Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes

Death-associated protein kinase (DAP-kinase), a proapoptotic serine/threonine kinase, is a candidate tumor suppressor gene. We studied the methylation status of DAP-kinase of 194 bone marrow samples from 160 patients with acute myeloid leukemia (AML) and 34 with a myelodysplastic syndrome (MDS) at the time of initial diagnosis by polymerase chain reaction (PCR). Hypermethylation of DAP-kinase was present in 27.5% (44 of 160) of AML and in 47% (16 of 34) of MDS specimens and significantly correlated to loss of DAP-kinase expression (P =.008). It was significantly more frequent in AML secondary to therapy for other malignancies (s-AML; 14 of 29, 48.3%), as compared to de novo AML (30 of 131, 22.9%, P =.01). DAP-kinase hypermethylation in AML was associated with myelodysplastic changes in the bone marrow at the time of the initial diagnosis (P =.002) and with the presence of cytogenetic abnormalities (P =.02). Alteration in the apoptotic response due to the loss of DAP-kinase function may be an early event in the transformation pathway to secondary leukemia via myelodysplasia.     

Impact of drug-eluting balloon (pre- or post-) dilation on neointima formation in de novo lesions treated by bare-metal stent: the IN-PACT CORO trial

The efficacy of DEB in modifying the high restenosis risk associated with BMS implantation is doubtful. Optical coherence tomography (OCT) may allow precise assessment of neointimal formation after stent implantation. We performed a single-center, prospective, 1:2 randomized trial comparing BMS implantation alone (BMS group) vs. additional DEB (DEB group). DEB patients were further randomized 1:1 to DEB before stenting (pre-DEB group), or after stenting (post-DEB group). Primary endpoint was OCT-assessed neointimal hyperplasia (expressed both as mean in-stent neointimal area and as percentage obstruction of the mean stent area) at 6 months. Secondary endpoints were the percentage of uncovered and malapposed stent struts. Thirty patients were enrolled and randomized to BMS (n = 10), pre-DEB (n = 10), post-DEB (n = 10). At 6-month OCT follow-up, DEB significantly reduced neointimal area compared with BMS: mean neointimal area 2.01 ± 0.89 vs. 3.03 ± 1.07 mm² (p = 0.02), percentage area obstruction 24.56 ± 12.50 vs. 37.51 ± 12.26 % (p = 0.02). The percentage of uncovered and malapposed stent struts did not differ significantly between BMS and DEB. In the comparison between pre-DEB and post-DEB, no significant difference was observed for both primary and secondary endpoints. In de novo coronary lesions treated with BMS, DEB use could be associated with a mild reduction in neointimal hyperplasia at 6 months; this effect could be unrelated to the timing of DEB dilation (pre- or post-stenting).Clinical Trial Registration Information: http://www.clinicaltrials.gov. Identifier: NCT01057563.     

Three-year Follow-up of Patients With Bifurcation Lesions Treated With Sirolimus- or Everolimus-eluting Stents: SEAside and CORpal Cooperative Study

Introduction and objectives

To compare the 3-year incidence of major events in patients with bifurcation lesions treated with provisional sirolimus-eluting stents vs everolimus-eluting stents.

Methods

A pooled analysis of 2 prospective randomized trials with similar methodology (SEAside and CORpal) was performed. In these trials, 443 patients with bifurcation lesions were randomly assigned to treatment with either sirolimus-eluting stents or everolimus-eluting stents. The clinical follow-up was extended up to 3 years to assess major adverse cardiovascular events (death or acute myocardial infarction or target vessel revascularization).

Results

At 3 years, survival free of major adverse cardiovascular events was 93.2% vs 91.3% in the everolimus-eluting stent group vs the sirolimus-eluting stent group (P = .16). Exploratory land-mark analysis for late events (occurring after 12 months) showed significantly fewer major adverse cardiovascular events in the everolimus-eluting stent group: 1.4% vs 5.4% in the sirolimus-eluting stent group (P = .02).

Conclusions

Provisional stenting with either sirolimus-eluting stents or everolimus-eluting stents in bifurcation lesions is associated with low rates of major adverse events at 3-years’ follow-up. The results of a subanalysis of events beyond 1 year, showing a lower event rate with everolimus-eluting stents than with sirolimus-eluting stents, suggest that studies exploring the long-term clinical benefit of the latest generation of drug-eluting stents are warranted.     

Do mobile family planning clinics facilitate vasectomy use in Nepal?

Background

Nepal has a distinct topography that makes reproductive health and family planning services difficult to access, particularly in remote mountain and hill regions where over a quarter of modern contraceptive users rely exclusively on vasectomy.

Study design

A three-level random intercept logistic regression analysis was applied on data from the 2011 Nepal Demographic and Health Survey to investigate the extent of influence of mobile family planning clinics on the odds of a male or a female sterilization, adjusting for relevant characteristics including ecological differences and random effects. The analyses included a sample of 2014 sterilization users, considering responses from currently married women of reproductive ages.

Results

The odds of a male sterilization were significantly higher in a mobile clinic than those in a government hospital (odds ratio, 1.65; 95% confidence interval, 1.21–2.25). The effects remained unaltered and statistically significant after adjusting for sociodemographic and clustering effects. Random effects were highly significant, which suggest the extent of heterogeneity in vasectomy use at the community and district levels. The odds of vasectomy use in mobile clinics were significantly higher among couples residing in hill and mountain regions and among those with three or more sons or those with only daughters.

Conclusion

Mobile clinics significantly increase the uptake of vasectomy in hard-to-reach areas of Nepal. Reproductive health interventions should consider mobile clinics as an effective strategy to improve access to male-based modern methods and enhance gender equity in family planning.

Implications

Family planning interventions in hard-to-reach communities could consider mobile clinic as an effective strategy to promote male-based modern methods. Improving access to vasectomy could substantially reduce unmet need for family planning in countries experiencing rapid fertility transition.     

Extremely low‐frequency electromagnetic fields enhance the survival of newborn neurons in the mouse hippocampus

In recent years, much effort has been devoted to identifying stimuli capable of enhancing adult neurogenesis, a process that generates new neurons throughout life, and that appears to be dysfunctional in the senescent brain and in several neuropsychiatric and neurodegenerative diseases. We previously reported that in vivo exposure to extremely low‐frequency electromagnetic fields (ELFEFs) promotes the proliferation and neuronal differentiation of hippocampal neural stem cells (NSCs) that functionally integrate in the dentate gyrus. Here, we extended our studies to specifically assess the influence of ELFEFs on hippocampal newborn cell survival, which is a very critical issue in adult neurogenesis regulation. Mice were injected with 5‐bromo‐2′‐deoxyuridine (BrdU) to label newborn cells, and were exposed to ELFEFs 9 days later, when the most dramatic decrease in the number of newly generated neurons occurs. The results showed that ELFEF exposure (3.5 h/day for 6 days) enhanced newborn neuron survival as documented by double staining for BrdU and doublecortin, to identify immature neurons, or NeuN labeling of mature neurons. The effects of ELFEFs were associated with enhanced spatial learning and memory. In an in vitro model of hippocampal NSCs, ELFEFs exerted their pro‐survival action by rescuing differentiating neurons from apoptotic cell death. Western immunoblot assay revealed reduced expression of the pro‐apoptotic protein Bax, and increased levels of the anti‐apoptotic protein Bcl‐2, in the hippocampi of ELFEF‐exposed mice as well as in ELFEF‐exposed NSC cultures, as compared with their sham‐exposed counterparts. Our results may have clinical implications for the treatment of impaired neurogenesis associated with brain aging and neurodegenerative diseases.     

Significance of longitudinal changes in the default‐mode network for cognitive recovery after stroke

Although a considerable number of patients suffer from cognitive impairments after stroke, the neural mechanism of cognitive recovery has not yet been clarified. Repeated resting‐state functional magnetic resonance imaging (fMRI) was used in this study to examine longitudinal changes in the default‐mode network (DMN) during the 6 months after stroke, and to investigate the relationship between DMN changes and cognitive recovery. Out of 24 initially recruited right‐hemispheric stroke patients, 11 (eight males, mean age 55.7 years) successfully completed the repeated fMRI protocol. Patients underwent three fMRI sessions at 1, 3 and 6 months after stroke. Their DMNs were analysed and compared with those of 11 age‐matched healthy subjects (nine males, mean age 56.2 years). Correlations between DMN connectivity and improvement of the cognitive performance scores were also assessed. The stroke patients were found to demonstrate markedly decreased DMN connectivity of the posterior cingulate cortex, precuneus, medial frontal gyrus and inferior parietal lobes at 1 month after stroke. At 3 months after stroke, the DMN connectivity of these brain areas was almost restored, suggesting that the period is critical for neural reorganization. The DMN connectivity of the dorsolateral prefrontal cortex in the contralesional hemisphere showed a significant correlation with cognitive function recovery in stroke patients, and should be considered a compensatory process for overcoming cognitive impairment due to brain lesion. This is the first longitudinal study to demonstrate the changes in DMN during recovery after stroke and the key regions influencing cognitive recovery.     

Clinical,neurophysiological, and skin biopsy findings in peripheral neuropathy associated with hepatitis C virus-related cryoglobulinemia

Hepatitis C virus (HCV)-related cryoglobulinemia commonly causes disabling complications including peripheral neuropathy and neuropathic pain. In this prospective clinical, neurophysiological, and skin biopsy study we aimed at assessing clinical characteristics and risk factors of peripheral neuropathy and neuropathic pain in patients with HCV-related cryoglobulinemia. We enrolled 69 consecutive patients with HCV-related cryoglobulinemia. We diagnosed neuropathic pain with the DN4 (Neuropathic Pain Diagnostic) questionnaire, and rated the various neuropathic pains with the Neuropathic Pain Symptom Inventory (NPSI). All patients underwent a standard nerve conduction study to assess Aβ-fiber function, laser-evoked potentials to assess Aδ-fiber function, and skin biopsy to assess C-fiber terminals. Of the 69 patients studied, 47 had a peripheral neuropathy, and 29 had neuropathic pain. Patients with peripheral neuropathy were older than those without (P < 0.0001). While peripheral neuropathy was significantly associated with the duration of HCV infection (P < 0.01), it was unrelated to the duration of cryoglobulinemia and cryocrit (P > 0.5). The severity of peripheral neuropathy significantly correlated with the duration of HCV infection (P < 0.05). Laser-evoked potential amplitudes were significantly lower in patients with than in those without neuropathic pain (P < 0.05). Conversely, no difference was found in nerve conduction study and skin biopsy findings (P > 0.05). Our findings show that peripheral neuropathy is related to age and HCV infection, rather than to cryoglobulinemia, and neuropathic pain is associated with damage to nociceptive pathways as assessed with laser-evoked potentials; this might be useful for designing more effective clinical interventions for these common HCV related-cryoglobulinemia complications.     

Current status of COVID-19 treatment: An opinion review

The pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has garnered the attention of scientists worldwide in the search for an effective treatment while also focusing on vaccine development. Several drugs have been used for the management of coronavirus disease 2019 (COVID-19), which has affected many hospitals and health centers worldwide. Statistically significant results are lacking on the effectiveness of the experimented drugs in reducing COVID-19 morbidity or mortality, as there are very few published randomized clinical trials. Despite this, the literature offers some material for study and reflection. This opinion review attempts to address three burning questions on COVID-19 treatment options. (1) What kind of studies are currently published or ongoing in the treatment of patients with COVID-19? (2) What drugs are currently described in the literature as options of treatment for patients affected by the infection? And (3) Are there specific clinical manifestations related to COVID-19 that can be treated with a customized and targeted therapy? By answering these questions, we wish to create a summary of current COVID-19 treatments and the anti-COVID-19 treatments proposed in the recent clinical trials developed in the last 3 mo, and to describe examples of clinical manifestations of the SARS-CoV-2 infection with a cause-related treatment.