RESUMEN
INTRODUCTION: Glioblastoma is the most common primary brain tumour. Despite advances in treatment, its prognosis remains dismal, with a mean survival time of about 14 months. Many articles have addressed direct costs, those associated with the diagnosis and treatment of the disease. Indirect costs, those associated with loss of productivity due to the disease, have seldom been described. MATERIAL AND METHOD: We conducted a retrospective study in patients diagnosed with glioblastoma at Hospital Universitario Donostia between January 1, 2010 and December 31, 2013. We collected demographics, data regarding the treatment received, and survival times. We calculated the indirect costs with the human capital approach, adjusting the mean salaries of comparable individuals by sex and age and obtaining mortality data for the general population from the Spanish National Statistics Institute. Past salaries were updated to 2015 euros according to the annual inflation rate and we applied a discount of 3.5% compounded yearly to future salaries. RESULTS: We reviewed the records of 99 patients: 46 women (mean age 63.53) and 53 men (mean age 59.94); 29 patients underwent a biopsy and the remaining 70 underwent excisional surgery. Mean survival was 18.092 months for the whole series. The total indirect cost for the series was 11 080 762 (2015). Mean indirect cost per patient was 111 926 (2015). DISCUSSION: Although glioblastoma is a relatively uncommon type of tumour, accounting for only 4% of all cancers, its poor prognosis and potential sequelae generate disproportionately large morbidity and mortality rates which translate to high indirect costs. Clinicians should be aware of the societal impact of glioblastoma and indirect costs should be taken into account when cost effectiveness studies are performed to better illustrate the overall consequences of this disease.
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Neoplasias Encefálicas , Costo de Enfermedad , Glioblastoma/cirugía , Hospitales , Neoplasias Encefálicas/economía , Análisis Costo-Beneficio , Femenino , Glioblastoma/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Between January 1993 and December 2003, 19 patients with familial prion diseases due to the D178N mutation were referred to the regional epidemiological registry for spongiform encephalopathies in the Basque Country in Spain, a small community of some 2,100,000 inhabitants. METHODS: Ten further patients belonging to the same pedigrees were retrospectively ascertained through neurological or neuropathological records. In four of the patients, the diagnosis was confirmed by analysing DNA obtained from paraffin blocks. In this article, we report on the clinical, genetic, and pathological features of the 23 patients carrying the D178N mutation confirmed by genetic molecular analysis. Haplotyping studies suggest a founder effect among Basque born families, explaining in part this unusually high incidence of the D178N mutation in a small community. Only two patients (8%) lack familial antecedents. RESULTS: We have observed a phenotypic variability even among homozygous 129MM patients. Our findings challenge the currently accepted belief that MM homozygosity in codon 129 is always related to a fatal familial insomnia (FFI) phenotype. Indeed, seven out of 17 patients with a 129MM genotype in this series presented with a Creutzfeldt-Jakob disease (CJD) clinicopathological picture. CONCLUSIONS: The considerable clinical and pathological overlapping observed among homozygous 129MM patients favours the view that FFI and CJD178 are the extremes of a spectrum rather than two discrete and separate entities. Other genetic or environmental factors apart from the polymorphism in codon 129 may play a role in determining the phenotypic expression of the D178N mutation in the PRNP gene.
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Amiloide/genética , Síndrome de Creutzfeldt-Jakob/genética , Variación Genética/genética , Fenotipo , Mutación Puntual/genética , Adulto , Edad de Inicio , Anciano , Codón , Síndrome de Creutzfeldt-Jakob/etnología , Análisis Mutacional de ADN , Femenino , Efecto Fundador , Haplotipos , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Proteínas PrPSc/genética , Estudios Prospectivos , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiología , EspañaRESUMEN
We present here the clinical, molecular and biochemical findings from 238 limb-girdle muscular dystrophy type 2A (LGMD2A) patients, representing approximately 50% (238 out of 484) of the suspected calpainopathy cases referred for the molecular study of the calpain 3 (CAPN3) gene. The mean age at onset of LGMD2A patients was approximately 14 years, and the first symptoms occurred between 6 and 18 years of age in 71% of patients. The mean age at which the patients became wheelchair bound was 32.2 years, with 84% requiring the use of a wheelchair between the age of 21 and 40 years. There was no correlation between the age at onset and the time at which the patient became wheelchair bound, nor between the sex of the patient and the risk of becoming wheelchair bound. Of the cases where the CAPN3 gene was not affected, approximately 20% were diagnosed as LGMD2I muscular dystrophy, while facioscapulohumeral muscular dystrophy (FSHD) was uncommon in this sample. We identified 105 different mutations in the CAPN3 gene of which 50 have not been described previously. These were distributed throughout the coding region of the gene, although some exons remained free of mutations. The most frequent mutation was 2362AG-->TCATCT (exon 22), which was present in 30.7% of the chromosomes analysed (146 chromosomes). Other recurrent mutations described were N50S, 550DeltaA, G222R, IVS6-1G-->A, A483D, IVS17+1G-->T, 2069-2070DeltaAC, R748Q and R748X, each of which was found in >5 chromosomes. The type of mutation in the CAPN3 gene does not appear to be a risk factor for becoming dependent on a wheelchair at a determined age. However, in the cases with two null mutations, there were significantly fewer patients that were able to walk than in the group of patients with at least one missense mutation. Despite the fact that the results of phenotyping and western blot might be biased due to multiple referral centres, producing a diagnosis on the basis of the classical phenotype is neither sufficiently sensitive (86.7%) nor specific (69.3%), although western blot proved to be even less sensitive (52.5%) yet more specific (87.8%). In this case LGMD2I was a relevant cause of false-positive diagnoses. Considering both the clinical phenotype and the biochemical information together, the probability of correctly diagnosing a calpainopathy is very high (90.8%). However, if one of the analyses is lacking, the probability varies from 78.3 to 73.7% depending on the information available. When both tests are negative, the probability that the sample comes from a patient with LGMD2A was 12.2%.
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Calpaína/genética , Isoenzimas/genética , Proteínas Musculares/genética , Distrofia Muscular de Cinturas/genética , Adolescente , Adulto , Edad de Inicio , Teorema de Bayes , Western Blotting , Niño , Análisis Mutacional de ADN/métodos , Progresión de la Enfermedad , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Muscular de Cinturas/epidemiología , Mutación Missense , Fenotipo , Estudios RetrospectivosRESUMEN
OBJECTIVE: To reduce variability in the diagnosis and treatment of acute pharyngitis, reaching an established standard of quality. DESIGN: Noncontrolled intervention study, consisting of sequential quality improvement cycles. SETTING: Unscheduled attention at the outpatient clinic of an internal medicine service. PARTICIPANTS: a baseline sample and 7 bimonthly follow-up samples were randomly selected from 2764 visits for acute pharyngitis and tonsillitis, resulting in a total sample of 910 visits. We include patients of both sexes who were at least 15 years old. A staff of 19 physicians are in charge of the outpatient clinic. Seventy five visits (8.2%) were eliminated because of lack of data. INTERVENTIONS (CLINICAL PROGRAM): a) elaboration of the CP; b) information to the physicians; c) monitoring of the indicators every two months; and d) introduction of corrective measures after the basal measurement and after each monitoring, including the communication to the professionals of the global and individual results. MAIN MEASUREMENTS: The following indicators were obtained from the computerized medical record: use of rapid antigen test for streptococcus (URAT), total antibiotic prescription (TAP), suitable antibiotic use (SAU) and first choice antibiotic selection (FCAS). The respective standards were adapted from international guidelines with the consensus of the intervening professionals, namely: URAT 50%; TAP 20%; SAU 100% and FCAS 100%. STATISTICAL ANALYSIS: the indicators temporal variations were analyzed according the chi square test for linear trend. RESULTS: the URAT increased significantly from the basal 30% and reached the 50% standard (P=.01). The basal TAP was 36% and it did not change significantly with the intervention (P=.53). The SAU improved significantly from basal 34% to values between 60 and 80% (P<.0001), about half of the maximal attainable improvement. The FCAS was 18% in the basal sample and climbed to 75% in the last measurements (P<.0001), about two thirds of the maximal attainable improvement. CONCLUSIONS: Although the physicians' attitude has changed, it is still a long way from the established standard. It is necessary to maintain the monitoring of the quality indicators and the regular and customized interventions until the consolidation of the practice is achieved.
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Faringitis/diagnóstico , Faringitis/tratamiento farmacológico , Evaluación de Programas y Proyectos de Salud , Enfermedad Aguda , Adolescente , Adulto , Femenino , Humanos , MasculinoRESUMEN
The objective of this research was to evaluate the validity of Hodkinson's Abbreviated Mental Test (AMT) in screening for dementia and to identify the optimum cut-off point to use in a prevalence survey. The study included two groups of persons: (i) a random sample of 183 individuals selected from census data, 96 of whom completed the study and (ii) another 36 persons with dementia were selected from a hospital outpatients department by sampling consecutive cases. The DSM-IV criteria were used as the "gold standard" to establish a diagnosis of dementia. The AMT was administered to the 132 participants who subsequently underwent independent clinical evaluation. In the community sample, 11 persons were diagnosed with dementia and 85 without. In the total sample, a score of 7 maximizes the efficacy of the test. The sensitivity for this cut-off point is 91.5% (78.7-97.2%) and the specificity is 82.4% (72.2-89.5%). A score of 9 gives 100% sensitivity, but the proportion of false positives rises to 66%. Our results are consistent with other studies and suggest that the AMT is a valid instrument for use in screening for dementia in populations similar to the one in this study.
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Demencia/diagnóstico , Pruebas Neuropsicológicas/normas , Factores de Edad , Anciano , Anciano de 80 o más Años , Demencia/psicología , Reacciones Falso Positivas , Femenino , Humanos , Lenguaje , Masculino , EspañaRESUMEN
Friedreich's ataxia is caused by mutations in the FRDA gene that encodes frataxin, a nuclear-encoded mitochondrial protein. Most patients are homozygous for the expansion of a GAA triplet repeat within the FRDA gene, but a few patients show compound heterozygosity for a point mutation and the GAA-repeat expansion. We analyzed DNA samples from a cohort of 241 patients with autosomal recessive or isolated spinocerebellar ataxia for the GAA triplet expansion. Patients heterozygous for the GAA expansion were screened for point mutations within the FRDA coding region. Molecular analyses included the single-strand conformation polymorphism analysis, direct sequencing, and linkage analysis with FRDA locus flanking markers. Seven compound heterozygous patients were identified. In four patients, a point mutation that predicts a truncated frataxin was detected. Three of them associated classic early-onset Friedreich's ataxia with an expanded GAA allele greater than 800 repeats. The other patient associated late-onset disease at the age of 29 years with a 350-GAA repeat expansion. In two patients manifesting the classical phenotype, no changes were observed by single-strand conformation polymorphism (SSCP) analysis. Linkage analysis in a family with two children affected by an ataxic syndrome, one of them showing heterozygosity for the GAA expansion, confirmed no linkage to the FRDA locus. Most point mutations in compound heterozygous Friedreich's ataxia patients are null mutations. In the present patients, clinical phenotype seems to be related to the GAA repeat number in the expanded allele. Complete molecular definition in these patients is required for clinical diagnosis and genetic counseling.
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Ataxia de Friedreich/genética , Proteínas de Unión a Hierro , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Adulto , Edad de Inicio , Alelos , Niño , Preescolar , Análisis Mutacional de ADN , Salud de la Familia , Genes Recesivos , Ligamiento Genético , Genotipo , Heterocigoto , Humanos , Repeticiones de Microsatélite , Linaje , Fenotipo , Mutación Puntual , Polimorfismo Conformacional Retorcido-Simple , Expansión de Repetición de Trinucleótido , Repeticiones de Trinucleótidos , FrataxinaRESUMEN
We report a large family with a temporal partial epilepsy syndrome inherited in an autosomal dominant mode, with a penetrance of about 80%. This epilepsy syndrome is benign, with age of onset in the second or third decade of life. It is characterized by rare partial seizures, usually secondarily generalized, arising mostly during sleep, without postictal confusion. There is a good response to the antiepileptic therapy but often a recurrence of seizures after drug withdrawal. The partial component, visual (lights, colors, and simple figures) or auditory (buzzing or "humming like a machine"), the existence of temporo-occipital interictal electroencephalographic epileptiform abnormalities, and the hypoperfusion in the temporal lobe detected by interictal hexamethylpropyleneamine oxime-technetium 99m (HMPAO-Tc99m) single-photon emission computed tomography, strongly suggest a lateral temporal lobe origin. The genetic analysis found linkage to chromosome 10q, and localized a gene in a 15-cM interval that overlaps a previously found localization for partial epilepsy in a large three-generation family. This syndrome could be called autosomal dominant lateral temporal epilepsy.
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Cromosomas Humanos Par 10/genética , Epilepsia del Lóbulo Temporal/genética , Lateralidad Funcional , Ligamiento Genético , Femenino , Genotipo , Humanos , Escala de Lod , Masculino , LinajeRESUMEN
We report a 61-year-old alcoholic man who presented with subacute physical deterioration and severe dysarthria. MRI, suggestive of corpus callosum demyelination with associated white matter involvement in both cerebral hemispheres, indicated the diagnosis of Marchiafava-Bignami disease. During his stay in hospital the patient showed remarkable improvement, and was discharged 22 days after admission. On MRI 2 months later, the extracallosal lesions had disappeared. This case raises questions about some previous ideas on this disease, such as the prognosis of its acute forms and the significance of the extracallosal lesions seen on neuroimaging.
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Alcoholismo/complicaciones , Encefalopatías/etiología , Enfermedades Desmielinizantes/etiología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encefalopatías/diagnóstico , Encefalopatías/diagnóstico por imagen , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Enfermedades Desmielinizantes/diagnóstico , Enfermedades Desmielinizantes/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pronóstico , Tomografía Computarizada por Rayos XRESUMEN
The concept of limb-girdle muscular dystrophy (LGMD) is changing rapidly due to the advances in molecular genetics. Recently, seven different gene loci have been described, demonstrating that limb-girdle muscular dystrophy is a heterogeneous syndrome, which includes different diseases with a similar phenotype. In isolated populations which have little genetic exchange with neighbouring populations, an accumulation of cases may be found. We carried out an epidemiological study in Guipúzcoa, a small mountainous Basque province in northern Spain, and found the highest prevalence rate of LGMD described so far: 69 per million. Genetic studies demonstrated that 38 cases corresponded to the LGMD2A type, due to calpain-3 gene mutations. Only one patient with alpha-sarcoglycanopathy was found, and in 12 patients the genetic defect was not identified. Moreover, the particular calpain-3 mutation predominant in Basque chromosomes (exon 22, 2362AG-->TCATCT), has only been rarely found in the rest of the world. This observation strongly suggests a founder effect in the indigenous population of Guipúzcoa. The clinical characteristics of the patients with calpain-3 gene mutations were quite homogeneous and different from the other groups (sarcoglycanopathy and unknown gene defect), allowing for a precise clinical diagnostic. The disease onset was between the ages of 8 and 15 years, in most cases in the pelvic girdle, and the patients became wheelchair-bound between 11 and 28 years after onset. No pseudohypertrophy of calves or contractures were observed. No clear correlations were found between the nature and site of the mutation and the resulting phenotype.
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Calpaína/genética , Cromosomas Humanos Par 15 , Isoenzimas/genética , Proteínas Musculares , Distrofias Musculares/epidemiología , Distrofias Musculares/genética , Adulto , Edad de Inicio , Anciano , Secuencia de Bases , Mapeo Cromosómico , Cartilla de ADN , Exones , Femenino , Genotipo , Geografía , Humanos , Incidencia , Masculino , Registros Médicos , Persona de Mediana Edad , Músculo Esquelético/patología , Distrofias Musculares/fisiopatología , Mutación , Fenotipo , Mutación Puntual , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Prevalencia , Estudios Retrospectivos , España/epidemiología , SíndromeRESUMEN
Linkage studies have confirmed the existence of clinical an genetic heterogeneity among the muscular dystrophies due to adhalin deficiency. We present the clinical, histological and genetic characteristics in a case of primary adhalinopathy (deficiency of the 50 kD subunit or alpha-sarcoglycan). It was a 19 years-old woman, born of non consanguineous parents, who shows a long evolution myopathy with onset before age 7, a severe evolution and becoming wheelchair bound at 10 years. She showed evident calf pseudohypertrophy and serum creatinkinase (CK) levels were elevated (40-180 times the standard level). The histological pattern showed a destructed fascicular architecture in agreement with severe muscular dystrophy, normal staining with anti-dystrophin monoclonal antibodies and abnormal staining pattern with anti-adhalin antibodies. The molecular study evidenced an homozygous point mutation (Arg-->Cys) at position 77 of exon 3 of the gene coding for the 50 kD subunit of the alpha-sarcoglycan complex localised in chromosome 17. In the light of this case, we suggest a revision of the diagnostic orientation in the muscular dystrophies and we review the new taxonomy of the limb-girdle muscular dystrophies, remarking the clinical signs which could indicate a given genetic locus.
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Cromosomas Humanos Par 17 , Proteínas del Citoesqueleto/genética , Glicoproteínas de Membrana/genética , Distrofias Musculares/genética , Adulto , Edad de Inicio , Distrofina/metabolismo , Femenino , Humanos , Inmunohistoquímica , Distrofias Musculares/metabolismo , Distrofias Musculares/patología , Mutación Puntual , Polimorfismo Conformacional Retorcido-Simple , SarcoglicanosRESUMEN
INTRODUCTION: Thalamic infarcts in paramedian artery territory are seen fairly frequently owing to certain peculiarities of the vascularization of the thalamus. However, clinical diagnosis is usually difficult because of the many varieties and peculiarities of the symptomatology. MATERIAL AND METHODS: We present a review of twelve cases of bilateral paramedian infarcts of the thalamus seen in our Department of Neurology and in a private surgery. We analyze the symptoms and their relationship to the neuro-radiological findings. Finally we compare our observations with the descriptions published by other authors and seek and anatomo-functional relationship for each of the symptoms and signs observed. RESULTS: The usual clinical outline in our patients included disorders of consciousness, different types of oculomotor disorders and cerebellar symptoms, mainly of gait. Other less common findings were memory disorders and abnormal movements. In no case were there sensory changes and pyramidal signs were rare in the absence of significant extra-thalamic lesions. CONCLUSIONS: Our findings, although generally comparable to those described in the literature consulted, were somewhat different with regard to cerebellar symptoms and the absence of sensory and pyramidal signs. We also emphasize the marked differences seen between the individual patients in our series. A good knowledge of the possible clinical variants of these lesions is necessary for a correct initial diagnostic approach in the study of these patients.
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Infarto Cerebral , Tálamo/irrigación sanguínea , Adulto , Anciano , Amnesia/etiología , Ataxia/etiología , Enfermedades de los Ganglios Basales/etiología , Cerebelo/patología , Infarto Cerebral/complicaciones , Infarto Cerebral/patología , Trastornos de la Conciencia/etiología , Disartria/etiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Trastornos de la Motilidad Ocular/etiología , Tálamo/patologíaRESUMEN
We report the clinical characteristics of 7 patients (5 women) from 61 through 84 years of age who were diagnosed within the last 3 years as having corticobasal ganglionic degeneration. The disease begin clinically in all patients with on asymmetric motor syndrome. Four experienced tremulousness and myoclonus in one hand, with apraxia and cortical sensory symptoms, astereognosia and sensory extinction. In 3 others, the progressive motor symptoms was mainly a pyramidal syndrome. Hand apraxia caused severe disability in the affected member and was disproportionate to the degree of motor symptoms suffered by the patient. In 3 patients with right side involvement, language-related difficulties were present; in 2 patients with aphasia, difficulties of articulation were partly caused by bucorespiratory apraxia. We believe that this disease, which is more common than believed, has a highly characteristic clinical profile that often allows its clinical diagnosis.
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Ganglios Basales/fisiopatología , Degeneración Nerviosa , Anciano , Antiparkinsonianos/uso terapéutico , Ganglios Basales/diagnóstico por imagen , Enfermedades de los Ganglios Basales/tratamiento farmacológico , Femenino , Lateralidad Funcional , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , RadiografíaAsunto(s)
Corea/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Hiperglucemia/fisiopatología , Anciano , Anciano de 80 o más Años , Corea/diagnóstico , Corea/tratamiento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Quimioterapia Combinada , Femenino , Humanos , Hiperglucemia/diagnóstico , Hiperglucemia/tratamiento farmacológico , Insulina/administración & dosificación , Examen Neurológico/efectos de los fármacos , Tetrabenazina/administración & dosificaciónAsunto(s)
Antieméticos/efectos adversos , Aprindina/efectos adversos , Benzamidas/efectos adversos , Buformina/efectos adversos , Enfermedad de Parkinson Secundaria/inducido químicamente , Anciano , Antieméticos/administración & dosificación , Aprindina/administración & dosificación , Benzamidas/administración & dosificación , Buformina/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson Secundaria/diagnósticoRESUMEN
OBJECTIVE: To evaluate the efficacy of high-dose intravenous gammaglobulin (IGIV) versus plasmapheresis in patients with severe Guillain-Barré syndrome (GBS) and compare the costs of both treatments. DESIGN: Retrospective review of all severely disabled GBS patients admitted between January 1 and December 31, 1990. SETTING: Neurologic unit of a tertiary-care center. PATIENTS: Six patients fulfilling the criteria for the diagnosis of GBS agreed upon by the ad hoc National Institute of Neurological and Communicative Disorders and Stroke committee. INTERVENTION: Four patients treated with plasmapheresis underwent three to six sessions of plasma exchange. Two patients received IGIV 0.4 g/kg/d administered over a five-day period. MAIN OUTCOME MEASURES: Recovery time, functional assessment (performed according to the grading scale used in the North American trial) at 30, 60, and 90 days after treatment. Cost of plasmapheresis, IGIV, and bed/day were compared. RESULTS: Clinical recovery appeared to be faster and more complete in the IGIV group than in the plasmapheresis group. No adverse reactions related to IGIV treatment appeared. The total cost was greater in the plasmapheresis group. CONCLUSIONS: These preliminary results suggest that IGIV may be more beneficial and less expensive than plasmapheresis in treatment of GBS. Definitive conclusions regarding the efficacy of IGIV in GBS will need to await the final analysis of the Ducht randomized multicenter trial comparing IGIV with plasmapheresis.
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Inmunoglobulinas Intravenosas/administración & dosificación , Plasmaféresis , Polirradiculoneuropatía/terapia , Adulto , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Persona de Mediana Edad , Plasmaféresis/economía , Estudios RetrospectivosAsunto(s)
Distonía/etiología , Ejercicio Físico , Flecainida/efectos adversos , Femenino , Humanos , Persona de Mediana EdadRESUMEN
The subjects were 20 patients with Parkinson's disease. They were aged 52 to 76 years and the duration of the disease ranged from four to 25 years (mean, 12.5 years). All the patients were receiving levodopa alone or in combination with tricyclic antidepressants, amantadine, bromocriptine, anticholinergic agents, or lisuride. Each patient received 1,000 mg of citicoline intramuscularly daily for 15 days and then 500 mg daily for 15 days. After 30 days of treatment, the scores on the Columbia rating scale improved 7.3%; rigidity was improved 18.8%; times to walk 10 m and turn over were reduced 17.5% and 37.4%; and the handwriting test scores improved 19.7%. No side effects were reported. Four patients with advanced parkinsonian symptoms and psychotic side effects received 2,000 mg of citicoline subcutaneously or intravenously for seven days. No improvements in symptoms or treatment side effects were noted.