Effect of iloprost on serum creatine kinase and lactate dehydrogenase isoenzymes after isoprenaline-induced cardiac damage in rats.

The effect of iloprost was investigated in an experimental model of cardiac damage in rats after isoprenaline (isoproterenol) treatment. Iloprost was administered by continuous subcutaneous infusion at a dose of 0.44 micrograms/kg body weight (b.w.)/min over a total period of 9 days. On day 8, 5 mg isoprenaline/kg b.w. was applied subcutaneously to induce the cardiac damage. The determinations of creatine kinase (CK, EC 2.7.3.2) and CK isoenzymes, lactate dehydrogenase (LDH, EC 1.1.1.27) and LDH isoenzymes as well as a-hydroxybutyrate dehydrogenase (a-HBDH, no EC) were performed 2, 6 and 24 h after isoprenaline application. Immediately after the last blood sampling, the animals were sacrificed and the hearts were examined histologically. Iloprost-pretreated animals showed a reduction in the rise in heart-specific isoenzymes CK-MB and LDH1-3 in the serum after isoprenaline application. A decrease in isoenzymes CK-BB and LDH4-5 in the serum was also observed in iloprost-pretreated rats. However, no difference could be detected histologically in the extent of myocardial necrosis between animals treated with isoprenaline alone or in combination with iloprost. These results suggest a biochemical cardioprotective effect of iloprost in this rat model after isoprenaline application and the lack of correlation with histological findings is discussed.

Serum isoenzyme pattern of creatine kinase and lactate dehydrogenase in various animal species.

The creatine kinase and lactate dehydrogenase isoenzyme pattern were determined in the serum of normal and untreated rats, rabbits, dogs, monkeys and pigs. The relative distribution of all isoenzymes in the serum and an electrophoretic pattern for each animal species are presented. The isoenzyme serum pattern showed a great variation between the species. The diagnostic value of serum creatine kinase isoenzyme MB and lactate dehydrogenase isoenzymes 1 and 2 in predicting cardiac lesions in different animal species is briefly discussed.

Synthesis of dehydro-oogoniol, a female-activating hormone of Achlya: the progesterone route.

The structure of dehydro-oogoniol (3 beta,11 alpha,15 beta,29-tetrahydroxystigmasta-5,24(28)(E)-dien-7-one), a female-activating hormone of the water mold Achlya, has been confirmed by synthesis. The starting material was progesterone, which was converted to the 11 alpha, 15 beta-dihydroxy derivative by microbiological hydroxylation with Aspergillus giganteus (ATCC 10059). The side chain was constructed in a stepwise manner by means of Wittig and Horner-Emmons reactions, and the C-7 ketone was then introduced by allylic oxidation. The biological activity of the synthetic compound was the same as that of the natural hormone.

Diagnostic value of serum creatine kinase and lactate dehydrogenase isoenzyme determinations for monitoring early cardiac damage in rats.

Serum activities of creatine kinase (CK, EC 2.7.3.2) and CK isoenzymes, lactate dehydrogenase (LDH, EC 1.1.1.27) and LDH isoenzymes, alpha-hydroxybutyrate dehydrogenase (alpha-HBDH, no EC) and the LDH/alpha-HBDH ratio were studied following a single s.c. application of 5-250 mg isoproterenol/kg body weight (b.w.) in rats. Measurements of the serum enzymes and histological and enzyme-histochemical examinations of hearts were performed 2, 4, 6, 8 and 24 h after treatment. A drastic increase in serum levels of the isoenzymes CK-MB, LDH1, LDH2 and alpha-HBDH and decrease in the ratio LDH/alpha-HBDH were observed from 2 h onwards after isoproterenol application in all dose groups, the maximum effect being after 4-8 h. Focal cellular injury in the myocardium could also be observed from 2 h onwards after isoproterenol application by an enzyme-histochemical method using nitro blue tetrazolium (NBT) whereas the earliest histological alterations using haematoxylin and eosin (HE) stain could be detected 6 h after treatment. A dose-dependent effect as to enzyme values as well as to myocardial necrosis was observed 24 h after isoproterenol application. No kidney damage could be detected on the basis of serum urea nitrogen and histological examinations. Thus, measurement of serum activities of CK-MB isoenzyme alone or LDH1-2 isoenzymes in combination with other tests to exclude kidney damage are valuable indicators of cardiac lesions in rats.

An aminopterin-like syndrome without aminopterin (ASSAS).

In two patients that closely resembled the phenotype of the syndrome produced by aminopterin in early pregnancy, no evidence of maternal exposure could be elicited. These, plus two similar cases from the literature, suggest the existence of an "aminopterin-like syndrome sine aminopterin" (ASSA) syndrome. Characteristic traits are: ossification defects of the cranium, temporal recession of hairline with upswept frontal hair pattern, ocular hypertelorism, prominent nose root, low set posteriorly rotated ears, limited elbow movement, variable digital defects, simian creases, short stature, and mild to moderate psychomotor retardation. Autosomal recessive inheritance is a possibility.

Spondylocostal/spondylothoracic dysostosis: the clinical basis for prognosticating and genetic counseling.

Short trunk dwarfism involving skeletal anomalies of vertebrae and ribs have been reported under various names. Both dominant and recessive and severe and mild conditions are found. We report on a patient without a severe handicap by age 3 years despite severe involvement of the thorax at birth, suggesting that a more complete classification of such anomalies is needed for counseling. We have used an objective method to classify 39 informative patients from the literature, 35 said to have a recessive disease and four a dominant one. Two patients with the costovertebral segmentation defect with mesomelia (COVESDEM) syndrome were added for comparison with our patient. The results of cluster analysis show that there are three phenotypic groups of patients. Cluster 1 contains 19 patients with a severe form of spondylothoracic dysplasia; cluster 2 includes patients with a mild autosomal recessive and a dominant type; cluster 3 groups the two sibs with the COVESDEM syndrome and our patient. One must be cautious in advising families of the prognosis for a child with severe structural chest deformity since it may not be severe from a functional point of view. More data are needed for complete discrimination between the mild autosomal recessive and dominant forms.

Diagnosis of chromosome 3 duplication q23----qter, deletion p25----pter in a patient with the C (trigonocephaly) syndrome.

The cells of a deceased patient previously reported to have the C (trigonocephaly) syndrome were reinvestigated because his phenotype resembled that of a patient with a duplication-deficiency of chromosome 3. This diagnosis was confirmed using fibroblasts grown from frozen cells, and his mother was shown to carry an inversion of chromosome 3 in her peripheral blood leukocytes. His findings are compared to those of another patient with the C trigonocephaly syndrome with normal chromosomes and to others from the literature. At least one other patient from the literature has a phenotype compatible with "3q duplication syndrome."

Heterogeneity by cluster analysis techniques of Graves' patients typed for HLA DR and IgG heavy chain markers.

In a previous study we were able to separate, using cluster analysis, 196 patients with Graves' disease evaluated for a large number of clinical and laboratory characteristics, including HLA-A and HLA-B typing into one subset with recurring disease and a high prevalence of ophthalmopathy and another subset with mild disease and little ophthalmopathy. Prevalence of HLA-B8 was much higher in the first as compared to the second group. The present study was undertaken in 117 new patients with Graves' disease, typed for HLA-A, HLA-B, HLA-C and DR antigens and IgG heavy chain markers, to determine whether these characteristics could be used to segregate patients into clinically relevant subsets. There was a greater proportion of Gm fb homozygotes among patients than among controls (chi2 = 4.71, p less than 0.05) as well as individuals with HLA-B8 and DR3, previously documented for this disease. Two patient clusters were identified. In one (C1), there is a high incidence of exophthalmos, recurrence of hyperthyroidism after drug treatment, high titres of anti-thyroglobulin antibody, and an association with other autoimmune (including thyroid) diseases, a tendency for the disease to be familial and the presence of larger goitres. The incidence of HLA-B8 was greater in C1, while HLA-B12 was more frequent in the mild cluster, C2. HLA-DR3 was found to be associated with patients in the severe cluster and HLA-DR2 with patients in the mild cluster.(ABSTRACT TRUNCATED AT 250 WORDS)

A prognostic score for Graves' disease.

We have reanalysed the clinical and laboratory data on 196 individuals with Graves' disease. The consensus of two clustering techniques and a new method of allocating patients to a cluster resulted in two groups of patients, those with a severe and others with a mild disease. The severe disorder is characterized by a high frequency of HLA-B8 and -Al, a low complement level, high titres of circulating immune complex and anti-thyroglobulin antibody, a high lymphocyte transformation index and serum T3 level, a low level of active E-rosettes, large goitres and a high value for the Crooks test. The mild disorder shows a higher frequency of HLA-B12 and an abnormally low absolute lymphocyte number. A weight was calculated for each character according to the relative frequency in the two clusters. A total score could then be calculated for each patient based on their clinical and laboratory findings. There were two distinct distributions of scores corresponding to the two subgroups. This suggests different aetiological factors which may be more easily studied in these more homogeneous groups. Prognostic predictions can be made using the score. The risk of recurrence and the frequency and severity of ophthalmopathy increases dramatically as the score increases. The use of the score in making therapeutic decisions needs to be tested.

Noonan syndrome: the changing phenotype.

Among the multiple congenital anomalies (MCA) syndromes, the Noonan syndrome (NS) is a cardiofacial syndrome in which affected individuals may be short and mildly mentally retarded. Autosomal dominant inheritance of Noonan syndrome with variable expressivity has been documented in many families. Genetic heterogeneity has been postulated in Noonan syndrome because of the wide phenotypic variability, the relatively high incidence, and the occasional recurrence in sibs with apparently normal parents. Clinical variability is usual in autosomal dominant disorders, and mildly affected individuals may be difficult to recognize as gene carriers. Thus, a family with two or more affected children may simulate autosomal recessive inheritance. We have studied serial and family photographs of NS individuals in order to assess the likelihood of gene carriers' being missed in genetic studies. We have confirmed wide clinical variability within families, and more importantly, we have documented marked change of phenotype with age from the newborn period, infancy, childhood, and adolescence to adulthood. Manifestations in adults may be subtle and some without a known heart defect or other medically significant problems may have been considered normal in the past. Our study, while not ruling out causal heterogeneity, suggests that the change of phenotype with age may have been falsely perceived as clinical heterogeneity. A particular and subtle phenotype must be searched for in parents of affected children.

A taxonomic approach to the del(4p) phenotype.

The findings of 23 patients with the del(4p) phenotype are compared systematically. Three patients with a small deletion evident only on analysis of extended chromosomes have a phenotype comparable to 13 patients with a more extensive chromosomal deletion. Two patients with no detectable deletion also fit into the phenotypic spectrum of patients with del(4p), suggesting the same etiology. Five patients with fewer typical and more atypical findings probably represent a heterogeneous group of other syndromes. Numerical analysis of the phenotype allows one to identify patients who most likely have a deletion requiring a more intensive cytogenetics analysis.

Clinical confusion of the Noonan syndrome with the Börjeson-Forssman-Lehmann syndrome.

The diagnosis of Börjeson-Forssman-Lehmann syndrome in a patient reported by Veall et al. (1979) is challenged. The clinical findings were compared with those in 32 patients with the Noonan syndrome using the extensive description, dermatoglyphics, photographs and anthropometric measurements provided in the paper. The patient's findings are compatible with the Noonan syndrome based on his overall phenotypic similarity to the 32 patients, even though the severity of his mental retardation is atypical.

Trisomy 9 (pter----q1 to q3): the phenotype as an objective aid to karyotypic interpretation.

The phenotypic findings of three patients whose karyotypic interpretations were uncertain were compared to patients with trisomy 9 (pter---q1 to q3). One with an extra, small acrocentric chromosome and another with a trisomy due to an inherited C/G translocation have a phenotype compatible with the trisomy 9 (pter----q1) syndrome. In a third patient reported with 47,XY,?16+, the trisomy 9p probably extends past the q1 region.

The Williams syndrome: objective definition and diagnosis.

Fifty-two patients referred for suspicion of the Williams syndrome have been evaluated and divided into those with and without the syndrome by numerical analysis. A diagnostic index using 50 characters separates patients into two groups with an expected accuracy of 99%. An index using 40 of the characteristics is expected to be applicable to young infants without a substantial decrease in accuracy.

Differential diagnosis of the Williams and the Noonan syndromes.

A diagnostic index has been devised to distinguish between the Noonan and the Williams syndromes. Twins from the literature reported as having the Williams syndrome more likely represent the Noonan syndrome.

The Marshall and Stickler syndromes: objective rejection of lumping.

To answer the question of whether nosological splitting of the Marshall and Stickler syndromes is justified at the phenotypic level, we surveyed published reports on the two syndromes and applied an objective method to determine this. A set of 18 patients with clinical description, photographs, and radiographs was used to tabulate a list of 53 signs. Cluster analysis using these signs showed that there are two groups of patients with different phenotypes. An index score based on the 20 most discriminating signs was applied to other reported patients and the authors' diagnosis confirmed. There is therefore no objective reason to consider that these two syndromes are not separate dominant disorders with variable expressivity.

An oculocerebral hypopigmentation syndrome.

An oculocerebral hypopigmentation syndrome consisting of growth retardation, dolichocephaly, cataracts, high arched palate, small, widely spaced teeth, generalized hypopigmentation, psychomotor retardation, progressive neurological manifestations and hypochromic anemia is described in sibs. The finding of parental consanguinity supports autosomal recessive inheritance. The syndrome resembles the Cross syndrome (1,2).

Definition and diagnosis of the Brachmann-De Lange syndrome.

We have classified patients referred for suspicion of the Brachmann-De Lange syndrome (BDLS) into two groups using techniques of numerical taxonomy. Patients with the syndrome share an array of abnormal characteristics, and those without it have different abnormal characteristics. A group of 30 characters that best distinguish the two groups of patients was used to construct a diagnostic index. The index score is expected to divide 99% of patients into those with and without the syndrome, leaving 1% in a "zone of doubt." All 46 patients used to construct the index and 16 new patients had scores in either the BDLS or non-BDLS range and none were in the zone of doubt. A previously published index using metacarpal-phalangeal measurements, although less discriminatory, confirmed our findings in 84% of 25 patients tested, the remainder having scores in the zone of doubt for that index.