Transcutaneous Electrical Stimulation of PC5 and PC6 Acupoints Modulates Autonomic Balance in Heart Transplant Patients: A Pilot Study

The increased resting heart rate (HR) in heart transplant patients is associated with enhanced metabolic demand, the potential for fatigue, and lower quality of life. In the present study, we hypothesized that transcutaneous electrical acupoint stimulation (TEAS) could modulate autonomic balance and reduce resting HR in these patients. A single-arm clinical trial was conducted with patients aged > 18 years, at ambulatorial accompaniment after heart transplantation, who were submitted to a single TEAS (40 minutes at pericardium channel acupoints PC5 and PC6). The arterial blood pressure and RR interval were recorded from 20 minutes before to 20 minutes after TEAS. The RR intervals were used to calculate HR variability (HRV) and the sympathovagal index. Linear mixed models were used for comparing variables before, during, and after TEAS. The significance level was set as P < 0.05. TEAS acutely improved HRV in transplant patients and enhanced the sympathovagal index during its application. Significant increases in systolic and diastolic blood pressure and mean arterial pressure were observed at recovery, such as a slight, but significant, decrease in HR. In conclusion, TEAS at PC5 and PC6 acutely modulates HRV and hemodynamics in transplant patients.     

Genetic heterogeneity in Pakistani microcephaly families

Autosomal recessive primary microcephaly (MCPH) is caused by mutations in at least eight different genes involved either in cell division or DNA repair. Most mutations are identified in consanguine families from Pakistan, Iran and India. To further assess their genetic heterogeneity and mutational spectra, we have analyzed 57 consanguine Pakistani MCPH families. In 34 MCPH families, we detected linkage to five out of the eight well‐characterized disease loci and identified mutations in 27 families, leaving seven families without mutations in the coding exons of the presumably underlying MCPH genes. In the MCPH cohort 23 families could not be linked to any of the known loci, pointing to remarkable locus heterogeneity. The majority of mutations were found in ASPM followed by WDR62, CENPJ, CEP152 and MCPH1. One ASPM mutation (p.Trp1326*) was found in as many as eight families suggesting a Pakistani founder mutation. One third of the families were linked to ASPM followed by WDR62 confirming previous data. We identified three novel ASPM mutations, four novel WDR62 mutations, one novel MCPH1 mutation and two novel CEP152 mutations. CEP152 mutations have not been described before in the Pakistani population.     

Cep164 is a mediator protein required for the maintenance of genomic stability through modulation of MDC1, RPA, and CHK1

The activation of the ataxia telangiectasia mutated (ATM) and ATM/Rad3-related (ATR) kinases triggers a diverse cellular response including the initiation of DNA damage-induced cell cycle checkpoints. Mediator of DNA Damage Checkpoint protein, MDC1, and H2AX are chromatin remodeling factors required for the recruitment of DNA repair proteins to the DNA damage sites. We identified a novel mediator protein, Cep164 (KIAA1052), that interacts with both ATR and ATM. Cep164 is phosphorylated upon replication stress, ultraviolet radiation (UV), and ionizing radiation (IR). Ser186 of Cep164 is phosphorylated by ATR/ATM in vitro and in vivo. The phosphorylation of Ser186 is not affected by RPA knockdown but is severely hampered by MDC1 knockdown. siRNA-mediated silencing of Cep164 significantly reduces DNA damage-induced phosphorylation of RPA, H2AX, MDC1, CHK2, and CHK1, but not NBS1. Analyses of Cep164 knockdown cells demonstrate a critical role of Cep164 in G2/M checkpoint and nuclear divisions. These findings reveal that Cep164 is a key player in the DNA damage-activated signaling cascade.     

Haploinsufficiency of ZNF238 is associated with corpus callosum abnormalities in 1q44 deletions

A variety of candidate genes have been proposed to cause corpus callosum abnormalities (CCAs) in patients with terminal chromosome 1q deletions. Recent data excluded AKT3 and implicated ZNF238 and/or CEP170 as genes causative of corpus callosum anomalies in patients with 1q43–1q44 deletions. We report on a girl with dysmorphic features, seizures beginning in infancy, hypotonia, marked developmental delay, and dysgenesis of the corpus callosum. Chromosomal microarray analysis detected a de novo 1.47 Mb deletion at 1q44. The deleted interval encompasses the ZNF238 gene but not the CEP170 or AKT3 genes, thus providing additional evidence for the former and against the latter as being causative of corpus callosum anomalies in patients with such deletions. © 2013 Wiley Periodicals, Inc.     

Functional characterization of the first missense variant in CEP78, a founder allele associated with cone‐rod dystrophy,hearing loss,and reduced male fertility

Inactivating variants in the centrosomal CEP78 gene have been found in cone‐rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state—in trans with c.1462‐1G>T—in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggest impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss‐of‐function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities.     

Age related macular degeneration and drusen: neuroinflammation in the retina

Inflammation protects from dangerous stimuli, restoring normal tissue homeostasis. Inflammatory response in the nervous system ("neuroinflammation") has distinct features, which are shared in several diseases. The retina is an immune-privileged site, and the tight balance of immune reaction can be disrupted and lead to age-related macular disease (AMD) and to its peculiar sign, the druse. Excessive activation of inflammatory and immunological cascade with subsequent induction of damage, persistent activation of resident immune cells, accumulation of byproducts that exceeds the normal capacity of clearance giving origin to a chronic local inflammation, alterations in the activation of the complement system, infiltration of macrophages, T-lymphocytes and mast-cells from the bloodstream, participate in the mechanisms which originate the drusen. In addition, aging of the retina and AMD involve also para-inflammation, by which immune cells react to persistent stressful stimuli generating low-grade inflammation, aimed at restoring function and maintaining tissue homeostasis by varying the set point in relation to the new altered conditions. This mechanism is also seen in the normal aging retina, but, in the presence of noxious stimuli as in AMD, it can become chronic and have an adverse outcome. Finally, autophagy may provide new insights to understand AMD pathology, due to its contribution in the removal of defective proteins. Therefore, the AMD retina can represent a valuable model to study neuroinflammation, its mechanisms and therapy in a restricted and controllable environment. Targeting these pathways could represent a new way to treat and prevent both exudative and dry forms of AMD.     

Lumpers or Splitters? The Role of Molecular Diagnosis in Leber Congenital Amaurosis

Clarification and classification of the congenital form of blindness known as Leber congenital amaurosis (LCA) continues to provide its challenges and dilemmas. Until recently, seven genes have been identified that cause LCA. Clarifying the relation between LCA and associated neurological abnormalities such as autism, seizures, and hypotony, and unraveling the relationship between the ocular LCA phenotype and that associated with distinct systemic entities such as Joubert syndrome, Senior-Loken syndrome and Saldino-Mainzer syndrome has taken on new importance with the discovery that a substantial proportion of patients with LCA have mutations in the CEP290 gene that causes Joubert syndrome. This commentary explores the implications of this recent discovery and revisits the classification of LCA.     

Abdominal obesity,dynapenia and dynapenic-abdominal obesity as factors associated with falls

ObjectiveTo investigate whether abdominal obesity, dynapenia and dynapenic-abdominal obesity are associated to the prevalence of single or recurrent falls in older adults.MethodsWe analyzed data from 1,046 community-dwelling participants of the SABE Study (Saúde, Bem-estar e Envelhecimento/Health, Well-Being and Ageing). Participants were classified as non-dynapenic/non-abdominal obese, abdominal obese only, dynapenic only, and dynapenic-abdominal obese based on waist circumference (>102 cm for men and >88 cm for women) and handgrip strength (<26 kg for men and <16 kg for women). Multinomial logistic regression models were ran to determine associations between dynapenia/obesity/dynapenic-abdominal obesity and single/recurring falls, taking non-fallers as reference.ResultsAbdominal obesity (RRR = 1.90 95% CI: 1.02–3.55), dynapenia (RRR = 1.80 95% CI: 1.02–3.19), and dynapenic-abdominal obesity (RRR = 2.06 95% CI: 1.04–4.10) were associated with a single fall. A stronger association for dynapenic-abdominal obesity compared to the other two conditions alone was found. Dynapenia was the unique condition associated with recurrent falls (RRR = 2.33, 95% CI: 1.13–4.81).ConclusionThe present findings have important implications for the identification of older adults with a greater chance of falls and can help in the development of rehabilitation strategies. Therefore, abdominal obese, dynapenic, and dynapenic abdominal obese individuals should be target groups for the management of falls and their consequences.