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Biomedical subjects

K Johnson

Publications and source records attributed to K Johnson.

At least 19 recordsLinked to original sources
PubMed1992

[Molecular genetics diagnosis of Steinert's myotonic dystrophy].

Myotonic dystrophy (DM) is the most common neuromuscular disease with adult onset (incidence 1 in 8000). The biochemical basis of this autosomal dominantly inherited disease is still unknown. The most striking features are myotonia and progressive muscular wasting. There is high variability of disease severity in patients from different families, but also within the same family. For practical reasons three subtypes can be defined: The classical adult onset form of the disease, a mild form with late onset and/or very moderate symptoms, eg. cataracts only, and the most severe congenital form which is transmitted by affected females. Furthermore, the progression of DM in affected families may exhibit an increase in the severity of the disease in successive generations. This observation is called anticipation. Very recently the DM gene has been cloned and an unstable DNA sequence specific for the disease has been characterized. Detection of an enlarged DNA fragment due to the expansion of a trinucleotide (CTG) repeat within the DM gene can be used for direct DNA diagnosis in affected individuals and persons at risk. Furthermore, there is a strong correlation between the length of fragment expansion and the degree of disease severity in gene carriers. We report here our preliminary results of the investigation of over 70 patients and demonstrate the clinical usefulness of this new method by the findings in three families.

Adult↗
PubMed1992

Mutations that eliminate the requirement for the vertex protein in bacteriophage T4 capsid assembly.

The capsid of bacteriophage T4 is composed of two essential structural proteins, gp23, the major constituent of the capsid, and gp24, a less prevalent protein that is located in the pentameric vertices of the capsid. gp24 is required both to stabilize the capsid and to allow it to be further matured. This requirement can be eliminated by bypass-24 (byp24) mutations within g23. We have isolated, cloned and sequenced several new byp24 mutations. These mutations are cold-sensitive in the absence of gp24, and are located in regions of g23 not known to contain any other mutations affecting capsid assembly. The cold-sensitivity of the byp24 mutations can be reduced by further mutations within g23 (trb mutations). Cloning and sequencing of these trb mutations has revealed that they lie in regions of g23 that contain clusters of mutations that cause the production of high levels of petite and giant phage (ptg mutations). Despite the proximity of the trb mutations to the ptg mutations, none of the ptg mutations has a Trb phenotype. The mutation ptE920g, which is also located near one of the ptg clusters, and which produces only petite and wild-type phage, has been shown to confer a Trb but not a Byp24 phenotype. The relevance of these observations to our understanding of capsid assembly is discussed.

Alleles↗
PubMed1992

Prospective multicentre study of pregnancy outcome after lithium exposure during first trimester.

Lithium carbonate is an effective drug for prophylaxis and treatment of major affective disorders. In-utero exposure to lithium during the first trimester of pregnancy might be associated with an increased risk of cardiac malformations, especially the rare Ebstein's anomaly. We prospectively recruited and followed 148 women (mean age 30 years, SD 5 range 15-40) using lithium during the first trimester of pregnancy, who consulted four teratogen information centres in the USA and Canada. Pregnancy outcome was compared with that of controls matched for maternal age. We had complete follow-up of pregnancy outcome in 138 of 148 patients recruited. In the other 10, fetal echocardiograms were available but postnatal follow-up was not done. Mean daily dose of lithium was 927 mg (SD 340). Rates of major congenital malformations did not differ between the lithium (2.8%) and control (2.4%) groups. 1 patient in the lithium group chose to terminate pregnancy after Ebstein's anomaly was detected by a prenatal echocardiogram. There was 1 ventricular septal defect in the controls. Birthweight was significantly higher in the lithium-exposed infants than in the controls despite identical gestational ages (3475 [660] g vs 3383 [566] g, p = 0.02). The true difference in birthweight might have been even larger, since significantly more women using lithium than controls were cigarette smokers (31.8% vs 15.5%, p = 0.002). These results indicate that lithium is not an important human teratogen. Women with major affective disorders who wish to have children may continue lithium therapy, provided that adequate screening tests, including level II ultrasound and fetal echocardiography, are done.

Abnormalities, Drug-Induced↗
PubMed1992

Myotonic dystrophy: another case of too many repeats?

Myotonic dystrophy (DM) is an adult form of muscular dystrophy affecting about 1 in 8,000 individuals in most populations. Although common symptoms include progressive muscle weakness and stiffness, it is characterised by a heterogeneous clinical picture. Despite this variation in both the nature and severity of the symptoms seen in affected individuals, DM is genetically homogeneous, segregating as a single locus on the proximal long arm of human chromosome 19. As the biochemical abnormality underlying the disease was unknown, a reverse genetics (or positional cloning) strategy for identifying the gene responsible was adopted. The resulting collaborative effort culminated in the detection of the molecular mutation event and the gene within which it lies: the expansion of a trinucleotide repeat (CTG) at the 3' end of a gene encoding a member of the cyclic AMP-dependent protein kinase family. This has diagnostic implications since an easy, reliable and predictive test can now be offered to individuals with a family history of DM. These findings are also a prerequisite for further studies concerning the biochemical and physiological aetiology of DM and possible therapeutic strategies. In addition, the striking similarity between findings at the DNA level in DM and those in fragile X syndrome and spinal and bulbar muscular atrophy suggests that the mechanism leading to the increase in copy number of trinucleotide repeats at particular loci may be responsible for a number of other genetic diseases.

Base Sequence↗
PubMed1992

Experience with the symbion total artificial heart as a bridge to transplantation.

From December 1985 through January 1991, 9 patients underwent bridging to transplantation using a Symbion J-7-70 total artificial heart. There were 4 female and 5 male patients aged 31 +/- 14 years (range, 15 to 52 years). Five patients were supported on an intraaortic balloon pump before total artificial heart support, and 2 had biventricular assist devices as well. Total artificial heart support was maintained for 17 +/- 12 days (range, 4 to 44 days); all patients underwent transplantation. Three patients died after transplantation on day 0 (primary donor organ failure), 25 (acute rejection), and 256 (multiorgan failure). The remainder were discharged at 41 +/- 32 days (range, 13 to 101 days). One patient died 28 months after transplantation of late acute rejection. Actuarial 1-year and 3-year survival is 67% and 55%. There were no surgical wound infections. Problems encountered in the J-7-70 period and the period after transplantation were for the most part related to patient condition in the period before implantation. The Symbion J-7-70 total artificial heart is an effective device for total circulatory support in patients with end-stage cardiogenic shock when an organ donor is not available. Organ system failure and infection before implantation may persist into the transplantation period resulting in long-term complications, increased mortality, and prolonged hospital stay; therefore, early implantation of the device when indicated should be applied.

Adolescent↗
PubMed1992

Radiation-reduced hybrids for the myotonic dystrophy locus.

The myotonic dystrophy (DM) gene maps to the long arm of human chromosome 19 and is flanked by markers ERCC1 and D19S51. Also mapping to this region is the polio virus receptor gene (PVS). To produce more markers for this interval, we have constructed radiation-reduced hybrids by selecting for the retention of ERCC1 and for the loss of PVS. One of the cell lines produced has been characterized extensively and contains about 2 Mb of human DNA derived exclusively from chromosome 19, and includes ERCC1 and D19S51. Phage libraries constructed from DNA of this cell line have been screened and several new markers identified, including two for which cDNAs have been isolated. These represent candidate genes for DM. The new markers have also been used to extend the long-range restriction map of this region.

Base Sequence↗
PubMed1992

Protein export in Escherichia coli.

The export of protein from Escherichia coli has been studied by genetic, biochemical and biophysical techniques. These studies have defined a number of steps in the export pathway and have identified the cellular components required for the translocation process. New information is presented on the function of some of these components.

Bacterial Proteins↗
PubMed1992

Effectiveness of dexamethasone in preventing extubation failure in preterm infants at increased risk for airway edema.

We studied 50 preterm infants who had multiple or traumatic endotracheal intubations, or whose duration of endotracheal intubation was > or = to 14 days, and who were considered at high risk for airway edema. These infants were enrolled in a prospective, randomized, controlled clinical trial to assess whether prophylactic dexamethasone therapy would be effective in the prevention of postextubation stridor and respiratory distress. At study entry, both groups had similar weights, postnatal ages, methylxanthine use, ventilator settings, blood gas values, and pulmonary function test results (dynamic compliance, total respiratory resistance, tidal volume, peak-to-peak transpulmonary pressure, minute ventilation, and peak inspiratory and expiratory flow rates). Patients underwent blood gas studies, physical examinations, and pulmonary function testing at baseline (4 hours before extubation) and again 2 to 4 hours and 18 to 24 hours after extubation. Twenty-seven infants received dexamethasone, 0.25 mg/kg per dose, at baseline, and then every 8 hours for a total of three doses; 23 infants received saline solution at corresponding times. Eighteen to twenty-four hours after extubation, total pulmonary resistance increased by 225% from baseline in the control group compared with 33% in the dexamethasone group (p < 0.006), and the dexamethasone group had a greater tidal volume, a greater dynamic compliance, and a lower arterial carbon dioxide pressure. Of 23 control infants, 10 had postextubation stridor compared with 2 of 27 dexamethasone-treated patients (p < 0.006). Of the 23 control patients, 4 required reintubation compared with none of the treated group (p < 0.05). We conclude that the prophylactic use of corticosteroids for the prevention of postextubation stridor and respiratory distress is efficacious in low birth weight, high-risk preterm infants.

Carbon Dioxide↗
PubMed1992

Nuclear localization of androgen receptor in heterogeneous samples of normal, hyperplastic and neoplastic human prostate.

To facilitate an understanding of how androgens participate in the genesis of human benign hyperplasia and carcinoma we assayed androgen receptor in the epithelium and stroma of human prostatic tissue from 57 patients. Immunohistochemical staining of human androgen receptor was performed on 106 sections of normal prostate, benign prostatic hyperplasia (BPH) and prostate cancer. To determine variability of androgen receptor staining sections taken from different portions of the gland were studied. Frozen tissue sections were incubated with monoclonal antiandrogen receptor antibodies and staining was completed by the indirect avidin-biotin peroxidase method. Antibody staining was found mainly in the nucleus of prostatic epithelial cells, although some stromal cells also showed positive staining. Unlike normal prostate, there was a heterogeneous distribution of androgen receptor in BPH and prostate cancer. The androgen receptor content in well differentiated adenocarcinoma epithelium was significantly higher compared to moderately (p less than 0.05) and poorly (p less than 0.05) differentiated adenocarcinoma. Regardless of the origin of stromal tissue, some staining was observed. In each specimen studied the androgen receptor staining was consistent qualitatively and quantitatively for each pathological component throughout the specimen. These data confirm that androgen receptor is a nuclear receptor protein. Furthermore, they show the ability of monoclonal antibodies to reveal cellular/subcellular distribution of androgen receptor, and demonstrate a correlation between the degree of tumor differentiation and androgen receptor content in epithelial but not in stromal cells. These observations may have important implications for understanding the variable tumor response to hormone therapy.

Adenocarcinoma↗
PubMed1992

Chronic myopathy in a patient suspected of carrying two malignant hyperthermia susceptibility (MHS) mutations.

Malignant hyperthermia (MH) is a pharmacogenetic myopathy triggered by a variety of anaesthetic agents and muscle relaxants. In humans, susceptibility to MH is inherited as an autosomal dominant trait, and susceptible patients do not show a clinically relevant myopathy unless having suffered from a MH crisis. Homozygosity for the MHS trait is thought to be an uncommon finding, and so far only a few cases of patients suggested to be homozygous for MH on the basis of pedigree information were reported and described as having a more severe form of this condition resulting in clinical symptoms also in the absence of triggering agents. We report clinical findings in a patient with chronic myopathy beginning at the age of 2 yr and associated with a number of unique features, the most important being a family history of MHS present in both parents. She became symptomatic with marked muscular weakness and elevated serum CK levels. A muscle biopsy showed a distinct enlargement and increase of muscle mitochondria. In the in vitro contracture test the patient's muscle responded with unusually high contractures already at basal levels of triggering agents indicating a particularly severe MHS condition. DNA markers for the MHS1 locus, described previously on chromosome 19q12-13.2 in Irish and Canadian pedigrees, could not be used to confirm her homozygous state because our molecular genetic studies had previously excluded the MHS trait in this pedigree from this locus.(ABSTRACT TRUNCATED AT 250 WORDS)

Child, Preschool↗
PubMed1992

Unstable DNA may be responsible for the incomplete penetrance of the myotonic dystrophy phenotype.

Myotonic dystrophy (DM) is associated with the expansion and instability of a trinucleotide (CTG) repeat in a sequence encoding a cAMP-dependent protein kinase. The normal copy number of 5-35 repeats is exceeded in DM patients, with the size of the expansion broadly correlating with the severity of symptoms experienced. In most families reported, the unstable DNA sequence has increased in size on transmission to affected offspring, thereby providing a molecular explanation for the phenomenon of anticipation in DM, i.e. an increase in the severity of symptoms associated with an earlier age at onset of the disease in successive generations of a family. Here we present the first reported case of a family where the transmission of the affected chromosome from father to son is accompanied by a reduction in the size of the triplet expansion, such that it falls within the normal range. As the son remains asymptomatic, this type of molecular event may provide an explanation for the incomplete penetrance of the disease phenotype reported for this disorder. The implications for genetic counselling of DM families and the mechanistic considerations of the trinucleotide instability are discussed.

Adult↗
PubMed1992

Determination of dextromethorphan and its O-demethylated metabolite from urine.

A high-performance liquid chromatography (HPLC) assay for the simultaneous quantitation of dextromethorphan and its O-demethylated metabolite dextrorphan from urine is described. A cyano analytical column was used with a mobile phase consisting of MeOH 16%, acetonitrile 3%, and triethylamine 0.06% at pH 2.8 and a flow rate of 1.0 ml/min. Betaxolol was used as the internal standard. Standard curves from 50 ng/ml to 10,000 ng/ml (dextrorphan), and from 50 ng/ml to 8,000 ng/ml (dextromethorphan) were developed. The peaks eluted at 7.8 min (dextrorphan), 12.2 min (betaxolol), and 17.8 min (dextromethorphan). The coefficients of variance ranged from 1.3 to 4.5% at 250 ng/ml and 0.9 to 2.5% at 5,000 ng/ml. This assay was used to determine dextromethorphan/dextrorphan molar ratios in healthy male volunteers for the purpose of determining phenotype status for the P450IID6 isozyme.

Chromatography, High Pressure Liquid↗
PubMed1992

Comparison of the myotonic dystrophy associated CTG repeat in European and Japanese populations.

Gene amplification using polymerase chain reaction (PCR) was carried out on DNA samples from a total of 92 normal subjects and 52 subjects with myotonic dystrophy (DM) from European and Japanese populations, to determine the copy number of the CTG repeat associated with DM for each group. In the two populations, the number of repeats on normal chromosomes only were compared, as CTG copy number on DM chromosomes was difficult to determine by PCR alone. In this study, normal chromosomes were found which had as many as 35 copies of the repeat, which is larger than the normal range reported previously but still does not overlap with the repeat number associated with DM pathology, which is at least 50 copies. Using data from normal chromosomes from unrelated subjects, the frequencies of five, 11, and 13 copies of the CTG repeat were found to be significantly different between the two populations, with five and 11 copies more commonly seen in the European population and 13 copies in the Japanese population. This difference may be the result of natural divergence of the normal chromosomes between the population groups.

Alleles↗
PubMed1992

Expansion of the myotonic dystrophy gene in Italian and Spanish patients.

Myotonic dystrophy results from expansion of a (CTG)n repeat at the 3' untranslated region of the myotonin-protein kinase gene. We show here the genomic analysis of 322 symptomatic patients with the cDNA-25 probe detecting disease specific EcoRI restriction fragments. The expansion was found in the majority of Italian and Spanish patients (92%). The implications of these results for the detection of symptomatic patients in southern Europe are discussed.

Adult↗
PubMed1992

Psychotropic and medical drug interactions.

In a number of situations, drugs used to treat psychiatric and physical illnesses are coadministered to patients suffering primarily from a psychiatric illness. Hence, coadministration of medical and psychiatric drugs is not uncommon. With increasing use of multiple drugs, our ability to treat a number of disorders has increased, but simultaneously, the problem of drug interactions has also assumed importance. A number of factors contribute to such drug interactions in psychiatric patients. All these interactions are both pharmacologically and genetically determined. Genetic susceptibility is not practical to determine. It is therefore essential for the physician to employ drug combinations only when necessary, be aware of the known clinically significant interactions, anticipate and watch for them, avoid dangerous combinations, and monitor the patients receiving combination of drugs with vigilance.

Anti-Bacterial Agents↗