 of them (81%) were artificially inseminated. Rates of conception were 35% and 38% in the GnRH and the artificially inseminated groups, respectively (P>0.05). Total pregnancy rate for the EPD group increased significantly (74%) (P<0.01) when compared to the control cows (54%) within the same period. In conclusion, our field study demonstrated that re-insemination of non-pregnant cows following EPD is highly efficacious not only in improving the rate of fertility via reducing inter-insemination and inter-calving intervals, but also aids in the early detection of ovarian disorders.
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High yielding dairy cows experience a negative energy balance (NEB) early post-partum and it was hypothesized that this may be aggravated under summer heat stress (HS) conditions. In this study, which was performed in Egypt, 20 Holstein cows were followed during summer (n=10) and winter (n=10) seasons. All cows were multiparous and kept at the same herd. Blood was sampled from each cow starting 1 week before the expected calving date and then at 1-week intervals until week 6 post-partum. From week 2 to 6 post-partum follicular fluid was collected through transvaginal follicular fluid aspiration at 6 days intervals. Ambient air temperature (AT) and relative humidity (RH) were recorded and temperature-humidity index (THI) was calculated as well. Respiration rate (RR), rectal temperature (RT), and body condition score (BCS) were recorded for each cow at the time of blood sampling. Concentrations of glucose, insulin like growth factor-1 (IGF-1), non-esterified fatty acids (NEFA), urea and total cholesterol (TC) were measured in each blood and follicular fluid sample. All the cows showed a significantly higher RR and RT in summer (95.5+/-1.1 and 39.88+/-0.06, respectively) than in winter (43.89+/-0.61 and 38.94+/-0.07, respectively) (P<0.001). Body condition score loss during the early post-partum period was higher in summer than in winter (1.1+/-0.07 vs. 0.85+/-0.06 point, respectively) (P<0.001). The average dominant follicle diameter was significantly lower in summer than in winter during the period of negative energy balance (11.6+/-0.7mm vs. 15.3+/-1.2mm, respectively) (P<0.01). Under summer heat stress, the concentrations of glucose (2.98+/-0.07 and 2.19+/-0.04mmol/L), IGF-1 (106.7+/-2.9 and 99.0+/-3.4ng/ml) and TC (137.3+/-5.3 and 62.2+/-5.1mg/dl) in blood and FF, respectively, were significantly lower than winter concentrations by (0.17+/-0.03mmol/L, P<0.001 and 0.26+/-0.06mmol/L, P<0.001), (12.3+/-3.6ng/ml, P<0.001 and 9.0+/-2.7ng/ml, P<0.001) and (20.7+/-1.8mg/dl, P<0.001 and 7.3+/-1.1mg/dl, P<0.01), respectively. However, the concentrations of NEFA (0.68+/-0.14 and 0.22+/-0.02mmol/L) and urea (9.27+/-0.34 and 9.96+/-0.25mmol/L) in blood and FF, respectively, were significantly higher in summer compared to winter (0.50+/-0.08mmol/L, P<0.001 and 0.20+/-0.02mmol/L, P<0.001) and (8.77+/-0.23mmol/L, P<0.05 and 8.96+/-0.29mmol/L, P<0.001), respectively, throughout the experimental period. The results of the present study indicate that heat stress early post-partum aggravates NEB in high yielding dairy cows, reduces BCS, dominant follicle diameter and alters the biochemical concentrations in the follicular fluid of the dominant follicle which may result in inferior oocyte and granulosa cell quality and hence poorer fertility.
Asunto(s)
Industria Lechera , Líquido Folicular/química , Calor , Folículo Ovárico/química , Estrés Fisiológico/fisiología , Animales , Biomarcadores/análisis , Biomarcadores/metabolismo , Glucemia/análisis , Temperatura Corporal/fisiología , Bovinos , Tamaño de la Célula , Eficiencia/fisiología , Metabolismo Energético/fisiología , Ácidos Grasos no Esterificados/análisis , Ácidos Grasos no Esterificados/metabolismo , Femenino , Líquido Folicular/metabolismo , Calor/efectos adversos , Factor I del Crecimiento Similar a la Insulina/análisis , Factor I del Crecimiento Similar a la Insulina/metabolismo , Lactancia/sangre , Lactancia/metabolismo , Lactancia/fisiología , Folículo Ovárico/citología , Folículo Ovárico/metabolismo , Periodo Posparto/sangre , Periodo Posparto/metabolismo , Periodo Posparto/fisiología , Estaciones del AñoRESUMEN
Chromatid breaks in cells exposed to low dose irradiation are thought to be initiated by DNA double-strand breaks (DSB), and the frequency of chromatid breaks has been shown to increase in DSB rejoining deficient cells. However, the underlying causes of the wide variation in frequencies of G2 chromatid breaks (or chromatid 'radiosensitivity') in irradiated T-lymphocytes from different normal individuals and cancer cases are as yet unclear. Here we report evidence that topoisomerase II alpha expression level is a factor determining chromatid radiosensitivity. We have exposed the promyelocytic leukaemic cell line (HL60) and two derived variant cell lines (MX1 and MX2) that have acquired resistance to mitoxantrone and low expression of topoisomerase II alpha, to low doses of gamma-radiation and scored the induced chromatid breaks. Chromatid break frequencies were found to be significantly lower in the variant cell lines, compared with their parental HL60 cell line. Rejoining of DSB in the variant cell lines was similar to that in the parental HL60 strain. Our results indicate the indirect involvement of topoisomerase II alpha in the formation of radiation-induced chromatid breaks from DSB, and suggest topoisomerase II alpha as a possible factor in the inter-individual variation in chromatid radiosensitivity.