A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants

Background

Cluster Headache (CH) is a severe primary headache, with a poorly understood pathophysiology. Complex genetic factors are likely to play a role in CH etiology; however, no confirmed gene associations have been identified. The aim of this study is to identify genetic variants influencing risk to CH and to explore the potential pathogenic mechanisms.

Methods

We have performed a genome-wide association study (GWAS) in a clinically well-defined cohort of 99 Italian patients with CH and in a control sample of 360 age-matched sigarette smoking healthy individuals, using the Infinium PsychArray (Illumina), which combines common highly-informative genome-wide tag SNPs and exonic SNPs. Genotype data were used to carry out a genome-wide single marker case-control association analysis using common SNPs, and a gene-based association analysis focussing on rare protein altering variants in 745 candidate genes with a putative role in CH.

Results

Although no single variant showed statistically significant association at the genome-wide threshold, we identified an interesting suggestive association (P?=?9.1?×?10^?6) with a common variant of the PACAP receptor gene (ADCYAP1R1). Furthermore, gene-based analysis provided significant evidence of association (P?=?2.5?×?10^?5) for a rare potentially damaging missense variant in the MME gene, encoding for the membrane metallo-endopeptidase neprilysin.

Conclusions

Our study represents the first genome-wide association study of common SNPs and rare exonic variants influencing risk for CH. The most interesting results implicate ADCYAP1R1 and MME gene variants in CH susceptibility and point to a role for genes involved in pain processing. These findings provide new insights into the pathogenesis of CH that need further investigation and replication in larger CH samples.

     

Precocious Ossification of the Tympanoperiotic Bone in Fetal and Newborn Dolphins: An Evolutionary Adaptation to the Aquatic Environment?

The present study, performed with a dual‐energy X‐ray (DXA) bone densitometer on a series of fetal and newborn striped and short‐beaked common dolphins, shows that the bone density of the area of the tympanic bulla within the tympanoperiotic complex starts with 0.483 g cm^?2 in 5‐ to 6‐month‐old specimens of striped (or common) dolphin fetuses and reaches 1.841 g cm^?2 in newborn striped dolphins, with values consistently higher than in other parts of the skull or elsewhere in the skeleton. The same results apply to the common bottlenose dolphins, in which the area of the tympanic bulla has a density of 0.312 g cm^?2 in 5‐month‐old specimens and becomes four times as much in newborns. Regardless of the areal bone density results correlated to the DXA‐technique, comparisons with DXA‐bone density data in the literature referred to other mammals emphasize the presence of very high mineral deposition in the area of the tympanoperiotic bone in fetal and newborn dolphins and the most dense part of it belongs to the tympanic bulla. The early osseous maturation of the tympanic bulla area may be compared to what described in fin whales and may represent an unique ontogenetic and phylogenetic feature of cetaceans, possibly related to the development of essential acoustic sense and establishment of immediate post‐natal mother–calf relationship. Anat Rec, 298:1294–1300, 2015. © 2015 Wiley Periodicals, Inc.     

Free fatty acids as mediators of adaptive compensatory responses to insulin resistance in dexamethasone-treated rats

BACKGROUND: Chronic low-dose dexamethasone (DEX) treatment in rats is associated to insulin resistance with compensatory hyperinsulinaemia and reduction in food intake. We tested the hypothesis that the elevation in circulating free fatty acids (FFAs) induced by DEX is the common mediator of both insulin resistance and insulin hyperproduction. METHODS: For this purpose, an anti-lipolytic agent was administered during DEX treatment to lower lipacidaemia for several hours prior to glucose and insulin tolerance tests. Leptin expression in adipose tissue (by Northern blot) and plasma leptin levels (by radioimmunoassay) were also investigated to verify whether a rise in circulating leptin could be responsible for the anorectic effect of DEX. RESULTS: Our data show that a transient pharmacological reduction of elevated plasma FFA levels abates the post-loading hyperinsulinaemia and counteracts the insulin resistance induced by DEX, supporting the hypothesis that the chronic elevation in FFAs is the common mediator of DEX-induced changes. Despite enhanced leptin expression in white adipose tissue, DEX-treated rats show no significant increase in plasma leptin levels. This suggests that the anorectic effect of DEX should be mediated, at least partially, by other factors, possibly related to the influence of concomitantly elevated plasma FFA and insulin levels on the hypothalamic centers regulating feeding. CONCLUSIONS: Our results sustain the idea that a prolonged increase in plasma FFA levels plays an important role in the adaptive regulation of glucose and energy homeostasis, not only by potentiating insulin secretion but also by providing a signal of 'nutrient abundance' capable of restraining food intake.     

Establishment and characterization of EBV-positive and EBV-negative primary effusion lymphoma cell lines harbouring human herpesvirus type-8

In this study we report on the establishment and characterization of two novel lymphoma cell lines (CRO-AP/3 and CRO-AP/5) which carry infection by human herpesvirus type-8 (HHV-8) and have derived from AIDS-related primary effusion lymphoma (PEL). These two cell lines are representative of different virologic subtypes of PEL, i.e. HHV-8⁺/EBV^? PEL in the case of CRO-AP/3 and HHV-8⁺/EBV⁺ PEL in the case of CRO-AP/5. Consistent with the diagnosis of PEL, both CRO-AP/3 and CRO-AP/5 expressed indeterminate (i.e. non-B, non-T) phenotypes although immunogenotypic studies documented their B-cell origin. Both cell lines are devoid of genetic lesions of c-MYC, BCL-2 and p53 as well as gross rearrangements of BCL-6. Detailed histogenetic characterization of these novel PEL cell lines suggests that PEL may derive from a post-germinal centre B cell which has undergone pre-terminal differentiation. The CRO-AP/3 and CRO-AP/5 cell lines may provide a valuable model for clarifying the pathogenesis of PEL. In particular, these cell lines may help understand the relative contribution of HHV-8 and EBV to PEL growth and development and may facilitate the identification of recurrent cytogenetic abnormalities highlighting putative novel cancer related loci relevant to PEL.     

Early recurrences after atrial fibrillation ablation: prognostic value and effect of early reablation

Introduction: Early arrhythmia recurrences are common within the first month after atrial fibrillation (AF) ablation. The long-term consequences of these early recurrences (ER) are controversial. We investigated whether ER were predictive of late recurrences and the impact of early reablation on clinical outcome.
Methods: Three hundred two consecutive patients with paroxysmal or persistent AF were studied. Arrhythmia recurrence was defined as documented episode of AF or atrial tachycardia. Of 151 patients with ER, a subset of 61 patients had reablation within the first month following the index ablation (early reablation). In the remaining 90 patients, a repeat procedure was only performed for later arrhythmia recurrences occurring beyond 1 month. Patients were followed with clinical interview and ambulatory 24 hours monitoring.
Results: Patients with and without early reablation had similar baseline characteristics including echocardiographic parameters and type of AF. During a mean follow-up of 11 ± 11 months, 82 patients (91%) without early reablation experienced late clinical recurrences. In contrast, patients with early reablation had lower rate of clinical recurrences (51% vs 91%, P < 0.0001) and fewer additional procedures (36% vs 91%, P < 0.0001). However, the total number of procedures over the entire follow-up was greater in those patients with early reablation (2.5 ± 0.7 vs 2.2 ± 0.6, P = 0.02).
Conclusion: An overwhelming majority of patients with recurrences within the first month after ablation have late recurrences. An early reablation reduces the incidence of further recurrences. However, the overall number of procedures is higher in the medium-term follow-up. The optimal timing for the second procedure remains to be defined.