Erenumab for the preventive treatment of chronic migraine complicated with medication overuse headache: an observational,retrospective, 12-month real-life study

Background

Erenumab is a monoclonal antibody blocking the calcitonin gene–related peptide receptor, which has been approved for the preventive treatment of chronic migraine (CM). The aim of this study was to explore the safety and effectiveness of erenumab in patients suffering from CM and medication overuse headache (MOH) in a real-life setting, up to 1 year.

Methods

Data regarding 81 patients treated with erenumab were retrospectively analyzed. Every 3 months, the following variables were collected: the mean number of headache days per month (headache index (HI)), the average number of painkillers taken per month (analgesic consumption (AC)), the mean number of days with painkiller consumption (number of days on medication (NDM)), the headache intensity (numeric rating scale (NRS) score), the 6-item Headache Impact Test (HIT-6), and the Self-Reported Instrument to Assess Work-Related Difficulties in Patients With Migraine (HEADWORK) scores.

Results

The HI, AC, and NDM and the NRS, HIT-6, and HEADWORK scores were significantly lower at every time point from the 3rd month onward compared to baseline (all P < 0.0001). No significant differences were found between patients who underwent painkiller detoxification before starting erenumab and those who did not (all P > 0.05). No significant differences were found between patients taking erenumab in combination with other preventive treatments and the ones taking it alone (all P ≥ 0.05). Five patients dropped out because of adverse events, which resolved after stopping erenumab.

Conclusion

Erenumab was safe and effective for CM complicated with MOH. Painkiller withdrawal and the association with other preventive treatment(s) seem useless.

     

Larvicidal activity of lipophilic extract of Hypericum carinatum (Clusiaceae) against Aedes aegypti (Diptera: Culicidae) and benzophenones determination

In this study, the larvicidal activity of an enriched fraction of the major lipophilic phenolic compounds from Hypericum carinatum Griseb. (Clusiaceae) was investigated against larvae of Aedes aegypti (Diptera: Culicidae), the main vector of dengue virus in Brazil. The larval mortality rate ranged 37.33 to 72.00 % at concentrations of 66–200 μg/mL. The effect demonstrated to be dose-dependent. The lethal concentration 50 % and confidence interval were 100 and 88–111 μg/mL, respectively. The results could be attributed to the presence of cariphenone A and cariphenone B in concentrations of 1.24?±?0.04 and 0.56?±?0.01 %, respectively, determined by high-performance liquid chromatography. Besides, the results reinforce the potential of genus Hypericum as source of alternative insecticides.     

Multivariate analysis of the influence of peri-implant clinical parameters and local factors on radiographic bone loss in the posterior maxilla: a retrospective study on 277 dental implants

Clinical Oral Investigations - The aim of the present study was to investigate whether peri-implant clinical parameters (modified plaque index (mPI), bleeding and/or suppuration on probing (B/SOP))...     

Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele‐Specific Expression

Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication‐based mechanisms such fork stalling and template switching or microhomology‐mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele‐specific LMNB1 expression levels.     

Comparison of pregnenolone sulfate,pregnanolone and estradiol levels between patients with menstrually-related migraine and controls: an exploratory study

BackgroundNeurosteroids affect the balance between neuroexcitation and neuroinhibition but have been little studied in migraine. We compared the serum levels of pregnenolone sulfate, pregnanolone and estradiol in women with menstrually-related migraine and controls and analysed if a correlation existed between the levels of the three hormones and history of migraine and age.MethodsThirty women (mean age ± SD: 33.5 ± 7.1) with menstrually-related migraine (MM group) and 30 aged- matched controls (mean age ± SD: 30.9 ± 7.9) participated in the exploratory study. Pregnenolone sulfate and pregnanolone serum levels were analysed by liquid chromatography-tandem mass spectrometry, while estradiol levels by enzyme-linked immunosorbent assay.ResultsSerum levels of pregnenolone sulfate and pregnanolone were significantly lower in the MM group than in controls (pregnenolone sulfate: P = 0.0328; pregnanolone: P = 0.0271, Student’s t-test), while estradiol levels were similar. In MM group, pregnenolone sulfate serum levels were negatively correlated with history of migraine (R² = 0.1369; P = 0.0482) and age (R² = 0.2826, P = 0.0025) while pregnenolone sulfate levels were not age-related in the control group (R² = 0.04436, P = 0.4337, linear regression analysis).ConclusionLow levels of both pregnanolone, a positive allosteric modulator of the GABAA receptor, and pregnenolone sulfate, a positive allosteric modulator of the NMDA receptor, involved in memory and learning, could contribute either to headache pain or the cognitive dysfunctions reported in migraine patients. Overall, our results agree with the hypothesis that migraine is a disorder associated with a loss of neurohormonal integrity, thus supporting the therapeutic potential of restoring low neurosteroid levels in migraine treatment.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01231-9.     

Ischemic necrosis of the femoral head: An experimental rabbit model

To describe the morphology of the proximal femoral epiphysis in a rabbit model from the ischemic insult to the end of the revascularization process. Ischemia of the femoral head was induced in 32 rabbits at the 8th day of life, by sectioning the joint capsule and the ligamentum teres and dislocating the femoral head. Rabbits were sacrificed at 4, 8, 12, 18, 21, 26, 34, and 48 days after surgery and femoral heads were observed histologically. During the first days following the ischemic injury, large areas underwent necrotic changes. Both epiphyseal and physeal cartilage were thicker than normal and less trabecular bone formation was evident. Bone marrow was also diffusely necrotic within the secondary center of ossification. After day 12th, reparative process started with formation of extensive areas of fibrocartilage and several secondary centers of ossifications. At that stage femoral head deformity was already evident. In the following days the secondary centers of ossification cohalesced and epiphyseal and physeal cartilage resumed a normal appearance, but the femur showed a permanent deformity. In newborn rabbits, the ischemic injury to the femoral head blocked the ossification of the epiphyseal and physeal cartilage associated to necrotic bone marrow within the secondary center of ossification of the femoral head as well as to extensive areas of necrosis of epiphyseal and physeal cartilage. Extensive areas of fibrocartilage and small newly formed ossification centers within the femoral epiphysis were the results of the revascularization process, and femoral head deformity became stable afterward. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:535–541, 2015.     

Brain Neuronal Degeneration Caused by Episodic Alcohol Intoxication in Rats: Effects of Nimodipine, 6,7-Dinitro-quinoxaline-2,3-dione, and MK-801

Rats repeatedly intoxicated with alcohol (ethanol, three times daily) over a 4-day period display neuronal degeneration in the dentate gyrus; entorhinal, piriform, insular, orbital, and perirhinal cortices; and in the olfactory nerve fibers and terminals in the olfactory bulb. Postulating a role for excitotoxicity, we have attempted to prevent the degeneration using antagonists that are neuroprotective in this type of brain damage. In an initial study, continuous subcutaneous infusion of a high dose of the glutamate/NMDA receptor antagonist MK-801 (2 mg/kg/day) by itself caused extensive neuronal degeneration in several brain regions and severe behavioral intoxication that precluded survival if combined with high blood alcohol levels (～300 mg/dl). Moreover, the lower, nonneurotoxic blood alcohol levels (～150 mg/dl) that were compatible with survival worsened the MK-801-induced brain damage. In a subsequent experiment, daily intraperitoneal injections of a lower dose of MK-801 (1 mg/kg/day) resulted in no MK-801 toxicity and, when combined with neurotoxic levels of alcohol, no reduction in alcohol-induced neurotoxicity. Nimodipine, a voltage-gated Ca²⁺ channel blocker, reduced the neuronal damage in the dentate gyrus, but greatly increased it in the piriform cortex when administered intragastrically at 600 mg/kg/day; it provided no protection from alcohol-dependent degeneration when given intragastrically at 100 mg/kg/day. Continuous intracere-broventricular delivery of 0.24 to 0.29 mg/day of 6,7-dinitro-quinoxa-line-2,3-dione, a glutamate/α-amino-3-hydroxy-5-methyl-4-isoxazole receptor antagonist, failed to diminish alcohol-dependent neuronal damage in any brain region. We conclude that brain damage from episodic “binge” alcohol intoxication is not primarily mediated by excitotoxic mechanisms, implying that other, nonexcrtotoxic pathophysiological mechanisms, are involved. Furthermore, MK-801, far from protecting from the alcohol-induced damage, at high doses causes widespread neuropathology that is significantly potentiated by alcohol.     

Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma

Rare biallelic BLM gene mutations cause Bloom syndrome. Whether BLM heterozygous germline mutations (BLM^+/−) cause human cancer remains unclear. We sequenced the germline DNA of 155 mesothelioma patients (33 familial and 122 sporadic). We found 2 deleterious germline BLM^+/− mutations within 2 of 33 families with multiple cases of mesothelioma, one from Turkey (c.569_570del; p.R191Kfs*4) and one from the United States (c.968A>G; p.K323R). Some of the relatives who inherited these mutations developed mesothelioma, while none with nonmutated BLM were affected. Furthermore, among 122 patients with sporadic mesothelioma treated at the US National Cancer Institute, 5 carried pathogenic germline BLM^+/− mutations. Therefore, 7 of 155 apparently unrelated mesothelioma patients carried BLM^+/− mutations, significantly higher (P = 6.7E-10) than the expected frequency in a general, unrelated population from the gnomAD database, and 2 of 7 carried the same missense pathogenic mutation c.968A>G (P = 0.0017 given a 0.00039 allele frequency). Experiments in primary mesothelial cells from Blm^+/− mice and in primary human mesothelial cells in which we silenced BLM revealed that reduced BLM levels promote genomic instability while protecting from cell death and promoted TNF-α release. Blm^+/− mice injected intraperitoneally with asbestos had higher levels of proinflammatory M1 macrophages and of TNF-α, IL-1β, IL-3, IL-10, and IL-12 in the peritoneal lavage, findings linked to asbestos carcinogenesis. Blm^+/− mice exposed to asbestos had a significantly shorter survival and higher incidence of mesothelioma compared to controls. We propose that germline BLM^+/− mutations increase the susceptibility to asbestos carcinogenesis, enhancing the risk of developing mesothelioma.

In the United States, the incidence rate of mesothelioma varies between fewer than one case per 100,000 persons in states with no asbestos industry to two to three cases per 100,000 persons in states with an asbestos industry (1, 2). Asbestos causes DNA damage and apoptosis (3) and promotes a chronic inflammatory reaction that supports the emergence of malignant cells (4). Fortunately, only a small fraction of exposed individuals develop mesothelioma; for example, 4.6% of deaths in miners who worked in asbestos mines for over 10 y were caused by mesothelioma (1). Therefore, multiple cases of mesothelioma in the same family are rare and suggest genetic predisposition (5). In 2001, we discovered that susceptibility to mesothelioma was transmitted in a Mendelian fashion across multiple generations in some Turkish families exposed to the carcinogenic fiber erionite, pointing to gene × environment interaction (G×E) as the cause (6). In 2011, we discovered that carriers of heterozygous germline BRCA1-associated protein–1 (BAP1) mutations (BAP1^+/−) developed mesothelioma and uveal melanoma (5), findings expanded and confirmed by us and by multiple research teams (reviewed in refs. 1, 7, 8). Moreover, heterozygous germline Bap1 mutations (Bap1^+/−) significantly increased susceptibility to asbestos-induced mesothelioma in mice (9, 10), evidence of G×E. Reduced BAP1 levels impair DNA repair (11) as well as different forms of cell death (3, 12) and induce metabolic alterations (13–15) that together favor cancer development and growth.Recent studies revealed that mesothelioma may also develop among carriers of germline mutations of additional tumor-suppressor genes that cause well-defined cancer syndromes, including MLH1 and MLH3 (Lynch syndrome), TP53 (Li–Fraumeni syndrome), and BRCA1-2 (Breast and Ovarian Cancer syndrome) (16, 17). When all germline mutations are combined, it has been estimated that about 12% of mesotheliomas occur in carriers of heterozygous germline mutations of BAP1, the most frequent mutation among patients with mesothelioma, or of other tumor suppressors. Some of these mutations may sensitize the host to asbestos carcinogenesis, according to a G×E scenario (17). Thus, presently, mesothelioma is considered an ideal model to study G×E in cancer (17). As part of the Healthy Nevada Project (HNP), we are studying G×E in northern Nevada, a region with an unusually high risk of exposure to carcinogenic minerals and arsenic, which may be related to the high cancer rates in this region (18). We are investigating genetic variants that may increase cancer risk upon exposure to carcinogens to implement preventive strategies.Biallelic mutations of the Bloom syndrome gene (BLM) cause Bloom syndrome, an autosomal-recessive tumor predisposition syndrome characterized by pre- and postnatal growth deficiency, photosensitivity, type 2 diabetes, and greatly increased risk of developing various types of cancers. BLM is a RecQ helicase enzyme that modulates DNA replication and repair of DNA damage by homologous recombination (19). In patients affected by Bloom syndrome, the absence of the BLM protein causes chromosomal instability, increased number of sister chromatid exchanges, and increased numbers of micronuclei (20–22). In addition, BLM is required for p53-mediated apoptosis (23), a process critical to eliminate cells that have accumulated DNA damage. Impaired DNA repair together with altered apoptosis resulted in increased cancer incidence (17, 24). Of course, inactivating germline BLM heterozygous (BLM^+/−) mutations are much more common than biallelic BLM (BLM^−/−) mutations, with an estimated frequency in the general population of 1 in 900 based on data from the Exome Aggregation Consortium (25). BLM^+/− mutation carriers do not show an obvious phenotype; however, some studies have suggested that carriers of these mutations may have an increased cancer risk (17, 24). Mice carrying Blm^+/− mutations are prone to develop a higher rate of malignancies in the presence of contributing factors, such as concurrent heterozygous mutations of the adenomatous polyposis coli (Apc) gene, or upon infection with murine leukemia virus (26). However, in studies in which Blm^+/− mice were crossed with tuberous sclerosis 1-deficient (Tsc1^+/−) mice that are predisposed to renal cystadenomas and carcinomas, Wilson et al. found that Tsc1^+/− Blm^+/− mice did not show significantly more renal cell carcinomas compared with Tsc1^+/− Blm^WT mice (27). In humans, a large study involving 1,244 patients with colon cancer and 1,839 controls of Ashkenazi Jewish ancestry, in which BLM^+/− frequency is as high as 1 in 100 individuals (28), suggested that carriers of germline BLM^+/− mutations might have a twofold increase in colorectal cancer (CRC) (29). A smaller study did not confirm these results, but reported a trend of increasing incidence of adenomas—premalignant lesions—among BLM^+/− mutation carriers (30). In addition, BLM^+/− mutations were found overrepresented among early-onset (<45 y old) CRC patients (25). Other studies associated BLM^+/− mutations to an increased risk of breast (31, 32) and prostate cancer (33), but the low power of these studies hampered definite conclusions. In summary, it appears possible that BLM^+/− mutations may increase cancer risk in the presence of contributing factors.