Nusinersen treatment in adults with severe spinal muscular atrophy: A real-life retrospective observational cohort study.

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease due to homozygous loss-of-function of the survival motor neuron gene SMN1 with absence of the functional SMN protein. Nusinersen, a costly intrathecally administered drug approved in 2017 in Europe, induces alternative splicing of the SMN2 gene, which then produces functional SMN protein, whose amount generally increases with the number of SMN2 gene copies. METHODS: We retrospectively collected data from consecutive wheelchair-bound adults with SMA managed at a single center in 2018-2020. The following were collected at each injection, on days 1, 14, 28, 63, 183, and 303: 32-item Motor Function Measurement (MFM) total score and D2 and D3 subscores; the Canadian Occupational Performance Measure (COPM) performance and satisfaction scores; and lung function tests. The patients were divided into two groups based on whether their MFM total score was

[Technique of complex mammary irradiation: Mono-isocentric 3D conformational radiotherapy and helical tomotherapy]. / Techniques d'irradiation mammaire complexe : radiothérapie conformationelle tridimensionnelle mono-isocentrique et nomothérapie hélicoïdale.

PURPOSE: To evaluate the dosimetric contribution of helical tomotherapy for breast cancers compared with conformal radiotherapy in mono-isocentric technique. PATIENTS AND METHOD: For 23 patients, the dosimetric results in mono-isocentric 3D conformational radiotherapy did not satisfy the constraints either of target volumes nor organs at risk. A prospective dosimetric comparison between mono-isocentric 3D conformational radiotherapy and helical tomotherapy was therefore carried out. RESULTS: The use of helical tomotherapy showed a benefit in these 23 patients, with either an improvement in the conformity index or homogeneity, but with an increase in low doses. Of the 23 patients, two had pectus excavatum, five had past thoracic irradiation and two required bilateral irradiation. The other 14 patients had a combination of morphology and/or indication of lymph node irradiation. For these patients, helical tomotherapy was therefore preferred to mono-isocentric 3D conformational radiotherapy. CONCLUSIONS: Tomotherapy appears to provide better homogeneity and tumour coverage. This technique of irradiation may be justified in the case of morphological situations such as pectus exavatum and in complex clinical situations. In other cases, conformal radiotherapy in mono-isocentric technique remains to be favoured.

Gene transfer of two entry inhibitors protects CD4⁺ T cell from HIV-1 infection in humanized mice.

Targeting viral entry is the most likely gene therapy strategy to succeed in protecting the immune system from pathogenic HIV-1 infection. Here, we evaluated the efficacy of a gene transfer lentiviral vector expressing a combination of viral entry inhibitors, the C46 peptide (an inhibitor of viral fusion) and the P2-CCL5 intrakine (a modulator of CCR5 expression), to prevent CD4⁺ T-cell infection in vivo. For this, we used two different models of HIV-1-infected mice, one in which ex vivo genetically modified human T cells were grafted into immunodeficient NOD.SCID.γc⁻/⁻mice before infection and one in which genetically modified T cells were derived from CD34⁺ hematopoietic progenitors grafted few days after birth. Expression of the transgenes conferred a major selective advantage to genetically modified CD4⁺ T cells, the frequency of which could increase from 10 to 90% in the blood following HIV-1 infection. Moreover, these cells resisted HIV-1-induced depletion, contrary to non-modified cells that were depleted in the same mice. Finally, we report lower normalized viral loads in mice having received genetically modified progenitors. Altogether, our study documents that targeting viral entry in vivo is a promising avenue for the future of HIV-1 gene therapy in humans.

[Potential indications for helical tomotherapy in breast cancers]. / Indications potentielles de la tomothérapie hélicoïdale dans les cancers du sein.

PURPOSE: To evaluate the dosimetric gain obtained in either the planning target volume or organs at risk coverage by the use of intensity-modulated radiation therapy in some particular postoperative breast cancers. PATIENTS AND METHOD: Prospective dosimetric comparison between monoisocentric conformal radiotherapy and intensity-modulated radiation therapy in nine patient files. RESULTS: Using intensity-modulated radiation therapy was shown to improve in each case, at least one conformity, homogeneity, and coverage index either for planning target volumes or for organs at risk. Intensity-modulated radiation therapy was therefore always chosen rather than conformal monoisocentric radiotherapy. CONCLUSIONS: Indications to retain intensity-modulated radiation therapy would consist of bilateral lesions, pectus excavatum, past thoracic irradiation (Hodgkin's disease) and complex volumes in obese or overweight patients.

[Conventional 2D and monoisocentric 3D techniques in breast and lymphatic irradiation: a dosimetric comparison]. / Techniques classique bidimensionnelle et mono-isocentrique tridimensionnelle dans l'irradiation du sein et des aires ganglionnaires : comparaison dosimétrique.

PURPOSE: The activity of our radiation oncology department mainly relies on breast pathology. Since July 2009, all the irradiations delivered simultaneously to the breast (CTV1), the surgical bed (CTV2), the internal mammary chain and the supra- and infraclavicular areas have been carried out using a mono-isocentric technique. This study aimed to compare dosimetric results between conventional 2D and mono-isocentric 3D techniques with or without optimization. PATIENTS AND METHODS: From January to August 2009, 20 patients with breast cancer in whom irradiation of the CTV1, CTV2, internal mammary chain and supra- and infraclavicular areas was retained, were included in a specific cohort. In each case, we have compared dosimetric results obtained with the conventional technique and with a mono-isocentric 3D technique, either with manual field in the field segmentation or with automatic segmentation (Oncentra Masterplan(®) from Nucletron(®), Optimizer(®) solution). Selected criteria were as follows: V95, V107 and mean dose (Dmean) to the target volumes, V20 and V30 to the ipsilateral lung, V35 and mean dose to the heart and maximal dose (Dmax) to the spinal cord. RESULTS: Supra- and infraclavicular areas irradiation was significantly better using the mono-isocentric 3D technique (V95 %: 89.7 % vs. 77.1 %; P=0.001) as well as dose homogeneity (Dmean: 46.3 Gy vs. 45.1 Gy; P=0.008). No statistical difference was observed for the other target volumes. Heart and spinal cord protection were better with the mono-isocentric 3D technique (respectively Dmean: 8.4Gy vs. 11.1 Gy; P<0.0001 and Dmax: 29.2 Gy vs. 35.8 Gy; P=0.0003). CONCLUSION: Mono-isocentric irradiation of the breast and lymphatic areas is a modern technique that benefits from imaging and computer progresses while being simple to carry out using standard planning system and linear accelerators. Mono-isocentric 3D irradiation with manual segmentation of the breast and the nodal areas provides a target volume irradiation comparing with conventional technique 2D and a better protection of the heart and of the spinal cord.

Anaphylaxis to pork kidney is related to IgE antibodies specific for galactose-alpha-1,3-galactose.

BACKGROUND: Carbohydrate-specific IgE antibodies present on nonprimate mammalian proteins were incriminated recently in delayed meat anaphylaxis. The aim of this study was to explore whether anaphylaxis to mammalian kidney is also associated with galactose-α-1,3-galactose (αGal)-specific IgE. METHODS: Fourteen patients with anaphylaxis to pork or beef kidney underwent prick tests to meat and kidney. Some patients also underwent skin tests to Erbitux(®) (cetuximab). IgE antibodies to αGal, swine urine proteins, beef and pork meat, serum albumin proteins, cat, and rFel d 1 were measured by ImmunoCAP(®). The αGal levels were estimated in meats and kidney by ELISA inhibition assay. Cross-reactivity between αGal and pork kidney was studied with the ImmunoCAP(®) inhibition assay. RESULTS: Among the 14 patients, 12 presented with anaphylactic shock. Reactions occurred within 2 h from exposure in 67% of patients. Associated risk factors were observed in 10 cases, and alcohol was the main cofactor. Three patients underwent an oral challenge to pork kidney, and anaphylaxis occurred after ingestion of small quantities (1-2 g). Prick tests to kidney were positive in 54% of patients. All tested patients showed positive skin tests to Erbitux(®). All patients tested positive for IgE to αGal, with levels ranging from 0.4 to 294 kU/l. IgE binding to αGal was inhibited by raw pork kidney extract (mean, 77%; range, 55-87%), which showed a high amount of αGal determinants. CONCLUSIONS: Pork or beef kidney anaphylaxis is related to αGal IgE. Its peculiar severity could be due to an elevated content of αGal epitopes in kidney.

[Cartography and risk management in radiotherapy: A collaborative work of the department of radiotherapy and the department of quality and risk management at the Jean-Godinot Institute]. / Cartographie et gestion des risques en radiothérapie : un travail commun du département de radiothérapie et du département de la qualité et de la gestion des risques de l'institut Jean-Godinot.

PURPOSE: To deploy an inductive process for radiotherapy risk management in a regional cancer centre and to infer the actions required to solve the situations of criticality. METHODS: Close collaboration between the department of radiation oncology-biophysics and the department of quality and risk management in the same institution allowed to create a multiprofessional and multidisciplinary task force and to make the experience feedback easier. A preliminary risk analysis method was used to identify the generic dangers, the mapping of risks and the specification of the scales of criticality. This method helped to evaluate and to rate each apprehended event. Four scales have been defined: seriousness scale in five levels, likelihood scale in five classes, endeavour scale in four levels and criticality scale in three categories: acceptable (criticality 1) tolerable under control (criticality 2) and unacceptable (criticality 3). RESULTS: Fifty-seven level 1 dangerous situations linked to 78 scenarios of criticality acceptable, tolerable and unacceptable in 24, 44 and 10 cases respectively have been identified in the department of radiotherapy leading to carry out 28 risk reduction actions. CONCLUSIONS: The performed risk analysis offered an original frame for a collective thinking among the care providers and contributed to modify their mode of conceiving both security and radioprotection. The study allowed us to give a relevant answer to the High Authority of Health and the Authority of Nuclear Security demands either in terms of efficient management of the risks in radiotherapy or regarding the daily concerns of the caregivers.

The efficiency of purifying selection in Mammals vs. Drosophila for metabolic genes.

The nearly neutral theory of molecular evolution states that the efficiency of natural selection depends on the effective population size. By using a wide range of multispecies data on nucleotide polymorphism, we have tried to ascertain whether there are any differences in the level of selective constraints of metabolic process genes between Mammals and Drosophila species. The results are consistent with a higher selective constraint in Drosophila than in Mammals, according to the expected under the nearly neutral model: purifying selection seems to be more efficient in species with a larger effective population size.

Selection efficiency and effective population size in Drosophila species.

A corollary of the nearly neutral theory of molecular evolution is that the efficiency of natural selection depends on effective population size. In this study, we evaluated the differences in levels of synonymous polymorphism among Drosophila species and showed that these differences can be explained by differences in effective population size. The differences can have implications for the molecular evolution of the Drosophila species, as is suggested by our results showing that the levels of codon bias and the proportion of adaptive substitutions are both higher in species with higher levels of synonymous polymorphism. Moreover, species with lower synonymous polymorphism have higher levels of nonsynonymous polymorphism and larger content of repetitive sequences in their genomes, suggesting a diminished efficiency of selection in species with smaller effective population size.

The economic costs of severe anaphylaxis in France: an inquiry carried out by the Allergy Vigilance Network.

BACKGROUND: The prevalence of severe anaphylaxis, between 1 and 3 per 10,000, has increased sharply over recent years, with a rate of lethality of 1%. The economic burden is unknown. OBJECTIVE: The aim of this study was to estimate the economic costs of anaphylaxis, including direct costs of treatment, hospitalization, preventive and long-care measures, and the indirect cost: absenteeism. METHODS: Analysis of 402 patients of anaphylaxis declared by 384 allergists was reported to the Allergy Vigilance Network. The global cost was estimated from the national data of hospital admissions: ICD-10 coding available for 2003, 2004 and 2005. RESULTS: Three work/classroom days were lost per patient. Diagnosis required oral challenge with hospitalization in 18% of cases. The estimated mean total cost was 1895 euros for food- and drug-related anaphylaxis (5610 euros for the most severe), and 4053 euros for Hymenoptera anaphylaxis. National statistics recorded 2575 patients in 2005; 22% more than in 2003. The estimated annual cost was 4,789,500 euros. The possible reasons for this being an under-estimate include: data coming only from hospitalized patients, poor identification by medical teams unfamiliar with ICD-10 codes, peri-operative anaphylaxis being insufficiently declared, rush-immunotherapy and maintenance treatments for Hymenoptera anaphylaxis. Similarly, the extra cost of cow milk substitutes, as well as insurance costs where deaths are followed by litigation were not taken into account. CONCLUSIONS: The mean cost of anaphylaxis was 1895-5610 euros in nonfatal patients. The prevalence was under-estimated because of many biases, leading to under-estimation of the national cost. Further studies would be necessary to evaluate the value of preventive strategies.

Oral desensitization in children with milk and egg allergies obtains recovery in a significant proportion of cases. A randomized study in 60 children with cow's milk allergy and 90 children with egg allergy.

BACKGROUND: Food allergy is treated by avoidance diets in order to prevent anaphylactic reactions and to cure chronic associated symptoms. However, the natural history is left unchanged. OBJECTIVE: To search for a beneficial effect of an oral desensitization protocol to allergenic foods in IgE-dependent milk or egg allergies in children. METHODS: 60 children with documented cow's milk allergy (13 months-6.5 years), and 90 children with egg allergy (12 months-8 years), were consecutively included after 6-12 months of avoidance diet, if a SBPCFC to 60 ml milk (60 ml) or to 965 mg of raw egg white was negative. They were randomized for uninterrupted avoidance or oral desensitization (group A or OD). Six months later, a new SBPCFC was performed with, up to 200 ml of milk or 7g of raw egg white. Prick tests and specific IgE levels were carried out simultaneously. RESULTS: Data were obtained for 57 children with CMA (30 A and 27 OD), and 84 children with EA (35 A and 49 OD). The two groups (AD or OD group) were similar with regard to means of ages, the size of PT wheals and the level of IgEs at baseline. MILK ALLERGY: A SBPCFC to milk was positive in 11.1% of those following OD vs. 40% after A (p < .025). The size of PT decreased after OD and increased after A (-3.4 mm vs. +0.84 mm; p < .002). EGG ALLERGY: The SBPCFC to egg was positive in 30.6% after OD vs. 48.6% after A (p < .1). After 6 months, in the OD group, the mean size of the PT and the level of specific IgE were significantly reduced compared to the A group. In the A group, the threshold of reactivity was often lower, or more serious symptoms were observed. CONCLUSION: Oral desensitization helps the egg and milk allergic children to overcome their allergies. Since the avoidance of these foods is likely to increase sensitization as well as to lower the threshold of reactivity, an active treatment is required. Further attempts to standardize the procedures of oral desensitization are expected.

Mutation analysis in 16 patients with mtDNA depletion.

Sixteen unrelated Southern European patients with the mitochondrial depletion syndrome (MDS) were analyzed for mutations in the TK2 and DGUOK genes. Three novel mutations were identified in TK2 (R183G, R254X, and 142insG). When we analyzed additional genes involved in the dNTPs pool, such as SLC25A19 (DNC) and NT5M (d-NT2), we did not detect mutations. The current study suggest that scanning the TK2, DGUOK, SLC25A19, and NT5M genes is likely to help about 10% of MDS families in terms of genetic counseling. Also, our findings indicate that genotype-phenotype correlations are not straightforward in MDS.

Experience of a combination including indinavir 400 mg plus ritonavir 200 mg twice daily in HIV-infected patients: pharmacokinetic data.

Low doses of ritonavir, a strong inhibitor of cytochrome P450 3A4, enhances the pharmacokinetic profile of indinavir with increased serum levels. We assessed the indinavir-ritonavir 400/200 twice daily combination in 17 HIV-infected patients focusing on the pharmacokinetic data and the tolerance of this regimen. IDV trough and peak concentrations were measured by high-performance liquid chromatography. Median indinavir trough and peak concentrations were 553 ng/ml and 3626 ng/ml, respectively. A good tolerance was observed except for three patients who experienced a major toxicity. Only one dose adjustment was related to indinavir toxicity. Considering the fact that Cmax is mainly responsible of the adverse effects, particularly renal stones, the indinavir-ritonavir 400/200 mg twice daily regimen offers a well-tolerated combination with an increased Cmin but a lower Cmax compared with both the standard tid regimen and higher dose of IDV-RTV regimens.

Germ cell tumors in patients infected by the human immunodeficiency virus.

BACKGROUND: The objective of this study was to assess the natural history of the two disease courses, patient immune system tolerance, and results of therapy in human immunodeficiency virus (HIV)-infected patients with germ cell tumors (GCT). METHODS: From 1985 to 1996, 34 HIV-infected men received a diagnosis of GCT. Their charts were analyzed retrospectively. RESULTS: Sixteen patients had seminomas, and 18 had nonseminomatous GCTs (NSGCT); 71% had International Union Against Cancer (UICC), 1997 Stage I-II GCTs. At the time of chemotherapy, 69%, 6%, and 25% of patients with advanced NSGCT were in the International Germ Cell Consensus Classification (IGCCC) good, intermediate, and poor prognostic group, respectively. All except 1 of the 10 patients with advanced seminomas were in the IGCCC good prognostic group. At diagnosis of GCT, 85% of patients were classified as having asymptomatic HIV infection or only persistent generalized lymphadenectomy. The median CD4 cell count was 325/microL (range, 6-1125). Overall, 26 patients were given chemotherapy, but the planned dose intensity was respected in only 15 (57%) patients. Severe toxic effects included febrile neutropenia in 35% of patients. During chemotherapy, zidovudine, prophylactic granulocyte colony-stimulating factor (G-CSF), and a Pneumocystis carinii prophylaxis were given in 19%, 23%, and 35% of cases, respectively. CD4 cell count decreased in 7 (64%) of 11 patients during chemotherapy. Infradiaphragmatic radiotherapy was given in 10 cases and was clinically well tolerated. At a median follow-up of 27 months (range, 3-150), 50% of patients were alive, and only 18% of patients died of GCT. Two patients developed a non-GCT malignancy while in complete remission, namely, Hodgkin disease and an acute leukemia. CONCLUSIONS: The prognosis of GCT in HIV-infected patients is mostly dictated by the HIV infection. Patients should be treated according to stage and histologic subtype, although dose reduction of chemotherapy might be necessary in approximately half of the patients. Close surveillance of neutrophil and CD4 cells counts, as well as the use of G-CSF and systematic anti-Pneumocystis carinii prophylaxis are recommended during chemotherapy. The use of highly active antiretroviral therapy during chemotherapy for GCT requires a prospective assessment.

Technical knockout, a Drosophila model of mitochondrial deafness.

Mutations in mtDNA-encoded components of the mitochondrial translational apparatus are associated with diverse pathological states in humans, notably sensorineural deafness. To develop animal models of such disorders, we have manipulated the nuclear gene for mitochondrial ribosomal protein S12 in Drosophila (technical knockout, tko). The prototypic mutant tko(25t) exhibits developmental delay, bang sensitivity, impaired male courtship, and defective response to sound. On the basis of a transgenic reversion test, these phenotypes are attributable to a single substitution (L85H) at a conserved residue of the tko protein. The mutant is hypersensitive to doxycyclin, an antibiotic that selectively inhibits mitochondrial protein synthesis, and mutant larvae have greatly diminished activities of mitochondrial redox enzymes and decreased levels of mitochondrial small-subunit rRNA. A second mutation in the tko gene, Q116K, which is predicted to impair the accuracy of mitochondrial translation, results in the completely different phenotype of recessive female sterility, based on three independent transgenic insertions. We infer that the tko(25t) mutant provides a model of mitochondrial hearing impairment resulting from a quantitative deficiency of mitochondrial translational capacity.

Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome.

One form of congenital muscular dystrophy, rigid spine syndrome (MIM 602771), is a rare neuromuscular disorder characterized by early rigidity of the spine and respiratory insufficiency. A locus on 1p35-36 (RSMD1) was recently found to segregate with rigid spine muscular dystrophy 1 (ref. 1). Here we refine the locus and find evidence of linkage disequilibrium associated with SEPN1, which encodes the recently described selenoprotein N (ref. 2). Our identification and analysis of mutations in SEPN1 is the first description of a selenoprotein implicated in a human disease.

Simultaneous occurrence of kaposi's sarcoma and chronic myelogenous leukemia.

We report here a 75-year-old man from South France who developed Kaposi's Sarcoma (KS) 5 months after diagnosis of Philadelphia-chromosome positive chronic myelogenous leukemia (CML). He was found positive for HHV-8 by PCR, negative for both HIV 1 and HIV 2 by serology, and had a normal CD4/CD8 ratio. Favourable evolution of both CML and KS has been obtained with vinblastine and interferon alpha treatment. The patient is currently alive in complete remission of SK and major cytogenetic remission of CML with a 48 month follow-up. Since no immune deficiency could be documented in the patient, this rare observation suggests that CML may have triggered the onset of SK through cytokine release.

Quantitative analysis, by ultrastructural in situ hybridization, of mitochondrial genomes and their expression in mid-gut and ovarian cells of a mutant strain of Drosophila subobscura.

In the mitochondrial deletion mutant strain studied here, two types of DNA coexist (heteroplasmy): intact mtDNA (15.9 kb) and mutant mtDNA (10.9 kb), which represents about 80% of the mitochondrial genomes in somatic tissues. The heteroplasmy level is lower in ovary (63%). Mutation is transmitted unchanged through generations. Quantitative analysis of in situ DNA hybridization demonstrated that for the 12SrDNA probe, of a gene outside the deletion, the mitochondrial DNA cellular content in the studied cells of the mutant strain is 1.5 times higher than in the wild-type strain. For the probe encoding Cyto b, a mitochondrial gene affected by the mutation, the ratios (mutant versus wild-type content) differ according to cell type: close to 0.4 in MGE cells and 0.7 in ovary cells. These values indicate heteroplasmic levels of about 72% in MGE cells and 50% in stage 10 oocytes, which is lower than that previously reported for stage 14 oocytes (60%) and embryos (69%). Analysis of in situ RNA hybridization showed that for the 12SrDNA probe, the transcript concentrations do not differ significantly between MGE cells and cells of germinal origin from the two strains. For the Cyto b probe, the mutant RNA/wild-type RNA ratios are lower in somatic cells than in stage 10 nurse cells and oocytes, but in each case less than expected. These studies indicate that the progressive heteroplasmy increase may be related to intense phases of mitochondria biogenesis and that different compensatory phenomena may exist.