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Biomedical subjects

P Gustavsson

Publications and source records attributed to P Gustavsson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Urban air pollution and lung cancer in Stockholm.

We conducted a population-based case-control study among men 40-75 years of age encompassing all cases of lung cancer 1985-1990 among stable residents of Stockholm County 1950-1990. Questionnaires to subjects or next-of-kin (primarily wives or children) elicited information regarding smoking and other risk factors, including occupational and residential histories. A high response rate (>85%) resulted in 1,042 cases and 2,364 controls. We created retrospective emission databases for NOx/NO2 and SO2 as indicators of air pollution from road traffic and heating, respectively. We estimated local annual source-specific air pollution levels using validated dispersion models and we linked these levels to residential addresses using Geographical Information System (GIS) techniques. Average traffic-related NO2 exposure over 30 years was associated with a relative risk (RR) of 1.2 (95% confidence interval 0.8-1.6) for the top decile of exposure, adjusted for tobacco smoking, socioeconomic status, residential radon, and occupational exposures. The data suggested a considerable latency period; the RR for the top decile of average traffic-related NO2 exposure 20 years previously was 1.4 (1.0-2.0). Little association was observed for SO2. Occupational exposure to asbestos, diesel exhaust, and other combustion products also increased the risk of lung cancer. Our results indicate that urban air pollution increases lung cancer risk and that vehicle emissions may be particularly important.

Adult↗
PubMed2000

A microdeletion in 19q13.2 associated with mental retardation, skeletal malformations, and Diamond-Blackfan anaemia suggests a novel contiguous gene syndrome.

Diamond-Blackfan anaemia (DBA) is a constitutional red blood cell hypoplasia which may be associated with a variety of developmental abnormalities. A gene for DBA was recently mapped to chromosome 19q13.2 and subsequently cloned. Analysis of 19q marker alleles in DNA of sporadic DBA cases showed de novo microdeletions in three patients also presenting with mental retardation. We have studied one of these patients and characterised the deletion by fluorescence in situ hybridisation (FISH) to extended DNA fibres. The deletion was shown to be continuous over a 3.2 Mb region and the fibre-FISH analysis showed both chromosomal breakpoints. In combination, the clinical and molecular findings suggest a contiguous gene syndrome with a gene locus for mental retardation and, probably, skeletal malformations included in the deletion.

Bone and Bones↗
PubMed2000

Mortality and cancer incidence among Swedish lumberjacks exposed to phenoxy herbicides.

OBJECTIVES: To determine mortality and cancer incidence relative to exposure to phenoxy herbicides. METHODS: A cohort of Swedish lumberjacks of which 261 were exposed to phenoxy herbicides, and 250 were unexposed, was followed up for mortality from 1954 to 1994, and for cancer incidence from 1958 to 1992. The number of days of exposure to phenoxy herbicides was determined from pay slips. With the county population as a reference, standardised mortality ratios and cancer incidence ratios (SMR and SIR) were calculated. RESULTS: Mortality and cancer incidence were low with two exceptions; a small but highly exposed group of foremen showed an increased cancer incidence (SIR 274, 95% confidence interval (95% CI) 100 to 596), and over all mortality (SMR 141, 95% CI 68 to 260). Of three cases of non-Hodgkin's lymphoma, two were found among the most exposed workers. CONCLUSIONS: The results provide some support to claims of previous studies that exposure to phenoxy herbicides might be related to non-Hodgkin's lymphoma and to an increased overall cancer risk.

Cohort Studies↗
PubMed2000

Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor.

Familial hyperparathyroidism (HPT), characterized by hypercalcemia and hypercalciuria, and familial benign hypocalciuric hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. The calcium-sensing receptor (CaR) regulates PTH secretion and renal calcium excretion. Heterozygous inactivating mutations of the gene cause FHH, whereas CaR gene mutations have not been demonstrated in HPT. In a kindred with 20 affected individuals, the hypercalcemic disorder segregated with inappropriately higher serum PTH and magnesium levels and urinary calcium levels than in unaffected members. Subtotal parathyroidectomy revealed parathyroid gland hyperplasia/adenoma and corrected the biochemical signs of the disorder in seven of nine individuals. Linkage analysis mapped the condition to markers flanking the CaR gene on chromosome 3q. Sequence analysis revealed a mutation changing phenylalanine to leucine at codon 881 of the CaR gene, representing the first identified point mutation located within the cytoplasmic tail of the CaR. A construct of the mutant receptor (F881L) was expressed in human embryonic kidney cells (HEK 293), and demonstrated a right-shifted dose-response relationship between the extracellular and intracellular calcium concentrations. The hypercalcemic disorder of the present family is caused by an inactivating point mutation in the cytoplasmic tail of the CaR and displays clinical characteristics atypical of FHH and primary HPT.

Adult↗
PubMed1999

Mutations in ribosomal protein S19 gene and diamond blackfan anemia: wide variations in phenotypic expression.

Mutations of the ribosomal protein S19 (RPS19) gene were recently identified in 10 patients with Diamond Blackfan anemia (DBA). To determine the prevalence of mutations in this gene in DBA and to begin to define the molecular basis for the observed variable clinical phenotype of this disorder, the genomic sequence of the 6 exons and the 5' untranslated region of the RPS19 gene was directly assessed in DBA index cases from 172 new families. Mutations affecting the coding sequence of RPS19 or splice sites were found in 34 cases (19.7%), whereas mutations in noncoding regions were found in 8 patients (4.6%). Mutations included nonsense, missense, splice sites, and frameshift mutations. A hot spot for missense mutations was identified between codons 52 and 62 of the RPS19 gene in a new sequence consensus motif W-[YFW]-[YF]-x-R-[AT]-A-[SA]-x-[AL]-R-[HRK]-[ILV]-Y. No correlation between the nature of mutations and the different patterns of clinical expression, including age at presentation, presence of malformations, and therapeutic outcome, could be documented. Moreover, RPS19 mutations were also found in some first-degree relatives presenting only with isolated high erythrocyte adenosine deaminase activity and/or macrocytosis. The lack of a consistent relationship between the nature of the mutations and the clinical phenotype implies that yet unidentified factors modulate the phenotypic expression of the primary genetic defect in families with RPS19 mutations.

Adolescent↗
PubMed1999

Monosomy 18q syndrome and atypical Rett syndrome in a girl with an interstitial deletion (18)(q21.1q22.3).

We describe a 6 1/2-year-old girl with an interstitial deletion of chromosome arm 18q (18q21.1q22.3). Her clinical manifestations are a combination of those found in monosomy 18q syndrome and those of Rett syndrome. Cytogenetic analysis demonstrated a deletion of the long arm of chromosome 18, defined by molecular analysis with polymorphic markers as a de novo interstitial deletion, paternally derived. The findings typical of the 18q- syndrome included mental retardation, midface hypoplasia, and hypoplasia of labia majora, and those typical of Rett syndrome were severe mental retardation, autistic behavior, inappropriate hand-washing movements, epilepsy, attacks of sighing and hyperventilation, and progressive scoliosis since the age of 5 years. She did not have microcephaly, and the mental delay was obvious from an early age without a period of normal development, which makes the diagnosis of Rett syndrome atypical. Previously, a girl with mosaicism for a monosomy 18q associated with Rett syndrome has been described. That girl had a terminal deletion of chromosome 18q, which seems to coincide in part with that in the present girl. It is possible that genes in the distal region of 18q are involved in the etiology of Rett syndrome.

Child↗
PubMed1999

Mortality and cancer incidence in biomedical laboratory personnel in Sweden.

BACKGROUND: The work in biomedical laboratories is associated with exposure to a mixture of known and potential chemical carcinogens, mutagens, and teratogens. Previous studies have suggested an excess of brain tumors and hematopoietic system malignancies as well as breast cancers in women. METHODS: This retrospective cohort study investigated the standardized mortality ratio (SMR) and the standardized incidence ratio (SIR) for cancer in biomedical research laboratory personnel in Swedish universities 1970-1992. The cohort comprised 5,035 laboratory and, as an internal reference group, 2,923 nonlaboratory employees. RESULTS: The overall death rate was lower in both groups than in the general population. The SIR for brain tumors among male laboratory workers was 1.69 (0.62-3.68) and among male laboratory scientists, after more than 10 years of work (4 cases), it was 3.11 (0.85-7.56). There was an elevated SIR for malignant melanoma among female scientists in laboratories (3.51, 0.96-8.98) and for male scientists in nonlaboratory departments (2.86, 1.05-6.22). The SIR for breast cancer among female laboratory scientists was 1.62 (0.78-2.98). CONCLUSIONS: The present findings lend some support to an excess of brain tumors among male scientists and of breast cancer in female scientists in biomedical research laboratories.

Adult↗
PubMed1999

Truncating ribosomal protein S19 mutations and variable clinical expression in Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a rare constitutional erythroblastopenia characterized by a specific defect in erythroid differentiation. Recently, mutations in the gene encoding ribosomal protein (RP) S19 were found in a subset of patients with the disease. To characterize further RPS19 mutations and to investigate genotype-phenotype relationships, we screened this gene for mutations in patients with DBA by direct sequencing and Southern-blot analysis. Four novel mutations were identified. A G120A nonsense mutation resulting in a stop at codon 33, a C302T nonsense mutation introducing a premature stop at codon 84, and a 327delG which results in a frame shift at codon 103. A fourth and more complex mutation (TT157-158AA, 160insCT) resulting in a Leu45Gln and a frame shift from codon 47 was found in three affected family members with variable phenotypes. The different clinical expression for identical mutations suggest the presence of other modulating factors for the disease. The mutations presented here further support the role of RPS19 in erythropoietic differentiation and proliferation.

Adult↗
PubMed1999

Mortality and cancer incidence among laboratory technicians in medical research and routine laboratories (Sweden).

OBJECTIVES: To investigate cancer incidence and mortality among laboratory employees. METHODS: Mortality and cancer incidence were investigated among 2553 female and male laboratory workers employed at the Karolinska Institute and Karolinska Hospital in Stockholm between 1950 and 1989. Mortality was followed from 1952-1993 and cancer incidence from 1958-1992. Expected numbers were based on the general population in Stockholm, standardizing for age, gender, and calendar period. RESULTS: The overall mortality and cancer incidence in the cohort was lower than expected. There were in all 10 cases of hemato-lymphatic malignancies (three acute myeloid leukemias, four non-Hodgkin lymphomas, two Hodgkin's lymphomas, and one multiple myeloma) in the cohort. The standardized incidence ratio (SIR) for hematolymphatic tumors was increased among workers who had ever been employed in laboratories with a high probability for chemical exposure, SIR 224 (95% CI 108-412). The risk of breast cancer among women was increased after more than 10 years of work in high-exposure laboratories, SIR 225 (128-365). The number of malignant melanomas exceeded those expected. CONCLUSIONS: The findings support earlier observations of an increased risk of hematolymphatic cancer among laboratory workers. The routine for handling chemicals and functionality of ventilatory equipment must be under continuous supervision.

Adult↗
PubMed1999

A microdeletion syndrome due to a 3-Mb deletion on 19q13.2--Diamond-Blackfan anemia associated with macrocephaly, hypotonia, and psychomotor retardation.

We report on a boy with congenital pure red blood cell aplasia [Diamond Blackfan anemia (DBA)] and severe congenital hypotonia, macrocephaly, hypertelorism, a broad and tall forehead, medial epicanthus, and facial hypotonia with mouth-breathing and drooling, an affable and out-going personality, and a general psychomotor retardation. These features show similarity to the phenotype of the X-linked FG syndrome. DBA was diagnosed at the age of 4 months, and the boy underwent treatment with transfusion and with prednisolone. He had a normal 46, XY karyotype, but fluorescence in situ hybridization (FISH) analysis to metaphase chromosomes revealed a 3-Mb deletion on 19q13.2. This chromosomal region has previously been linked to the DBA phenotype and one 19q13 microdeletion has been identified in a patient with DBA. This deletion coincides with the deletion reported here. We suggest that the complex phenotype of our patient, including both DBA and the associated features, represent a microdeletion syndrome.

Chromosome Deletion↗
PubMed1999

The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia.

Diamond-Blackfan anaemia (DBA) is a constitutional erythroblastopenia characterized by absent or decreased erythroid precursors. The disease, previously mapped to human chromosome 19q13, is frequently associated with a variety of malformations. To identify the gene involved in DBA, we cloned the chromosome 19q13 breakpoint in a patient with a reciprocal X;19 chromosome translocation. The breakpoint occurred in the gene encoding ribosomal protein S19. Furthermore, we identified mutations in RPS19 in 10 of 40 unrelated DBA patients, including nonsense, frameshift, splice site and missense mutations, as well as two intragenic deletions. These mutations are associated with clinical features that suggest a function for RPS19 in erythropoiesis and embryogenesis.

Amino Acid Sequence↗
PubMed1999

Deletion including the oligophrenin-1 gene associated with enlarged cerebral ventricles, cerebellar hypoplasia, seizures and ataxia.

Non-specific X-linked mental retardation is a heterogeneous group of disorders with an incidence of approximately 1 in 500 males. A recently identified gene in Xq12, encoding a Rho-GTPase-activating protein, was found to be mutated in individuals with mental retardation. We describe here two sisters with a 46,XY karyotype and a microdeletion of the oligophrenin-1 gene and 1.1 Mb of flanking DNA. We have characterised the molecular interval defining this microdeletion syndrome with the fibre-FISH technique. A visual physical map of 1.2 Mb was constructed which spans the oligophrenin-1 gene and the androgen receptor gene. The analysis of the patients revealed a deletion which extended from the 5' end of the AR gene to a region approximately 80 kb proximal to the EPLG2 gene. The clinical manifestations of the two sisters include psychomotor retardation, seizures, ataxia, hypotonia and complete androgen insensitivity. Cranial MRI scans show enlargement of the cerebral ventricles and cerebellar hypoplasia. Our findings give further support for the involvement of the oligophrenin-1 gene in specific morphological abnormalities of the brain which is of importance in the investigation of male patients presenting with mental retardation. In combination with our results from physical mapping we suggest that a region around the oligophrenin-1 locus is relatively bereft of vital genes.

Ataxia↗
PubMed1999

Diamond-Blackfan anaemia in the Italian population.

Diamond-Blackfan anaemia (DBA) is a congenital disease characterized by defective erythroid progenitor maturation: 30% of patients have congenital malformations. The link between these malformations and defective erythropoiesis is unclear: a defect in a molecule acting both on embryo development and haemopoiesis has been proposed. Inheritance is autosomal dominant in most familial cases, but recessive families have also been reported. Many cases are sporadic. A DBA locus has been mapped on chromosome 19q13.2 (Gustavsson et al, 1997), but several families unlinked to this locus have also been reported (Gustavsson et al, 1998). This paper presents clinical, epidemiological and molecular data for DBA in the Italian population. Segregation analysis of 19q markers in patients with DBA showed exclusion of this locus in 5/12 families with inherited DBA. There was evidently locus heterogeneity for DBA in this population. A new microdeletion was identified in one patient. Other families, in which DBA segregates concordantly with the 19q critical region, suggest incomplete penetrance and expressivity of the DBA gene.

Child↗
PubMed1999

High-risk occupations for breast cancer in the Swedish female working population.

OBJECTIVES: The purpose of this study was to estimate, for the period 1971 through 1989, occupation-specific risks of breast cancer among Swedish women employed in 1970. METHODS: Age-period standardized incidence ratios were computed. Log-linear Poisson models were fitted, with geographical area and town size taken into account. Risks were further adjusted for major occupational group, used as a proxy for socioeconomic status. Risk estimators were also calculated for women reporting the same occupation in 1960 and 1970. RESULTS: Most elevated risks among professionals, managers, and clerks were reduced when intragroup comparisons were carried out, indicating the confounding effect of socioeconomic status. Excess risks were found for pharmacists, teachers of theoretical subjects, schoolmasters, systems analysts and programmers, telephone operators, telegraph and radio operators, metal platers and coaters, and hairdressers and beauticians, as well as for women working in 1960 and 1970 as physicians, religious workers, social workers, bank tellers, cost accountants, and telephonists. CONCLUSIONS: While the high risks observed among professional, administrative, and clerical workers might be related to lower birth rates and increased case detection, excess risks found for telephone workers and for hairdressers and beauticians deserve further attention.

Adult↗
PubMed1998

High adenosine deaminase level among healthy probands of Diamond Blackfan anemia (DBA) cosegregates with the DBA gene region on chromosome 19q13. The DBA Working Group of Société d'Immunologie Pédiatrique (SHIP).

Phenotypic characterization of Diamond Blackfan Anemia (DBA) patients and their relatives was performed in 54 families. Complete blood count, fetal hemoglobin level, erythrocyte i antigen expression, and erythrocyte adenosine deaminase (eADA) activities were quantitated in patients and relatives. eADA was elevated in 28 of 34 transfusion-independent DBA patients, whereas persistence of erythrocyte i antigen was noticed in only 10 of 20 DBA patients. High eADA activities were also found in 14 of 149 healthy family members, allowing us to identify an isolated high eADA phenotype in these families. In contrast, increase in erythrocyte i antigen expression, elevated fetal hemoglobin levels, and macrocytosis were much less frequently noted in nonaffected members of the DBA families studied. Importantly, isolated high eADA phenotype was found to be significantly associated with genetic markers on chromosome 19 that segregate with the DBA phenotype. Isolated high eADA phenotype thus seems to reflect a silent phenotype of DBA in affected families. These findings suggest that elevated eADA activity in unaffected individuals needs to be taken into account during genetic assessment of DBA families and could be used for accurate assessment of mode of inheritance.

Adenosine Deaminase↗
PubMed1998

Smoking tobacco, oral snuff, and alcohol in the etiology of squamous cell carcinoma of the head and neck: a population-based case-referent study in Sweden.

BACKGROUND: This case-referent study was conducted to elucidate the role of selected exogenous agents in the etiology of head and neck cancer. The factors studied were tobacco smoking, alcohol intake, the use of moist oral snuff, dietary factors, occupational exposures, and oral hygiene. In this first report, the authors discuss the impact of tobacco smoking, the use of oral snuff, and alcohol consumption. METHODS: The study base was approximately 2 million person-years at risk and consisted of Swedish males age 40-79 years living in 2 geographic regions during the years 1988-1990. A total of 605 cases were identified in the base, and 756 controls were selected by stratified random sampling from population registries covering the base. RESULTS: Among those who were tobacco smokers at the time of the study, the relative risk of head and neck cancer was 6.5% (95% confidence interval, 4.4-9.5%). After cessation of smoking, the risk gradually declined, and no excess risk was found after 20 years. The relative risk associated with alcohol consumption of 50 grams or more per day versus less than 10 grams per day was 5.5% (95% confidence interval, 3.1-9.6%). An almost multiplicative effect was found for tobacco smoking and alcohol consumption. CONCLUSIONS: Tobacco smoking and alcohol intake had a strong interactive effect on the risk of squamous cell carcinoma of the head and neck. Moderate alcohol intake (10-19 grams per day) had little or no effect among nonsmokers. No increased risk was found for the use of Swedish oral snuff.

Adult↗
PubMed1998

Identification of microdeletions spanning the Diamond-Blackfan anemia locus on 19q13 and evidence for genetic heterogeneity.

Diamond-Blackfan anemia (DBA) is a rare pure red-cell hypoplasia of unknown etiology and pathogenesis. A major DBA locus has previously been localized to chromosome 19q13.2. Samples from additional families have been collected to identify key recombinations, microdeletions, and the possibility of heterogeneity for the disorder. In total, 29 multiplex DBA families and 50 families that comprise sporadic DBA cases have been analyzed with polymorphic 19q13 markers, including a newly identified short-tandem repeat in the critical gene region. The results from DNA analysis of 29 multiplex families revealed that 26 of these were consistent with a DBA gene on 19q localized to within a 4.1-cM interval restricted by loci D19S200 and D19S178; however, in three multiplex families, the DBA candidate region on 19q13 was excluded from the segregation of marker alleles. Our results suggest genetic heterogeneity for DBA, and we show that a gene region on chromosome 19q segregates with the disease in the majority of familial cases. Among the 50 families comprising sporadic DBA cases, we identified two novel and overlapping microdeletions on chromosome 19q13. In combination, the three known microdeletions associated with DBA restrict the critical gene region to approximately 1 Mb. The results indicate that a proportion of sporadic DBA cases are caused by deletions in the 19q13 region.

Chromosome Mapping↗