Clinical predictors of incident somatic morbidity in a sample of depressed patients: A 16–30 years follow-up study

Background and objectives: We investigated the independent associations between various characteristics at trial entrance and subsequent development of somatic morbidity in patients participating trials on antidepressants.Methods338 in-patients diagnosed with major depression who had participated in trials on antidepressants conducted between 1983 and 1994 were followed for up to 30 years in Danish registers. By applying a Cox regression model with incident diagnoses of somatic disease as outcome, explanatory variables such as age at first episode, duration of index episode, bipolarity and scores on the Hamilton Depression Scale and subscales hereof, were investigated.ResultsCardiovascular diseases were associated with increasing number of previous depressive episodes at baseline (HR 1.06, 95% CI (1.00–1.11)). The risk of diabetes was associated with increasing duration of index episode (HR 1.01, 95% CI (1.00–1.01) as was respiratory disease (HR 1.00, 95% CI (1.00–1.01)). Diagnoses of infection were associated with increasing score on HAM-D6 (HR 1.11, CI 95 % (1.01–1.22)).ConclusionsThe association between number of previous depressive episodes and CVD is in line with previous results. The findings of associations between the psychometric measures and specific diseases should be interpreted with caution, as well as the associations between duration of episodes, higher severity and higher number of previous episodes, and increased risks of somatic morbidity, albeit these are in line with previous evidence. (AU)

Identification of positional candidates for neurological disorders on chromsome 13q14-->q22.

In the course of a research project aimed at the molecular characterization of balanced chromosome rearrangements associated with mental retardation (MR), several YACs spanning MR-associated chromosomal rearrangements in the 13q14-->q22 region were identified. To facilitate the search for relevant candidate genes, we have analyzed a total of 102 EST clones from this region. Sequence comparisons revealed that these 102 clones represent up to 72 distinct transcripts. When no physical mapping data were available, a minimal YAC contig was screened for each unique transcript by the polymerase chain reaction (PCR) or hybridization. Fifty-eight independent ESTs could be localized to YAC clones between the markers D13S1248 and D13S1201. Several ESTs are located on YAC clones detecting chromosomal rearrangements in MR patients. One EST was mapped within the critical region for Rieger syndrome type 2, and three transcripts were identified in the region for the nocturnal enuresis type 1. Some ESTs showed homologies to known genes, including the cadherin-related tumor suppressor gene from Drosophila, the yeast mitotic control protein DIS3, and the human alpha-2-macroglobulin receptor associated protein.

Fifty probands with extra structurally abnormal chromosomes characterized by fluorescence in situ hybridization.

Extra structurally abnormal chromosomes (ESACs) are small supernumerary chromosomes often associated with developmental abnormalities and malformations. We present 50 probands with ESACs characterized by fluorescence in situ hybridization using centromere-specific probes and chromosome-specific libraries. ESAC-specific libraries were constructed by flow sorting and subsequent amplification by DOP-PCR. Using such ESAC-specific libraries we were able to outline the chromosome regions involved. Twenty-three of the 50 ESACs were inverted duplications of chromosome 15 [inv dup(15)], including patients with normal phenotypes and others with similar clinical symptoms. These 2 groups differed in size and shape of the inv dup(15). Patients with a large inv dup(15), which included the Prader-Willi region, had a high risk of abnormality, whereas patients with a small inv dup(15), not including the Prader-Willi region, were normal. ESACs derived from chromosomes 13 or 21 appeared to have a low risk of abnormality, while one out of 3 patients with an ESAC derived from chromosome 14 had discrete symptoms. One out of 3 patients with an ESAC derived from chromosome 22 had severe anomalies, corresponding to some of the manifestations of the cat eye syndrome. Small extra ring chromosomes of autosomal origin and ESACs identified as i(12p) or i(18p) were all associated with a high risk of abnormality.

[Minor head injuries. Prognostic factors in the evaluation of patients]. / Lettere hovedtraumer. Prognostiske faktorer ved vurdering af patienter.

In order to identify signs to be used in the decision whether or not to admit patients after minor head injuries (MHI), the records of 713 females and 1163 males were reviewed. Skull X-ray was not obtained routinely, all patients were able to talk and walk when they reached medical contact. Nine patients developed an intracranial complication, three had an operation and one died. The risk of developing an ICC was 16.7% when the patient was agitated, 3.4% in the presence of impaired consciousness and 2.1% when positive neurological signs were observed at the time of examination. Based on the medical history, amnesia for more than five minutes and vomiting were associated with a risk of 3.3% and 1.2% respectively. The risk increased considerably in the presence of two of the above mentioned signs and was 60% if the patient was agitated and had amnesia for more than five minutes. Consequently, we recommend that all patients with one or more of the above symptoms or alcohol intoxication after a MHI should be admitted for observation. This policy may hold the possibility of considerable economic savings.

Prognostic signs in the evaluation of patients with minor head injury.

To assess signs that might be used in the decision whether or not to admit a patient with minor head injury, the records of 713 female and 1163 male patients were reviewed. Skull radiographs were not obtained routinely; all patients were able to walk and talk when they reached medical contact. Nine patients developed an intracranial complication. The risk of developing such a complication was 16.7 per cent when the patient was agitated, 3.4 per cent in the presence of impaired consciousness and 2.1 per cent when positive neurological signs were observed at the time of examination. Based on the medical history, amnesia for > 5 min and vomiting were associated with a risk of 3.3 and 1.2 per cent respectively; the risk increased considerably in the presence of both. It is recommended that all patients presenting themselves with one or more of the above symptoms or signs, or with alcohol intoxication, after a minor head injury be admitted for observation. If these guidelines had been used, all patients with an intracranial complication would have been detected, and 44.5 per cent of the bed-days used would have been saved.

[CPAP treatment of newborn infants. A historical review]. / CPAP-behandling af nyfødte. En historisk oversigt.

Treatment of new-born infants with continuous positive air pressure (CPAP) is reviewed historically on the basis of the available literature. CPAP treatment for this group of patients was introduced just over 20 years ago. Advantages and disadvantages of different methods of use are discussed.

The fragile X mutation does not have any major effect on the expression of the hypoxanthine phosphoribosyltransferase (HPRT) locus in human fibroblasts.

The possible influence of the fragile X mutation at Xq27 on the expression of the neighbouring gene (at Xq26) for hypoxanthine phosphoribosyl transferase (HPRT) was studied by determination of the levels of HPRT-RNA and HPRT enzyme activity in fibroblast cell cultures from 7 fragile X patients. These levels were lower (although not statistically significantly lower) than in normal fibroblast cultures. Hence, these data do not support the notion of a major effect of the fragile X mutation on the expression of the HPRT gene.

[Minor head injuries in a Copenhagen district. 1. Epidemiology]. / Mindre hovedtraumer i et københavnsk omegnsområde. 1. Epidemiologi.

The records of 1,218 males and 743 females admitted to Copenhagen County Hospital in Glostrup between January 1 1985 and December 31 1986 were studied. The mean age was 28.2 years (SD = 20.3 years). The incidence rate was 360 per 100,000 inhabitants per year and was between 30 and 130% larger for males than females (p less than 0.001), the incidence rate was 26% higher in this study as compared to the rate in Denmark as a whole. Patients between 0 and 14 years were most frequently admitted between noon and the early evening hours and those between 15 and 64 years most frequently from late in the afternoon until the early night. The distribution was uniform throughout the week. There was a tendency towards more frequent admissions in the April and July trimesters. 74% of the patients were admitted at hours when the staff was minimal. This category comprised 4.9% of all patients admitted as emergencies to the hospital. The mean hospitalization was 1.6 days (range 1-14 days). Females were hospitalized longer than males (p less than 0.001). Furthermore, hospitalization was significantly longer, the older the patients were (p = 0.005). Patients with minor head trauma constitute a considerable work load in the hospital, especially outside normal working-hours.

[Minor head injuries in a Copenhagen district. 2. Causes, simultaneous lesions, alcohol and economic aspects]. / Mindre hovedtraumer i et københavnsk omegnsområde. 2. Arsager, konkurrerende laesioner, alkohol og økonomiske aspekter.

In order to elucidate causes, simultaneous lesions, alcohol intoxication and economic aspects of admission of patients with minor head traumas, the records of 1,961 patients admitted in 1985 and 1986 were reviewed. 35% were admitted after traffic accidents, 18% after assaults and 17% because of home accidents. In the age group 30-39 years, 40% of the males were admitted after assaults. 7% sustained fractures of the extremities, 4% facial fractures and 3% and 1% thoracic and abdominal lesions respectively. At least 28% of all patients, more than 50% of the patients admitted during evening- and night hours and 51% of the males between 14 and 65 years were clinically alcohol intoxicated. 1,876 patients were admitted solely for observation, nine developed an intracranial complication, three were operated upon and one died. The bed day expenditure was 2.7 mill. Dkr. (pounds 225,000), and for the entire nation 64.8 mill. Dkr (pounds 5,400,000). The costs for diagnosing one case of intracranial lesion in Denmark were 925.000 Dkr. (approximately pounds 80,000) and 2.1 mill. Dkr. (pounds 180,000) to find the cases requiring treatment (1985 level).

Molecular identification of a small supernumerary marker chromosome by in situ hybridization: diagnosis of an isochromosome 18p with probe L1.84.

A dysmorphic child was found by cytogenetic analysis to have an extra small marker chromosome. The marker chromosome was shown to possess a chromosome 18 centromere by in situ hybridization, and probably represents an isochromosome 18p. Centromere specific probes should be of value in identifying extra small marker chromosomes, and thereby provide better understanding of the clinical significance of these.

Aicardi syndrome: early neuroradiological manifestations and results of DNA studies in one patient.

A patient with Aicardi syndrome is presented. We report results of DNA analysis from the patient and her parents with probes mapped to Xp21.3-22.3 in an attempt to localize a deletion in this region. No signs of a microdeletion could be detected, using 5 different DNA markers. Further, it is suggested that a specific combination of cerebral abnormalities may be characteristic of the syndrome and that antenatal ultrasonographic diagnosis may be feasible.

Cognitive development in offspring of untreated and preconceptionally treated maternal phenylketonuria.

A survey is given of literature reports on the effect of performance in offspring from 26 maternal PKU pregnancies treated prior to conception. The survey includes two women who were referred to us for genetic counselling because they had both given birth to microcephalic, mentally retarded children. The women were discovered to suffer from unrecognized maternal PKU with fasting phenylalanine concentration of 1.1-1.5 mmol/L. A strict diet was introduced prior to planned pregnancy and after some months on diet (phenylalanine concentrations less than 0.6 mmol/L) they became pregnant again. Serum phenylalanine levels were monitored weekly throughout pregnancy, and adjustments in the diet were made to keep serum phenylalanine concentration within the range of 0.18-0.42 mmol/L. The outcome of the pregnancies were healthy children who have developed normally. Their IQs are 105 and 119 at ten and four years of age, respectively and their head circumferences are normal. Our data show that the effect of preconceptional dietary treatment was children with a normal performance, contrary to their older siblings born following untreated pregnancies. These results are in agreement with the survey of ten years' promising experiences with preconceptional treatment in maternal PKU. The data may help to motivate young PKU women to accept planned pregnancies and to encourage them to return to the strict diet, which has prevented them from being retarded.

Substitution of serine for alpha 1(I)-glycine 844 in a severe variant of osteogenesis imperfecta minimally destabilizes the triple helix of type I procollagen. The effects of glycine substitutions on thermal stability are either position of amino acid specific.

Recent reports have demonstrated that a series of probands with severe osteogenesis imperfecta had single base mutations in one of the two structural genes for type I procollagen that substituted amino acids with bulkier side chains for glycine residues and decreased the melting temperature of the triple helix. Here we demonstrate that the type I procollagen synthesized by cultured fibroblasts from a proband with a severe form of osteogenesis imperfecta consisted of normal molecules and molecules over-modified by post-translational reactions. The thermal stability of the intact type I collagen was normal as assayed by protease digestion under conditions in which a decrease in thermal stability was previously observed with eight other substitutions for glycine in the alpha 1(I) chain. In contrast, the thermal stability of the one-quarter length B fragment generated by digestion with vertebrate collagenase was decreased by 2-3 degrees C under the same conditions. Nucleotide sequencing of cDNAs and genomic DNA established that the proband had a substitution of A for G in one allele of the pro alpha 1(I) gene that converted the codon for alpha 1-glycine 844 to a codon for serine. The results also established that the alpha 1-serine 844 was the only mutation that could account for the decrease in thermal stability of the collagenase B fragment. There are at least two possible explanations for the failure of the alpha 1-serine 844 substitution to decrease the thermal stability of the collagen molecule whereas eight similar mutations decreased the melting temperature. One possibility is that the effects of glycine substitutions are position specific because not all glycine residues make equivalent contributions to cooperative blocks of the triple helix that unfold in the predenaturation range of temperatures. A second possible explanation is that substitutions of glycine by serine have much less effect on the stability of protein than the substitutions by arginine, cysteine, and aspartate previously studied.

[The fetal hydantoin syndrome]. / Det føtale hydantoinsyndrom.

A boy with dysplasia/hypoplasia of nails and fingertips is reported. He was born to a woman who had been medicated during pregnancy with hydantoin for epilepsy. The clinical and radiological features of the fetal hydantoin syndrome are described. It is suggested that hydantoinexposed fetuses should be examined by ultrasound and serum folate monitored during pregnancy.

A lethal variant of osteogenesis imperfecta has a single base mutation that substitutes cysteine for glycine 904 of the alpha 1(I) chain of type I procollagen. The asymptomatic mother has an unidentified mutation producing an overmodified and unstable type I procollagen.

A fraction of the pro alpha 1(I) and pro alpha 2(I) chains in type I procollagen synthesized by the fibroblasts from a proband with a lethal variant of osteogenesis imperfecta were overmodified by posttranslational reactions. After digestion with pepsin, some of the alpha 1(I) chains were recovered as disulfide-linked dimers. Mapping of cyanogen bromide peptides indicated that the disulfide link was contained in alpha 1-CB6, the cyanogen bromide fragment containing amino acid residues 823-1014 of the alpha 1(I) chain. Nucleotide sequencing of cDNA clones demonstrated a substitution of T for G that converted glycine 904 of the alpha 1(I) chain to cysteine. A large fraction of the type I procollagen synthesized by the proband's fibroblasts had a thermostability that was 3-4 degrees C lower than the normal type I procollagen as assayed by brief proteinase digestion. In addition, the type I procollagen synthesized by the proband's fibroblasts was secreted with an abnormal kinetic pattern in that there was a lag period of about 30 min in pulse-chase experiments. The mutation of glycine to cysteine was not found in type I procollagen synthesized by fibroblasts from the proband's parents. Therefore, the mutation was a sporadic one. However, the mother's fibroblasts synthesized a type I procollagen in which part of the pro alpha chains were overmodified and had a lower thermostability. Therefore, the proband may have inherited a mutated allele for type I procollagen from her mother that contributed to the lethal phenotype. The mother was asymptomatic. She was somewhat short and had slightly blue sclerae but no definitive signs of a connective tissue abnormality. The observations on the mother indicated, therefore, that a mutation that causes synthesis of a type I procollagen with a lowered thermal stability does not necessarily produce a heritable disorder of connective tissue.

Interstitial deletion 13q: further delineation of the syndrome by clinical and high-resolution chromosome analysis of five patients.

Five patients with interstitial deletion 13q are reported. High-resolution chromosome banding established the diagnosis in two cases and stated the exact breakpoints in three remaining cases. All parents had normal chromosomes. An unequal and so far unexplained sex ratio of previously published and present cases was found: M:F = 1:2.75. Moderate to severe growth retardation was prominent in all patients. The patients were followed with psychological tests and growth data for 3-10 years. Mild to moderate mental retardation was present. Considerable phenotypic similarities were found in two patients with del(13)(q21.33 q31.3) and one with del(13)(q14.3q22.3). Repeat ophthalmological examinations showed no evidence of retinoblastoma in a male with del(13)(q13.1q21.1). In conclusion, the long-term study of five patients with interstitial deletion 13q, all evaluated with high-resolution banding, contributed to a more reliable mental and growth prognosis in such patients.

Aarskog syndrome in a Danish family: an illustration of the need for dysmorphology in paediatrics.

The first Danish case of Aarskog syndrome is reported. The child had attended several specialized out-patient clinics before the diagnosis was suggested. This underlines the need for dysmorphology in paediatrics.

Investigation of three XX males by cytogenetic and DNA analyses. Suggestion of Y chromosome inversion polymorphism.

We report cytogenetic and DNA studies in three XX males. Two males seemed to have extra chromosomal material on the tip of one X chromosome. All three males were shown to have Y chromosome material as indicated by hybridization of Y-specific DNA probes to genomic DNA. One male was unusual in that as he showed the 15-kb fragment detected by pDP34 that is thought to map close to the Y centromere. It is suggested that this finding might point to an inversion on the Y chromosome.