Is miR‐34a a Well‐equipped Swordsman to Conquer Temple of Molecular Oncology?

Overwhelmingly increasing advancements in miRNA biology have opened new avenues for pharmaceutical companies to initiate studies on designing effective, safe, and therapeutically active candidates using miRNA mimetics and miRNA inhibitors. In accordance with this approach, development of miravirsen and SPC3649, an LNA‐based (locked nucleic acid) antisense molecule against miR‐122, to treat hepatitis C has sparked interest in identifying most efficient microRNAs for journey from bench‐top toward pharmaceutical industry and breakthroughs in delivery technology will pave the way to ‘final frontier’. MRX34, a liposome‐formulated mimic of miR‐34 for treatment of metastatic cancer with liver involvement and unresectable primary liver cancer, has also entered in clinical trial. There is a successive increase in the research work related to miR‐34 biology and miRNA regulation of modulators of intracellular signaling cascades. We partition this review into how miR‐34a is regulated by different proteins and how Wnt‐ and TGF‐induced intracellular signaling cascades are modulated by miR‐34a. In this review, we bring to limelight how miR‐34a regulates its target genes to induce apoptosis and inhibit cell proliferation as evidenced by in vitro and in vivo analysis. We also discuss miR‐34 regulation of PDGFR and c‐MET and recent advancements in nanotechnologically delivered miR‐34a. Spotlight is also set on modulation of chemotherapeutic sensitivity by miR‐34a in cancer cells using reconstruction studies. Clinical trial of miR‐34 is indicative of its tremendous potential, and continuous cutting research will prove to be effective in efficiently translating laboratory findings into clinically effective therapeutics.     

Like father like son? Sons of patients of European or Indian origin with coronary artery disease reflect their parents' risk factor patterns.

OBJECTIVE--To investigate the extent to which risk factor patterns associated with coronary artery disease (CAD) in patients of Indian origin and in those of North European origin undergoing coronary angiography for suspected angina were reflected in their apparently healthy sons aged 15-30 years. DESIGN--Prospective study in which risk markers were measured in patients of Indian origin and in matched European patients undergoing angiography and in their sons. SETTING--Patients attending a regional cardiac centre and their families. PATIENTS--102 consecutive male patients of Indian origin undergoing diagnostic coronary angiography for suspected angina and 89 of their sons aged between 15 and 30 years; 102 age matched male European patients and 82 sons. MAIN OUTCOME MEASURES--Father son correlations for risk markers predicting the severity of parental CAD; differences in mean levels of these markers between young males of Indian origin and those of North European origin. RESULTS--Lp(a) lipoprotein, total cholesterol, and serum insulin were independent predictors of the severity of CAD in patients of Indian origin and in those of North European origin. In both groups, there was strong correlation between paternal and filial serum insulin (r = 0.41 Indian origin, r = 0.49 North European, P < 0.001), Lp(a) lipoprotein (r = 0.44 Indian origin, r = 0.48 North European, P < 0.001), and total cholesterol (r = 0.39 Indian origin, r = 0.45 North European, P < 0.001) concentrations, and the risk factor profiles of the sons were predictive of CAD severity in their fathers. Sons of patients of Indian origin had significantly higher serum insulin (Indian origin 14.3 mU/l v North European 8.4 mU/l, P = 0.002) and Lp(a) lipoprotein (Indian origin 19.1 mmol/l v North European 10.5 mmol/l, P = 0.001) concentrations than sons of patients of North European origin. CONCLUSIONS--Apparently healthy young men aged 15-30 years from either ethnic community already reflect risk marker patterns associated with coronary artery disease in their parents, both for genetically determined factors such as Lp(a) lipoprotein and environmentally influenced factors such as insulin and cholesterol. Health promotion measures aimed at reducing the prevalence of CAD should include the adolescent and young adult populations, particularly those with a family history of CAD, or who are from ethnic communities in which this diagnosis is prevalent.     

DFNB79: reincarnation of a nonsyndromic deafness locus on chromosome 9q34.3

Genetic analysis of an inbred Pakistani family PKDF280, segregating prelingual severe to profound sensorineural hearing loss, provided evidence for a DFNB locus on human chromosome 9q34.3. Co-segregation of the deafness trait with marker D9SH159 was determined by a two-point linkage analysis (LOD score 9.43 at θ=0). Two additional large families, PKDF517 and PKDF741, co-segregate recessive deafness with markers linked to the same interval. Haplotype analyses of these three families refined the interval to 3.84 Mb defined by D9S1818 (centromeric) and D9SH6 (telomeric). This interval overlaps with the previously reported DFNB33 locus whose chromosomal map position has been recently revised and assigned to a new position on chromosome 10p11.23–q21.1. The nonsyndromic deafness locus on chromosome 9q segregating in family PKDF280 was designated DFNB79. We are currently screening the 113 candidate DFNB79 genes for mutations and have excluded CACNA1B, EDF1, PTGDS, EHMT1, QSOX2, NOTCH1, MIR126 and MIR602.     

Serum ECP levels and methacholine challenge in infants with recurrent wheezing.

BACKGROUND: High levels of serum eosinophil cationic protein (sECP) as a marker of eosinophilic airway inflammation have been described as a predictor of childhood asthma. Bronchial hyperreactivity (BHR) appears to be secondary to the release of inflammatory mediators. OBJECTIVE: We investigated the possible correlation between eosinophilic inflammation and BHR in 72 infants with recurrent wheezing. METHODS: To determine bronchial reactivity, lung function measurements with methacholine challenge were performed in 72 infants, aged 12 to 30 months, and the degree of BHR to methacholine was compared with sECP values. Patients were grouped according to low (group 1, <10 microg/L, n = 22), medium (group 2, 10 to 20 microg/L, n = 23), and high (group 3, >20 microg/L, n = 27) sECP values. RESULTS: In group 1, sECP levels ranged from 3.1 to 9.9 microg/L, mean 6.6 microg/L +/- standard deviation [SD] 2.3, in group 2, from 10.3 to 19.8 microg/L, mean 14.3 microg/L +/- SD 2.8, and in group 3 from 23.0 to 66.7 microg/L, mean 34.5 microg/L +/- SD 9.5. Distribution of provocative methacholine concentration among groups was as follows: group 1, 30 to 976 microg, mean 350.9 microg +/- SD 258.3; group 2, 36 to 752 microg, mean 340.7 microg +/- SD 226.3; group 3, 41 to 848 microg, mean 301.3 microg +/- SD 189.8 methacholine. CONCLUSION: There was no significant correlation between sECP levels and bronchial reactivity in all groups (r = -0.076, P = 0.6), indicating that these parameters reflect two independent pathogenic mechanisms in the etiology of childhood asthma.     

Effects of growth hormone treatment on thyroid function in pediatric patients with Prader–Willi syndrome

It is unclear whether hypothyroidism is present in patients with Prader–Willi syndrome (PWS). This study aimed to clarify the state of the hypothalamic–pituitary–thyroid axis and the effects of growth hormone (GH) treatment on thyroid function in pediatric patients with PWS. We retrospectively evaluated thyroid function in 51 patients with PWS before GH treatment using a thyroid‐releasing hormone (TRH) stimulation test (29 males and 22 females; median age, 22 months). We also evaluated the effect of GH therapy on thyroid function by comparing serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) levels at baseline, 1 year, and 2 years after GH therapy. TSH, fT4, and fT3 levels were 2.28 μU/ml (interquartile range [IQR]; 1.19–3.61), 1.18 ng/dl (IQR; 1.02–1.24), and 4.02 pg/dl (IQR; 3.54–4.40) at baseline, respectively. In 49 of 51 patients, the TSH response to TRH administration showed a physiologically normal pattern; in two patients (4.0%), the pattern suggested hypothalamic hypothyroidism (delayed and prolonged TSH peak after TRH administration). TSH, fT4, and fT3 levels did not change significantly during 1 or 2 years after GH treatment. The TSH response to TRH showed a normal pattern in most patients, and thyroid function did not change significantly during the 2 years after initiating GH treatment.     

Testing the utility of the newest vital sign (NVS) health literacy assessment tool in older African-American patients

Objective

To evaluate utility of the newest vital sign (NVS) which can be completed in 3 min compared to the short version test of functional literacy in adults (S-TOFHLA) that takes 7 min for health literacy in the older African American patients.

Methods

We enrolled 62 older (age > 65 years) African American patients and administered the NVS and the S-TOFHLA. A score of less than 4 for the NVS and less than 16 for the S-TOFHLA was indicative of limited health literacy.

Results

Mean age of our patients was 73.2 + 7.9 years with an average education level of twelfth grade. Using S-TOFHLA 51% of the subjects were deemed to be sufficiently literate, with a score of 23.0 + 8.6 compared to 56% on the NVS with a score of 3.0 + 1.9. The average time for completing the NVS was 11 min in our patient population.

Conclusion

Based on our data, while health literacy level can be assessed with the NVS its practicality as a quick screening tool in the elderly population appears limited.

Practice implications

Knowing the level of patient's health literacy may help physicians deliver health information in the format that patients can understand.     

Dengue determinants: Necessities and challenges for universal dengue vaccine development

Dengue illness can range from mild illness to life-threatening haemorrhage. It is an Aedes-borne infectious disease caused by the dengue virus, which has four serotypes. Each serotype acts as an independent infectious agent. The antibodies against one serotype confer homotypic immunity but temporary protection against heterotypic infection. Dengue has become a growing health concern for up to one third of the world's population. Currently, there is no potent anti-dengue medicine, and treatment for severe dengue relies on intravenous fluid management and pain medications. The burden of dengue dramatically increases despite advances in vector control measures. These factors underscore the need for a vaccine. Various dengue vaccine strategies have been demonstrated, that is, live attenuated vaccine, inactivated vaccine, DNA vaccine, subunit vaccine, and viral-vector vaccines, some of which are at the stage of clinical testing. Unfortunately, the forefront candidate vaccine is less than satisfactory, and its performance depends on serostatus and age factors. The lessons from clinical studies depicted ambiguity concerning the efficacy of dengue vaccine. Our study highlighted that viral structural heterogeneity, epitope accessibility, autoimmune complications, genetic variants, genetic diversities, antigen competition, virulence variation, host-pathogen specific interaction, antibody-dependent enhancement, cross-reactive immunity among Flaviviruses, and host-susceptibility determinants not only influence infection outcomes but also hampered successful vaccine development. This review integrates dengue determinants allocated necessities and challenges, which would provide insight for universal dengue vaccine development.