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.

Protocol for the treatment of cystoid macular edema secondary to retinitis pigmentosa and other inherited retinal dystrophies.

Inherited retinal dystrophies (IRD) are the leading cause of legal blindness in the working population. Cystic macular edema (CME) is one of the treatable causes of visual loss, affecting up to 50% of the patients. A bibliographic review has been carried out combining "inherited retinal dystrophy", "retinitis pigmentosa", "macular oedema" and a diagnostic-therapeutic protocol according to the levels of evidence and recommendations of the "US Agency for Healthcare Research and Quality". This protocol has been discussed in the monthly meetings of the XAREA DHR group with the participation of more than 25 ophthalmologists, creating a consensus document. The etiology of CME is multifactorial: dysfunction of the blood-retinal barrier, retinal pigment epithelium, and Müller cells, inflammation, and vitreous traction. OCT is the test of choice for the diagnosis and follow-up of CME associated with IRD. The drugs with the highest degree of scientific evidence are carbonic anhydrase inhibitors (IAC). Intravitreal corticosteroids, anti-VEGF, and vitrectomy with peeling of the internal limiting membrane do not have sufficient evidence. A treatment scheme is proposed for the CME in IRD in adults, another for pediatric patients and another for IRD and cataract surgery. Oral and topical IACs are effective in the treatment of CME secondary to IRD. Treatment with corticosteroids, anti-VEGF, and vitrectomy are second-line options. Randomized clinical trials are required to establish the therapeutic scale in these patients.

Latrogenic Cushing’s syndrome by an interaction between cobicistat and fluticasone: a case report / Síndrome de Cushing yatrogénico asociado a la interacción entre cobicistat y fluticasona: caso clínico

We report a case of iatrogenic Cushing’s syndrome associated with an interaction between cobicistat and fluticasone in a seropositive woman treated with elvitegravir/cobicistat/emtricitabina/TAF (Genvoya®). This case highlights the importance to review interactions between antirretroviral therapy and other drugs, especially when antirretroviral scheme includes protease inhibitors enhanced with ritonavir or cobicistat. These enhancers interfere the cytochrome P-450 metabolic pathway. A large number of drugs are metabolized by cytochrome P-450 and may be altered by cobicistat or ritonavir. (AU)

Presentamos un caso de síndrome de Cushing asociado a la interacción entre cobicistat y fluticasona en una mujer seropositiva en tratamiento con elvitegravir/cobicistat/emtricitabina/TAF (Genvoya®). Este caso pone de manifiesto la importancia de la revisión de las interacciones entre el tratamiento antirretroviral y otros tratamientos concomitantes, especialmente cuando el esquema antirretroviral contiene inhibidores de proteasa potenciados con ritonavir o cobicistat. Esta potenciación afecta a la ruta metabólica mediada por el citocromo P450. Un elevado número de fármacos son metabolizados por el citocromo P450, y por tanto pueden verse afectados cuando se administran con ritonavir o cobicistat. (AU)

[Thoracic insufficiency syndrome]. / Síndrome de insuficiencia torácica.

The compendium of disorders that affect the normal growth or function of the thorax will cause Thoracic Insufficiency Syndrome (TIS). TIS is defined as the inability of the chest to sustain normal breathing and/or lung growth. The etiology of the syndrome may be secondary to spinal deformities, global deformities of the chest, neuromuscular dysfunction or the combination of any these. Its manifestation is based on a history that highlights respiratory symptoms, a physical examination that demonstrates chest deformity, abnormal radiographic findings and/or computed tomography of the chest, accompanied by alterations in lung function or other studies of respiratory function. This syndrome must be treated with haste since it progressively worsens with the aggravation of the underlying condition(s) which is unfavorable to the irreversible physiological changes of the lung that occur during development, and are directly related to the respiratory insufficiencies. The vertical expandable prosthetic titanium rib (VEPTR) was developed as a treatment procedure that aims to restore the volume and function of the thorax with the purpose of enabling thoracic growth during the development of the child or adolescent. The treatment targets the components of the rib cage as a unit, in order to prevent or treat respiratory insufficiencies. Its indications include children with early development scoliosis who are prone to develop SIT. The proposed procedure entails a high incidence of complications and conflicting results that limit its efficacy as a treatment, which is why it is a subject of great controversy in the medical literature.

Los procesos que afecten el crecimiento normal o la función del tórax causarán el síndrome de insuficiencia torácica (SIT). Éste se define como la incapacidad del tórax de sostener una respiración normal y/o crecimiento pulmonar. La etiología del síndrome puede ser secundaria a deformidades de la columna, deformidades globales del tórax, disfunción neuromuscular o la combinación de éstas. Su manifestación se basa en un historial que resalta síntomas respiratorios, un examen físico que demuestra deformidad del tórax, hallazgos anormales radiográficos y/o tomografía computarizada del pecho, acompañados de alteración en la función pulmonar o de otros estudios de la función respiratoria. Este síndrome debe ser tratado con premura debido a que progresivamente empeora con el agravamiento de la condición subyacente, lo que resulta irreversiblemente desfavorable en los cambios fisiológicos del pulmón y se relaciona con insuficiencia respiratoria durante el desarrollo. El tratamiento expansor de costilla conocido en inglés como vertical expandable prosthetic titanium rib (VEPTR) propone restaurar el volumen y la función torácica con el propósito de permitir el crecimiento del tórax a través del desarrollo del paciente. El tratamiento se dirige a los componentes de la caja torácica como una unidad, con el fin de prevenir o tratar la insuficiencia respiratoria. Sus indicaciones incluyen niños con escoliosis de desarrollo temprano que sean propensos a desarrollar el SIT. El procedimiento propuesto conlleva una alta incidencia de complicaciones y resultados conflictivos que limitan su eficacia como tratamiento, por lo que es un tema de gran controversia en la literatura médica.

Genetics of ancestry-specific risk for relapse in acute lymphoblastic leukemia.

The causes of individual relapses in children with acute lymphoblastic leukemia (ALL) remain incompletely understood. We evaluated the contribution of germline genetic factors to relapse in 2225 children treated on Children's Oncology Group trial AALL0232. We identified 302 germline single-nucleotide polymorphisms (SNPs) associated with relapse after adjusting for treatment and ancestry and 715 additional SNPs associated with relapse in an ancestry-specific manner. We tested for replication of these relapse-associated SNPs in external data sets of antileukemic drug pharmacokinetics and pharmacodynamics and an independent clinical cohort. 224 SNPs were associated with rapid drug clearance or drug resistance, and 32 were replicated in the independent cohort. The adverse risk associated with black and Hispanic ancestries was attenuated by addition of the 4 SNPs most strongly associated with relapse in these populations (for blacks: model without SNPs hazard ratio (HR)=2.32, P=2.27 × 10-4, model with SNPs HR=1.07, P=0.79; for Hispanics: model without SNPs HR=1.7, P=8.23 × 10-5, model with SNPs HR=1.31, P=0.065). Relapse SNPs associated with asparaginase resistance or allergy were overrepresented among SNPs associated with relapse in the more asparaginase intensive treatment arm (20/54 in Capizzi-methorexate arm vs 8/54 in high-dose methotrexate arm, P=0.015). Inherited genetic variation contributes to race-specific and treatment-specific relapse risk.

Genome-Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy.

Remission induction therapy for acute lymphoblastic leukemia (ALL) includes medications that may cause hepatotoxicity, including asparaginase. We used a genome-wide association study to identify loci associated with elevated alanine transaminase (ALT) levels after induction therapy in children with ALL enrolled on St. Jude Children's Research Hospital (SJCRH) protocols. Germline DNA was genotyped using arrays and exome sequencing. Adjusting for age, body mass index, ancestry, asparaginase preparation, and dosage, the PNPLA3 rs738409 (C>G) I148M variant, previously associated with fatty liver disease risk, had the strongest genetic association with ALT (P = 2.5 × 10-8 ). The PNPLA3 rs738409 variant explained 3.8% of the variability in ALT, and partly explained race-related differences in ALT. The PNPLA3 rs738409 association was replicated in an independent cohort of 2,285 patients treated on Children's Oncology Group protocol AALL0232 (P = 0.024). This is an example of a pharmacogenetic variant overlapping with a disease risk variant.

Successful challenges using native E. coli asparaginase after hypersensitivity reactions to PEGylated E. coli asparaginase.

PURPOSE: Asparaginase is an essential component of pediatric acute lymphoblastic leukemia (ALL) therapy. However, asparaginase-induced hypersensitivity reactions can compromise its efficacy either by directly influencing the pharmacokinetics of asparaginase or by leading to a discontinuation of asparaginase treatment. Here, we report successful challenges using native Escherichia coli asparaginase after previous hypersensitivity reactions to both PEGylated E. coli asparaginase and Erwinia asparaginase. PATIENTS AND METHODS: The two patients included in this case report were diagnosed with B-precursor ALL at St. Jude Children's Research Hospital and were treated with a common regimen. Both patients developed hypersensitivity reactions to PEGylated E. coli asparaginase and Erwinia asparaginase early in treatment, and they were challenged with native E. coli asparaginase. Serum samples were collected for estimating the pharmacokinetic parameters of each patient during native E. coli asparaginase therapy. RESULTS: Challenges with native E. coli asparaginase were successful, and asparaginase serum concentrations above therapeutic levels were attained in both patients. CONCLUSIONS: These two cases suggest that some patients can be given native E. coli asparaginase after hypersensitivity reactions to PEGylated asparaginase and achieve therapeutic concentrations of the drug in serum.

[Alcoholic ketoacidosis and reversible neurological complications due to hypophosphataemia]. / Cetoacidosis alcohólica y complicaciones neurológicas reversibles de la hipofosfatemia.

A 57-year-old man with chronic alcoholism was admitted to our hospital due to disturbance of consciousness and polyradiculitis. Laboratory examination revealed metabolic acidosis, hypokalemia and hypophosphataemia. Alcoholic ketoacidosis is a common disorder in alcoholic patients. All patients present with a history of heavy alcohol misuse, preceding a bout of particularly excesive intake, which had been terminated by nausea, vomiting and abdominal pain. The most important laboratory results are: normal or low glucose level, metabolic acidosis with a raised anion GAP, low or absent blood alcohol level and urinary ketones. The greatest threats to patients are: hypovolemia, hypokaliemia, hypoglucemia and acidosis. Alcohol abuse may result in a wide range of electrolyte and acid-base disorders including hypophosphataemia, hypomagnesemia, hypocalcemia, hypokalemia, metabolic acidosis and respiratory alkalosis. Disturbance of consciousness in alcoholic patients is observed in several disorders, such drunkenness, Wernicke encephalopathy, alcohol withdrawal syndrome, central pontine myelinolysis, hepatic encephalopathy, hypoglucemia and electrolyte disorders.

Concordance of DMET plus genotyping results with those of orthogonal genotyping methods.

There are several hurdles to the clinical implementation of pharmacogenetics. One approach is to employ pre-prescription genotyping, involving interrogation of multiple pharmacogenetic variants using a high-throughput platform. We compared the performance of the Drug Metabolizing Enzymes and Transporters (DMET) Plus array (1,931 variants in 225 genes) with that of orthogonal genotyping methods in 220 pediatric patients. A total of 1,692 variants had call rates >98% and were in Hardy-Weinberg equilibrium. Of these, 259 were genotyped by at least one independent method, and a total of 19,942 single-nucleotide polymorphism (SNP)-patient sample pairs were evaluated. The concordance rate was 99.9%, with only 28 genotype discordances observed. For the genes deemed most likely to be clinically relevant (TPMT, CYP2D6, CYP2C19, CYP2C9, VKORC1, DPYD, UGT1A1, and SLCO1B1), a total of 3,799 SNP-patient sample pairs were evaluable and had a concordance rate of 99.96%. We conclude that the DMET Plus array performs well with primary patient samples, with the results in good concordance with those of several lower-throughput genotyping methods.

Clinical utility and implications of asparaginase antibodies in acute lymphoblastic leukemia.

Hypersensitivity to asparaginase is common, but the differential diagnosis can be challenging and the diagnostic utility of antibody tests is unclear. We studied allergic reactions and serum antibodies to E. coli asparaginase (Elspar) in 410 children treated on St. Jude Total XV protocol for acute lymphoblastic leukemia. Of 169 patients (41.2%) with clinical allergy, 147 (87.0%) were positive for anti-Elspar antibody. Of 241 patients without allergy, 89 (36.9%) had detectable antibody. Allergies (P=0.0002) and antibodies (P=6.6 × 10(-6)) were higher among patients treated on the low-risk arm than among those treated on the standard/high-risk arm. Among those positive for antibody, the antibody titers were higher in those who developed allergy than in those who did not (P<1 × 10(-15)). Antibody measures at week 7 of continuation therapy had a sensitivity of 87-88% and a specificity of 68-69% for predicting or confirming clinical reactions. The level of antibodies was inversely associated with serum asparaginase activity (P=7.0 × 10(-6)). High antibody levels were associated with a lower risk of osteonecrosis (odds ratio=0.83; 95% confidence interval, 0.78-0.89; P=0.007). Antibodies were related to clinical allergy and to low systemic exposure to asparaginase, leading to lower risk of some adverse effects of therapy.

Metabolically stabilized long-circulating PEGylated polyacridine peptide polyplexes mediate hydrodynamically stimulated gene expression in liver.

A novel class of PEGylated polyacridine peptides was developed that mediate potent stimulated gene transfer in the liver of mice. Polyacridine peptides, (Acr-X)(n)-Cys-polyethylene glycol (PEG), possessing 2-6 repeats of Lys-acridine (Acr) spaced by either Lys, Arg, Leu or Glu, were Cys derivatized with PEG (PEG(5000 kDa)) and evaluated as in vivo gene transfer agents. An optimal peptide of (Acr-Lys)(6)-Cys-PEG was able to bind to plasmid DNA (pGL3) with high affinity by polyintercalation, stabilize DNA from metabolism by DNAse and extend the pharmacokinetic half-life of DNA in the circulation for up to 2 h. A tail vein dose of PEGylated polyacridine peptide pGL3 polyplexes (1 µg in 50 µl), followed by a stimulatory hydrodynamic dose of normal saline at times ranging from 5 to 60 min post-DNA administration, led to a high level of luciferase expression in the liver, equivalent to levels mediated by direct hydrodynamic dosing of 1 µg of pGL3. The results establish the unique properties of PEGylated polyacridine peptides as a new and promising class of gene delivery peptides that facilitate reversible binding to plasmid DNA, protecting it from DNase in vivo resulting in an extended circulatory half-life, and release of transfection-competent DNA into the liver to mediate a high-level of gene expression upon hydrodynamic boost.

Effectiveness of retinoic acid treatment for redifferentiation of thyroid cancer in relation to recovery of radioiodine uptake.

BACKGROUND: Retinoic acid (RA) treatment has been used for redifferentiation of metastatic thyroid neoplasia that have lost radioiodine (131I) uptake with heterogeneous results. AIM: Retrospective analysis of the recovery rate of 131I uptake after RA treatment in patients from 11 Spanish hospitals. METHODS: Twenty-seven patients (14 men, 13 women) with papillary [21], follicular [4], and oncocytic [2] thyroid cancer initially treated with total thyroidectomy plus 131I, and with 131I negative metastatic disease, were given 13-cis RA (0.66-1.5 mg/kg for 5-12 weeks) followed by a therapeutic 131I dose (3700-7400 MBq); 3 months later thyroglobulin levels and computed tomography imaging were performed. RESULTS: In 9 out 27 cases (33%) (8 papillary, 1 follicular) optimal positive 131I scan was observed after RA treatment; in the remaining 18, 10 had a suboptimal uptake (7 papillary, 2 follicular, 1 oncocytic) and in the rest there was no 131I uptake recovery (6 papillary, 1 follicular, 1 oncocytic). In 17 positive responses to RA (either optimal or suboptimal) in which image follow-up was available, decrease or stabilization of metastatic growth was observed in 7, while tumor mass increased at short term in the remaining 10. No major side effects were detected. CONCLUSION: Quite a high rate of 131I uptake recovery after RA treatment may be obtained in advanced differentiated thyroid cancer, but the potential modification of the natural course of the disease is uncertain. A better biological characterization of these tumors allowing the identification of potential responders to RA may improve the outcome of RA coadjuvant therapy.

Smoking is associated with an age-related decline in exhaled nitric oxide.

Age-related declines in forced expiratory volume in one second are accelerated in smokers. Smoking is associated with decreased exhaled nitric oxide fraction (F(eNO)). The aim of the present study was to determine the impact of age on F(eNO) in otherwise healthy smokers and nonsmokers. F(eNO) and serum cotinine levels were measured in 994 healthy subjects aged 18-40 yrs. American Thoracic Society questionnaire data on smoking habits was used to validate serum cotinine levels as a surrogate marker for categorisation of smokers and nonsmokers in the cohort. Serum cotinine levels were a good discriminator of smokers (n = 99) and nonsmokers (n = 895). F(eNO) levels were significantly lower in otherwise healthy smokers compared with nonsmokers. There was an inverse correlation of serum cotinine levels with F(eNO). No correlation of age with F(eNO) was found in nonsmokers but an inverse correlation of F(eNO) with age in smokers was found. F(eNO) was significantly lower in smokers aged 21-40 yrs compared with nonsmokers aged 21-40 yrs, but was not lower in smokers aged 18-20 yrs compared with nonsmokers of the same age. Smoking was associated with decreased exhaled nitric oxide. The greatest smoking-related declines in exhaled nitric oxide occurred in older subjects. This suggests that smoking is associated with age-related declines in exhaled nitric oxide and justifies future mechanistic studies that address the impact of exhaled nitric oxide decline on lung function.

[Malignant oncocytic papilloma. An infrequent type of sinonasal papilloma]. / Papiloma oncocítico malignizado. Una variante infrecuente de papiloma nasosinusal.

Oncocytic scheneiderian papilloma (OSP), or cylindrical cell papilloma, is the less frequent of the three morphologically distinct papillomas occurring in the nose and paranasal sinuses. We report a case of a patient with an OSP and review on the diagnostic and prognostic implications of this type of tumor.

[Our experience with extranodal lymphomas of the ORL region]. / Nuestra experiencia en linfomas extranodales del área ORL.

Head and neck extranodal lymphomas are rare. Waldeyer lymphatic ring is the most common localisation of these lymphomas, followed by oral cavity and parothoid glands. We have done a retrospective study of patients with extranodal lymphomas diagnosed in our hospital between 1991 and 1999. We have included in this study 23 patients, 15 males and 9 females. We have used the REAL classification. All of them have been non-Hodgkin lymphomas. The rhinopharynx has been the most affected region, followed by the palatine tonsils and oral cavity. Most of them were of medium degree and they were in the initial stages. The presentation symptoms varied depending on the localisation. The age, stage and histologic degree were important for the treatment election.

Improvement in recovery of embryos/ova using a shallow uterine horn flushing technique in superovulated Holstein heifers.

The aim of this study was two-fold: (1). to compare recovery of embryos/ova from superovulated Holstein heifers by flushing the uterine horns through insertion of the catheter very close to the tip of the horn (deep) or just after the uterine bifurcation (shallow) and (2). to evaluate the hormonal and superovulatory response to estradiol benzoate (EB) treatment prior to superovulation. Ten Holstein heifers (12-16 months) underwent two superovulatory treatments in a cross-over design. Heifers were treated with decreasing doses of FSH from Days 8 to 12.5 of a synchronized estrous cycle. At 4 days prior to superovulation, half of the heifers received EB (5mg, i.m.) or served as Controls, followed by the alternative treatment in the subsequent superovulation. At embryo recovery, one uterine horn was flushed with deep ( approximately 7 cm caudal to the tip of the horn) and the other with shallow ( approximately 5 cm cranial to the beginning of the uterine bifurcation) flushing techniques. Embryos/ova were recovered, counted, and scored. Number of ovulations was estimated by ultrasound. Pretreatment with EB reduced circulating FSH and regressed the first wave dominant follicle with no change in number of large follicles, number of ovulations, number of embryos/ova recovered, or number of transferable embryos. The shallow flushing technique was superior to the deep technique for number of embryos/ova recovered per horn (5.4+/-1.1 versus 3.9+/-0.8) or percentage of embryos/ova recovered per CL (63.9+/-8.6% versus 37.4+/-6.5%). Thus, flushing the entire uterine horn increased recovery of embryos/ova.