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Biomedical subjects

M R Johnson

Publications and source records attributed to M R Johnson.

At least 145 records · Page 8Linked to original sources
PubMed1995

Neurofibromatosis 1 and multiple sclerosis.

Neurofibromatosis 1 is a common autosomal dominant disease that principally involves the skin and peripheral nervous system. The gene for the disorder has been located on chromosome 17q11.2 and there are three embedded genes within the neurofibrosis gene. One of these genes codes for oligodendrocyte-myelin glycoprotein, is found in the CNS during myelination, and may have a role in myelin formation. The case histories of five patients, including two siblings, who have both neurofibromatosis 1 and multiple sclerosis are reported. All five had the primary progressive form of multiple sclerosis, which forms only 15% of multiple sclerosis in population surveys. The coincidence of neurofibromatosis 1 and multiple sclerosis might be due to a mutation in the embedded oligodendrocyte-myelin glycoprotein gene.

Adult↗
PubMed1995

Could abnormalities in insulin-like growth factors and their binding proteins during pregnancy result in gestational diabetes?

A number of dramatic changes have been documented in the insulin-like growth factors (IGFs-I and -II) and their binding proteins (IGFBPs) during pregnancy. In this study we have tested the hypothesis that a failure of the normal proteolytic modification of IGFBP-3 is responsible for gestational diabetes by examining serum samples taken in the third trimester from 29 women with uncomplicated pregnancies, 21 women with established Type 1 diabetes and 20 women with gestational diabetes. Analysis of IGFBP-3 by Western immunoblotting revealed that it was present in a modified form, migrating at around 29 kDa, in the circulation of all of the women investigated. Semiquantification of the activity of the protease which modifies the IGFBP-3 demonstrated considerable variation between individuals in their ability to fragment radiolabelled IGFBP-3 following a 45-min co-incubation. Surprisingly, in one individual (with gestational diabetes) there was no detectable protease activity even though her endogenous IGFBP-3 had been modified. However, overall there was no clear-cut difference in protease activity between the different groups. Radioimmunometric analysis of IGF-I revealed significantly higher levels in women with gestational diabetes than either of the other two groups (P < 0.05). Similarly IGFBP-3 levels were also increased in these same women (P < 0.05). In contrast, IGF-II levels did not alter between the three groups. In conclusion, our hypothesis was not supported by these data and gestational diabetes was found not to be associated with any reduction in the activity of the circulating IGFBP-3 protease which could have decreased the availability of the IGF nor with any alteration in IGFs which could explain the onset of diabetes in these women.

Adult↗
PubMed1995

Panic disorder. Pathophysiology and drug treatment.

Advances over the past 2 decades in our understanding of the biology of panic disorder have paralleled a remarkable increase in the development of new pharmacological agents with antipanic effects. Although we can not presently use biological tests to help with our choice of therapeutic agent for individual patients, we can use this biological understanding in the development of overall pharmaco-therapeutic strategies. Current evidence does not support the hypothesis that panic disorder is associated with a primary disorder in one neurotransmitter system. Rather, the data suggest that the biological aetiology of panic disorder is related to abnormalities in the function of a variety of neurotransmitters including serotonin (5-hydroxytyrptamine; 5-HT), noradrenaline (norepinephrine), gamma-aminobutyric acid (GABA), dopamine, and cholecystokinin. It is likely, however, that panic disorder is a biologically heterogeneous condition and that biological subtypes may exist in which the primary abnormality may involve one or a few neurotransmitter systems. Currently, the data best support the hypothesis that pharmacotherapeutic agents with primary action at sites within the GABA and serotonin systems are the most effective in the treatment of panic disorder. Nevertheless, some patients will respond well to drugs with predominant activity in other systems, or may require pharmacotherapy designed to affect the function of more than 1 neurotransmitter. As our understanding of the biological aetiology of panic disorder evolves, the pharmacotherapeutic agents and strategies used in the treatment of this disorder will continue to evolve as well.

Benzodiazepines↗
PubMed1995

Hematologic and serum chemistry values of captive Canadian lynx.

We present baseline values for 12 hematologic and 17 serum chemistry parameters collected from 22 captive lynx (Felis lynx canadensis) in December 1992, at Ronan, Montana (USA). There were no significant differences in hematologic parameters between yearlings and adults or between sexes. Lynx originally captured in the wild had significantly higher mean (+/- SE) counts of neutrophils (7.7 +/- 0.37 x 10(3) versus 7.2 +/- 0.35 x 10(3)) and lower counts of lymphocytes (1.1 +/- 0.05 x 10(3) versus 1.6 +/- 0.08 x 10(3)) compared to lynx born and raised in captivity. Yearling lynx had significantly higher values for alkaline phosphatase than adults (51.0 +/- 6.0 IU/l versus 17.5 +/- 0.8 IU/l.

Aging↗
PubMed1995

The neurobiology of anxiety disorders.

The use of pharmacologic challenges and the application of new brain imaging technologies in the study of patients with anxiety disorders have led to an improvement in the understanding of the neurobiologic basis of these disorders. Abnormal function of noradrenergic, serotonergic, GABAergic, and dopaminergic neural systems as well as abnormal chemoreceptor reactivity have all been implicated in the pathophysiology of anxiety. Functional imaging data have revealed abnormal patterns of cortical and subcortical activity in anxiety patients. These data have allowed significant improvements in the available anatomic models of the anxiety disorders. Further improvements in research technique and technology likely will lead in the near future to a significantly clearer image of the neurobiologic processes involved in anxiety disorders.

Anxiety Disorders↗
PubMed1995

Structure-activity relationships defining the ACD-tricyclic cannabinoids: cannabinoid receptor binding and analgesic activity.

Previous studies of the structure-activity relationships (SAR) for binding of a series of AC-bicyclic cannabinoid structures to the cannabinoid receptors in rat brain (believed to comprise the CB1 subtype) demonstrated the importance of the A-ring aryl C-3 side chain and phenolic hydroxyl substituents, and elucidated the importance of a C-ring hydroxyalkyl substituent [Melvin et al. Mol. Pharmacol. 44, 1008-1015 (1993)]. The present investigation examines the SAR surrounding this region (D-ring) of the molecule that is not present in the structure of delta(9)-THC and other classical cannabinoid compounds. Both rigid fused ring benzo and cyclohexyl derivatives (creating the D-ring) retained binding affinity for the cannabinoid receptor. Extension of ketone or hydroxyl substituents from the C2 position of the D-ring resulted in a 3-fold increase in binding affinity over the unsubstituted structure. However, the fused ring structure is not critical for the interaction with the receptor in as much as opening the ring did not decrease the potency. Extension of the D-ring C-2 alcohol by one carbon in length resulted in a pair of structures, for which the greatest affinity for the CB1 receptor occurred for the hydroxymethyl group in the axial conformation [(+/-)-CP-55,244]. Upon resolution, the latter provided a pair of enantiomers: (-)-CP-55,244 was approximately 3-fold more potent than the racemic mixtures, and (+)-CP-55,244 failed to bind to the CB1 receptor with an IC50 below 1 mM. Opening of the D-ring of these structures resulted in a loss of binding affinity. This study demonstrates that the potency could be optimized in (-)-CP-55,244 for both binding to the CB1 receptor and the biological activity of analgesia. In addition, the rigid positioning of the hydroxypropyl moiety of CP-55,940 enforced by the decalin ring structure of CP-55,244 increased the enantioselectivity by greater than 100-fold. These data define the critical stereochemistry for a region of the nonclassical ACD-tricyclic cannabinoid structure that contributes a potential hydrogen bonding component to the ligand-receptor interaction mechanism. Inasmuch as this region of the molecule is not present on classical ABC-tricyclic cannabinoid compounds, these studies elucidate a unique agonist recognition site on the CB1 receptor.

Analgesics↗
PubMed1994

Does heart transplantation confer additional benefit over medical therapy to patients who have waited > 6 months for heart transplantation?

OBJECTIVES: This study compared the survival of patients with heart failure who have waited > 6 months for heart transplantation with that patients who undergo heart transplantation after a similarly prolonged waiting period. BACKGROUND: There are little data describing outcome in patients with severe heart failure who have waited for extended periods of time on the heart transplant waiting list. METHODS: Sixty-three consecutive patients who spent > 6 months on the heart transplant waiting list were examined. Mean (+/- SD) age was 53 +/- 9 years, mean left ventricular ejection fraction was 19 +/- 6%, and all were taking digoxin and diuretic and vasodilator agents. Patients who underwent transplantation during the follow-up period were censored from the pretransplantation analysis, and their survival was examined as part of the posttransplantation phase of the study. RESULTS: Of the 63 original patients examined, 25 underwent transplantation, 10 during inotropic or mechanical circulatory support. The pretransplantation mortality rate was 6% at 6 months after the 6-month milestone on the waiting list, 12% at 12 months and 22% at 18 months. The posttransplantation mortality rate was 5% at 6 months, 10% at 12 months and 24% at 18 months. There were no differences in survival at any time between the two phases of the study. CONCLUSIONS: Survival of patients who have survived > 6 months on the heart transplant waiting list is generally good. Although heart transplantation did not appear to confer additional survival advantage over medical therapy, a large proportion of the patients who underwent transplantation were critically ill at the time of transplantation and would undoubtedly have died of progressive heart failure had they not undergone transplantation. We conclude that heart transplantation should still be considered a therapeutic alternative in patients with heart failure even after a prolonged waiting period on the heart transplant waiting list.

Actuarial Analysis↗
PubMed1994

Risk/benefit ratio of perioperative OKT3 in cardiac transplantation.

To evaluate the risk/benefit ratio of perioperative OKT3 in cardiac transplant patients receiving triple-drug immunosuppression, patients who underwent cardiac transplantation between July 1, 1988 and December 31, 1989 (n = 33) and who received perioperative OKT3 were retrospectively compared with patients who underwent transplantation between January 1, 1990 and June 30, 1991 (n = 46), and who received no perioperative anti-T cell therapy. To allow similar follow-up, data were analyzed through June 30, 1990 for the OKT3 group and through December 31, 1991 for the no anti-T cell therapy group. Patients in the no anti-T cell therapy group waited longer for a donor organ; other pretransplant characteristics did not differ. The azathioprine dose 1 month after transplant was higher in the no anti-T cell therapy group (144 +/- 63 mg vs 109 +/- 55 mg, p = 0.016); other post-transplant immunosuppression was similar. The incidence of total and treated rejection and the time to the first rejection did not differ between the groups. The OKT3 group had a higher number of infections (0.8 +/- 0.9 vs 0.3 +/- 0.3, p = 0.006) and intravenously treated infections (0.5 +/- 0.6 vs 0.1 +/- 0.2, p = 0.004) per patient per month. Cytomegalovirus infection developed in 46% of the OKT3 group versus 22% of the no anti-T cell therapy group (p = 0.025). Patient survival did not differ between the groups. Thus, an immunosuppressive regimen that includes perioperative OKT3 increases infections, especially cytomegalovirus infections, without decreasing or delaying rejection or increasing survival.

Adult↗
PubMed1994

Glycine and taurine conjugation of bile acids by a single enzyme. Molecular cloning and expression of human liver bile acid CoA:amino acid N-acyltransferase.

In order to establish whether a single enzyme in human liver was capable of conjugating bile acids with both glycine and taurine, a cDNA encoding human liver bile acid-CoA:amino acid N-acyltransferase (hBAT) has been isolated and characterized. A specific immunoaffinity-purified rabbit anti-hBAT polyclonal antibody was used to screen a lambda Zap XR human liver cDNA library resulting in the isolation of two unique clones. hBAT8 and hBAT9 (1669 and 1491 base pairs in length, respectively) were isolated following screening of 4 x 10(5) clones of the cDNA library. Restriction mapping and sequence analysis demonstrated that the cDNAs were identical except hBAT8 contained an additional 178 bases of 5' sequence; hBAT8 was completely sequenced, characterized, and used for all subsequent studies. hBAT8 consisted of a 184-nucleotide 5'-nontranslated region, an open reading frame of 1,254 bases predicting a protein of 418 amino acids with a molecular mass of 46,296 Da, and a 3'-nontranslated region of 209 nucleotides followed by a poly(A)+ tail. The identity of the cDNA was confirmed by the following findings: 1) the open reading frame began with an ATG codon and was followed by a nucleotide sequence which, when translated, corresponded exactly to the first 17 NH2-terminal amino acids of purified human liver BAT; 2) cytosol of Escherichia coli XL1-Blue cells transfected with hBAT8 subcloned into an expression vector, pKK233-2, demonstrated significant enzymatic activity for the conjugation of both taurine and glycine with cholic acid; 3) bacterial expression of hBAT8 generated a protein that comigrated with hBAT from human liver during SDS-polyacrylamide gel electrophoresis and cross-reacted with a specific polyclonal rabbit anti-hBAT antibody during immunoblot analysis; 4) kinetic characteristics of the expressed enzyme were very similar to those reported for purified liver BAT. These data demonstrate that a single cDNA is present in human liver which codes for a protein capable of catalyzing the conjugation of cholic acid with both glycine and taurine.

Acyltransferases↗
PubMed1994

Factors associated with the development of persistently depressed cardiac output during the first year after cardiac transplantation.

The purpose of this study was to determine factors associated with the development of a persistently depressed cardiac output during the first year after cardiac transplantation. With this aim in mind, the records of 133 consecutive patients undergoing orthotopic cardiac transplantation and surviving for > or = 1 year after transplantation were reviewed. For each patient, the mean cardiac index for each of the 3-month periods, 0-3, 4-6, 7-9, and 10-12 months after transplantation was calculated. Of the 133 patients, 19 (14%) had a mean cardiac index < 2.4 l/min/m2 during > or = 3 of these 3-month periods. The pre- and post-transplantation clinical, immunologic, and hemodynamic data of these 19 patients (study group) were compared with the remaining 114 patients (control group). Compared with the control group, the patients in the study group were older (56 +/- 5 vs. 46 +/- 15 years; p = 0.0001), more frequently had ischemic heart disease as the original diagnosis (58 vs. 37%; p < 0.05), had a lower preoperative cardiac index (1.91 +/- 0.53 vs. 2.71 +/- 1.0 l/min/m2; p = 0.0001), more frequently did not receive perioperative anti-T cell therapy (47 vs. 25%; p = 0.046), and had a greater median number of infections during the first year after transplantation (5 vs. 3; p = 0.027). However, only one factor--a low preoperative cardiac index--emerged as an independent predictor of the development of a persistently depressed cardiac index during the first year after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1994

Regulation of corpus luteum function.

The effects have been studied of different ovulation induction regimens [either clomiphene citrate or buserelin in combination with human menopausal gonadotrophin (HMG)] on the circulating concentrations of progesterone, oestradiol, relaxin and human chorionic gonadotrophin (HCG) during the first trimester of pregnancy. Ovulation induction with clomiphene resulted in elevated concentrations of gonadotrophins in both phases of the cycle, while during ovulation induction with buserelin, gonadotrophin concentrations were elevated in the follicular phase only. The concentrations of all corpus luteum products were greater in clomiphene pregnancies compared with spontaneous pregnancies, but only oestradiol and relaxin concentrations were greater in clomiphene pregnancies compared with buserelin pregnancies. The concentrations of HCG were significantly reduced in clomiphene pregnancies compared to natural pregnancies. Relaxin concentrations were significantly higher from 7 weeks gestation in buserelin compared with spontaneous pregnancies, while progesterone, oestradiol and HCG concentrations were not consistently different. Consistent associations were found between relaxin and HCG concentrations in spontaneous pregnancies and between the concentrations of relaxin and both progesterone and oestradiol in pregnancies achieved after ovulation induction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Endometrial thickness: a predictor of implantation in ovum recipients?

In a retrospective study, the relationship between endometrial thickness and pregnancy rate has been studied in 59 ovum recipient women. Transvaginal ultrasound assessment of endometrial thickness was performed immediately prior to ovum transfer: 19 pregnant recipients had a mean endometrial thickness of 10.24 mm +/- 2.63 SD, 40 nonpregnant recipients had an endometrial thickness of 8.62 mm +/- 3.49 SD (t = 1.805, P = 0.0382). Only two pregnancies occurred in 15 recipients with an endometrial thickness < 7.5 mm, and none when the endometrial thickness was < 5 mm. Our results indicate that endometrial thickness is related to the functional receptivity of the endometrium.

Adult↗
PubMed1994

Relaxin concentrations in exoembryonic fluids during the first trimester.

In 15 women undergoing therapeutic termination of pregnancy (8-13 weeks), the median concentration of relaxin was 1000 ng/l in maternal serum, 122 ng/l in coelomic fluid and 9 ng/l in amniotic fluid. Its presence in coelomic fluid suggests that relaxin may be present in the fetal circulation and thus be able to influence embryonic development during the period of organogenesis.

Abortion, Induced↗
PubMed1994

Neurofibromin can inhibit Ras-dependent growth by a mechanism independent of its GTPase-accelerating function.

The NF1 gene, which is altered in patients with type 1 neurofibromatosis, has been postulated to function as a tumor suppressor gene. The NF1 protein product neurofibromin stimulates the intrinsic GTPase activity of active GTP-bound Ras, thereby inactivating it. Consistent with a tumor suppressor function, we have found that the introduction of NF1 in melanoma cell lines that are deficient in neurofibromin inhibited their growth and induced their differentiation. In addition, overexpression of neurofibromin in NIH 3T3 cells was growth inhibitory but did not alter the level of GTP.Ras in the cells. Transformation by v-ras, whose protein product is resistant to GTPase stimulation by neurofibromin, was inhibited in a cell line overexpressing neurofibromin, while transformation by v-raf was not altered. The results demonstrate that NF1 is a tumor suppressor gene that can inhibit Ras-dependent growth by a regulatory mechanism that is independent of neurofibromin's ability to stimulate Ras GTPase.

3T3 Cells↗
PubMed1994

Intracoronary ultrasound assessment of morphological and functional abnormalities associated with cardiac allograft vasculopathy.

BACKGROUND: The diffuse nature of cardiac allograft vasculopathy makes early detection of the disease by traditional noninvasive methods or coronary angiography difficult. The aim of this study was to determine if there is a relation between abnormalities in vessel wall morphology, as assessed by intracoronary ultrasound, and a decreased vasodilatory response to the endothelium-dependent vasodilator papaverine hydrochloride and if cardiac allograft vasculopathy detected by coronary angiography is associated with specific intracoronary ultrasound findings. METHODS AND RESULTS: Twenty-three heart transplant recipients underwent 25 intracoronary ultrasound studies and 24 studies of coronary vasomotor tone 10 days to 8.3 years after surgery using a 20-mHz intracoronary ultrasound catheter. The studies were divided in two groups according to the presence (n = 7, group 1) or absence (n = 18, group 2) of angiographically evident cardiac allograft vasculopathy. Qualitative assessment of vessel wall morphology and quantitative analysis of the vasodilator response to the injection of papaverine hydrochloride into the coronary artery distal to the imaging site were performed off-line, and results for the two study groups were compared. A significantly higher percentage of patients with than without angiographic evidence of cardiac allograft vasculopathy had a three-interface vessel wall morphology by intracoronary ultrasound (100% versus 11%, P < .001). In two recipients who underwent two serial studies, the appearance of three interfaces in the vessel wall or a progressive thickening of the inner interface of the vessel wall occurred in conjunction with the appearance of angiographic cardiac allograft vasculopathy. The vasodilator response to papaverine was less in patients with than in those without angiographically evident cardiac allograft vasculopathy both in terms of absolute and relative increases in lumen diameter (+0.1 +/- 0.12 mm versus +0.3 +/- 0.17 mm, P < .05, and +5.1 +/- 5.3% versus +8.2 +/- 5.3%, P = NS) and lumen cross-sectional area (+0.5 +/- 0.6 mm2 versus +1.7 +/- 1.1 mm2, P < .02, and +7.1 +/- 8.8% versus 16.6 +/- 11.0%, P = .055), respectively. CONCLUSIONS: Intracoronary ultrasound assessment of vessel wall morphology and evaluation of vascular response to endothelium-dependent vasodilators are useful techniques for detecting cardiac allograft vasculopathy.

Cardiac Catheterization↗
PubMed1994

Pharmacokinetics and efficacy of the long-acting somatostatin analogue somatuline in acromegaly.

The aim of this work was to assess the use of a sustained-release formulation of somatuline, a long-acting analogue of somatostatin, in the treatment of acromegaly. Fifteen patients with active acromegaly, as defined by random growth hormone (GH) levels greater than 10 mU/l, which fail to be suppressed to less than 5 mU/l following an oral glucose load, were studied. Somatuline was administered as an intramuscular injection in two regimens: eight patients were given a single injection of the sustained-release formulation and blood samples taken over the next month for the measurement of both basal levels of GH and the GH response to thyrotrophin-releasing hormone; and eight patients were given injections of the sustained-release formulation at 2-week intervals over a 6-month period and basal plasma GH levels and the GH response to both an oral glucose load and to thyrotrophin-releasing hormone was assessed. Following a single intramuscular dose of the sustained-release preparation, random GH levels were reduced to below 10 mU/l in five patients and by greater than 50% of basal levels in the remainder. The insulin-like growth factor I (IGF-I) levels fell to within the normal range in three patients. In the long-term efficacy study. GH levels were reduced to < 10 mU/l in 7/8 patients. The IGF-I levels were normalized in four patients. Five of the eight patients experienced diarrhoea, two of mild and three of moderate severity; none of the patients withdrew from the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗