Environmental and genetical contributions to class difference: a model experiment.

Flies were divided into two groups on the basis of the number of their bristles, and raised under different environmental (temperature) conditions. In each generation, offspring of the two groups were retained in their group or transferred to the other group, depending on the number of their bristles. After nine generations it was found that the genetic component of the intergroup difference was 42 percent; the portion of the intragroup variance that was genetic phenomena.

Nucleotide sequence and expression of the sn-glycerol-3-phosphate dehydrogenase gene in Locusta migratoria.

The sn-glycerol-3-phosphate dehydrogenase gene (Gpdh) in the locust (Locusta migratoria) encodes three mature transcripts and a number of isozymes. Gpdh expression is tissue- and developmentally regulated such that two transcripts are unique to flight muscle. Identical proteins are encoded by two transcripts which are generated by alternative splicing downstream of the stop codon in the penultimate exon.

Chromosome Inversion Polymorphisms in DROSOPHILA MELANOGASTER. I. Latitudinal Clines and Associations between Inversions in Australasian Populations.

Nineteen Australasian populations of Drosophila melanogaster have been screened for chromosome inversion polymorphisms. All 15 of the inversion types found are paracentric and autosomal, but only four of these, one on each of the major autosome arms, are common and cosmopolitan. North-south clines occur, with the frequencies of all four of the common cosmopolitan inversions increasing toward the equator. These clines in the Southern Hemisphere mirror north-south clines in the Northern Hemisphere, where the frequencies of all four of the common cosmopolitan inversions again increase towards the equator.-While few of the Australasian populations show significant disequilibrium between linked common cosmopolitan inversions, those that do invariably have excesses of coupling gametes, which is consistent with other reports. We also find nonrandom associations between the two major autosomes, with the northern populations in Australasia (those with high inversion frequencies) tending to be deficient in gametes with common cosmopolitan inversions on both major autosomes, while the southern populations in Australasia (low inversion frequencies) tend to have an excess of this class of gametes.-The clines and the nonrandom associations between the two major autosomes are best interpreted in terms of selection operating to maintain the common cosmopolitan inversion polymorphisms in natural populations of D. melanogaster.

Measuring selection coefficients affecting the alcohol dehydrogenase polymorphism in Drosophila melanogaster.

This paper describes a perturbation experiment on the frequency of the F and S Alcohol dehydrogenase (Adh) alleles of D. melanogaster. Fifty-four iso-female lines set up from three wild populations and with initial F frequencies of either 0.25, 0.50 or 0.75 were maintained on standard laboratory food medium at 22 degrees. At generations 4, 12 and 20 the lines were again scored for Adh gene frequencies. Maximum likelihood procedures were used to estimate selection coefficients for the Adh genotypes. An analysis of deviance was used to compare the coefficients against expectations under the hypotheses of neutrality and of constant values for the three base populations, and for the three initial gene frequency classes. Highly-significant departures from neutrality were observed; over all 54 lines, the set of relative fitnesses for S/S:F/S:F/F was estimated as 1.00:1.08:1.08. In addition, there were significant differences between lines in the outcome of selection which were not attributable to differences between base populations or initial F frequencies. These residual between-line differences, as well as some between-generation, within-line differences are discussed in terms of linkage disequilibria with background genes and electrophoretically cryptic variation at the Adh locus.

sn-Glycerol-3-phosphate dehydrogenase in the honey bee Apis mellifera -an unusual phenotype associated with the loss of introns.

In comparison with the numerous Drosophila species and the mouse, the Gpdh gene in the honey bee Apis mellifera lacks most introns. This prevents the gene from producing different GPDH isoforms by alternative splicing, which occurs in Drosophila melanogaster. The sequences of the cDNA and genomic Gpdh of A. mellifera are described and show that at the amino acid level they share 84% similarity and 71% identity with D. melanogaster. The identity at the nucleotide level is 62% in the coding region, but no significant similarities were detected in the UTRs. Northern analyses revealed an accumulation of unspliced Gpdh pre-mRNA in the honey bee, probably reflecting splicing inefficiency, although it is also possible that splicing is a regulated step in Gpdh expression in A. mellifera. It is suggested that the intron loss occurred via reverse transcription of a mature Gpdh transcript.

Sugar nucleotide concentrations in red blood cells of patients on protein- and lactose-limited diets: effect of galactose supplementation.

Uridine diphosphate (UDP) galactose, a pivotal compound in the metabolism of galactose, is the obligate donor of galactose in the formation of complex glycoconjugates. The cellular UDPgalactose concentration has been thought to be maintained by the interconversion of UDPglucose and UDPgalactose by UDPgalactose-4-epimerase. However, recent findings of lower average red blood cell (RBC) UDPgalactose concentrations in galactose-1-phosphate uridyltransferase-deficient patients suggest that other factors play a role in determining its concentration. To test the hypothesis that the amount of galactose traversing the Leloir pathway contributes to the cellular UDPgalactose pool, we determined RBC UDPgalactose in patients with maple syrup urine disease (MSUD), phenylketonuria (PKU), and other metabolic diseases who were treated with a low-protein, and consequently, low-lactose diet. Six patients with MSUD were also supplemented with 19 g galactose/d and their UDPhexose concentrations were measured at intervals. We show that young patients with MSUD or PKU have decreased average RBC UDPgalactose concentrations when compared with similarly aged healthy subjects. Galactose supplementation of MSUD patients significantly increased their UDPgalactose concentrations in both RBCs and white blood cells (WBCs) from 29.5 +/- 1.5 to 42.3 +/- 5.8 nmol/g hemoglobin and from 69.0 +/- 7.5 to 193.0 +/- 49.0 nmol/g protein, respectively. Discontinuation of supplementation was associated with a return to basal values in RBCs and a reattainment of the pretreatment ratio of UDPglucose to UDPgalactose in WBCs. These observations demonstrate that dietary galactose is a factor in establishing the steady state concentrations of the uridine sugar nucleotides and imply that galactose metabolism modulates the achievement of an epimerase-mediated equilibrium.

Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome.

BACKGROUND: Down syndrome, or trisomy 21, is a complex genetic disease resulting from the presence of 3 copies of chromosome 21. The origin of the extra chromosome is maternal in 95% of cases and is due to the failure of normal chromosomal segregation during meiosis. Although advanced maternal age is a major risk factor for trisomy 21, most children with Down syndrome are born to mothers <30 y of age. OBJECTIVE: On the basis of evidence that abnormal folate and methyl metabolism can lead to DNA hypomethylation and abnormal chromosomal segregation, we hypothesized that the C-to-T substitution at nucleotide 677 (677C-->T) mutation of the methylenetetrahydrofolate reductase (MTHFR) gene may be a risk factor for maternal meiotic nondisjunction and Down syndrome in young mothers. DESIGN: The frequency of the MTHFR 677C-->T mutation was evaluated in 57 mothers of children with Down syndrome and in 50 age-matched control mothers. Ratios of plasma homocysteine to methionine and lymphocyte methotrexate cytotoxicity were measured as indicators of functional folate status. RESULTS: A significant increase in plasma homocysteine concentrations and lymphocyte methotrexate cytotoxicity was observed in the mothers of children with Down syndrome, consistent with abnormal folate and methyl metabolism. Mothers with the 677C-->T mutation had a 2.6-fold higher risk of having a child with Down syndrome than did mothers without the T substitution (odds ratio: 2.6; 95% CI: 1.2, 5.8; P < 0.03). CONCLUSION: The results of this initial study indicate that folate metabolism is abnormal in mothers of children with Down syndrome and that this may be explained, in part, by a mutation in the MTHFR gene.

Defective P element insertions affect the expression of sn-glycerol-3-phosphate dehydrogenase alleles in natural populations of Drosophila melanogaster.

A distinctive and geographically widespread category of low-activity variant at the Gpdh locus in Drosophila melanogaster is shown to have defective P elements inserted between the TATA box and the transcription start site. In four examples the insertion was a single 1.15 kilobase (kb) KP element, whereas in another variant there were two KP elements in tandem. A sixth example contained a 0.61 kb defective P element. The target site for all of the insertions is GTGCAAAC. There was no sequence variation either between the insertions or in comparison with two other KP elements previously described from natural populations. The insertions cause a reduction in GPDH mRNA, and are the most likely cause of the low GPDH activity.

Molecular analysis of a Drosophila melanogaster sn-glycerol-3-phosphate dehydrogenase allozyme variant that has cold labile activity.

A rare naturally occurring allele, GpdhACb62, at the sn-glycerol-3-phosphate dehydrogenase locus in Drosophila melanogaster, encodes an enzyme with an electrophoretic mobility that is more cathodal than that produced by the common slow electrophoretic allele. After electrophoresis and staining of extracts of single adult flies there is a single band of activity corresponding in position to GPDH-1, but, using highly concentrated extracts, a faint band corresponding to GPDH-3 is observed. In GpdhACb62 homozygotes there is about 26% of the normal level of activity in adults, and less than 6% in third instar larvae. The reduction in activity is significantly greater than the decrease in GPDH immunologically cross-reacting material (CRM). Northern analyses, and rapid amplification of the cDNA ends (RACE) of the 3' regions of the transcripts, show that the levels and structures of the poly(A)+RNAs are similar in homozygotes for GpdhACb62 and for a normal activity allele GpdhAC8. Hybridization to oligonucleotide probes specific for the GPDH-1 and GPDH-3 transcripts was of a similar intensity in GpdhACb62 and GpdhAC8 adult flies. In third instar larvae the main transcript is for GPDH-3 and again the hybridization signals were similar in each line. The activity of the enzyme produced by GpdhACb62 was unstable both at 50 degrees C and at 0 degrees C. The activity lost at 0 degrees C was recovered by incubation at 20 degrees C. The complete GpdhACb62 gene, and the partial Gpdh tandem duplication 3' to this gene, were cloned and sequenced. Comparisons with two normal activity GpdhF genes revealed 31 unique changes in the first copy of GpdhACb62. In exon 4, a T to G substitution changes cysteine to glycine and may disrupt a disulphide bond and be responsible for the distinctive properties of GPDH-ACb62.

Effects of a novel antioxidant during resuscitation from severe blunt chest trauma.

Previous work suggests that neutrophils (PMNs) and/or prostaglandins might mediate the progressive respiratory failure after severe pulmonary contusion. Since reactive oxygen metabolites are closely associated with both these factors, we examined the actions of a novel antioxidant after swine received a unilateral injury followed by 25% hemorrhage. An infusion (2mL/kg/h intravenously x 6 h) of either polynitroxylated 5% Dextran + Tempol (PND, n = 9), 5% Dextran (D, n = 6), or lactated Ringers (LR, n = 13) was begun 60 min post-injury to mimic 'pre-hospital resuscitation.' After 15 min, standard resuscitation was initiated (3x shed blood as LR in 30 min) plus further LR for 6 h to maintain hemodynamics. The total LR requirement was lower with PND (1,772+/-267 mL) versus D (3,040+/-689, P = 0.0563) or LR (4145+/-398, P = 0.0005). The ipsilateral bronchoalveolar lavage (BAL) PMN count with PND (8+/-2 x 10(5)/mL), was not different from its baseline (P = 0.131), but the counts with D (16+/-3) and LR (17+/-4) were both higher than their baselines (P = 0.0184 and 0.0431). Similarly, BAL protein with PND (1,560+/-350 mg %) was not elevated from its baseline (P = 0.0721), but the values with D (2,560+/-498) and LR (2,474+/-899) were both higher than their baselines (P = 0.0169 and 0.0325). In the contralateral (uninjured) lung, the effects were similar, but the increases were less for PMNs (8+/-2 versus 10+/-2 or 14+/-4 x 10(5)/mL) and for protein (609 +/-153 versus 1,955+/-671 or 1486+/-357 mg %). Despite these significant BAL changes, there was no obvious improvement in cardiopulmonary dysfunction. Thus oxidants probably have some role in the pathogenic mechanism of progressive secondary injury after thoracic trauma, but further work is needed to determine the therapeutic potential of antioxidants because no clinical improvement was detected.

Comparison of erythrocyte uridine sugar nucleotide levels in normals, classic galactosemics, and patients with other metabolic disorders.

By limiting galactosylation mechanisms, a cellular deficiency of the uridine sugar nucleotide, UDPgalactose, has been implicated as a cause of the long-term complications seen in patients with classic galactosemia despite dietary treatment. As a result, great interest has been generated in the accurate assessment of UDPgalactose, as well as UDPglucose, from which UDPgalactose may be derived by the function of a ubiquitous, active UDPgalactose-4-epimerase. Since several series of values for the concentration of these compounds in red blood cells (RBCs) of galactosemics have been flawed by the use of methods subsequently shown to be unsuitable, we have quantified erythrocyte UDPgalactose and UDPglucose levels by an accurate high-performance liquid chromatography (HPLC) assay in 116 normals, 76 galactosemics, and 39 patients with other metabolic disorders. These large groups have permitted the evaluation of age, diet, and genotype as influential factors in the steady-state RBC levels of the sugar nucleotides. The data show that age is an important determinant of RBC levels, with children younger than 10 years having higher values than individuals older than 10 years. Mean UDPgalactose levels in galactosemic children younger than 10 years and those older than 10 years were 30% and 18% lower, respectively, than levels in comparable normals. Although the mean differences were highly significant, there was considerable overlap of individual values. There was no difference in UDPglucose levels between galactosemics and normals.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastric outlet obstruction resulting from peptic ulcer disease requiring surgical intervention is infrequently associated with Helicobacter pylori infection.

BACKGROUND: Gastric outlet obstruction (GOO) secondary to peptic ulcer disease requiring therapeutic intervention remains a common problem. The incidence of Helicobacter pylori infection in this cohort has not been well defined. Pneumatic dilatation (PD) has been proposed as first-line therapy before surgical intervention. If H pylori infection in patients with GOO is infrequent, PD may not offer permanent control without the need for longterm antacid therapy. STUDY DESIGN: The purpose of this study was to examine the incidence of H pylori infection and surgical outcomes in patients undergoing resection for GOO. The records of all patients having resection (vagotomy and antrectomy) for benign disease from 1993 to 1998 for GOO at the University of Tennessee affiliated hospitals were reviewed retrospectively. Smoking history, NSAID use, weight loss, previous ulcer treatment, previous treatment for H pylori, and previous attempts at PD were among the factors examined. H pylori infection was documented by Steiner stain from either preoperative biopsy or, in most patients, final surgical specimens. Surgical complications and patient satisfaction were ascertained from inpatient records, postoperative clinical notes, and, where possible, followup telephone surveys. RESULTS: Twenty-four patients underwent surgical resection during the study period. There were 16 men and 8 women, with a mean age of 61 years (range 40 to 87 years). Weight loss was documented in 58% and averaged 27 lb. Five of 24 patients had previous attempts at PD, 3 of whom were H pylori negative. All five had further weight loss after these failed attempts. Of the 24 patients reviewed, only 8 (33%) were H pylori positive. There were no procedure-related deaths. Longterm clinical followup was possible in 16 of 24 patients, and all but one demonstrated dramatic clinical improvement by Visick score. CONCLUSIONS: We conclude the following: 1) In this cohort, H pylori infection was present in a minority; 2) previous attempts at PD were unsuccessful, which may be related to the H pylori-negative status of the patients; 3) mortality related to the operation was zero; and 4) patient satisfaction was positive by the Visick scale. Patients with H pylori-negative GOO resulting from peptic ulcer disease should be strongly considered for an early, definitive, acid-reducing surgical procedure.

Ocular motor signs in an infant with carbohydrate-deficient glycoprotein syndrome type Ia.

PURPOSE: To document the evolution of ocular motor abnormalities in an infant with carbohydrate-deficient glycoprotein syndrome. METHODS: Case report. An infant with carbohydrate-deficient glycoprotein syndrome type 1a underwent magnetic resonance imaging and infrared eye movement recording. RESULTS: A 10-month-old male with carbohydrate-deficient glycoprotein syndrome type Ia had rapid horizontal oscillations of the eyes when startled or awakened from sleep. Clinical examination confirmed this finding and disclosed congenital ocular motor apraxia with a reduced vestibulo-ocular reflex. Infrared eye movement recording showed ocular flutter and square wave jerks superimposed on a horizontal pendular nystagmus. Magnetic resonance imaging showed diffuse cerebellar hypoplasia. CONCLUSION: Carbohydrate-deficient glycoprotein syndrome type Ia can be associated with multiple cerebellar eye signs including ocular flutter, square-wave jerks, and congenital ocular motor apraxia.

Kimura's disease: a clinico-pathological study of 21 cases and its distinction from angiolymphoid hyperplasia with eosinophilia.

Kimura's disease is a chronic inflammatory condition producing subcutaneous tumour-like nodules chiefly in the head and neck region. It is characterized histologically by lymphoid follicles, intense aggregations of eosinophils, vascular proliferation and fibrosis. Superficial lymph nodes and parotid glands are sometimes involved. The lesions may persist unchanged for years and new ones are apt to occur. Recurrences are also common. There are no systemic manifestations apart from peripheral blood eosinophilia. The lesion has been recognised as a distinct clinicopathological entity in the Far East for over 40 years. We describe 21 cases of Kimura's disease and discuss its relationship to angiolymphoid hyperplasia with eosinophilia. Although the pathogenesis and etiology of both these lesions are unknown we believe that there are sufficient significant clinical and pathological differences to justify their separation.

Genetic variation at the alcohol dehydrogenase locus in Drosophila melanogaster in relation to environmental variation: Ethanol levels in breeding sites and allozyme frequencies.

Ethanol levels in Drosophila breeding sites in seepages of unfortified wine inside wineries have been found to be similar to those in many decaying fruits and vegetables. Fortified wine seepages inside wineries have ethanol levels on average three times as high as other breeding sites. However there was no evidence that this variation in ethanol levels was associated with differences in Adh F frequencies in D. melanogaster at sites either within wineries or outside wineries. D. simulans was at lower frequencies at sites inside wineries compared to sites outside although this difference may not be related to ethanol levels. It is concluded that adaptation to natural levels of environmental ethanol by D. melanogaster does not necessarily modify Adh frequencies.

Synaptonemal complex damage induced by clastogenic and anti-mitotic chemicals: implications for non-disjunction and aneuploidy.

Mice were treated with mitomycin C, cyclophosphamide, amsacrine, colchicine, or vinblastine sulfate, and meiotic prophase cells analyzed for synaptonemal complex (SC) damage. All test agents caused synaptonemal complex breakage and synapsis irregularities, although propensities for inducing specific types of damage at S-phase or prophase stages varied among the chemicals. The data indicate that SC analysis can reveal chemical-specific alterations to meiotic homologue pairing/synapsis which have not generally been recognized, and which theoretically may be implicated in non-disjunction.

Synaptonemal complex damage as a measure of chemical mutagen effects on mammalian germ cells.

As heritable chromosome anomalies are implicated in a variety of human disabilities, their induction in germ cells by environmental chemicals is viewed as a threat to health (National Research Council, 1982; Hook, 1983). Synaptonemal complex (SC) analysis is a novel approach for the detection of germ-line chromosomal damage. This sensitive cytological procedure reveals induced structural damage and pairing abnormalities in SCs of meiotic prophase chromosomes, together with other germ-line toxic effects, in the testes of rodents treated with mitomycin C and cyclophosphamide. Our results demonstrate the effectiveness of SC analysis as a rapid and practical in vivo germ-line mutagen assay that lacks many of the short-comings of existing tests.

Synaptonemal complex damage in relation to meiotic chromosome aberrations after exposure of male mice to cyclophosphamide.

The genetic implications of induced synaptonemal complex (SC) damage are not known. However, on theoretical grounds, such aberrations could be involved in mechanisms leading to potentially heritable defects. Cyclophosphamide (CP), a chemical reported to cause structural and numerical chromosomal aberrations in the mouse, was used to determine if SC damage observed in meiotic prophase is related to subsequent metaphase chromosomal aberrations. Male mice were injected i.p. with CP. In some instances, mice were also injected simultaneously with tritiated thymidine to label DNA so that cells could be tracked autoradiographically through spermatogenesis. Prophase, primary metaphase (M1), and secondary metaphase (M2) samples were sequentially harvested at appropriate times from the same individual, and nuclei were examined for aberrations. Correlation coefficients between SC and metaphase chromosome aberrations were calculated. The inclusion of tritium labeling increased the number and significance of positive correlations. Positive correlations were found between (1) dose-dependent total SC damage and damage to M1, and to a lesser extent, M2 chromosomes; (2) SC breaks/fragments and M1 chains/rings as well as isochromatid breaks/fragments; (3) SC asynapsis and M1 chromatid breaks/fragments; (4) SC multi-axial configurations and M1 chains/rings as well as isochromatid and chromatid breaks/fragments; and (5) SC multi-axial configurations and M2 hyperploidy. These correlations do not define mechanistic or causal relationships between SC and chromosomal damage. However, taken together with the observation that induced SC damage is many times greater than ensuing metaphase chromosome damage, they substantiate SC analysis as a highly sensitive indicator of potentially heritable effects of this (and presumably other) genotoxic agents.

Hepatitis B surface antigen in hepatocytes at necropsy.

Seventy cases of cirrhosis and hepatocellular carcinoma (HCC) and 43 cases with no primary liver disease were investigated at necropsy by Gomori's aldehyde fuchsin stain for the presence of hepatitis B surface antigen (HBsAg) in liver cells. The results were correlated with serum HBsAg levels determined by radioimmunoassay and hemagglutination tests performed during the last three months of life or after death. In more than 90% of cases, a correlation was found between the results in tissue and in sera. The aldehyde fuchsin stain is a reliable tool for the detection of HBsAg in patients with cirrhosis and with HCC or without primary liver disease.

Hand preference and I.Q. in a group of Oxfordshire villages.

Verbal and performance scores in a standard intelligence test (WAIS) were considered in relation to patterns of hand preference (measured by questionnaire) in a large sample of the general population. Left-handers and mixed-handers did not obtain lower scores than right-handers. Indeed, there was a tendency for subjects who reported that they could use either hand for at least one of the questionnaire tasks to obtain higher I.Q.s. Otherwise, there were no significant differences in I.Q. with the exception of a consistent sex difference, in that men achieved higher scores on both verbal and performance scales.