Karyotype patterns, clinical features, and parental ages of three predominant live born autosomal trisomies of Northeast Malaysia.

Chromosomal abnormality is one of the causes of congenital disorders among newborns. Despite aneuploidy being the major cause of first trimester miscarriages, very few aneuploidies such as trisomies of chromosomes 13, 18 and 21 survive to birth. The results of 4,064 patients referred for cytogenetic analysis at Human Genome Centre, Universiti Sains Malaysia, Kelantan, Malaysia between 2008 and 2019 were reviewed. We retrospectively investigated the karyotype patterns, clinical features and parental ages of the three common live-born autosomal trisomies such as trisomy 13, trisomy 18 and trisomy 21. The relative frequency of cases with the total sample received and cultured was calculated in each group and compared with those reported elsewhere. Between 2008 and 2019, a total of 1034 live-born trisomic cases which accounted for 25.4% of the 4064 total referred cases and 73.7% of 1403 suspected trisomy cases, were identified, with age ranging from newborns to 57 years. Down syndrome was the commonest aneuploidy (857 cases; 21.1%) followed by Edwards syndrome (133 cases; 3.3%) and Patau syndrome (44 cases; 1.1%). The number of diagnosed cases for each of the trisomies was fairly stable from year to year. About two-thirds of both maternal and paternal ages were ≥ 35 years. This is the first cytogenetic report on the common live-born autosomal trisomies in the North-Eastern region of Malaysia. The prevalence of trisomies 21 was found to be higher compared to an earlier study in the North-Western region of Malaysia, wherein also, advanced maternal age was a significant risk factor.

Revisión bibliográfica de las actuaciones llevadas a cabo en materia de farmacogenética en farmacia comunitaria en distintos países / Bibliographic review of pharmacogenetic actions carried out in community pharmacy in different countries

JUSTIFICACIÓN: la farmacogenética se ha implementado principalmente para la dosificación de medicamentos en el ámbito hospitalario. Sin embargo, en los últimos 10 años ha tomado relevancia en el entorno de la farmacia comunitaria, especialmente en otros países europeos, EEUU y Canadá. Para plantear los futuros pasos a nivel nacional, se hace interesante conocer la situación en materia de investigación farmacogenética en farmacia comunitaria en estos países.OBJETIVO: conocer el tipo de estudios de investigación sobre farmacogenética en farmacia comunitaria desarrollados en distintos países.MATERIAL Y MÉTODOS: se realizó una revisión bibliográfica con el motor de búsqueda Pubmed, en la mayor base de datos de acceso libre de artículos científicos: Medline. Para encontrar los artículos de nuestro interés, es decir, que trataran de trabajos de investigación relacionados con la farmacogenética y que se hubieran llevado a cabo en farmacia comunitaria, se utilizaron los siguientes términos de búsqueda: pharmacogenetics; pharmacogenomics; community pharmacy; pilot study; service implementation; y testing. Las publicaciones identificadas se agruparon por temática relacionada en base a las similitudes metodológicas que presentaron.RESULTADOS: se identificaron 29 publicaciones relevantes para la revisión. De estas publicaciones, el 34,5 % se habían publicado entre los años 2020 y 2021. Además, el 65,5 % de ellas se basaban en trabajos realizados en farmacias comunitarias de EEUU y el 3,5 % en farmacias comunitarias españolas. Las temáticas de dichas publicaciones se agruparon de la siguiente forma: encuestas a farmacéuticos (37,9 %), ajustes de tratamientos guiados por test farmacogenéticos (34,5 %), entrevistas a pacientes (6,9 %), comparación de la implantación del servicio de farmacogenética y el servicio de farmacogenética junto con el manejo del tratamiento médico (6,9 %) y otros variados (13,8 %). (AU)

Evidencia farmacogenética disponible de los subgrupos terapéuticos más consumidos en España / Available pharmacogenetic evidence on the most widely used therapeutic subgroups in Spain

JUSTIFICACIÓN: la variabilidad interindividual en la respuesta a los medicamentos depende de muchos factores, entre los que se encuentra el perfil genético. Polimorfismos en los genes que codifican proteínas implicadas en la farmacocinética y farmacodinámica de los medicamentos pueden modificar su efecto, dando lugar a una respuesta pobre y por lo tanto un tratamiento inefectivo, o una respuesta exagerada lo que conlleva un riesgo alto de toxicidad. La presencia de polimorfismos en genes de transportadores, enzimas metabolizadoras o receptores podría implicar la necesidad o recomendación de un ajuste de dosis, sustitución y/o retirada de los medicamentos. Debido a esto, conocer qué evidencia existe en relación a la farmacogenética de los medicamentos de mayor consumo es de gran interés para los farmacéuticos comunitarios.OBJETIVO: identificar los medicamentos más consumidos en España y determinar la evidencia científica existente en cuanto al efecto que la farmacogenética tiene en ellos.MATERIAL Y MÉTODOS: se identificaron los 15 grupos de medicamentos más consumidos en España (clasificados por subgrupo terapéutico, ACT4) en base al último informe anual disponible de la Prestación Farmacéutica en el Sistema Nacional de Salud (2019).Para cada medicamento de dichos grupos se realizó una búsqueda de la evidencia científica disponible, en materia de farmacogenética, en las Guías Clínicas del CPIC y el DPWG y las anotaciones registradas en la base de datos sobre farmacogenética PharmGKB.RESULTADOS: los 15 subgrupos terapéuticos más dispensados en farmacia comunitaria en España en el 2019 sumaron el 48 % de todos los medicamentos dispensados. De ellos, 8 subgrupos disponen de guías clínicas publicadas de dosificación basada en farmacogenética (Antiulcerosos: inhibidores de la bomba de protones; Hipolipemiantes: inhibidores de la HMG CoA reductasa; Inhibidores de la agregación plaquetaria, excluyendo heparina. (AU)

Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma.

Aberrant activation of the JAK3-STAT signaling pathway is a characteristic feature of many hematological malignancies. In particular, hyperactivity of this cascade has been observed in natural killer/T-cell lymphoma (NKTL) cases. Although the first-in-class JAK3 inhibitor tofacitinib blocks JAK3 activity in NKTL both in vitro and in vivo, its clinical utilization in cancer therapy has been limited by the pan-JAK inhibition activity. To improve the therapeutic efficacy of JAK3 inhibition in NKTL, we have developed a highly selective and durable JAK3 inhibitor PRN371 that potently inhibits JAK3 activity over the other JAK family members JAK1, JAK2, and TYK2. PRN371 effectively suppresses NKTL cell proliferation and induces apoptosis through abrogation of the JAK3-STAT signaling. Moreover, the activity of PRN371 has a more durable inhibition on JAK3 compared to tofacitinib in vitro, leading to significant tumor growth inhibition in a NKTL xenograft model harboring JAK3 activating mutation. These findings provide a novel therapeutic approach for the treatment of NKTL.

Cyclophilin A (CypA) Plays Dual Roles in Regulation of Bone Anabolism and Resorption.

CypA (Cyclophilin A) is a peptidyl-prolyl isomerase previously shown to be required for chondrogenic differentiation and endochondral ossification. However, the effects of CypA on osteoclast activity and bone maintenance are entirely unknown. Here, we show that Ppia(-/-) mice demonstrate low bone mineral density, reduced osteoblast numbers, and increased osteoclast numbers. When isolated from the calvaria, Ppia(-/-) osteoblasts demonstrate decreased osteogenic differentiation, whereas Ppia(-/-) osteoclasts derived from the long bones showed increased osteoclastic activity. Overexpression and gene silencing of CypA verified osteogenic and anti-osteoclastic effects. In osteoblasts, CypA is necessary for BMP-2 (Bone Morphogenetic Protein-2)-induced Smad phosphorylation. In osteoclasts, loss of CypA activates BtK (Bruton's tyrosine kinase) and subsequently integrates with TRAF6 (TNF receptor-associated factor 6) and/or c-fos signaling to induce NFATc1 (nuclear factors of activated T cells, cytoplasmic 1). Collectively, CypA dually exerts pro-osteogenic and anti-osteoclastic effects. Thus, modulation of CypA may be useful in future efforts targeting osteoporosis.

Novel role for cyclophilin A in regulation of chondrogenic commitment and endochondral ossification.

Recent studies showed that cyclophilin A (CypA) promotes NF-κB/p65 nuclear translocation, resulting in enhanced NF-κB activity and altered expression of its target genes, such as the Sox9 transcriptional factor, which plays a critical role in chondrogenic differentiation and endochondral ossification. In this report, we unveil the role of CypA in signal-induced chondrogenic differentiation and endochondral ossification. Expression levels of the chondrogenic differentiation markers and transcriptional regulators Sox9 and Runx2 were all significantly lower in CypA knockdown chondrogenic cells than in wild-type cells, indicating that CypA plays a functional role in chondrogenic differentiation. In vitro differentiation studies using micromass cultures of mouse limb bud cells further supported the conclusion that CypA is needed for chondrogenic differentiation. Newborn CypA-deficient pups double stained with alcian blue and alizarin red exhibited generalized, pronounced skeletal defects, while high-resolution micro-computed tomography (microCT) analyses of the femurs and lumbar vertebrae revealed delayed or incomplete endochondral ossification. Comparative histology and immunohistochemistry (IHC) analyses further verified the effects of CypA deficiency on chondrogenic differentiation. Our results provide evidence for the important contribution of CypA as a pertinent component acting through NF-κB-Sox9 in regulation of chondrogenesis signaling. These findings are important to better understand signal-induced chondrogenesis of chondrogenic progenitors in physiological and pathophysiological contexts.

Primary localized cutaneous amyloidosis: association with atopic dermatitis.

BACKGROUND: Primary localized cutaneous amyloidosis (PLCA) is a chronic pruritic dermatological disorder of unknown aetiology. Genetic mutations in cases of familial PLCA have been mapped to the oncostatin-M receptor (OSMR) ß, a subunit of interleukin (IL)-31 receptor. IL-31 has been implicated in the pathogenesis of atopic dermatitis (AD). OBJECTIVES: To assess if AD is more prevalent in patients with PLCA compared to patients with other conditions attending the same dermatology clinic. Secondarily, to investigate if the prevalence of AD, severity of itch, morphology and locations of PLCA differ between familial and sporadic forms. METHODS: Consecutive patients with the clinical diagnosis of PLCA visiting a dermatology clinic were evaluated by a single investigator. Data on demographics, family history, morphological types and locations of PLCA, and itch score were collected and they were screened for concomitant AD based on history and physical examination. The control population consisted of consecutive patients with diagnoses other than PLCA seen in the same clinic. RESULTS: A total of 44 patients with and 97 controls were evaluated. The prevalence of AD in patients with PLCA was significantly higher than in controls, at 75% and 39.2% respectively (OR = 4.66, 95% CI = 2.10 to 10.3, p < 0.0005). The prevalence of AD in sporadic cases was significantly higher than familial cases, at 84.4% and 50% respectively (OR = 5.4, 95% CI = 1.23 to 23.7). Mean itch levels, morphological types and locations of PLCA did not differ between familial and sporadic cases. CONCLUSIONS: AD was associated with PLCA and the association was stronger with the sporadic compared to the familial cases.

The long-term predictive value of the neutrophil-to-lymphocyte ratio in Type 2 diabetic patients presenting with acute myocardial infarction.

BACKGROUND: Patients with diabetes mellitus have worse long-term outcomes after acute myocardial infarction (AMI) than non-diabetics. This may be related to differential contribution of neutrophil and lymphocyte to inflammation during AMI in diabetics vs. non-diabetics. We aim to determine the predictive value of neutrophil-to-lymphocyte ratio (NLR) for major adverse events post-AMI in Type 2 diabetics vs. non-diabetics. METHODS AND RESULTS: A total of 2559 consecutive patients admitted for AMI (61 ± 14 years, 73% male and 43% diabetic) were analyzed. A complete blood count was obtained and the NLR computed for each patient on admission. Across the cohort, the 1-year reinfarction rate was 8.4% (n = 214) and 1-year mortality was 14.5% (n = 370). Univariate determinants of the composite endpoint included age, hypertension, hyperlipidemia, smoking, revascularization and NLR (P < 0.001 for all). The cohort was divided into NLR quartiles. Admission NLR was significantly higher in the diabetic group, 5.2 ± 5.8 vs. 4.6 ± 5.4 (P = 0.007). A step-wise increase in the incidence of the composite endpoint was noted across NLR quartiles for diabetic subjects; hazard ratio (HR) was 2.41 for fourth vs. first quartile (95% confidence interval = 1.63-3.53, P < 0.001). Multivariate analysis of the diabetic group showed that NLR remains as an independent predictor of the composite endpoint (adjusted HR = 1.53, 95% confidence interval = 1.00-2.33, P = 0.048). However, in non-diabetics, HR for NLR was not significant (P = 0.35). CONCLUSION: Increased NLR post-AMI is an independent predictor of major adverse cardiac events in diabetics. Monitoring this easily obtainable new index allows prognostication and risk stratification.

Antecedent risk factors and their control in young patients with a first myocardial infarction.

INTRODUCTION: Identifying and controlling cardiovascular risk factors at an early age may prevent cases of young myocardial infarction (MI). We studied age-related differences in the cumulative incidence of risk factors and the adequacy of primary prevention by surveying 1,556 patients with a first MI admitted to a tertiary hospital in Singapore. METHODS: This is a single centre registry-based study on patients admitted with a first MI to a tertiary hospital in Singapore. We stratified the cohort into younger (45 years of age and younger) and older (older than 45 years of age) groups. The presence of five risk factors, namely: hypertension, diabetes mellitus (DM), smoking, a family history of premature MI, and hyperlipidaemia, was assessed at the point of care by interview and prior medical records when obtainable. We also determined by the same methods, if these patients were receiving active treatment for DM, hypertension or hyperlipidaemia prior to their first MI. Lipid levels were measured within 24 hours of admission. RESULTS: 96 percent of patients 45 years and younger and 92 percent of those older than 45 years had at least one antecedent risk factor. The 45 years and younger age group had a higher incidence of untreated hypertension (odds ratio 2.99, 95 percent confidence interval 2.00-4.46, p-value is less than 0.001) and hyperlipidaemia (odds ratio 1.71, 95 percent confidence interval 1.20 - 2.43, p-value is equal to 0.002). CONCLUSION: A majority of young patients with a first MI have at least one identifiable antecedent risk factor. There is significant undertreatment of hypertension and hyperlipidaemia in this age group.

Gender differences in life stressors associated with child and adolescent suicides in Singapore from 1995 to 2003.

AIMS: This study explored gender differences in life stressors of children and adolescents who died by suicide. Three main classes of life stressors have been identified by previous research to be significant risk factors for suicide in children and adolescents: interpersonal/relationship problems, family problems, and academic/school problems. METHODS: The sample consisted of 156 (89 males and 67 females) completed child and adolescent suicides in Singapore from 1995 to 2003. The age of these individuals ranged from 10 to 19 years with a mean age of 16.49 (SD = 2.59). RESULTS: Significantly more females were found to have had interpersonal/ relationship problems as recent life stressors compared with males. No gender differences were found for the other two life stressors, family problems and academic/school problems. In addition, among the three life stressors studied, only interpersonal/relationship problems emerged as a significant predictor of female child and adolescent suicide. CONCLUSIONS: Consistent with previous research literature, these findings contribute to a growing literature documenting the relatively larger impact of relational life stressors on child and adolescent female suicidality. Implications for suicide intervention and prevention, especially among young females, were discussed.

Fatal pulmonary haemorrhage with the combined use of abciximab and fibrinolytic agent.

The increased bleeding risk associated with the use of abciximab has been well reported. The risk appears to be amplified when abciximab is administered concurrently with a fibrinolytic agent. We report and review the literature on the occurrence of a case of fatal pulmonary haemorrhage, a rare bleeding complication, in a patient who received both these drugs.

A case of broken heart from blunt trauma.

A young man with blunt chest trauma presented acutely in shock as a result of cardiac rupture causing acute bloody tamponade. We discuss the clinical presentation, the importance of rapid and accurate diagnosis and management of such cases.

Value of troponin-T rapid assay, cardiac enzymes, electrocardiogram and history of chest pain in the initial diagnosis of myocardial infarction in the emergency department.

We conducted a prospective study of 152 adult patients presenting to an emergency department with chest pain or symptoms suggestive of acute myocardial infarction (AMI) to evaluate the first electrocardiogram (ECG), creatine kinase (CK)-MB and Troponin-T Rapid Assay (TnT) alone or in combination with chest pain in the initial diagnosis of AMI. A provisional diagnosis was made after the history, physical examination and the first ECG reading. Blood specimens were taken for TnT, CK and CK-MB mass. A final discharge diagnosis of AMI was made according to World Health Organization criteria. Seventy-six (50%) of patients had a final diagnosis of AMI. The sensitivities of the first ECG, first CK-MB mass and first TnT were 76.3% (95% confidence interval (CI), 66.8-85.9), 38.2% (95% CI, 27.2-49.1) and 31.6% (95% CI, 21.2-42.0) respectively. The area under the curve for a combination of ECG, CK-MB mass, TnT and chest pain was the highest at 0.937 when compared with chest pain with varying combinations of tests. A combination of the first ECG, CK-MB mass and TnT had a negative predictive value (NPV) of 87.9% (95% CI, 80.0-95.8). The first ECG was the most sensitive test while the combination of chest pain, ECG, cardiac enzymes and TnT gave the best results in the initial diagnosis of AMI. If the first ECG, CK-MB mass and TnT are all negative, the probability of having an AMI is 12%.

The use of abciximab in coronary angioplasty--an Asian centre's experience.

BACKGROUND: Abciximab, a monoclonal antibody to platelet glycoprotein IIb/IIIa receptor, has been shown to be effective in reducing ischemic complications after coronary angioplasty in recent trials. However, little is known about its efficacy and safety when used in Asian patients. METHODOLOGY: Based on our abciximab registry, we performed a retrospective analysis of 115 Asian patients who received the antiplatelet agent while undergoing percutaneous coronary intervention in our centre. They constituted 18.4% of the total number of patients undergoing percutaneous revascularisation during the corresponding period. The majority of the patients were males (84%). The mean age of the cohort was 54 and the mean weight was 70 kg. The ethnic composition of the study population was: Chinese 54%, Indians 21%, Malays 19% and Others 6%. All patients received aspirin 100 mg and weight-adjusted heparin before the procedure. Abciximab may be administered on a preplanned basis prior to the procedure or be given as a 'bailout' strategy. RESULTS: There was a high clinical success rate of 95.8% and low incidence of ischemic complications when abciximab was given during coronary angioplasty. There were 0% Q myocardial infarction, 3.3% non-Q myocardial infarction and 0.8% death in our series. Bleeding complications were uncommon at 7.6%, predominantly involving the groin and gingiva. Thrombocytopenia occurred in 5.8% of patients. Abciximab was noted to increase the procedural activated clotting time (ACT) by 38 seconds when given concomitantly with heparin. The mean maximal procedural ACT achieved was 323 +/- 51 seconds. CONCLUSIONS: Abciximab may be used safely and efficaciously in Asian patients undergoing coronary angioplasty. The drug confers protection against ischemic complications during the procedure whether it is administered electively or as a 'bailout'. There is however, a need to redefine the heparin regime for our patients, given the high ACT obtained when abciximab is administered.

Usefulness of ST elevation II/III ratio and ST deviation in lead I for identifying the culprit artery in inferior wall acute myocardial infarction.

In a study of 92 patients presenting with inferior wall acute myocardial infarction, the infarct-related artery was the right coronary artery in 72 patients (78%) and the left circumflex artery in 20 (22%). An ST II/III ratio of 1 or an isoelectric ST in lead I are sensitive and specific markers of left circumflex artery occlusion, whereas an ST II/III ratio <1 (ST elevation in lead III >II) or ST depression in lead I are sensitive and specific markers of right coronary artery occlusion.

Initial experience of radiofrequency catheter ablation of supraventricular tachycardia in paediatric patients.

INTRODUCTION: The management of supraventricular tachycardia (SVT) in paediatric patients until recently has frequently been pharmacologic therapy, but this approach suffers from the drawbacks of treatment failure, development of drug intolerance and/or side-effects. AIM: In keeping with recent advances in paediatric cardiology, we share our experience with radiofrequency catheter ablation as an alternative and definitive modality of therapy. MATERIALS AND METHOD: 4 young patients with recurrent SVT underwent electrophysiologic study followed by radiofrequency ablation of the accessory pathways. RESULTS: Resolution of symptoms was achieved in all patients and no major complication was encountered. CONCLUSIONS: The ability to ablate permanently the reentrant circuit responsible for SVT has now permitted cure by non-surgical means, and is an important alternative to drug therapy in the management of SVT in children.

Electrocardiographic patterns in posterior chest leads (V7, V8, V9) in normal subjects.

The electrocardiographic patterns in leads V7, V8, and V9 were studied in 225 young, normal men (age range 17 to 21 years). The prevalence of 0.5- to 1.0-mm ST-segment elevation in leads V7, V8, and Vg 0.08 second after the J point was 8.9%, 5.8%, and 3.1%, respectively; the ST-segment elevation was not >1.0 mm in any subject.