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PubMed2001

Effect of the mouse Nramp1 genotype on the expression of IFN-gamma gene in early response to Salmonella infection.

The early interferon-gamma (IFN-gamma) response after Salmonella infection was compared in resistant and susceptible congenic mice strains differing by the allele of Nramp1. IFN-gamma gene expression in vivo was studied by quantitative reverse transcription-PCR performed from the spleen of mice challenged by Salmonella either in multiplication or in resting phase. The spleen colonisation by Salmonella in vivo was investigated and was shown to be identical in a genetically defined host, whatever the initial phase of the bacteria. However, the bacterial load of the spleen was significantly reduced in Nramp1(r) (resistant) mice compared to Nramp1(s) (susceptible) mice. The background level of IFN-gamma mRNA was higher in the spleen of resistant mice than in the susceptible mice, before infection. Interestingly, the early upregulation of IFN-gamma gene transcription, which was observed after infection with Salmonella, was reproducibly delayed in susceptible mice compared to resistant mice. Finally, the kinetics of the host IFN-gamma response seems to be Nramp1 dependent. Resistant mice present the advantage of being more prompt to express this anti-infectious cytokine gene than susceptible mice in response to Salmonella infection.

Animals↗
PubMed2006

Engineering of the spinosyn PKS: directing starter unit incorporation.

The spinosyns are a family of potent and highly selective insect control agents that display a favorable environmental profile. As some regions of the spinosyn molecule are recalcitrant to chemical modification, a targeted genetic approach was carried out to generate new analogues. The polyketide synthase (PKS) loading modules from the avermectin PKS of Streptomyces avermitilis and the erythromcyin PKS of Saccharopolyspora erythraea were each used to replace the spinosyn PKS loading module. Both of the resulting strains containing hybrid PKS pathways produced the anticipated spinosyn analogues. Supplementation of the culture media with a range of exogenous carboxylic acids led to the successful incorporation of these novel elements to yield further novel spinosyn molecules, some of which demonstrated potent and new insecticidal activities. Furthermore, it has been demonstrated that semisynthesis of such novel metabolites can then be used to generate active analogues, demonstrating the effectiveness of utilizing these complementary methods to search the chemical space around this template.

Amino Acid Sequence↗
PubMed2005

Homocysteine levels--before and after methionine loading--in 51 Dutch families.

Elevated levels of homocysteine are a risk factor for vascular disease, thrombosis, neural tube defects and dementia. The 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene appears to be the most important single determinant of plasma homocysteine concentration. In the current study, we estimated heritability and fit a series of models of inheritance for both fasting and postmethionine-load homocysteine levels in the HOFAM-study (HOmocysteine in FAMilies study), which included 306 participants from 51 pedigrees, ascertained through a hyperhomocysteinemic proband. The crude heritability was 21.6% for fasting and 67.5% for postloading homocysteine. After adjustment for MTHFR 677C>T genotype, heritability dropped to 5.2 and 63.9%, respectively. Segregation analysis revealed that a nongenetic model with equal transmission was the best fitting and most parsimonious model for fasting homocysteine levels, while a two-distribution, Mendelian model with residual familial correlation was best for postmethionine-load homocysteine levels. This study shows that postload homocysteine levels have a stronger genetic determination than do fasting homocysteine levels. The heritability of postload homocysteine levels were not strongly affected by adjustment for MTHFR 677C>T genotype, in contrast to fasting homocysteine levels. Further studies are needed to identify the genes responsible for the inheritance of postload homocysteine levels.

Adult↗
PubMed1998

Is elevation of clinic blood pressure in patients with white coat hypertension who have normal ambulatory blood pressure associated with target organ changes?

BACKGROUND: The issue as to whether white coat hypertension is a pathologically significant entity, with associated target organ changes, or that the condition carries the same risk for target organ involvement as normotension, is undecided. Previous studies which have shown pathological correlates between white coat hypertension and target organ damage have not controlled for the most obvious confounder, mean 24 h blood pressure (BP). METHODS AND RESULTS: In this study we retrospectively identified 33 age and sex-matched pairs, one group with normal BP, the other with white coat hypertension. The white coat hypertensive group showed significantly greater left ventricular mass indexed for body surface area than normal controls (99.0 g/m2 vs 78.3 g/m2, P < 0.001). The population was then further matched for 24-h mean BP (20 pairs), and was again compared for cardiac muscle changes. The significantly increased left ventricular mass index in the white coat population remained after controlling for 24-h mean BP (101.1 g/m2 vs 81.0 g/m2, P < 0.021). CONCLUSION: White coat hypertension is indeed associated with a larger left ventricular muscle mass than normotensives and these changes are independent of the actual 24-h BP load, and may reflect increased BP lability, sympathetic nervous system derangement, or a genetic propensity in people with white coat hypertension to stress-related hypertensive reactions, as part of a pre-hypertensive state.

Adult↗
PubMed1999

Apolipoprotein E phenotypes in healthy normal controls and demented subjects with Alzheimer's disease and vascular dementia in Mie Prefecture of Japan.

In order to clarify the association between apolipoprotein E4 (ApoE4) and the pathogenesis of Alzheimer's disease (AD), we analyzed the distribution of the apolipoprotein E (ApoE) phenotypes and the frequency of the apo E alleles epsilon2, epsilon3, and epsilon4 in Japanese healthy controls (n = 1090, an average age of 51.2+/-12.6 years) and demented patients (n=103, mean age of 73.6+/-9.2 years). Demented subjects were divided into three subgroups: early-onset AD group (EOAD; n=25, mean age 63.0+/-6.2 years), late-onset AD group (LOAD; n=33, mean age 79.3+/-5.1 years), and vascular dementia group (VD; n=45, mean age 75.3+/-8.0 years). The apolipoprotein E phenotype was determined by isoelectric focusing and immunoblotting. There were no significant differences in the distribution of the apo E phenotypes by gender or age, and the estimated frequencies of epsilon2, epsilon3 and epsilon4 were 0.05, 0.86 and 0.09, respectively, in the normal controls. There was a significant difference in the distribution of the apo E phenotypes between LOAD and elderly controls aged more than 65 years (P<0.0001). The distribution of the apo E phenotypes in EOAD was the same as that in LOAD. The frequency of the epsilon4 allele was significantly higher in LOAD (0.35, P<0.0001) and EOAD (0.28, P<0.0001) than that in the control subjects (0.07), but not in VD (0.12, P=0.1630). The present findings suggest that ApoE4 is related with both EOAD and LOAD, but not with VD, and support the hypothesis that it is a genetic risk factor of AD.

Age of Onset↗
PubMed2004

[Differential diagnosis of a polyhydramnion in hyperprostaglandin E syndrome: a case report].

INTRODUCTION: A polyhydramnion is diagnosed in 0.4 to 3.3 % of all pregnancies. The most common causes of increased amniotic fluid include maternal diabetes mellitus, fetal malformations and chromosomal aberrations, twin-to-twin transfusion syndrome, rhesus incompatibility syndrome, and congenital infections. After exclusion of other etiologies for polyhydramnion, the very rare, autosomal-recessive transferred hyperprostaglandin E syndrome (HPS) has to be considered. PATIENTS AND METHODS: We report on a 31-year-old women who visited our obstetrical outpatient clinics at 22 + 4 weeks of gestation for prenatal ultrasound scanning and amniocentesis. This, the patient's third pregnancy had been without complications so far. She had delivered two children before, one of them bearing the HPS. The women herself suffered from epilepsy. At 26 + 0 weeks of gestation the pregnancy was complicated by a polyhydramnion requiring serial amniocentesis for reducing amniotic fluid load. Among others, her amniotic fluid was analyzed for chloride concentration and for genetic aberrations regarding HPS. Serological investigations and an oral glucose tolerance test (oGTT) were performed. RESULTS: Amniocentesis revealed a normal chromosomal pattern. The oGTT demonstrated values in the normal range. Serological investigations regarding TORCH infections were without pathological findings. The chloride concentration was highly increased in the amniotic fluid, which is suspicious for HPS. Finally, molecular analysis proved an NKCC2-mutation responsible for HPS. A cesarean section was performed at 33 + 3 weeks of gestation. CONCLUSION: If HPS is suspected to be the cause of polyhydramnions, the chloride concentrations in the amniotic fluid and molecular analysis for HPS should be performed. Interdisciplinary care, diagnostics and therapy in an experienced perinatal center are essential for an optimal outcome of the pregnancy and the newborn infant.

Adult↗
PubMed1994

The synthetic pathway for glucosylsphingosine in cultured fibroblasts.

The synthesis of glucosylsphingosine (GlcSph), a glucosylceramide (GlcCer) analogue devoid of fatty acids, in cultured fibroblasts was studied by using conduritol beta epoxide (CBE), an inhibitor of beta-glucosidase, and 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), an inhibitor of glucosylceramide (GlcCer) synthase (glucosyltransferase). When CBE was added to the culture medium, the intracellular beta-glucosidase activity decreased, and both GlcCer and GlcSph accumulated in the cells. After the addition of PDMP, the concentration of GlcCer decreased, while the content of GlcSph increased. When CBE and PDMP were added together, the intracellular accumulation of GlcSph to decreased to less than when CBE alone was added. Based on these results, the synthetic pathway for GlcSph was thus considered to not only be through the glucosylation of sphingosine, but also through the deacylation of GlcCer. When GlcCer (d18:1, C12:0) was added to the culture medium, the intracellular accumulation of GlcSph (d18:1) was evident, and it was also more pronounced in the presence of CBE. In addition, when GlcCer (d18:0, C12:0) was used, apparent accumulation of GlcSph (d18:0) was also observed. In order to determine whether or not the deacylase of GlcCer is identical to acid ceramidase, a deacylase of ceramide, the same experiments were carried out using fibroblasts from two patients with Farber disease, in which acid ceramidase is genetically deficient. The accumulation of GlcSph in the Farber disease fibroblasts after the loading of GlcCer for 7 days was found to be one-fifth of the control level.(ABSTRACT TRUNCATED AT 250 WORDS)

Acylation↗
PubMed2002

Evidence for a skeletal mechanosensitivity gene on mouse chromosome 4.

Differences in skeletal mechanical adaptation between C3H/HeJ (C3H) and C57BL/6J (B6) mouse strains suggest that these mice can be used to elucidate the genes involved in mechanosensitivity regulation. The C3H and B6 skeletons also differ in bone size, and several quantitative trait loci (QTL) have been mapped for bone size. We hypothesized that genes controlling bone size (external diameter) might exert their effect by influencing mechanosensitivity. The hypothesis was tested by applying mechanical loads to the ulnae of the B6.C3H-4T (4T) congenic mouse strain, which is genetically 98.4% B6 and carries the C3H chromosome 4 (Chr. 4) QTL genomic DNA. Mechanical strain was measured at the midshaft ulna in separate calibration animals. 4T mice were significantly more responsive to mechanical stimulation than B6 control mice, as assessed by changes in bone geometry and fluorochrome-derived bone formation rates. Bone formation rates were also greater in the ulnae and femora of 6-wk-old 4T mice engaged in normal cage activity compared with age-matched B6 mice. Collectively, the results might explain why 4T mice have wider femora and ulnae than do B6 control mice and suggest that mouse Chr. 4 contains a genetic locus that modulates the mechanosensitivity of bone tissue.

Animals↗
PubMed1991

Inheritance of blood pressure and haemodynamic phenotypes measured at rest and during supine dynamic exercise.

Thirty-two pairs of monozygotic and 21 pairs of dizygotic male twins aged between 18 and 31 years were studied. Blood pressure was measured and Doppler echocardiography at the level of the aorta was performed in resting conditions and at two levels of supine submaximal bicycle exercise (at a fixed work load of 60 W and at a work load corresponding to a heart rate of 110 beats/min). In resting conditions, a genetic component in the variability of systolic and diastolic blood pressure was found; during submaximal supine exercise only a minor genetic effect was observed. At rest, genetic variance was shown for left ventricular outflow haemodynamics and for peripheral vascular resistance. However, during exercise, the transmissible effect on haemodynamics and peripheral resistance was small.

Adult↗
PubMed1992

Effect of cow's milk protein absorption on the anaphylactic and systemic immune responses of young rabbits during bacterial diarrhoea.

In vivo and in vitro studies recently showed that intestinal permeability to cow's milk proteins such as beta-lactoglobulin increased transiently in infant rabbits infected by the enteroadherent Escherichia coli strain RDEC-1 at weaning. The consequences of this enhanced permeability for local anaphylactic and/or systemic immune responses were studied in infected and age-matched control rabbits at weaning, given either water or cow's milk diluted in water in addition to their solid diet. The systemic immune response was determined by measuring IgG, IgA, IgM, and IgE antibodies to cow's milk proteins. A rise in IgG and IgM, but not IgA or IgE, antibody titres to milk protein was observed. Further, infected milk-drinking rabbits had significantly higher beta-lactoglobulin and casein IgG titres than milk-drinking controls. The anaphylactic response was tested by mounting ileal segments in Ussing chambers, adding the milk proteins to the serosal side of the tissue and recording the variation in short-circuit current in order to detect any electrogenic chloride secretion. No change in short-circuit current was observed in the presence of milk proteins in infected or age-matched control milk-drinking rabbits, indicating the absence of any immediate hypersensitivity reaction. These results indicate that at weaning, the rabbit is not prone to developing anaphylactic responses to milk proteins. The rise in milk protein IgG antibodies that followed infection with RDEC-1 might favour the elimination of milk protein-IgG immune complexes from the systemic circulation. The present results emphasize the evidence that genetic background and/or animal species greatly influence the immune response to an antigenic load.

Anaphylaxis↗
PubMedDate not supplied

The clinical utility of string-PCR test in diagnosing Helicobacter pylori infection.

BACKGROUND/AIMS: Non-invasive string test has been reported as being convenient and capable of yielding bacteria by means of gastric juice sampling in the diagnosis of Helicobacter pylori infection. Molecular methods, such as polymerase chain reaction for the amplification of DNA, are desirable for the detection of minute quantities of H. pylori. We planned to evaluate the diagnostic efficiency of the combination of the string test and polymerase chain reaction and determine whether the string polymerase chain reaction test could obtain more information in conditions where the bacterial load is so low that other diagnostic tests fail to confirm the presence of H. pylori. METHODOLOGY: We enrolled 48 dyspeptic patients, including 29 males and 19 females, with a mean age of 52.5 years. Each patient received endoscopy and biopsy-based tests, including RUT (rapid urease test), cultures, and histology, followed by 13C-UBT (13Carbon urea breath test). We used the string test, (Entero-Test H. pylori, HDC Corporation, CA, US), for gastric juice sampling. The specimen was further analyzed by polymerase chain reaction for the presence of H. pylori with the primer for cagA gene, which is highly prevalent in Taiwan. H. pylori infection was considered as positive when either culture yield was positive, or when two of the other three tests, including RUT, histology, and 13C-UBT, were positive. RESULTS: Of the total 48 patients, 34 patients were H. pylori-positive, and 14 were H. pylori-negative. A fragment of 349 bp of polymerase chain reaction products was detected by agarose gel electrophoresis in 32 out of 34 patients who was classified as H. pylori-positive. The sensitivity, specificity, positive predictive value, and negative predictive value of the string polymerase chain reaction test were 94.12%, 96.97%, 92.86%, and 86.67%, respectively. These results are comparable to 13C-UBT and RUT, and better than histology and culture. One subject, who tested as H. pylori-negative according to the diagnostic criteria, had positive 13C-UBT and string polymerase chain reaction test results. Further sequencing of the DNA obtained from the results of polymerase chain reaction product was performed and it showed 98% identities with the known sequence of cagA strain H. pylori (GenBank accession number: AF249275). CONCLUSIONS: The string polymerase chain reaction test is non-invasive and provides direct bacterial yields. Its diagnostic efficiency is comparable with 13C-UBT and RUT in detecting H. pylori infection. Also, with the assistance of polymerase chain reaction and DNA sequencing, we can diagnose H. pylori infection even when the bacterial load is low. Further application of string polymerase chain reaction test in the genetic analysis of virulent and resistant strains seems promising.

Antigens, Bacterial↗
PubMed2002

Role of gravitational loading in the development of rat soleus muscle fibers.

Effects of hindlimb unloading during the first 3 months after birth on the development of soleus muscle fibers were studied in rats. The mean absolute weigh and cross-sectional area of whole soleus muscle in the unloaded rats were -1/3 and 1/4 of those in the controls, respectively. But the unloading did not affect the lengths of muscle, at 90 degrees of ankle joint angle, and of muscle fibers sampled from tendon to tendon, and the total sarcomere number. Since the total number of fibers in soleus was not affected either, the inhibited increase of muscle mass following unloading was mainly due to the smaller CSA of individual fibers. Numbers of both myonuclei and satellite cells were significantly less in unloaded than control rats. The % distribution of fibers expressing pure type I myosin heavy chain was significantly less in unloaded than controls (-23 %). Further, muscle fibers with multiple innervation were noted in the unloaded rats. It is suggested that the development and/or differentiation of soleus muscle fibers are closely associated with gravitational loading and that the growth-associated increase in fiber number may be genetically programmed.

Journal Article↗
PubMed1990

Use of embryonic heart grafted in oculo to assess neurohumoral controls of cardiac development.

Culture of embryonic heart in the anterior eye chamber allows neurohumoral and genetic controls of cardiac development to be separated from the influence of hemodynamic load. Hearts from 12-day gestation rat embryos grafted into the anterior eye chamber of an adult host rat attach to the iris and become vascularized and innervated by collaterals from the host iris. The spontaneous beating of grafts is pacemaker-driven and under functional neural control. Grafts do not beat against a pressure load, allowing the influence of neurohumoral factors to be separated from altered hemodynamic load. In oculo, embryonic heart differentiates into mature myocardium by most morphologic and biochemical criteria. Mature intercalated disks and myofibrils with well-defined Z-lines and M-lines are observed. Mature grafts express the high levels of alpha-myosin heavy chain characteristic of young adult myocardium. Surgical sympathetic denervation of the anterior eye chamber prior to grafting of embryonic hearts compromises growth and increases the intrinsic pacemaker rate. Since the grafts are perfused by the host circulation, the hormonal milieu of the graft can be altered by treatment of the host. Thus, the interaction between hormones and innervation of grafts can be studied using the in oculo model system.

Animals↗
PubMed2007

Effects of genotype by environment interactions on milk yield, energy balance, and protein balance.

Increases in genetic merit for milk yield are associated with increases in mobilization of body reserves. This study assessed the effects of genotype by environment (GxE) interactions on milk yield and energy and protein balances. Heifers (n = 100) with high or low genetic merit for milk yield were milked 2 or 3 times a day and received rations of low or high caloric density. The management factors were selected to induce substantial differences in milk production levels and model different management strategies. The 2 x 2 x 2 factorial arrangement enables the assessment of the effects of genotype, environment, and GxE interactions. Mean daily energy-corrected milk production in the first 100 d in milk varied between 21.8 and 35.2 kg among the groups. The experimental factors affected milk production in the presumed direction. Ration was the most determinant factor on milk production. Effects of milking frequency and genetic merit were significant only in the groups that were fed rations with high caloric density. Signs for severe negative energy balances, protein balances, and low body condition scores, all of which may be indicative of health risks, were not concentrated in the highest producing cows. Feed caloric density and milking frequency had stronger effects on energy balances and protein balances, with unfavorable effects of low caloric density feed and an extra milking. This emphasizes the possible effect of mismanagement on animal health risks. High genetic merit cows had significantly lower postpartum body condition scores. Genotype x environment interactions existed, but more information is needed to determine if cows of different genetic merit for milk yield are differently at risk for disease under specific conditions. High milk production levels per se will increase allostatic load, but need not compromise the health status of relatively young cows. Ongoing one-sided selection for high yield may be combined with good animal health, but because high genetic merit for milk yield seems intrinsically connected to the allocation of resources from maintenance toward milk, this puts increasing demands on farmers' time and management skills.

Animals↗
PubMed2006

Lumbar disc degeneration: epidemiology and genetics.

Research conducted over the past decade has led to a dramatic shift in the understanding of disc degeneration and its etiology. Previously, heavy physical loading-often associated with occupation-was the main suspected risk factor for disc degeneration, which was commonly viewed as a wear-and-tear phenomenon exacerbated by the precarious nutritional status of the disc. However, results of studies on twins suggest that physical loading specific to occupation and sport plays a relatively minor role in disc degeneration. Recent research indicates that heredity has a dominant role in disc degeneration, which would explain the variance of up to 74% seen in adult populations that have been studied to date. Since 1998, genetic influences have been confirmed by the identification of several gene forms associated with disc degeneration. This research is paving the way for a better understanding of the biologic mechanisms through which disc degeneration occurs, including specific interactions between genes and environment. Research into disc degeneration and genetics has become more limited by phenotypes or definitions and measures of disc degeneration than by DNA analysis. Standardized, universally accepted definitions of disc degeneration are lacking, in part due to limited knowledge of the process. The measurements that are selected depend on the method used to evaluate the disc and are often qualitative ordinal rating scales, lacking in precision. Although it is generally agreed that disc degeneration is common, the prevalence of specific findings is unclear. A review of the epidemiology of disc degeneration reveals wide-ranging prevalence estimates for various signs of disc degeneration in samples of the general population and in patients with back symptoms. The extreme variations in prevalence rates are likely largely due to inconsistencies in the definitions and measurements of disc degeneration. Such inconsistencies and inaccuracies impede epidemiologic research on disc degeneration.

Age Distribution↗
PubMed1987

Transient correction of genetic defects in cultured animal cells by introduction of functional proteins.

Material was introduced into cultures of cells by using the method of scrape loading, in which cells are simply rubbed from the surface of a plastic tissue culture dish by a rubber-tipped rod in the presence of a macromolecule of interest. The volume of solution introduced into cells was comparable to that generally injected in the direct microinjection method with glass capillaries, that is, about 50 to 100 fl per cell. Genetic defects (lack of hypoxanthine-guanine phosphoribosyltransferase and thymidine kinase) in several cell lines were transiently corrected by scraping the cells in the presence of crude cell extracts prepared from wild-type cells.

Animals↗
PubMed1976

Social work and genetic counseling.

Genetic counselors often impart anxiety-producing information to the patient and his family. A social worker should be available to help these individuals deal with the emotional impact of the genetic facts given them. Areas of concentration for the social worker in the genetics setting include aid in family planning, identification of psychosocial aspects of genetic disorders, and help in interpreting and understanding the genetic diagnosis and medical recommendations. The individual who discovers he possesses or transmits a defective gene needs help in improving his self-image and in relieving his guilt load.

Adult↗
PubMed1996

The role of presenilin 1 in the genetics of Alzheimer's disease.

Approximately 75% of AD patients have an onset of the disease after the age of 60 years, and 60% of AD patients have no family history of the disease. Some cases of EOAD are clearly inherited in an autosomal-dominant manner. The beta APP gene on chromosome 21, the PS-1 gene on chromosome 14, and the PS-2 gene on chromosome 1 have all been characterized as genes in which mutations lead to familial EOAD. For LOAD, the work on ApoE indicates that the epsilon 4 allele is a risk factor for developing AD. However, 35-50% of all AD patients do not have an epsilon 4 allele. Other loci contributing to LOAD remain to be mapped and characterized. As in other complex disorders, these additional loci may involve genetic interactions with the known AD loci. Identification of all susceptibility loci for AD is a major goal in resolving the pathogenesis of AD.

Alternative Splicing↗