Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma.

BACKGROUND: In the phase III HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) versus sorafenib; durvalumab monotherapy was noninferior to sorafenib for OS. Results reported herein are from a 4-year updated OS analysis of HIMALAYA. PATIENTS AND METHODS: Participants with uHCC and no previous systemic treatment were randomized to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The updated data cut-off was 23 January 2023. OS and serious adverse events (AEs) were assessed. Additionally, baseline characteristics and subsequent therapies were analyzed in long-term survivors (≥36 months beyond randomization). RESULTS: For STRIDE, durvalumab, and sorafenib, median [95% confidence interval (CI)] follow-up was 49.12 months (46.95-50.17 months), 48.46 months (46.82-49.81 months), and 47.31 months (45.08-49.15 months), respectively. OS hazard ratio (95% CI) for STRIDE versus sorafenib was 0.78 (0.67-0.92). The 36-month OS rate for STRIDE was 30.7% versus 19.8% for sorafenib. The 48-month OS rate remained higher for STRIDE at 25.2%, versus 15.1% for sorafenib. The long-term OS benefit of STRIDE was observed across clinically relevant subgroups and was further improved in participants who achieved disease control. Long-term survivors with STRIDE (n = 103) included participants across clinically relevant subgroups, and 57.3% (59/103) had no reported subsequent anticancer therapy. No new serious treatment-related AEs occurred with STRIDE from the primary analysis (17.5%; 68/388). Durvalumab maintained OS noninferiority to sorafenib and no late-onset safety signals were identified. CONCLUSIONS: These data represent the longest follow-up to date in phase III studies in uHCC. The unprecedented 3- and 4-year OS rates reinforce the sustained long-term OS benefit of STRIDE versus sorafenib. STRIDE maintained a tolerable yet differentiated safety profile from other current uHCC therapies. Results continue to support the long-term benefits of STRIDE in a diverse population, reflective of uHCC globally.

Gitelman syndrome associated with chondrocalcinosis and severe neuropathy: a novel heterozygous mutation in SLC12A3 gene.

Gitelman syndrome (GS) is an inherited salt-wasting tubulopathy characterized by hypocalciuria, hypokalemia, hypomagnesemia and metabolic alkalosis, due to inactivating mutations in the SLC12A3 gene. Symptoms may be systemic, neurological, cardiovascular, ophthalmological or musculoskeletal. We describe a 70 year-old patient affected by recurrent arthralgias, hypoesthesia and hyposthenia in all 4 limbs and severe hypokalemia, complicated by atrial flutter. Moreover, our patient reported eating large amounts of licorice, and was treated with medium-high dosages of furosemide, thus making diagnosis very challenging. Genetic analysis demonstrated a novel heterozygous mutation in the SLC12A3 gene; therefore, we diagnosed GS and started potassium and magnesium replacement. GS combined with chondrocalcinosis and neurological involvement is quite common, but this is the first case of an EMG-proven severe neuropathy associated with GS. Herein, we underline the close correlation between hypomagnesemia, chondrocalcinosis and neurological involvement. Moreover, we report a new heterozygous mutation in exon 23 (2738G>A), supporting evidence of a large genetic heterogeneity in this late-onset congenital tubulopathy.

Correction to: A PRISMA-compliant systematic review of the endpoints employed to evaluate symptomatic treatments for primary headaches.

Following publication of the original article [1], we have been notified that the name of author five was spelled incorrectly as M. Ferrili, when the correct spelling is MAN Ferilli.

A PRISMA-compliant systematic review of the endpoints employed to evaluate symptomatic treatments for primary headaches.

BACKGROUND: Primary headache are prevalent and debilitating disorders. Acute pain cessation is one of the key points in their treatment. Many drugs have been studied but the design of the trials is not usually homogeneous. Efficacy of the trial is determined depending on the selected primary endpoint and usually other different outcomes are measured. We aim to critically appraise which were the employed outcomes through a systematic review. METHODS: We conducted a systematic review of literature focusing on studies on primary headache evaluating acute relief of pain, following the PRISMA guideline. The study population included patients participating in a controlled study about symptomatic treatment. The comparator could be placebo or the standard of care. The collected information was the primary outcome of the study and all secondary outcomes. We evaluated the studied drug, the year of publication and the type of journal. We performed a search and we screened all the potential papers and reviewed them considering inclusion/exclusion criteria. RESULTS: The search showed 4288 clinical trials that were screened and 794 full articles were assessed for eligibility for a final inclusion of 495 papers. The studies were published in headache specific journals (58%), general journals (21.6%) and neuroscience journals (20.4%). Migraine was the most studied headache, in 87.8% studies, followed by tension type headache in 4.7%. Regarding the most evaluated drug, triptans represented 68.6% of all studies, followed by non-steroidal anti-inflammatories (25.1%). Only 4.6% of the papers evaluated ergots and 1.6% analyzed opioids. The most frequent primary endpoint was the relief of the headache at a determinate moment, in 54.1%. Primary endpoint was evaluated at 2-h in 69.9% of the studies. Concerning other endpoints, tolerance was the most frequently addressed (83%), followed by headache relief (71.1%), improvement of other symptoms (62.5%) and presence of relapse (54%). The number of secondary endpoints increased from 4.2 (SD = 2.0) before 1991 to 6.39 after 2013 (p = 0.001). CONCLUSION: Headache relief has been the most employed primary endpoint but headache disappearance starts to be firmly considered. The number of secondary endpoints increases over time and other outcomes such as disability, quality of life and patients' preference are receiving attention.

Microfluidic Programming of Compositional Hydrogel Landscapes.

A droplet microfluidics strategy to rapidly synthesize, process, and screen up to hundreds of thousands of compositionally distinct synthetic hydrogels is presented. By programming the flow rates of multiple microfluidic inlet channels supplying individual hydrogel building blocks, microgel compositions and properties are systematically modulated. The use of fluorescent labels as proxies for the physical and chemical properties of the microgel permits the rapid screening and discovery of specific formulations through fluorescence microscopy or flow cytometry. This concept should accelerate the discovery of new hydrogel formulations for various novel applications.

Headache and pregnancy: a systematic review.

This systematic review summarizes the existing data on headache and pregnancy with a scope on clinical headache phenotypes, treatment of headaches in pregnancy and effects of headache medications on the child during pregnancy and breastfeeding, headache related complications, and diagnostics of headache in pregnancy. Headache during pregnancy can be both primary and secondary, and in the last case can be a symptom of a life-threatening condition. The most common secondary headaches are stroke, cerebral venous thrombosis, subarachnoid hemorrhage, pituitary tumor, choriocarcinoma, eclampsia, preeclampsia, idiopathic intracranial hypertension, and reversible cerebral vasoconstriction syndrome. Migraine is a risk factor for pregnancy complications, particularly vascular events. Data regarding other primary headache conditions are still scarce. Early diagnostics of the disease manifested by headache is important for mother and fetus life. It is especially important to identify "red flag symptoms" suggesting that headache is a symptom of a serious disease. In order to exclude a secondary headache additional studies can be necessary: electroencephalography, ultrasound of the vessels of the head and neck, brain MRI and MR angiography with contrast ophthalmoscopy and lumbar puncture. During pregnancy and breastfeeding the preferred therapeutic strategy for the treatment of primary headaches should always be a non-pharmacological one. Treatment should not be postponed as an undermanaged headache can lead to stress, sleep deprivation, depression and poor nutritional intake that in turn can have negative consequences for both mother and baby. Therefore, if non-pharmacological interventions seem inadequate, a well-considered choice should be made concerning the use of medication, taking into account all the benefits and possible risks.

Quality indicators in headache care: an implementation study in six Italian specialist-care centres.

BACKGROUND: Headache disorders are highly prevalent, and have a substantial and negative impact on health worldwide. They are largely treatable, but differences in structure, objectives, organization and delivery affect the quality of headache care. In order to recognize and remedy deficiencies in care, the Global Campaign against Headache, in collaboration with the European Headache Federation, recently developed a set of quality indicators for headache services. These require further assessment to demonstrate fitness for purpose. This is their first implementation to evaluate quality in headache care as a multicentre national study. METHODS: Between September and December 2016, we applied the quality indicators in six Italian specialist headache centres (Bologna, Firenze, Modena, Padova, Roma Campus Bio-Medico and Roma Sapienza). We used five previously developed assessment instruments, translated into Italian according to Lifting The Burden's translation protocol for hybrid documents. We took data from 360 consecutive patients (60 per centre) by questionnaire and from their medical records, and by different questionnaires from their health-care providers (HCPs), including physicians, nurses, psychologists and nursing assistants. RESULTS: The findings, comparable between centres, confirmed the feasibility and practicability of using the quality indicators in Italian specialist headache centres. The questionnaires were easily understood by HCPs and patients, and were not unduly time-consuming. Diagnoses were almost all (> 97%) according to ICHD criteria, and routinely (100%) reviewed during follow-up. Diagnostic diaries were regularly used by 96% of physicians. Referral pathways from primary to specialist care existed in five of the six clinics, as did urgent referral pathways. Instruments to assess disability and quality of life were not used regularly, a deficiency that needs to be addressed. CONCLUSION: This Italy-wide survey confirmed in six specialist centres that the headache service quality indicators are fit for purpose. By establishing majority practice, identifying commonalities and detecting deficits as a guide to quality improvement, the quality indicators may be used to set benchmarks for quality assessment. The next step is extend use and evaluation of the indicators into non-specialist care.

A study of the neuropathy associated with transthyretin amyloidosis (ATTR) in the UK.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTR) is usually characterised by a progressive peripheral and autonomic neuropathy often with associated cardiac failure and is due to dominantly inherited transthyretin mutations causing accelerated amyloid deposition. The UK population is unique in that the majority of patients have the T60A missense mutation in ATTR where tyrosine is replaced by adenine at position 60. This has been traced to a single founder mutation from north-west Ireland. The neuropathy phenotype is less well described than the cardiac manifestations in this group. METHODS: We present the findings from an observational cohort study of patients with ATTR attending the National Hospital Inherited Neuropathy Clinic between 2009 and 2013. Detailed clinical neurological and electrophysiological data were collected on all patients alongside correlating autonomic and cardiac assessments. Follow-up data were available on a subset. RESULTS: Forty-four patients with genetically confirmed ATTR were assessed; 37 were symptomatic; mean age at onset=62 years, range=38-75 years; 75.7% male. T60A was the most common mutation (17/37), followed by V30M (5/37). A severe, rapidly progressive, predominantly length dependent axonal sensorimotor neuropathy was the predominant phenotype. T60A patients were distinguished by earlier and more frequent association with carpal tunnel syndrome; a predominance of negative sensory symptoms at onset; significant vibration deficits; and a non-length dependent progression of motor deficit. Progression of the neuropathy was observed over a relatively short follow-up period (2 years) in 20 patients with evidence of clinically measurable annual change in Medical Research Council (MRC) sum score (-1.5 points per year) and Charcot Marie Tooth Neuropathy Score (CMTNS:2.7 points per year), and a congruent trend in the electrophysiological measures used. CONCLUSION: The description of the ATTR neuropathy phenotype, especially in the T60A patients, should aid early diagnosis as well as contribute to the understanding of its natural history.

An atypical presentation of renal mass associated with BAP-1 tumor predisposition syndrome: Case report and review of literature.

BCRA-associated protein-1 (BAP-1) mutation has been associated with the development of a familiar syndrome that predisposes to tumors with a higher incidence than in general population, including melanoma and renal carcinoma. We report a 47-year-old woman diagnosed with a BAPoma (melanocytic tumor characterized by the loss of BAP-1). Due to her extensive family history with multiple neoplasms, a FDG PET-CT was performed. Consequently, she was diagnosed with an atypical renal mass, which is rarely linked to this syndrome. We review and discuss the available literature on the screening, diagnosis and treatment of renal tumors associated with BAP-1 tumor predisposition syndrome.

A comparison of genetic and genomic breeding values in Saanen and Alpine goats.

Nowadays, several countries are developing or adopting genomic selection in the dairy goat sector. The most used method to estimate breeding values is Single-Step Genomic Best Linear Unbiased Prediction (ssGBLUP) which offers several advantages in terms of computational process and accuracy of the estimated breeding values (EBVs). Saanen and Alpine are the predominant dairy goat breeds in Italy, and both have similar breeding programs where EBVs for productive traits are currently calculated using BLUP. This work describes the implementation of genomic selection for these two breeds in Italy, aligning with the selection practices already carried out in the international landscape. The available dataset included 3 611 genotyped animals, 11 470 lactation records, five traits (milk, protein and fat yields, and fat and protein percentages), and three-generation pedigrees. EBVs were estimated using BLUP, GBLUP, and ssGBLUP both with single and multiple trait approaches. The methods were compared in terms of correlation between EBVs and genetic trends. Results were also validated with the linear regression method excluding part of the phenotypic data. In both breeds, EBVs and GEBVs were strongly correlated and the trend of each trait was similar comparing the three methods. The average increase in accuracy across traits and methods amounted to +13 and +10% from BLUP to ssGBLUP for Alpine and Saanen breeds, respectively. Results indicated higher prediction accuracy and correlation for GBLUP and ssGBLUP compared to BLUP, implying that the use of genotypes increases the accuracy of EBVs, particularly in the absence of phenotypic data. Therefore, ssGBLUP is likely to be the most effective method to enhance genetic gain in Italian Saanen and Alpine goats.

Clinical practice guidelines for the diagnosis and management of Charcot-Marie-Tooth disease.

INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is classified according to neurophysiological and histological findings, the inheritance pattern, and the underlying genetic defect. The objective of these guidelines is to offer recommendations for the diagnosis, prognosis, follow-up, and treatment of this disease in Spain. MATERIAL AND METHODS: These consensus guidelines were developed through collaboration by a multidisciplinary panel encompassing a broad group of experts on the subject, including neurologists, paediatric neurologists, geneticists, physiatrists, and orthopaedic surgeons. RECOMMENDATIONS: The diagnosis of CMT is clinical, with patients usually presenting a common or classical phenotype. Clinical assessment should be followed by an appropriate neurophysiological study; specific recommendations are established for the parameters that should be included. Genetic diagnosis should be approached sequentially; once PMP22 duplication has been ruled out, if appropriate, a next-generation sequencing study should be considered, taking into account the limitations of the available techniques. To date, no pharmacological disease-modifying treatment is available, but symptomatic management, guided by a multidiciplinary team, is important, as is proper rehabilitation and orthopaedic management. The latter should be initiated early to identify and improve the patient's functional deficits, and should include individualised exercise guidelines, orthotic adaptation, and assessment of conservative surgeries such as tendon transfer. The follow-up of patients with CMT is exclusively clinical, and ancillary testing is not necessary in routine clinical practice.

[Craniofacial morphology and obstructive sleep apnoea-hypopnoea syndrome: a craniometric comparative analysis]. / Morfologia craniofacciale e sindrome delle apnee-ipopnee ostruttive nel sonno: un'analisi craniometrica comparativa.

PURPOSE: The aim of this study was to define the relationship between paediatric obstructive sleep apnoea-hypopnea syndrome (OSAHS) and craniofacial morphovolumetric features through comparative craniometric analyses between affected children and controls based on conventional cephalometry. MATERIALS AND METHODS: Cephalometric examinations of 40 children affected by OSAHS were retrospectively evaluated. Sixteen craniometric landmarks were identified, and 27 linear and angular indices related to craniofacial morphovolumetric features were measured. Subsequently, the same process of identifying landmarks and measuring indices was performed on the cephalometric examinations of 40 controls. For each index, we then calculated in both groups the mean, standard deviation, standard error and p value. By comparing the values obtained in the two series, we calculated the degree of significance of each difference between children with OSAHS and controls using the Student t test. RESULTS: Differences of only 5/27 linear and angular indices considered were not statistically significant between groups, thus confirming susceptibility to the disorder in relation to certain splanchnocranic morphovolumetric features. The most significant differences involved mandibular plane inclination and distance between landmark sella and hyoid bone, a reliable index being the vertical position of the latter. CONCLUSIONS: Despite the limitations associated with the 2D nature of conventional cephalometry, mainly related to projection and identification errors, and despite the upright position during examination, we consider the diagnostic value and information content of this technique high, thus reaffirming its role as a first-line imaging investigation in children with sleep-related breathing disorders.

OnabotulinumtoxinA in elderly patients with chronic migraine: insights from a real-life European multicenter study.

INTRODUCTION: Although migraine prevalence decreases with aging, some older patients still suffer from chronic migraine (CM). This study aimed to investigate the outcome of OnabotulinumtoxinA (OBT-A) as preventative therapy in elderly CM patients. METHODS: This is a post hoc analysis of real-life prospectively collected data at 16 European headache centers on CM patients treated with OBT-A over the first three treatment cycles (i.e., Cy1-3). We defined: OLD patients aged ≥ 65 years and nonOLD those < 65-year-old. The primary endpoint was the changes in monthly headache days (MHDs) from baseline to Cy 1-3 in OLD compared with nonOLD participants. The secondary endpoints were the responder rate (RR) ≥ 50%, conversion to episodic migraine (EM) and the changes in days with acute medication use (DAMs). RESULTS: In a cohort of 2831 CM patients, 235 were OLD (8.3%, 73.2% females, 69.6 years SD 4.7). MHDs decreased from baseline (24.8 SD 6.2) to Cy-1 (17.5 SD 9.1, p < 0.000001), from Cy-1 to Cy-2 (14.8 SD 9.2, p < 0.0001), and from Cy-2 to Cy-3 (11.9 SD 7.9, p = 0.001). DAMs progressively reduced from baseline (19.2 SD 9.8) to Cy-1 (11.9 SD 8.8, p < 0.00001), to Cy-2 (10.9 SD 8.6, p = 0.012), to Cy-3 (9.6 SD 7.4, p = 0.049). The 50%RR increased from 30.7% (Cy-1) to 34.5% (Cy-2), to 38.7% (Cy-3). The above outcome measures did not differ in OLD compared with nonOLD patients. CONCLUSION: In a population of elderly CM patients with a long history of migraine OBT-A provided a significant benefit, over the first three treatment cycles, as good as in non-old patients.

The benefits and risks of stem cell technology.

The potential impact of stem cell technology on medical and dental practice is vast. Stem cell research will not only provide the foundation for future therapies, but also reveal unique insights into basic disease mechanisms. Therefore, an understanding of stem cell technology will be necessary for clinicians in the future. Herein, we give a basic overview of stem cell biology and therapeutics for the practicing clinician.

Gene variants with suicidal risk in a sample of subjects with chronic migraine and affective temperamental dysregulation.

BACKGROUND: Risk factors for suicide are at least partially heritable and functional polymorphisms of targeted genes have been suggested to be implicated in the pathogenesis of this phenomenon. However, other studies examining the association between specific gene variants and suicide revealed inconsistent findings. We aims to evaluate the possible association between MAO-A3, CYP1A2*1F and GNB3 gene variants, hopelessness and suicidal risk in a sample of subjects with chronic migraine and affective temperamental dysregulation. METHODS: 56 women were genotyped for MAO-A3, CYP1A2*1F and GNB3 gene variants. Participants were also assessed using Beck Hopelessness Scale (BHS), the Temperament Evaluation of the Memphis, Pisa, Paris and San Diego-Autoquestionnaire (TEMPS-A), and the Suicidal History Self-Rating Screening Scale (SHSS). RESULTS: Patients with higher total scores on affective dysregulated temperaments are more likely to have higher BHS (11.27+/=5.54 vs. 5.73+/=3.81; t19.20 = -3.57; p < 0.01) and higher SHSS total scores (4.79+/=3.31 vs. 1.05±2.31; t17.74 = -3.90; p < 0.001) than those with lower total scores. 67% of patients in the dysregulated group has BHS total scores >= 9 indicating high levels of hopelessness. No association was found between MAO-A3, CYP1A2*1F and GNB3 gene variants and suicidal risk as assessed by BHS and SHSS. CONCLUSIONS: This study did not sustain the association between MAO-A3, CYP1A2*1F and GNB3 gene variants and increased suicidal risk in patients with chronic migraine and affective temperamental dysregulation. Further studies investigating the gene-environment interaction or focusing on other genetic risk factors involved in suicidal behaviour are needed.  

[Guidelines for molecular diagnosis of Charcot-Marie-Tooth disease]. / Guía diagnóstica en el paciente con enfermedad de Charcot-Marie-Tooth.

INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is the most frequent form of inherited neuropathy. In accordance with the inheritance pattern and degree of slowing of motor conduction velocity (MCV) of the median nerve, CMT encompasses five main forms: CMT1 (autosomal dominant [AD] or X-linked transmission and MCV < 38 m/s); CMT2 (AD or X-linked transmission and MCV > 38 m/s); CMT4 (autosomal recessive [AR] and severe slowing of MCV); AR-CMT2 (AR transmission and MCV > 38 m/s); and DI-CMT (intermediate form with AD transmission and MCV between 30 and 40 m/s). In spite of its stereotyped semiological repertoire (basically, symptoms and signs of sensory-motor polyneuropathy and pes cavus), CMT seems to be one of the most complex hereditary neurodegenerative syndromes, 31 causative genes having been cloned. DEVELOPMENT: This paper is aimed at performing a nosological review of the disease, emphasising the guidelines for its molecular diagnosis. Genetic epidemiological studies and genotypes reported in Spanish patients are revised. CONCLUSIONS: In the great majority of CMT cases, mutations involve a reduced number of genes, namely: for CMT1, PMP22, GJB1 and MPZ; for CMT2, MFN2 and GJB1; for CMT4, GDAP1, and NDRG1, HK1 and SH3TC2 (gypsies); for AR-CMT2, GDAP1; and for DI-CMT, GJB1 and MPZ. Given their low prevalence, mutations in other pathogenic genes should be investigated after discarding the previous ones. There is no place for the indiscriminate use of diagnostic CMT genetic panels.

Chronic migraine: current concepts and ongoing treatments.

Migraine is an episodic painful disorder occasionally developing into a chronic form. Such disorder represents one of the most common neurological diseases in clinical practice. Chronicization is often accompanied by the appearance of acute drugs overuse. Chronic migraine (CM) constitutes migraine's natural evolution in its chronic form and involves headache frequency of 15 days/month, with features similar to those of migraine attacks. Medication Overuse Headache (MOH) has been defined as a headache present on > or = 15 days/month, with regular overuse for > 3 months of one or more drugs used for acute and/or symptomatic headache management. Subtypes of MOH attributed to different medications were delineated. Misuse of ergots, triptans, opioids or combination analgesics on > or = 10 days/month was required to make the diagnosis of MOH, while > or = 15 days/month were needed for simple analgesic-overuse headache. CM's low prevalence produces an extremely high disability grade. Therefore, special attention should be paid to both control and reduction of risk factors which might favour the migraine chronicization process and/or the outbreak of MOH. In MOH sufferers, the only treatment of choice is represented by drug withdrawal. Successful detoxification is necessary to ensure improvement in the headache status when treating patients who overuse acute medications. Different procedures have been suggested for withdrawal namely at home, at the hospital, with or without the use of steroids, with re-prophylaxis performed immediately or at the end of the washout period. At the moment we have not a total agreement whether prophylactic treatment should be started before, during, or after discontinuation of the overuse drug. Both drugs have been approved for CM treatment in view of their well-defined resistance to previous prophylaxis drugs. Recently, the PREEMPT clinical program has confirmed onabotulinumtoxinA as an effective, safe, and well-tolerated prophylactic treatment for adults with CM.

Rimegepant for the treatment of migraine.

Rimegepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist developed with a novel quick-dissolve oral tablet formulation for the acute treatment of migraine by Biohaven Pharmaceuticals, under license from Bristol Myers Squibb. The completed phase II and III trials showed its efficacy in terms of pain freedom, pain relief, release of migraine symptoms and lifestyle recovery, with an effect sustained up to 48 h. Significant clinical efficacy has been reported with a rimegepant single dose. Rimegepant was well tolerated and the few adverse events were mild or moderate and did not cause trial discontinuation. It received Food and Drug Administration (FDA) approval on February 27, 2020, for the acute treatment of migraine headache. Three clinical trials are currently ongoing to evaluate: i) the long-term safety as migraine acute treatment; ii) the efficacy and safety as a preventive treatment for migraine; and iii) the efficacy and safety for refractory trigeminal neuralgia. Future studies should be designed also to evaluate potential drug-drug interactions.

Altered myogenesis and premature senescence underlie human TRIM32-related myopathy.

TRIM32 is a E3 ubiquitin -ligase containing RING, B-box, coiled-coil and six C-terminal NHL domains. Mutations involving NHL and coiled-coil domains result in a pure myopathy (LGMD2H/STM) while the only described mutation in the B-box domain is associated with a multisystemic disorder without myopathy (Bardet-Biedl syndrome type11), suggesting that these domains are involved in distinct processes. Knock-out (T32KO) and knock-in mice carrying the c.1465G > A (p.D489N) involving the NHL domain (T32KI) show alterations in muscle regrowth after atrophy and satellite cells senescence. Here, we present phenotypical description and functional characterization of mutations in the RING, coiled-coil and NHL domains of TRIM32 causing a muscle dystrophy. Reduced levels of TRIM32 protein was observed in all patient muscle studied, regardless of the type of mutation (missense, single amino acid deletion, and frameshift) or the mutated domain. The affected patients presented with variable phenotypes but predominantly proximal weakness. Two patients had symptoms of both muscular dystrophy and Bardet-Biedl syndrome. The muscle magnetic resonance imaging (MRI) pattern is highly variable among patients and families. Primary myoblast culture from these patients demonstrated common findings consistent with reduced proliferation and differentiation, diminished satellite cell pool, accelerated senescence of muscle, and signs of autophagy activation.

Migraine as possible red flag of PFO presence in suspected demyelinating disease.

OBJECTIVES: To investigate a possible association between isolated white matter lesions suggestive of demyelinating disease in magnetic resonance imaging (MRI) and patent foramen ovale (PFO) evidence in migraine patients, with or without aura. MATERIALS: 31 migraine patients, 28 females and 3 males, with MRI evidence of white matter lesions suggestive of demyelinating disease according to the Barkhof Criteria. All patients underwent further diagnostics including lumbar puncture, autoimmunity panel and cardiological evaluation to detect the presence of PFO. The mean duration of follow-up was 3.46 years and MIPAV software was used to analyze MRI imaging. RESULTS: 14 of the 31 patients (45%) had PFO. A significant association was found between PFO and migraine with visual aura (p < 0.001). No difference in lesion number, volume or area between patients with and without PFO was found, but the distribution was mainly occipital (p < 0.001) in patients with PFO. The follow-up showed a stationary lesion load in all PFO patients; no infratentorial or spinal cord lesion and no enhancement or corpus callosum lesion was ever detected. At the end of follow-up four patients developed multiple sclerosis: younger age at first MRI and oligoclonal bands were associated risk factors. CONCLUSIONS: Migraine is often one of the main symptoms leading to MRI, and in many cases white matter lesions of unspecific significance are discovered, thus placing demyelinating diseases in the differential diagnosis. Our study underlines the potential pathogenetic role of PFO in generating white matter lesions in migraine patients (45%), particularly those with visual aura and occipital lesions. For this reason, we affirm that PFO represents a cardinal point in the differential diagnosis of suspected demyelinating disease.