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PubMed2002

SIV(mac) pathogenesis in rhesus macaques of Chinese and Indian origin compared with primary HIV infections in humans.

OBJECTIVE: To develop a SIV-rhesus macaque (Rh) model of AIDS that more closely approximates HIV pathogenesis in humans. DESIGN: The pathogenesis of SIV was compared in two different types of Rh, the Chinese (Ch) and Indian (Ind) subspecies. METHODS: Ch Rh and Ind Rh origin were identified genetically and infected with the SIV(mac)239 molecular clone. Plasma viral loads, depletion of intestinal lymphocytes with memory phenotype, humoral immune responses and CD4/CD8 cell ratios were compared during acute and steady-state periods of infection. RESULTS: Plasma viral loads from 7 days after infection through 240 days were significantly lower in Rh of Ch origin compared with Ind Rh. Viral loads in Ch Rh were closer to viral loads observed in untreated humans infected with HIV-1. Depletion of intestinal effector cells was less evident in SIV-infected Ch Rh compared with Ind Rh. An index of intestinal pathogenesis was devised that closely paralleled viral load and severity of infection. There were no rapid progressors to AIDS among 10 Ch Rh. In contrast, three of four Ind Rh progressed rapidly to AIDS. CONCLUSIONS: Compared with Ind Rh, SIV(mac) pathogenesis in Ch Rh was closer to HIV-1 infections in untreated adult humans. The differences were statistically significant. The Ch Rh subspecies is a suitable AIDS model and may have advantages over the rapid and highly pathogenic Ind Rh model. Moreover, Ind Rh supplies are limited and use of Ch Rh provides a new resource.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Maternal SDF1 3'A polymorphism is associated with increased perinatal human immunodeficiency virus type 1 transmission.

Genetic polymorphisms in chemokine and chemokine receptor genes influence susceptibility to human immunodeficiency virus type 1 (HIV-1) infection and disease progression, but little is known regarding the association between these allelic variations and the ability of the host to transmit virus. In this study, we show that the maternal heterozygous SDF1 genotype (SDF1 3'A/wt) is associated with perinatal transmission of HIV-1 (risk ratio [RR], 1.8; 95% confidence interval [CI], 1.0 to 3.3) and particularly postnatal breastmilk transmission (RR, 3.1; 95% CI, 1.1 to 8.6). In contrast, the infant SDF1 genotype had no effect on mother-to-infant transmission. These data suggest that SDF1, which is a ligand for the T-tropic HIV-1 coreceptor CXCR4, may affect the ability of a mother to transmit the virus to her infant. This suggests that a genetic polymorphism in a gene encoding a chemokine receptor ligand may be associated with increased infectivity of the index case and highlights the importance of considering transmission as well as clinical outcome in designing chemokine-based therapies for HIV-1.

3' Untranslated Regions↗
PubMed2026

Effect of inhaled interferon-β1a on SARS-CoV-2 diversity and evolution.

Interferon resistance has been implicated in SARS-CoV-2 escape from innate immunity, but exogenous interferon's impact on viral evolution and diversity is unknown. SNG001, an inhaled interferon-β1a treatment, was evaluated in the ACTIV-2/A5401 randomized controlled trial of therapeutics for COVID-19. We measured viral kinetics and performed whole-genome sequencing on longitudinal nasal swabs collected from ACTIV-2 participants who received either SNG001 or placebo to assess viral sequence diversity. No difference in nasal viral load decay was detected between study arms when stratifying by SARS-CoV-2 variant or by viral culture conversion. Compared to placebo participants, the SNG001-treated participants displayed significantly lower nonsynonymous amino acid average pairwise distance, indicating lower sequence diversity. Similarly, SNG001-treated individuals also developed numerically fewer nonsynonymous mutations during their infection in ORF1a, ORF1b, Spike, and Nucleocapsid. No specific emerging SARS-CoV-2 nonsynonymous amino acid changes indicating signatures of viral escape were enriched in those receiving SNG001. These in vivo data provide an intriguing signal that exogenous interferon-β1a may restrict SARS-CoV-2 viral diversity and add to growing evidence that interferon levels play a critical role in antiviral responses during COVID-19.IMPORTANCESARS-CoV-2 encodes several genes which can antagonize the interferon signaling cascade, preventing it from activating antiviral responses and thereby facilitating viral establishment and dissemination. It is unknown how the administration of exogenous interferon might affect viral evolution and immune escape. ACTIV-2/A5401 represents a unique opportunity to study the virologic effects of interferon treatment in a rigorous randomized, placebo-controlled clinical trial setting. Our characterization of longitudinal nasal samples shows that interferon-treated individuals had lower viral diversity and no evidence of viral escape mutations.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04518410.

Humans↗
PubMed2000

Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes.

Malignant gliomas exhibit alkaline intracellular pH (pH(i)) and acidic extracellular pH (pH(e)) compared with nontransformed astrocytes, despite increased metabolic H(+) production. The acidic pH(e) limits the availability of HCO(-)(3), thereby reducing both passive and dynamic HCO(-)(3)-dependent buffering. This implies that gliomas are dependent upon dynamic HCO(-)(3)-independent H(+) buffering pathways such as the type 1 Na(+)/H(+) exchanger (NHE1). In this study, four rapidly proliferating gliomas exhibited significantly more alkaline steady-state pH(i) (pH(i) = 7.31-7.48) than normal astrocytes (pH(i) = 6.98), and increased rates of recovery from acidification, under nominally CO(2)/HCO(-)(3)-free conditions. Inhibition of NHE1 in the absence of CO(2)/HCO(-)(3) resulted in pronounced acidification of gliomas, whereas normal astrocytes were unaffected. When suspended in CO(2)/HCO(-)(3) medium astrocyte pH(i) increased, yet glioma pH(i) unexpectedly acidified, suggesting the presence of an HCO(-)(3)-dependent acid loading pathway. Nucleotide sequencing of NHE1 cDNA from the gliomas demonstrated that genetic alterations were not responsible for this altered NHE1 function. The data suggest that NHE1 activity is significantly elevated in gliomas and may provide a useful target for the development of tumor-selective therapies.

Acids↗
PubMedDate not supplied

Regression of structural cardiovascular changes by antihypertensive therapy.

Left ventricular (LV) hypertrophy is the structural adaptation of the heart in response to chronic LV pressure load. Studies in spontaneously hypertensive rats (SHR), which represent a model of genetically determined arterial hypertension, reveal that cardiac hypertrophy can be controlled by long-term blood pressure normalization with the use of various antihypertensive agents, such as arterial vasodilatators (hydralazine), converting enzyme inhibitors (captopril), beta-receptor blockers (metoprolol), antiadrenergic substances (alpha-methyldopa, guanethidine), and calcium antagonists (nifedipine, felodipine). Additional drug-specific effects modulate the mechanical effect of LV systolic unloading on cardiac hypertrophy: after a combined treatment with metoprolol and hydralazine, LV hypertrophy was quantitatively lower than after single hydralazine therapy, although blood pressure had been lowered to the same extent. LV collagen concentration remained unchanged when medical treatment prevented the development of myocardial hypertrophy. However, when therapy was begun after hypertrophy had been completely established, reversal of hypertrophy was associated with an increased LV collagen concentration. In concentric LV hypertrophy with normal systolic wall stress, LV function was not impaired. Consequently, antihypertensive therapy could not improve LV function in this condition. However, in the case of LV dilatation with increased systolic wall stress, LV systolic unloading by antihypertensive therapy could considerably improve LV pumping function. Preventive studies reveal that chronic blood pressure control can prevent cardiac dysfunction in SHR, as frequently is seen in the later phase of untreated arterial hypertension in humans.

Animals↗
PubMed1981

[Comparison in genetically hyperlipoproteinemic and normal rats of the captation and incorporation of isotopic oleic acid and glycerol at high concentration by the perfused liver].

Perfusions of isolated livers from genetically hyperlipoproteinemic Zucker fa/fa and normolipemic Zucker Fa/- rats are performed with loads of ]9,10-3H2] oleic acid and [1-14C] glycerol. The hepatic acylglycerols anabolism from these precursors is higher in the fa/fa rat than in the control Fa/- rats. Synthesis by esterification (of oleic acid) is more increased than de novo synthesis (from glycerol). The increase in lipid anabolism is due to an augmentation of the hepatic cellular mass, but this anabolism is not regulated in the same way than in the normal rat.

Animals↗
PubMed1989

[Arteriosclerosis and blood lipids].

In our examinations of the new-born and their parents, of the patients with coronary heart disease and their relations, of the healthy test persons of different age and of the families of the long-lived persons we have found that in the atherogenesis genetic factors and blood lipids play a great part. In future it is perhaps possible already early to recognize in children a genetically conditioned hyperlipoproteinaemia, all the more since in the patients with hereditary load was to be observed a clear increase of the indices of lipid metabolism in comparison to the healthy test persons. Furthermore, a connection between a hyperlipoproteinaemia and the AB0 blood groups was stated. A combination of the hyperlipoproteinaemia of type IIb with the blood group A in new-born and in patients after myocardial infarction belongs to the most important risk factors for the atherogenesis. On account of these findings it is possible to establish a hyperlipoproteinaemia in childhood in children with hereditary load, which gives the possibility by means of normalization of the lipids to perform an early prophylaxis of the arteriosclerosis. The examination of the long-lived persons showed that the arteriosclerosis is not certainly an accompanying appearance of old age, for the autopsies of persons 100 years of age and more did not show any arteriosclerotic changes of the vessels.

ABO Blood-Group System↗
PubMed1978

[Circadian periodicity and stomach ulcer. An animal experiment model for the detection of rhythm factors in the genesis of civilization diseases].

Against the background of clinical experience attesting to the role of the circadian and circannual rhythm stage in gastric ulcerogenesis, animal experiments provide a model where by circadian stage and sex are both revealed as determinants of gastric ulcerogenesis. Experiments on the genetically mesor-hypertensive Okamoto rat demonstrate the critical interaction of multiple loads in ulcerogenesis, in keeping with a report by Glavin and Mikhail. While stimulation by single loads of a certain intensity--immobilization, food deprivation or cooling--did not regularly lead to the production of gastric ulcers, the combination of these same loads did so as a function of circadian state at the beginning of exposure time.

Animals↗
PubMed1980

[Painful hip joint with epiphyseal dysplasia (author's transl)].

Among patients who visited our hip clinic, eighteen patients from ten families were diagnosed as mild or atypical cases of spondyloepiphyseal dysplasia or multiple epiphyseal dysplasia. Clinical and X-ray examinations of these patients showed common characteristic features as follows. 1. They usually had short stature but were not dwarfs. Their facial features and body proportions did not suggest hereditary bone dysplasia. 2. Although the disease might be transmitted in an autosomal dominant manner, its occurrence among these families was found to be sporadic. 3. Symptoms of the hip joint mainly resulted from limited range of motion, coxalgia being usually less than expected from X-ray findings. 4. Joints were always affected bilaterally although the degree might be different on each side. 5. In the majority of the cases, the spine, shoulder (in 7 cases), knee (in 6 cases), elbow (in 3 cases), ankle, and wrist joint (in 2 cases) were also affected. 6. Characteristic X-ray findings of the hip joints were as follows. a) Coxa vara, flattening or rectanglar deformity of the femoral head and shortening of the femoral neck. b) The trabecular pattern of the femoral head was irregular and subchondral cysts were often observed. c) Joint space was relatively better restored than expected from the deformity and subchondral bony changes of the femoral head. Spondyloepiphyseal dysplasia and multiple epiphyseal dysplasia are genetic disorders of the epiphyseal and apophyseal cartilage. The hip joint is loading greater mechanical force than any other joint. In both spondyloepiphyseal dysplasia and multiple epiphyseal dysplasia, the hip joint is always affected. As the hip joint is most vulnerable when there is some disorder of the epiphyseal cartilage, it is probably the only detectable abnormal joint. In relatively short period (1972-1978), the diagnosis of mild or atypical spondyloepiphyseal dysplasia was made in 18 patients in our hip clinic. This means that the mild or atypical cases of spondyloepiphyseal dysplasia is not so rare as expected. They might be misdiagnosed as aseptic necrosis, deformity of the femoral head due to Perthes disease or primary osteoarthrosis. An extreme care should be taken when we examine such patients.

Adult↗
PubMed1993

Effect of chronic iron overload on procollagen gene expression.

The pathogenesis of hepatic fibrosis and cirrhosis in genetic hemochromatosis may involve a direct effect of excess iron on collagen synthesis in the liver. To investigate this theory, we measured procollagen messenger RNA levels (types I, III and IV) in the livers of rats in which we produced chronic parenchymal iron overload by feeding them dietary carbonyl iron (2.5%, wt/wt) for up to 18 mo. This feeding resulted in predominantly parenchymal iron deposition in a periportal distribution similar to that seen in genetic hemochromatosis. Increased amounts of collagen fibrils were observed in iron-loaded livers on electron microscopy; all iron-loaded livers showed some periportal fibrosis. Although very high hepatic iron concentrations (range = 340 to 1,100 mumol/gm dry wt) were achieved in the carbonyl iron-loaded rats, we saw no consistent difference between steady-state messenger RNA levels for procollagens types I, III and IV in control and iron-loaded livers examined at five different time points up to 18 mo. Messenger RNA levels of the cytokine transforming growth factor-beta 1, which has been implicated as having a role in the production of extracellular matrix proteins, were also measured. No significant differences were observed between iron-loaded and control livers. These results suggest that excess parenchymal iron does not have a direct effect on the expression of the procollagens or transforming growth factor-beta 1 genes in iron-loaded livers and that factors other than, or in addition to, iron are necessary for fibrosis to occur.

Animals↗
PubMed1998

Inferences on genome-wide deleterious mutation rates in inbred populations of Drosophila and mice.

A theoretical analysis was carried out on the mutation load observed in long-maintained inbred lines from two experiments with Drosophila and mice. The rate of decline in fitness and its sampling distribution were predicted for both experiments using Monte Carlo simulation with a range of mutational parameters and models. The predicted rates of change in fitness were compared to the empirical observed rates, which were close to zero. The classical hypothesis of many deleterious mutations (about one event per genome per generation) of small effect (1-2%) resulting in a mutation pressure for fitness of about 1% per generation is incompatible with the data. Recent estimates suggesting an overall mutation pressure for fitness traits of about 0.1% are, however, compatible with the observed load.

Animals↗
PubMed1998

Requisite mutational load, pathway epistasis and deterministic mutation accumulation in sexual versus asexual populations.

A measure of the equilibrium load of deleterious mutations is developed that explicitly incorporates the level of genome-wide linkage disequilibrium. This measure, called the requisite mutational load, is based on the minimal net reproductive rate of the least mutated class necessary to prevent the deterministic mutation accumulation. If this minimal net reproductive rate is larger than ecological or physiological constraints allow, then: a) the population is driven to extinction via deterministic mutation accumulation, or b) a mutational Red-Queen ensues with adaptation counterbalancing mutation accumulation. Two population parameters determine the requisite mutational load: a) the equilibrium strength of selection, measured as a selection gradient, and b) the equilibrium opportunity for selection, measured as the variance in number of mutations per genome. The opportunity for selection is decomposed into the accumulation of mutations (average number per genome) and the level of genome-wide linkage disequilibrium. Recombination can substantially reduce the requisite mutational load, compared to clonal reproduction, when there is buffering and/or reinforcing epistasis and also when there is positive assortative mating for fitness. Recombination is advantageous because it reduces the negative (variance reducing) linkage disequilibrium induced by beneficial epistasis. The functional form of the expression for requisite mutational load illustrates why epistasis within pathways, i.e., among closely interacting genes, is a powerful alternative to genome-wide truncation selection, as a means of reducing mutational load.

Animals↗
PubMed1988

Genetics and salt modulate renal responses to atrial natriuretic factor.

We examined the consequences of genetic susceptibility or resistance to NaCl-induced hypertension and of prior salt loading (high or low NaCl intake) on the responses of isolated perfused Dahl salt-sensitive (DS) and Dahl salt-resistant rat (DR) kidneys to atriopeptin II. Atriopeptin II increased the glomerular filtration rate only in kidneys from high NaCl-fed rats, irrespective of their DS or DR status. Superimposition of norepinephrine on atriopeptin II further increased the glomerular filtration rate only in kidneys from low NaCl-fed rats (which had not reacted to atriopeptin II alone), irrespective of their DS or DR status, and did not change the glomerular filtration rate of high NaCl-fed rats. Norepinephrine alone, without atriopeptin II, uniformly decreased the glomerular filtration rate by about 80%. Atriopeptin II increased sodium excretion of high NaCl and low NaCl DR kidneys by more than five times as much as in the corresponding DS kidneys. Therefore, the glomerular filtration rate response to atriopeptin II varied globally with dietary NaCl, independently of genetic predisposition or resistance to NaCl-induced hypertension. The natriuretic response to atriopeptin II was blunted in kidneys from rats genetically susceptible to NaCl-induced hypertension, independently of their NaCl consumption. Atriopeptin II also ameliorated or reversed the adverse effect of norepinephrine on the glomerular filtration rate.

Animals↗
PubMed1981

Furosemide and bumetanide-sensitive Na+ fluxes in erythrocytes from genetically hypertensive rats (SHR).

Na+ and K+ fluxes from erythrocytes of SHR and WKY control rats have been studied. Fluxes were measured in both fresh and sodium-loaded (after exposure to ouabain or PCMBS) erythrocytes. Pump activity appears higher and furosemide or bumetanide sensitive Na+ efflux lower in SHR compared to WKY suggesting a similar abnormality in SHR genetic hypertension as in human hypertension.

4-Chloromercuribenzenesulfonate↗
PubMed2000

[Syndrome of apparent mineralocorticoid excess caused by a deficiency of 11 beta-hydroxysteroid dehydrogenase: clinical and genetic study in a Chilean family followed for 19 years].

An 11-year old girl was seen in 1981 with hypokalemia, low renin, low aldosterone, and severe hypertension. A medical adrenalectomy with dexamethasone and aminoglutethimide, and the blockade of mineralocorticoid receptors with spironolactone improved her condition, but the blockade of glucocorticoid receptors with RU-486 worsened it. An aldosterone infusion induced no changes. A sister was born in 1982 with similar findings. Both patients had an impaired ability to convert cortisol to cortisone after an oral load of 200 mg cortisol. In urine, an elevated ratio for metabolites of cortisol to metabolites of cortisone was found. These data suggested a defect in the activity of renal 11 beta-hydroxysteroid dehydrogenase. Both parents were asymptomatic, phenotypically normal and non-consanguineous. Their urinary metabolites of cortisol and cortisone were normal before and after stimulation with ACTH. However, the mother reached a peak plasma cortisone concentration 3 SD below the mean reached by normal subjects after an oral 200-mg cortisol load, a fact that suggests that this test could be used to detect heterozygotes. The genetic studies revealed a homozygous mutation on exon 3 of the HSD11K gene, which by substituting TGC for CGC changes Arg 213 for Cys and induces a loss of 84% of the enzymatic activity in transfected cells. Both unrelated parents had the same heterozygous mutation. Both patients have been treated with dexamethasone but have also required spironolactone. The older sister has also required high doses of nifedipine to lower her blood pressure. After 19 years of follow-up, the older sister has become normotensive and normokalemic under therapy, and reached a final height of 140 cm at age 17. The younger sister has increased her mean blood pressure at a rate of 1 mm Hg per year, in spite of treatment. Her final height is 143.5 cm.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2003

Noninvasive detection of new simian immunodeficiency virus lineages in captive sooty mangabeys: ability to amplify virion RNA from fecal samples correlates with viral load in plasma.

The sooty mangabey (SM) (Cercocebus atys) is the natural host of a simian immunodeficiency virus, termed SIVsm, which gave rise to human immunodeficiency virus type 2. Data on the geographic distribution, prevalence, and genetic diversity of SIVsm in the wild remains limited. To address this issue, noninvasive strategies based on screening SM fecal and urine specimens for SIVsm-specific antibodies and virion RNA (vRNA) were developed, and the results were correlated with viral loads in plasma. Twenty-three SIVsm-infected and 27 uninfected SMs were evaluated. Time-matched urine, fecal and plasma samples were collected over a 2-month period from 16 captive naturally infected SMs. The remaining 7 infected and 27 uninfected SMs were sampled once. Each specimen was subjected to enhanced chemiluminescence-Western blot analysis and nested reverse transcriptase (RT) PCR. The results showed that urine was highly sensitive (96%) and specific (100%) for detection of SIVsm antibodies, while fecal detection was much less sensitive (16%). Conversely, vRNA detection was more sensitive in feces (50%) than in urine (2%) samples. Fecal-vRNA detection correlated with viral loads in plasma (P < 0.002). SMs with detectable fecal vRNA had a mean viral load in plasma of 458,006 copies/ml, while those with undetectable fecal vRNA had a mean viral load in plasma of 29,428 copies/ml. Moreover, for every log increase in the viral load in plasma, the odds of detecting virus in fecal samples increased 87-fold. Genetic diversity of SIVsm in the SM colony was characterized by sequencing partial gag (846 bp) and gp43 (439 bp) fragments. Surprisingly, four new SIVsm lineages were identified, two of which were initially detected by fecal RT-PCR. This study documents the suitability of noninvasive methods for the detection and molecular characterization of new SIV variants. These assays will be useful for studying the phylogeny and epidemiology of SIVsm infections in the wild, and they hold promise as tools for investigating natural SIV infections in endangered nonhuman primates.

Animals↗