Status of head and neck brachytherapy in Spain in 2022.

PURPOSE: Brachytherapy (BT) has been used for many years for disease control in tumours of the head and neck area (H&N). It is currently performed with high dose rate (HDR) or pulsed dose rate (PDR), but its use has been reduced due to the implementation of new non-invasive external beam radiotherapy techniques such as intensity modulation (IMRT) and volumetric modulated arc therapy (VMAT) and the improvement of surgical techniques. METHODS: The Spanish Brachytherapy Group (GEB) has carried out a survey to find out the number of centres in Spain that continue to use BT in H&N and its indications and expectations for the future. RESULTS: The results were presented at the XX GEB Consensus Meeting held on October 21, 2022, in Valencia (Spain) and it was confirmed that, although there are fewer and fewer centres that use BT in H&N, there are still units with extensive experience in this technique that should be positioned as referral centres. CONCLUSION: It is necessary to carry out continuous work with other specialities involved, such as H&N surgeons, and other radiation oncologists, to improve the training of residents, both oncologists and medical physicists.

Protocol for a multi-phase, multi-center, real-world, hybrid effectiveness-implementation study of a digital intervention for pediatric chronic pain co-designed with patients (Digital SPA).

Background: Children and adolescents with chronic pain are a vulnerable population who often lack the resources to manage their condition. Due to high personal, social, and economic consequences, proper management in its early stages is key to reducing disability. The aim of this project is to co-develop a digital intervention for pediatric chronic pain (Digital SPA) with end-users and to evaluate its effectiveness and implementation outcomes in Spain. Methods: (Phase 1) Focus groups with patients, parents, and clinicians (n = 5-6 each) will inform about unmet pain care needs and provide a starting point for co-designing the intervention. (Phase 2) Content creation and usability testing will be based on the results of Phase 1, and the theory-driven development will follow the latest available evidence. The intervention will use validated psychological techniques focused on improving functioning by teaching pain coping skills. (Phase 3) Hybrid effectiveness-implementation trial. Participants (n = 195) will be adolescents aged 12-17 years old with chronic pain and one of their parents. Assessments include physical function, pain, sleep, anxiety, mood, satisfaction and adherence to the treatment, and number of visits to the emergency room. A qualitative framework analysis will be conducted with data from Phase 1. Effects of the intervention will be evaluated using linear multilevel modeling. The Consolidated Framework for Implementation Research (CFIR) and Behavioral Interventions Using Technology (BIT) frameworks will be used to evaluate implementation. Discussion: This study is expected to produce a co-created evidence-based digital intervention for pediatric chronic pain and a roadmap for successful implementation. Trial registration number TRN and date of registration: ClinicalTrials.gov (registered on 26 June 2023: https://clinicaltrials.gov/study/NCT05917626). Contributions to the literature The implementation of digital health interventions has two major gaps: (1) adherence to treatment is suboptimal, and (2) the process of making the interventions available to the end-user in a sustainable way is often unsuccessful.In this study, we expect that assessing users' needs and co-designing an intervention with them will improve adherence.Documenting the implementation process from the project inception and integrating the results into an implementation framework will allow for replication and extension in different contexts.This study will increase the knowledge about implementation in a vulnerable population: adolescents with chronic pain without access to in-person multidisciplinary pain care.

Functional Evidence of CCDC186 as a New Disease-Associated Gene with Endocrine and Central Nervous System Alterations.

CCDC186 protein is involved in the maturation of dense-core vesicles (DCVs) in the trans-Golgi network in neurons and endocrine cells. Mutations in genes involved in DCV regulation, other than CCDC186, have been described in patients with neurodevelopmental disorders. To date, only one patient, within a large sequencing study of 1000 cases, and a single case report with variants in CCDC186, had previously been described. However, no functional studies in any of these two cases had been performed. We identified three patients from two gypsy families, unrelated to each other, with mutations in the CCDC186 gene. Clinically, all patients presented with seizures, frontotemporal atrophy, hypomyelination, recurrent infections, and endocrine disturbances such as severe non-ketotic hypoglycemia. Low levels of cortisol, insulin, or growth hormone could only be verified in one patient. All of them had a neonatal onset and died between 7 months and 4 years of age. Whole exome sequencing identified a homozygous variant in the CCDC186 gene (c.2215C>T, p.Arg739Ter) in the index patients of both families. Protein expression studies demonstrated that CCDC186 was almost undetectable in fibroblasts and muscle tissue. These observations correlated with the transcriptomic analysis performed in fibroblasts in one of the patients, which showed a significant reduction of CCDC186 mRNA levels. Our study provides functional evidence that mutations in this gene have a pathogenic effect on the protein and reinforces CCDC186 as a new disease-associated gene. In addition, mutations in CCDC186 could explain the combined endocrine and neurologic alterations detected in our patients.

Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia.

Ataxia in children is a common clinical sign of numerous neurological disorders consisting of impaired coordination of voluntary muscle movement. Its most common form, cerebellar ataxia, describes a heterogeneous array of neurologic conditions with uncountable causes broadly divided as acquired or genetic. Numerous genetic disorders are associated with chronic progressive ataxia, which complicates clinical management, particularly on the diagnostic stage. Advances in omics technologies enable improvements in clinical practice and research, so we proposed a multi-omics approach to aid in the genetic diagnosis and molecular elucidation of an undiagnosed infantile condition of chronic progressive cerebellar ataxia. Using whole-exome sequencing, RNA-seq, and untargeted metabolomics, we identified three clinically relevant mutations (rs141471029, rs191582628 and rs398124292) and an altered metabolic profile in our patient. Two POLR1C diagnostic variants already classified as pathogenic were found, and a diagnosis of hypomyelinating leukodystrophy was achieved. A mutation on the MMACHC gene, known to be associated with methylmalonic aciduria and homocystinuria cblC type, was also found. Additionally, preliminary metabolome analysis revealed alterations in our patient's amino acid, fatty acid and carbohydrate metabolism. Our findings provided a definitive genetic diagnosis reinforcing the association between POLR1C mutations and hypomyelinating leukodystrophy and highlighted the relevance of multi-omics approaches to the disease.

[New anti-epileptic drugs in Paediatrics]. / Nuevos fármacos antiepilépticos en Pediatría.

It is estimated that about 70 million people all over the world suffer from epilepsy, half of which are children, in whom the prevalence is around 0.5 to 0.8%. Although there are several therapies, the treatment of epilepsy is based mainly on drugs, which, depending on the year of coming onto the market are classified as first, second, or third generation. In this article, a description is presented on the main characteristics of the latest generation of anti-epileptic drugs (lacosamide, eslicarbazepine acetate, brivaracetam, perampanel, retigabine, everolimus and cannabidiol). These, with the exception of retigabine (is not yet on the market), are considered safe and effective in the paediatric population. Everolimus and cannabidiol have very specific indications (tuberous sclerosis, Dravet syndrome, and Lennox Gastaut syndrome), while the rest are indicated in the management of seizures of focal origin in children from 4 years-old. These new molecules have been developed in order to provide a pharmaceutical profile and tolerance superior to the previously available drugs, and it is forecast that as their use increases, their true potential and profile will widen. Furthermore, for the first time in Paediatric Epileptology, the extrapolation of the efficacy data in adults have been used (together with specific safety and pharmacokinetic studies in the paediatric population), in order to speed up their approval for use in the child population.

Enhanced vector surveillance to control arbovirus epidemics in Colombia.

In the wake of the Zika epidemic, there has been intensified interest in the surveillance and control of the arbovirus vectors Aedes aegypti and Aedes albopictus, yet many existing surveillance systems could benefit from improvements. Vector control programs are often directed by national governments, but are carried out at the local level, resulting in the discounting of spatial heterogeneities in ecology and epidemiology. Furthermore, entomological and epidemiological data are often collected by separate governmental entities, which can slow vector control responses to outbreaks. Colombia has adopted several approaches to address these issues. First, a web-based, georeferenced Aedes surveillance system called SIVIEN AEDES was developed to allow field entomologists to record vector abundance and insecticide resistance data. Second, autocidal gravid oviposition (AGO) traps are deployed as an alternative way to measure vector abundance. Third, data collected by SIVIEN AEDES are used to develop mathematical models predicting Ae. aegypti abundance down to a city block, thus allowing public health authorities to target interventions to specific neighborhoods within cities. Finally, insecticide resistance is monitored through bioassays and molecular testing in 15 high-priority cities, providing a comprehensive basis to inform decisions about insecticide use in different regions. The next step will be to synchronize SIVIEN AEDES data together with epidemiological and climatic data to improve the understanding of the drivers of local variations in arbovirus transmission dynamics. By integrating these surveillance data, health authorities will be better equipped to develop tailored and timely solutions to control and prevent Aedes-borne arbovirus outbreaks.

Tras la epidemia del Zika, se ha intensificado el interés en vigilar y controlar los vectores de arbovirus Aedes aegypti y Aedes albopictus. Aun así, muchos de los sistemas existentes de vigilancia necesitan mejorar. En general son los gobiernos nacionales los que dirigen los programas de control de vectores, aunque estos programas se llevan a cabo a nivel local, por lo que no se tiene en cuenta la heterogeneidad del lugar en cuanto a las características ecológicas y epidemiológicas. Además, normalmente los datos entomológicos y epidemiológicos son recopilados por entidades gubernamentales distintas, lo que puede ralentizar el control de vectores durante un brote. Colombia ha puesto en marcha varias iniciativas para abordar estas cuestiones. La primera es un sistema en línea de geolocación del mosquito Aedes, llamado SIVIEN AEDES, para que los entomólogos de campo puedan registrar la abundancia de los mosquitos vectores y recoger datos sobre la resistencia a los insecticidas. La segunda es la implantación de ovitrampas autocidales para hembras grávidas (AGO, por su sigla en inglés), que son una manera alternativa de medir la abundancia de vectores. La tercera iniciativa es utilizar los datos recogidos por el sistema SIVIEN AEDES para elaborar modelos matemáticos que predigan la abundancia del A. aegypti hasta incluso en una cuadra de ciudad, de manera que las autoridades de salud pública puedan dirigir las intervenciones a vecindarios específicos dentro de las ciudades. Por último, Colombia está vigilando en quince ciudades prioritarias la resistencia a los insecticidas mediante ensayos biológicos y análisis moleculares, de esta forma se genera una base de datos exhaustiva sobre la que fundamentar las decisiones acerca del uso de insecticidas en las diferentes regiones. El paso siguiente será sincronizar los datos recopilados por el sistema SIVIEN AEDES con datos epidemiológicos y climáticos para poder entender mejor cómo se originan las variaciones locales en la dinámica de transmisión de los arbovirus. Al integrar estos datos de vigilancia, las autoridades sanitarias estarán mejor equipadas para encontrar soluciones oportunas y adecuadas para la situación específica, a fin de controlar y prevenir los brotes de arbovirus transmitidos por el Aedes.

Depois da epidemia de zika, intensificou-se o interesse na vigilância e controle dos vetores arbovirais Aedes aegypti e Aedes albopictus, mas muitos dos sistemas de vigilância existentes poderiam ser aprimorados. Muitos programas de controle de vetores são dirigidos pelos governos nacionais, mas implementados no âmbito local, o que leva à desconsideração de heterogeneidades espaciais em aspectos ecológicos e epidemiológicos. Além disso, é comum que dados entomológicos e epidemiológicos sejam coletados por agências governamentais separadas, o que pode desacelerar o controle de vetores em resposta aos surtos. A Colômbia adotou vários enfoques para abordar esses problemas. Primeiro, um sistema de vigilância de Aedes georreferenciado e baseado na Internet, chamado SIVIEN AEDES, foi desenvolvido para permitir aos entomólogos de campo registrar a abundância de vetores e a resistência aos inseticidas. Segundo, ovitrampas letais para fêmeas grávidas estão sendo mobilizadas como maneira alternativa de medir a abundância vetorial. Terceiro, os dados coletados pelo SIVIEN AEDES estão sendo utilizados para desenvolver modelos matemáticos para prever a abundância do Ae. aegypti até o nível de quadra/quarteirão, permitindo assim às autoridades de saúde pública direcionar intervenções para bairros específicos em cada município. Finalmente, a resistência aos inseticidas é monitorada através de ensaios biológicos e testes moleculares em 15 cidades de alta prioridade, o que proporciona uma base abrangente para subsidiar decisões sobre o uso de inseticida em diferentes regiões. O próximo passo será sincronizar os dados do SIVIEN AEDES com dados epidemiológicos e climáticos para melhorar a compreensão dos fatores que impulsionam variações locais na dinâmica da transmissão arboviral. Ao integrar esses dados de vigilância, as autoridades de saúde estarão mais bem equipadas para desenvolver soluções personalizadas e oportunas para controlar e prevenir os surtos de arbovírus transmitidos por mosquitos do gênero Aedes.

Clinical and molecular diagnosis of non-phosphomannomutase 2 N-linked congenital disorders of glycosylation in Spain.

The congenital disorders of glycosylation (CDG) are defects in glycoprotein and glycolipid glycan synthesis and attachment. They affect multiple organ/systems, but non-specific symptoms render the diagnosis of the different CDG very challenging. Phosphomannomutase 2 (PMM2)-CDG is the most common CDG, but advances in genetic analysis have shown others to occur more commonly than previously thought. The present work reports the clinical and mutational spectrum of 25 non-PMM2 CDG patients. The most common clinical symptoms were hypotonia (80%), motor or psychomotor disability (80%) and craniofacial dysmorphism (76%). Based on their serum transferrin isoform profile, 18 were classified as CDG-I and 7 as CDG-II. Pathogenic variations were found in 16 genes (ALG1, ALG6, ATP6V0A2, B4GALT1, CCDC115, COG7, DOLK, DPAGT1, DPM1, GFPT1, MPI, PGM1, RFT1, SLC35A2, SRD5A3, and SSR4). Overall, 27 variants were identified, 12 of which are novel. The results highlight the importance of combining genetic and biochemical analyses for the early diagnosis of this heterogeneous group of disorders.

PLA2G6-associated neurodegeneration: New insights into brain abnormalities and disease progression.

INTRODUCTION: PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features. METHODS: Observational clinical study in a cohort of infantile and childhood onset PLAN patients and genetic analysis of the PLA2G6 gene. We analysed chronological evolution in terms of age at onset and disease course through a 66-item questionnaire. We performed qualitative and quantitative assessment of MRI abnormalities and searched for clinical and radiological phenotype and genotype correlations. RESULTS: Sixteen PLAN patients (mean age: 10.2 years, range 3-33) were evaluated, with a median onset (years) of signs/symptoms as follows: neurological regression (1.5), oculomotor abnormalities (1.5), hypotonia (1.8), gait loss (2.2), pyramidal signs (3.0), axonal neuropathy (3.0), dysphagia (4.0), optic atrophy (4.0), psychiatric symptoms (4.0), seizures (5.9), joint contractures (6.0), dystonia (8.0), bladder dysfunction (13.0) and parkinsonism (15.0). MRI assessment identified cerebellar atrophy (19/19), brain iron deposition (10/19), clava hypertrophy (8/19) and T2/FLAIR hyperintensity of the cerebellar cortex (6/19). The mid-sagittal vermis relative diameter (MVRD) correlated with age at onset of clinical variants, meaning that the earlier the onset, the more severe the cerebellar atrophy. All patients harboured missense, nonsense and frameshift mutations in PLA2G6, including four novel variants. CONCLUSIONS: Cerebellar atrophy was a universal radiological sign in infantile and childhood onset PLAN, and correlated with the severity of the phenotype. Iron accumulation within the globus pallidum and substantia nigra was also a common and strikingly uniform feature regardless of the phenotype.

Interobserver variability in rectum contouring in high-dose-rate brachytherapy for prostate cancer: A multi-institutional prospective analysis.

PURPOSE: The aim of this study was to evaluate the interobserver variability (IOV) of rectum contouring, and its dosimetric consequences, for high-dose-rate brachytherapy in patients with prostate cancer across multiple institutions. METHODS AND MATERIALS: Five radiation oncologists contoured rectums in 10 patients on transperineal ultrasound image sets after establishing a delineation consensus. The D0.1cc, D1cc, and D2cc rectum volume parameters were determined. The mean, standard deviation, and range of each dose-volume histogram parameter were evaluated for each patient. The IOV was determined using the coefficient of variation, and the dosimetric impacts on the total dose were analyzed by estimating the biologically equivalent dose (EQD2α/ß = 3). RESULTS: The interobserver coefficients of variation (±standard deviation) for the reported D0.1cc, D1cc, and D2cc were 5 ± 1.84%, 4 ± 1.26%, and 4 ± 1.33%, respectively. As for the impact on the total dose, the mean dose differences for D0.1cc, D1cc, and D2cc were 10 Gy, 7.3 Gy, and 6.6 Gy, respectively. CONCLUSIONS: The D2cc is robust as evident by the low IOV (<5%). However, some variability ranges almost overlap with the clinical threshold level, which may present dosimetric and clinical complications. General rectal contouring guidelines for prostate high-dose-rate brachytherapy are desirable to reduce discrepancies in delineation.

High-dose-rate brachytherapy boost for prostate cancer: Analysis of dose-volume histogram parameters for predicting late rectal toxicity.

PURPOSE: To determine the significance of dose-volume histogram parameters for predicting late rectal toxicity (LRT) after single-fraction high-dose-rate brachytherapy (HDRBT) boost and external beam radiotherapy (EBRT) in prostate cancer. MATERIALS AND METHODS: Three hundred patients with intermediate- or high-risk prostate cancer were included between August 2010 and March 2015. Treatment comprised a single-fraction HDRBT boost of 15.0 Gy plus EBRT (46.0 Gy delivered in 23 fractions) or an HDRBT boost of 9.5 Gy plus EBRT (60.0 Gy delivered in 30 fractions) if the seminal vesicles were infiltrated using real-time transrectal ultrasound-based planning. LRT was evaluated every 3 months after the end of the combined treatment using the Common Terminology Criteria for Adverse Events, version 4.0. The minimum dose received by the most exposed 0.1 and 2.0 cm3 volume of the rectum (D0.1 cc/D2cc) was analyzed by estimating the biologically equivalent rectal dose according to the recommendations of the Groupe Européen de Curiethérapie/European Society for Radiotherapy and Oncology and an ordinal regression analysis was performed. RESULTS: LRT was observed in 62 patients (20.7%) at a median followup of 33 (range, 2-68) months. Twenty patients (6.7%) developed grade 2 and 3 patients (1%) developed grade 3 LRT. A significant association was observed between D2cc and the probability of developing grade 1-3 LRT (p = 0.04). CONCLUSIONS: D2cc is associated with the occurrence of LRT in HDRBT-treated prostate cancer patients. The dose constraints proposed and recommended by experienced HDRBT centers must be investigated to determine the threshold dose through long-term and prospective studies.

An evaluation of the robustness of organ-at-risk recommendations made by GEC/ESTRO according to interobserver variability: a single-center experience.

PURPOSE: Groupe Européen de Curiethérapie (GEC) and European Society for Radiotherapy & Oncology (ESTRO) has proposed a rectal dose constraint of the most exposed 2-cc volume (D2cc of ≤ 75 Gy EQD2α/ß = 3) during external-beam plus high-dose-rate brachytherapy (HDR-BT) in localized prostate cancer patients. This study aimed to evaluate D2cc for rectal contouring via interobserver variability. MATERIAL AND METHODS: Four blinded observers contoured rectums of 5 patients. Rectal contouring anatomical limits were determined through previous consensus. Dose-volume histogram (DVH) dosimetric parameters (D0.1cc, D1cc, and D2cc) were analyzed according to GEC/ESTRO recommendations and subjected to intra- and interobserver comparisons. Latter comparisons involved coefficients of variation. For each parameter, the mean, standard deviation (SD), and range were evaluated. The effect of interobserver variation on total dose was analyzed by estimating the biologically equivalent rectal dose (EQD2α/ß = 3). RESULTS: Interobserver coefficients of variation for D0.1cc, D1cc, and D2cc were 5.7%, 4.5%, and 4%, respectively. The highest interobserver rectal delineation variation yielded a rectal dose difference up to 5.8 Gy EQD2. Estimated intraobserver variation for the reported D2cc was 5.5% in the worst-case scenario (non-significant). CONCLUSIONS: We observed acceptable interobserver variability in EQD2 for D2cc, with strong impacts on clinical threshold levels (D2cc ≤ 75 Gy EQD2) in some cases. This small, single-center analysis will be extended in a multicenter study.

Medication reconciliation at admission to surgical departments.

RATIONALE, AIMS AND OBJECTIVES: We aim to determine the prevalence of reconciliation errors (REs) at admission to surgery departments, report their potential clinical impact and analyse possible risk factors. METHODS: Prospective observational study was conducted for 8 months in a regional public hospital in Spain. The study included patients consecutively hospitalized in the Department of Orthopedic Surgery and Traumatology or Department of Angiology and Vascular Surgery from May through December 2010. At 24-48 hours after hospital admission, the pre-admission pharmacological treatment of patients was compared with the medication received in hospital to identify REs, which were classified by type and potential severity. Multivariate logistic regression analysis was conducted with the presence of RE as dependent variable. RESULTS: The study included 176 patients, 60.8% of whom were aged >65 years and consumed a mean of 5.55 (±4.33) drugs. 55.1% had ≥1 RE, with a mean of 3.21 REs per patient [95% confidence interval (CI; 2.72-3.70)]. The most frequent RE was drug omission (84.1%). No clinical risk was posed by 50.5% of the REs. Multivariate analysis evidenced fourfold higher risk of an RE in patients admitted for elective versus emergency surgery and a 1.35-fold higher risk in patients receiving a larger number of drugs. CONCLUSIONS: There was a high prevalence of REs among patients admitted to the surgical departments, most frequently the omission of a drug. The risk of an RE was higher in patients admitted for elective versus emergency surgery, as well as with the receipt of a larger number of drugs before admission.

Spatial learning in a virtual reality-based task is altered in very preterm children.

Very preterm births prevent a complete development of the nervous system. The hippocampus is especially vulnerable in this population since the perinatal period is critical for its growth and development. Learning and memory abilities, like spatial memory, depend on the hippocampal integrity. In this study we applied virtual-reality-based tasks to assess spatial memory in a sample of 20 very preterm children of 7 and 8 years of age. Two different conditions of difficulty were used. Very preterm children performed poorly in the task in comparison with the control group. They committed more errors than controls searching for the rewarded positions. However, no significant differences were observed in the mean speed, an index of the motor abilities and joystick handling. These results suggest that the hippocampal function is affected in this sample. Nevertheless, other variables to consider are discussed.

Long-term results with oral fluoropyrimidines and oxaliplatin-based preoperative chemoradiotherapy in patients with resectable rectal cancer. A single-institution experience.

INTRODUCTION: Neoadjuvant 5-FU-based chemoradiotherapy in resectable rectal cancer (RC) is a standard of treatment. The use of oral fluoropyrimidines and new agents such as oxaliplatin may improve efficacy and tolerance. MATERIAL AND METHODS: Between 1999 and 2009, 126 RC patients with T3-T4 and/or N+ disease were given three successive protocols: UFT (32), UFT-oxaliplatin (75) and capecitabine-oxaliplatin (19), alongside 45 Gy of radiotherapy; with surgery 4-6 weeks after. Adjuvant treatment was given in all patients. The primary objective was pathologic complete response (pCR). RESULTS: Preoperative therapy was well tolerated, with no toxic deaths and a 15% grade 3-4 toxicity rate. Eighty-five percent of patients received the full chemotherapy dose, 56% had an abdominoperineal resection, 6% reinterventions and 57% received the full adjuvant chemotherapy planned. The pCR rate was 13%. The downstaging rate was 80%; 8% had progression of disease. The relapse rate was 20%, with local relapse in 6%. By 5 years of followup, 92% of relapses had occurred. Median follow-up was 73 months, 5- and 10-year disease-free survival rates were 75% and 50%, and 5- and 10-year overall survival rates were 79% and 66% respectively. There was no benefit from the use of oxaliplatin regarding survival or pCR rates. Older patients had worse long-term outcomes. CONCLUSIONS: Neoadjuvant chemoradiotherapy with oral fluoropyrimidines and oxaliplatin is feasible and well tolerated. The risk of early progression is low. However, there was no added benefit with the use of oxaliplatin. There were no relapses in patients with pCR. The role of adjuvant chemotherapy is unclear.

Genotype-phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant.

Sepiapterin reductase (SR) catalyzes the final step in the de novo synthesis of tetrahydrobiopterin, essential cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases. SR deficiency is a very rare disease resulting in monoamine neurotransmitter depletion. Most patients present with clinical symptoms before the first year of age corresponding to a dopa-responsive dystonia phenotype with diurnal fluctuations, although some patients exhibit more complex motor and neurological phenotypes. Herein, we describe four new cases from Spain, their clinical phenotype and the biochemical and genetic analyses. Two mutations in the SPR gene were functionally expressed to provide a basis to establish genotype-phenotype correlations. Mutation c.751A>T is functionally null, correlating with the severe phenotype observed. The novel mutation c.304G>T was identified in three siblings with a strikingly mild phenotype without cognitive delay and close to asymptomatic in the eldest sister. Minigene analysis demonstrated that this mutation located in the last nucleotide of exon 1 affects splicing although some normal transcripts can be produced, resulting in the missense mutant p.G102C that retains partial activity. These results may account for the mild phenotype and the variable clinical presentations observed, which could depend on interindividual differences in relative abundance of correctly spliced and aberrant transcripts.

Breast-conservative surgery with close or positive margins: can the breast be preserved with high-dose-rate brachytherapy boost?

PURPOSE: To evaluate the likelihood of preserving the breast in women who show close or positive margins after conservative surgery for early breast carcinoma. METHODS AND MATERIALS: Since 1996, 125 women with less than 5 mm or positive margins and positive separate cavity margin sampling were entered in a prospective trial with high-dose radiotherapy. A standard dose of 50 Gy to the whole breast was followed by a high-dose-rate brachytherapy application delivering 3 fractions of 4.4 Gy in 24 hours. The median follow-up was 84 months. RESULTS: There were only seven local recurrences, with an actuarial local control rate of 95.8% at 5 years and 91.1% at 9 years. Actuarial overall and cause-specific survival rates were 92.6% and 95% at 5 years and 86.7% and 90.4% at 9 years, respectively. Late fibrosis was the most common complication, in 30% of patients, with good or excellent cosmetic results in 77%. The final result was that 95.2% of breasts were preserved. CONCLUSIONS: Close or positive-margin breast cancer can be well managed with a high-dose boost in a wide tumor bed by means of high-dose-rate brachytherapy. This technique can avoid mastectomy or poor cosmetic resection, with minimal risk of local or general failure.

Molecular and functional analysis of SLC25A20 mutations causing carnitine-acylcarnitine translocase deficiency.

The enzyme carnitine-acylcarnitine translocase (CACT) is involved in the transport of long-chain fatty acids into mitochondria. CACT deficiency is a life-threatening, recessively inherited disorder of lipid beta-oxidation which manifests in early infancy with hypoketotic hypoglycemia, cardiomyopathy, liver failure, and muscle weakness. We report here the clinical, biochemical, and molecular features of six CACT-deficient patients from Italy, Spain, and North America who exhibited significant clinical heterogeneity. In five patients (Patients 1, 2, 4, 5, and 6) the disease manifested in the neonatal period, while the remaining patient (Patient 3), the younger sibling of an infant who had died with clinical suspicion of fatty acid oxidation defect, has been treated since birth and was clinically asymptomatic at 4.5 years of age. Patients 1 and 4 were deceased within 6 months from the onset of this study, while the remaining four are still alive at 8, 4.5, 3.5, and 2 years, respectively. Sequence analysis of the CACT gene (SLC25A20) disclosed five novel mutations and three previously reported mutations. Three patients were homozygous for the identified mutations. Two of the novel mutations (c.718+1G>C and c.843+4_843+50del) altered the donor splice site of introns 7 and 8, respectively. The 47-nt deletion in intron 8 caused both skipping of exon 8 only and skipping of exons 6-8. Four mutations [[c.159dupT;c.163delA] ([p.Gly54Trp;p.Thr55Ala]) c.397C>T (p.Arg133Trp), c.691G>C (p.Asp231His), and c.842C>T (p.Ala281Val)] resulted in amino acid substitutions affecting evolutionarily conserved regions of the protein. Interestingly, one of these exonic mutations (p.Ala281Val) was associated with a splicing defect also characterized by skipping of exons 6-8. The deleterious effect of the p.Arg133Trp substitution was demonstrated by measuring CACT activity upon expression of the normal and the mutant protein in E. coli and functional reconstitution into liposomes. Combined analysis of clinical, biochemical, and molecular data failed to indicate a correlation between the phenotype and the genotype.

Detección de adulteraciones en cera de abejas comercialización en Venezuela / Detection of adulterations in commercialized beeswax in Venezuela

La cera de abejas es un importante producto de la colmena, que resulta ser además una indispensable materia prima para el apicultor moderno. Las industrias cosméticas, de pulimentos y por supuesto la apícola, son los principales consumidores de cera de abejas en el país. La adulteración de este producto de la colmena ha ocasionado numerosas pérdidas a los apicultores en diversas regiones de Venezuela. En el presente trabajo se analizaron 30 muestras de cera de abejas procedentes de los Edos. Aragua, Bolívar, Carabobo, Mérida, Táchira y Yaracuy. Se detecto 10 por ciento de adulteración con grasa, 6.6 por ciento con esterina y 16.6 con parafina, empleando las técnicas cualitativas descritas por Bianchi (1988). El punto de fusión fue menor de 62§C en tres muestras que presentaban adulteración con parafina