Role of FAB classification of acute leukemias in era of immunophenotyping

French-American-British classification for leukemias had been widely accepted due to its objectiveness and good reproducibility. WHO classification of leukemias was formulated in 1997 with a purpose of further enhancing the objectivity. However, the requirement of cytogenetics and immunophenotyping makes it difficult for many countries like India to put WHO classification in routine use. This study was carried to know the effectiveness of FAB classification in an era of technical advancement. A retrospective analysis of all acute leukemias over a period of 2 years was done. Out of total of 469 cases of acute leukemias, 193 were diagnosed as Acute Lymphoblastic Leukemia (ALL), 200 as Acute Myeloid Leukemia (AML), and 76 cases diagnosed as Acute Leukemia, cytochemically undifferentiated. Hence, only 16% of all leukemias remained unclassifiable. Subclassification of AML cases revealed a much higher percentage of AML-M3, as compared to western literature. In conclusion, FAB classification, based on morphology and simple cytochemical stains, remains effective enough, although cytogenetics and immunophenotyping can add to diagnostic accuracy in some cases.     

Total bilirubin in young men and women: Association with risk markers for cardiovascular diseases

Objective

The aim of this study was to investigate whether high bilirubin concentration is a protective factor in cardiovascular disease (CAD) and how it correlates with parameters of oxidative stress in young males and females.

Methods

The study comprised 628 healthy subjects of both genders, 18–22 years of age. In fasting sera the concentration of total bilirubin (Tbil), parameters of cardiovascular risk and oxidative stress were determined. The results were analyzed by appropriate statistical methods.

Results

We found no gender differences in body mass index (BMI), blood pressure and lipid profile between subjects with low and high Tbil level. Men with high Tbil had higher concentrations of albumin and uric acid (p < 0.001) and lower of oxLDL (< 0.05), while women had higher albumin (p < 0.05) and lower TBARS (p < 0.05). Significant positive correlation in men was found between Tbil, uric acid and albumin, while for glucose and TBARS this association was negative. In female significant positive correlation was between Tbil, HDL-C, fibrinogen, albumin and uric acid and negative between Tbil and TBARS. The high concentration of Tbil in men was independently associated with uric acid (p < 0.05) and oxLDL (p < 0.001), while in women it was independently associated with TBARS (p < 0.05). After adjustment for traditional lipid parameters the predictive power of high bilirubin in men remained for uric acid (p < 0.001) and TBARS in women (p < 0.05).

Conclusion

These findings jointly support the concept that bilirubin via its antioxidant potential has a protective effect against cardiovascular disease in young male and female.     

New angiotensins

Accumulation of a large body of evidence during the past two decades testifies to the complexity of the renin–angiotensin system (RAS). The incorporation of novel enzymatic pathways, resulting peptides, and their corresponding receptors into the biochemical cascade of the RAS provides a better understanding of its role in the regulation of cardiovascular and renal function. Hence, in recent years, it became apparent that the balance between the two opposing effector peptides, angiotensin II and angiotensin-(1-7), may have a pivotal role in determining different cardiovascular pathophysiologies. Furthermore, our recent studies provide evidence for the functional relevance of a newly discovered rat peptide, containing two additional amino acid residues compared to angiotensin I, first defined as proangiotensin-12 [angiotensin-(1-12)]. This review focuses on angiotensin-(1-7) and its important contribution to cardiovascular function and growth, while introducing angiotensin-(1-12) as a potential novel angiotensin precursor.     

Lupus anticoagulant in a child with celiac disease: a rare association

Celiac disease or gluten-sensitive enteropathy is characterized by malabsorption, chronic inflammation of the small intestine mucosa, villous atrophy and crypt hyperplasia. Association of auto-immunity has been reported to be almost threefold higher in patients with celiac disease. While there are several reports of celiac disease in association with autoimmune diseases, there is paucity of literature on its association with antiphospholipid antibodies. We report here an 8-year-old girl child with celiac disease who was found to have lupus anticoagulant positivity, an extremely uncommon association. This child is perhaps the youngest ever patient of celiac disease in association with lupus anticoagulant.     

Examining gender differences in emerging tobacco use using the Adolescents' Need For Smoking Scale

Aims To investigate the influence of gender on emerging tobacco use by testing for gender‐based measurement invariance of the Adolescents' Need for Smoking Scale (ANSS) and examining gender differences on each dimension across increasing levels of amount smoked. Design Cross‐sectional survey. Setting Thirteen secondary schools located in British Columbia, Canada. Participants Data from 1425 youth who reported smoking at least once in the past month. Measurements Survey questions about demographic characteristics, tobacco smoking history and need for smoking. Findings The multi‐dimensional structure of the ANSS is equivalent in boys and girls and the ANSS questions are not gender‐biased. There were no significant gender differences in the levels of physical dependence across increasing levels of amount smoked. Girls scored higher than boys on levels of emotional dependence across increasing levels of life‐time cigarette exposure. Girls also had higher scores on the social dimension of the ANSS compared to boys among those who smoked 100 or more cigarettes. Conclusions Canadian girls score higher than boys on measures of emotional dependence and social attitudes associated with tobacco smoking.     

A novel splice-site variant in CDH23 in a patient with Usher syndrome type 1

ABSTRACT

Background: Gene editing has shown huge potential in correcting aberrant splicing and Cas13 has been identified as being particularly suitable for targeting RNA. It has therefore become increasingly important to highlight new splice site mutations that may be correctable, particularly in genes that are too large to be encoded by AAV vectors. About 20% of Usher Type 1 cases are caused by mutations in CDH23.

Purpose: To report a novel splice site mutation of CDH23 associated with Usher Type 1D.

Materials and Methods: Case report.

Results: A 35-year-old Caucasian female who is congenitally deaf with vestibular dysfunction presented with visual acuity of 6/12 in both eyes. Fundus examination revealed findings typical of retinitis pigmentosa with foveal preservation of photoreceptor layer. Next generation sequencing analysis revealed a novel homozygous variant, c.9319 + 1G>T in CDH23 consistent with the diagnosis of Usher Syndrome Type 1D. The c.9319 + 1G>T variant is predicted to affect splicing at the exon 65/intron 65 boundary, which highly likely leads to complete skipping of exon 65.

Conclusions: We describe a case of a typical Usher Syndrome Type 1D caused by a novel splice site variant in CDH23. Currently there are no treatments for CDH23 related retinal degeneration, partly because the cDNA size of 10kb is too large for AAV vector gene augmentation therapy. Alternative strategies include CRISPR-Cas9 adenine base editors and RNA editing with CRISPR-Cas13. Single-nucleotide editing represents a promising approach for targeting this variant in CDH23 to restore the wildtype splice donor site at this position.     

Evaluation of brivaracetam: a new drug to treat epilepsy

Introduction: High prevalence of therapy-resistant epilepsy demands development of anticonvulsants with new mechanisms of action. Brivaracetam is an analogue of levetiracetam which binds to the synaptic vesicle protein 2A (SV2A) and decreases release of excitatory neurotransmitters.

Areas covered: Relevant published studies were searched for by predefined strategy in MEDLINE, EBSCO and SCINDEKS electronic databases. Brivaracetam is effective as adjunctive therapy for uncontrolled partial-onset seizures with or without secondary generalization in patients 16 years and older with epilepsy. It reduces baseline-adjusted focal seizure frequency per week from 7.3 to 12.8% over placebo. Adverse events rate in patients with brivaracetam is not higher than in patients with placebo.

Expert opinion: Brivaracetam is an important step forward in the treatment of therapy-resistant partial-onset seizures with or without secondary generalization. Its development was systematic and targeted. Due to its efficacy and excellent safety profile, it is likely that brivaracetam will be often prescribed. In future, efficacy and safety of brivaracetam should be tested in monotherapy settings and also in the first-line therapy of partial-onset seizures.     

The Landscape of microRNA Targeting in Prostate Cancer Defined by AGO-PAR-CLIP

MicroRNA (miRNA) deregulation in prostate cancer (PCa) contributes to PCa initiation and metastatic progression. To comprehensively define the cancer-associated changes in miRNA targeting and function in commonly studied models of PCa, we performed photoactivatable ribonucleoside-enhanced cross-linking immunoprecipitation of the Argonaute protein in a panel of PCa cell lines modeling different stages of PCa progression. Using this comprehensive catalogue of miRNA targets, we analyzed miRNA targeting on known drivers of PCa and examined tissue-specific and stage-specific pathway targeting by miRNAs. We found that androgen receptor is the most frequently targeted PCa oncogene and that miR-148a targets the largest number of known PCa drivers. Globally, tissue-specific and stage-specific changes in miRNA targeting are driven by homeostatic response to active oncogenic pathways. Our findings indicate that, even in advanced PCa, the miRNA pool adapts to regulate continuing alterations in the cancer genome to balance oncogenic molecular changes. These findings are important because they are the first to globally characterize miRNA changes in PCa and demonstrate how the miRNA target spectrum responds to staged tumorigenesis.