[Quality guidelines for radiopharmacy: Development of a risk-assessment tool]. / Référentiel qualité en radiopharmacie : création d'un outil d'analyse des risques.

OBJECTIVES: The medical management of patients, which involves securing the drug circuit, is a major public health objective. As part of quality management, a number of risk assessment and risk management tools in care units are validated and available. However, medication management in radiopharmacy departments represents a complex and specific process. The aim of the "Quality guidelines for radiopharmacy" working group of the French society of radiopharmacy (SoFRa) was to develop a risk-assessment tool that is a priori adapted to radiopharmacy activity. METHODS: A qualitative risk matrix was developed, based on available analysis tools and current regulations concerning radiopharmacy practice. The tool was then programmed to obtain a summary and scoring for each risk category, as well as a quantitative analysis of the risks identified in radiopharmacy. RESULTS: Our tool contains 262 issues. The qualitative study integrates the risks related to the circuit of radiopharmaceuticals, but also risks related to personnel. The quantitative study makes it possible to carry out an automated analysis of the actions to carry out in priority to improve the practices. CONCLUSIONS: This work led to the development of a self-assessment tool for the a priori analysis of risks that are adapted to the practice of radiopharmacy. It allows easy analysis of the entire circuit of radiopharmaceuticals from a single tool and meet the expectations of health authorities. This common and validated tool is available to the pharmaceutical community.

Systematic review: colitis associated with anti-CTLA-4 therapy.

BACKGROUND: Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) has an important role in T-cell regulation, proliferation and tolerance. Anti-CTLA-4 agents, such as ipilimumab and tremelimumab, have been shown to prolong overall survival in patients with metastatic melanoma, and their use is being investigated in the treatment of other malignancies. Their novel immunostimulatory mechanism, however, predisposes patients to immune-related adverse effects, of which gastrointestinal effects such as diarrhoea and colitis are the most common. AIMS: To discuss the existing literature and summarise the epidemiology, pathogenesis and clinical features of anti-CTLA-4-associated colitis, and to present a management algorithm for it. METHODS: We searched PubMed for studies published through October 2014 using the terms 'anti-CTLA,' 'ipilimumab,' 'tremelimumab,' 'colitis,' 'gastrointestinal,' 'immune-related adverse effect,' 'immunotherapy,' 'melanoma,' and 'diarrhoea.' RESULTS: Watery diarrhoea is commonly associated with anti-CTLA-4 therapy (27-54%), and symptoms occur within a few days to weeks of therapy. Diffuse acute and chronic colitis are the most common findings on endoscopy (8-22%). Concomitant infectious causes of diarrhoea must be evaluated. Most cases may be successfully managed with discontinuation of anti-CTLA-4 and conservative therapy. Those with persistent grade 2 and grade 3/4 diarrhoea should undergo endoscopic evaluation and require corticosteroid therapy. Corticosteroid-resistant cases may respond to anti-tumour necrosis factor-alpha therapy such as infliximab. Surgery is reserved for patients with bowel perforation or failure of medical therapy. CONCLUSION: Given the increasing use of anti-CTLA-4 therapy, clinicians must be aware of related adverse events and their management.

Idiopathic inflammatory demyelinating disease of the central nervous system in patients with inflammatory bowel disease: retrospective analysis of 9095 patients.

BACKGROUND: Anti-TNFα biologics induce and maintain remission in inflammatory bowel disease (IBD). Also, they have been reported to induce or unmask idiopathic inflammatory demyelinating disease of the central nervous system (IIDD). AIM: To determine if anti-TNFα biologics increased the risk of IIDD in a large cohort of patients with IBD. METHODS: We retrospectively identified adult patients referred to the Mayo Clinic, Rochester, MN for management of IBD from a five state capture area (Minnesota, Wisconsin, North Dakota, South Dakota and Iowa) between 1996 and 2010. IIDDs were identified in both Crohn's disease (CD) and ulcerative colitis (UC) patients with and without anti-TNFα exposure using the 2010 McDonald MRI criteria. The risk of IIDDs in patients with and without anti-TNFα exposure was estimated for IBD; CD and UC groups separately. RESULTS: A total of 9095 patients with IBD were identified (4342 CD and 4753 UC). Four patients with CD with exposure to anti-TNFα agents (4/2054) and five patients with CD without anti-TNFα exposure (5/2288) developed a confirmed IIDD. One patient with UC with exposure to anti-TNFα agents (1/1371) and five patients with UC without anti-TNFα agents developed a confirmed IIDD (5/3382). The per cent of IIDDs in patients with and without anti-TNFα exposure was; IBD: 0.15% and 0.18% (RR = 0.83, 95% CI: 0.28-2.42; P = 0.729); CD: 0.19% and 0.22% (RR = 0.89, 95% CI: 0.24-3.31; P = 0.863); UC: 0.07% and 0.15% (RR = 0.49, 95% CI: 0.06-4.22; P = 0.510). CONCLUSION: Anti-TNFα biologics do not appear to impact the risk of developing clinical idiopathic inflammatory demyelinating disease in patients with inflammatory bowel disease.

Cell context reveals a dual role for Maf in oncogenesis.

Maf b-Zip transcription factors are involved in both terminal differentiation and oncogenesis. To investigate this apparent contradiction, we used two different primary cell types and performed an extensive analysis of transformation parameters induced by Maf proteins. We show that MafA and c-Maf are potent oncogenes in chicken embryo fibroblasts, while MafB appears weaker. We also provide the first evidence that MafA can confer growth factor independence and promote cell division at low density. Moreover, using MafA as a model, we identified several parameters that are critical for Maf transforming activities. Indeed, MafA ability to induce anchorage-independent cell growth was sensitive to culture conditions. In addition, the transforming activity of MafA was dependent on its phosphorylation state, since mutation on Ser65 impaired its ability to induce growth at low density and anchorage-independent growth. We next examined transforming activity of large Maf proteins in embryonic neuroretina cells, where they are known to induce differentiation. Unlike v-Jun, MafA, MafB and c-Maf did not show oncogenic activity in these cells. Moreover, they counteracted transformation induced by constitutive activation of the Ras/Raf/MEK pathway. Taken together, our results show that Maf proteins could display antagonistic functions in oncogenesis depending on the cellular context, and support a dual role for Maf as both oncogenes and tumor suppressor-like proteins.

Phylogenomic analysis and expression patterns of large Maf genes in Xenopus tropicalis provide new insights into the functional evolution of the gene family in osteichthyans.

We have performed an exhaustive characterization of the large Maf family of basic leucine zipper transcription factors in vertebrates using the genome data available, and studied the embryonic expression patterns of the four paralogous genes thus identified in Xenopus tropicalis. Our phylogenetic analysis shows that, in osteichthyans, the large Maf family contains four orthology classes, MafA, MafB, c-Maf and Nrl, which have emerged in vertebrates prior to the split between actinopterygians and sarcopterygians. It leads to the unambiguous assignment of the Xenopus laevis XLmaf gene, previously considered a MafA orthologue, to the Nrl class, the identification of the amphibian MafA and c-Maf orthologues and the identification of the zebrafish Nrl gene. The four X. tropicalis paralogues display partially redundant but nevertheless distinct expression patterns in the somites, developing hindbrain, pronephros, ventral blood island and lens. Comparisons with the data available in the mouse, chick and zebrafish show that these large Maf expression territories are highly conserved among osteichthyans but also highlight a number of differences in the timing of large Maf gene expression, the precise extent of some labelled territories and the combinations of paralogues transcribed in some organs. In particular, the availability of robust phylogenies leads to a reinterpretation of previous expression pattern comparisons, suggesting an important part for function shuffling within the gene family in the developing lens. These data highlight the importance of exhaustive characterizations of gene families for comparative analyses of the genetic mechanisms, which control developmental processes in vertebrates.

A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis.

OBJECTIVE: To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS. METHODS: A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival. RESULTS: Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis). CONCLUSIONS: At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.

Spinal accessory mononeuropathy following posterior fossa decompression surgery.

Isolated injury of the spinal accessory nerve is a well-recognized complication of surgeries involving the posterior triangle of the neck. The procedures most commonly implicated are lymph node biopsy and carotid endarterectomy. We present a patient with isolated injury to the spinal accessory nerve, localized proximal to the innervation of the sternocleidomastoid muscle, which was noted following suboccipital decompression for an Arnold-Chiari malformation. To our knowledge, this association has not been previously reported.

A pilot randomized trial of oxandrolone in inclusion body myositis.

BACKGROUND: Inclusion body myositis (IBM) remains without effective therapy. As anabolic steroids have myotrophic properties, the authors studied whether a synthetic androgen, oxandrolone, would have efficacy in IBM. METHODS: A double-blind, placebo-controlled, crossover design was used. Patients received oxandrolone or placebo for 12 weeks followed by a minimum 2-month washout period, followed by 12 weeks of the alternative treatment. Maximal voluntary isometric contraction testing (MVICT), manual muscle testing (MMT), and functional performance testing were obtained before and after each treatment period, with the whole-body MVICT score as the primary outcome measure. RESULTS: Of 19 patients enrolled, 16 (14 men, 2 women; median age 68.5 years) had complete data for at least the first treatment period, with 13 completing the entire study. Whole-body MVICT improved by a median of 15.5 kg with drug and 4.1 kg with placebo (p = 0.06), whereas MMT demonstrated a median increase of 2.0 Medical Research Council points with drug and 0.9 point with placebo (p = 0.33). Upper-extremity MVICT demonstrated a significant treatment effect, with strength increasing a median 6.3 kg with drug vs 2.5 kg with placebo (p = 0.006). Stair climbing also increased a median of 1 step on average with drug versus no change with placebo (p < 0.001). Minimal adverse effects occurred. CONCLUSIONS: Oxandrolone had a borderline significant effect in improving whole-body strength and a significant effect in improving upper-extremity strength as measured by MVICT. Given these findings, further study of this drug, possibly in combination with an immunomodulating agent, is warranted.

GABA and the ornithine delta-aminotransferase gene in vigabatrin-associated visual field defects.

Vigabatrin use in some epilepsy patients has been associated with persistent visual field constriction and retinal dysfunction. The mechanism is unknown, but could be related to vigabatrin, chronic epilepsy, GABA toxicity, or the effect of a metabolite in combination with a predisposing genotype. The aim of this study was to investigate the latter two hypotheses. Levels of brain gamma-aminobutyric acid (GABA) measured by nuclear magnetic resonance spectroscopy were similar in subjects taking vigabatrin who developed visual field constriction and those who did not. We tested whether allelic heterogeneity of the ornithine aminotransferase gene occurs in the affected patients. No clinically significant mutation was detected, although a common intronic polymorphism was identified.

Unusual clinical presentations in patients harboring the facioscapulohumeral dystrophy 4q35 deletion.

Facioscapulohumeral dystrophy (FSHD) is a dominantly inherited myopathy usually associated with a deletion at locus 4q35. Typically, FSHD patients present with a recognizable constellation of signs including weakness of facial, shoulder and pelvic girdle, humeral, and anterior foreleg muscles; preservation of some muscles including the deltoids; and other characteristic features including prominent scapular winging, anterior axillary folds, and horizontally positioned clavicles. We performed clinical and FSHD genetic studies on four patients with atypical clinical features who were cared for at a regional neuromuscular center. The four patients, each harboring 4q35 deletions, presented with atypical phenotypes including facial-sparing scapular myopathy, limb-girdle muscular dystrophy, distal myopathy, and asymmetric brachial weakness. This report demonstrates the expanding clinical heterogeneity in patients harboring the 4q35 deletion.

Adult-onset MLD: a gene mutation with isolated polyneuropathy.

A 22-year-old man presented with recurrent ulnar mononeuropathies and diffusely slow nerve conduction velocities. Arylsulfatase A (ASA) activity from leukocytes and fibroblasts was reduced, and urinary sulfatides were increased. Sural nerve biopsy revealed a reduction in myelinated fibers and Schwann cell inclusions. Results of studies of CNS integrity, including cranial MRI, evoked potentials, and neuropsychologic tests, were normal. Molecular genetic analyses revealed a novel homozygous missense mutation (Thr286Pro) in the ASA gene.

Autosomal dominant Emery-Dreifuss dystrophy due to mutations in rod domain of the lamin A/C gene.

BACKGROUND: Autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD) is a disorder characterized clinically by humeropelvic weakness, contractures, and cardiomyopathy, and genetically by mutations in the lamin A/C gene on 1q21.2-q21.3. Of the 14 lamin A/C gene mutations reported thus far, the four involving the rod domain have been associated with isolated cardiomyopathy and conduction-system disease. This is the first report of rod domain mutations in patients with the full EDMD-AD phenotype. METHODS: Clinical, pathologic, and genetic data are provided on two families with EDMD-AD. RESULTS: In both families, the full clinical spectrum of EDMD-AD was demonstrated. For the proband in family 1, sequence analysis detected a mutation within exon 2 of the lamin A/C gene. The missense mutation was due to a A448C base substitution causing a Thr150Pro amino acid change. For the proband of family 2, sequence analysis detected an in-frame 3-bp deletion (AAG 778-780 or 781-783) removing one of two adjacent lysine residues (K 260 or 261) of exon 4. Both mutations were in the central rod domain of the lamin A/C gene. CONCLUSIONS: Mutations in the rod domain of the lamin A/C gene may cause the full clinical spectrum of EDMD-AD.

FSH dystrophy 4q35 deletion in patients presenting with facial-sparing scapular myopathy.

OBJECTIVE: To evaluate the incidence of the facioscapulohumeral dystrophy (FSHD) 4q35 deletion in patients with facial-sparing scapular myopathy. BACKGROUND: Scapular winging is typical of FSHD but may also be prominent in other muscle disorders including scapuloperoneal syndromes. With DNA testing, it is possible to determine if patients with facial-sparing scapular myopathy have FSHD. METHODS: Fourteen of 17 unrelated patients with facial-sparing scapular myopathy, seen over a 7-year period at a regional neuromuscular center, agreed to have DNA testing for FSHD. The clinical and laboratory features of these patients were also noted. RESULTS: Of the 14 patients, 10 (71%) had restriction fragments consistent with the 4q35 deletion. The mean size of the smaller fragment following EcoRI digestion was 29.5 kb (range 20 to 39). The mean age at onset was 19.9 years; at presentation, 44.7 years. Except for the absence of facial weakness, most patients had clinical and laboratory features otherwise consistent with FSHD. Five patients (50%) had a positive family history of similar weakness. Following removal of outliers, the Pearson correlation coefficient (r) value between EcoRI fragment size and age at onset was 0.64, and between fragment size and limb muscle strength, 0.64. CONCLUSION: The FSHD 4q35 deletion was found in 71% of the facial-sparing scapular myopathy patients. They otherwise resemble typical FSHD patients in age at onset, physical characteristics, and association between fragment size and disease severity.

Late-Onset Friedreich's Ataxia Presenting as a Spastic Paraparesis.

A 55-year-old woman presented with a 10-yeai history of a progressive gait disorder. Her examination showed a spastic paraparesis with brisk deep tendon reflexes, but only minimal limb ataxia and no evidence for a sensory neuropathy The patient was found to be homozygous for the GAA trinucleotide repeal diagnostic of Friedreich's ataxia The presentation of Friedreich's ataxia as a spastic paraparesis reinforces the appreciation of the variable phenotype of this disease.

Treatable lower motor neuron disease due to vitamin D deficiency and secondary hyperparathyroidism.

Vitamin D deficiency and osteomalacia are frequently associated with muscle weakness and atrophy. We present a 78-year-old man with complaints of progressive painless weakness who was referred to us with a diagnosis of suspected motor neuron disease. Results of the neurological examination were remarkable, showing diffuse limb weakness and atrophy, rare fasciculations, normal sensory examination, no bulbar weakness, and no upper motor neuron signs. Electromyography revealed mild chronic changes, denervation and re-innervation, without fibrillations or positive waves. Serum laboratory studies showed an elevated serum parathyroid hormone and markedly reduced vitamin D level. Although the etiology of the vitamin D deficiency was not determined, the patient made a substantial clinical improvement following vitamin D therapy. Vitamin D deficiency and secondary hyperparathyroidism need to be included in the differential diagnosis of patients presenting with a progressive lower motor neuron disease.