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PubMed2003

Exertional headache--II. Clinical features Vågå study of headache epidemiology.

In connection with a large-scale study of headache epidemiology in the parish of Vågå, Norway (n = 1838), a prevalence of exertional headache (EH) of 12.3% was recently reported (n = 202). The principal aim of the present report is to have a closer look at various clinical features: particular attention has been given to the coexistence of EH and migraine. EH seemed to coexist with migraine in 46% of the cases. In spite of that finding, there was generally no plentitude of 'migraine features' in the EH attacks per se. The predominant 'migraine feature' in EH attacks was throbbing. EH attacks were generally more short-lasting and seemed to be more lenient than the corresponding migraine attacks. Nausea/vomiting, and unilaterality of pain were generally not inherent features of EH attacks. EH attacks in all probability are not abortive migraine attacks--rather, they seem to be 'migraine-like'.

Adolescent↗
PubMed2001

Inflammation and dietary protein intake exert competing effects on serum albumin and creatinine in hemodialysis patients.

BACKGROUND: Cross-sectional studies have shown an inverse correlation between serum C-reactive protein (CRP) and serum albumin concentration in hemodialysis patients. The net effects of inflammation and dietary protein intake on nutritional markers over time are unknown. METHODS: To explore the effects of CRP and normalized protein catabolic rate (nPCR) on serum albumin and creatinine, we analyzed six consecutive months of laboratory data from 364 hemodialysis patients, using a multivariable Mixed model with conservative biases. RESULTS: The overall trend over time in serum albumin was slightly positive (0.039 g/dL/month) and in serum creatinine slightly negative (-0.052 mg/dL/month). With increasing CRP, serum albumin declined significantly (-0.124 g/dL/month per unit increase in log CRP, adjusted for age, gender, race, diabetes, and nPCR, P < 0.0001). Serum albumin increased with increasing nPCR (0.021 g/dL/month per 0.1 g/kg/day, P < 0.0001). The effect of CRP on albumin was attenuated in African Americans and at a higher nPCR. Corresponding values for creatinine mirrored those for albumin. With increasing CRP, creatinine declined significantly [-0.142 mg/dL/month per unit increase in log CRP, adjusted for age, gender, race, diabetes (time since initiation of dialysis; vintage), Kt/V, and nPCR, P = 0.002]. Serum creatinine increased with increasing nPCR (0.183 mg/dL/month per g/kg/day, P < 0.0001). CONCLUSIONS: Proxies of inflammation and dietary protein intake exert competing effects on serum albumin and creatinine in hemodialysis patients. These data provide a rationale for prospective testing of dietary protein supplementation in hemodialysis patients with biochemical evidence of ongoing inflammation and "malnutrition."

Adult↗
PubMed1999

The effect of physical training on hormonal status and exertional hormonal response in patients with chronic congestive heart failure.

BACKGROUND: Physical training improves exercise capacity in patients with chronic heart failure. It decreases plasma noradrenaline at rest, which may be prognostically favourable. The effect on atrial natriuretic peptide, another prognostic factor, and on catabolic and anabolic hormones remains unknown. Furthermore, to our knowledge, the contribution of exertional hormonal responses to the improved exercise capacity has not been evaluated. METHODS: 27 patients with stable chronic heart failure (New York Heart Association class II-III) were randomized to training (n=12) and control (n=15) groups. The training group exercised on a bicycle ergometer for 30 min three times a week for 3 months. The load corresponded to 50-60% of their peak oxygen consumption. For the next 3 months they exercised at home according to personal instructions. The control group did not change its physical activities. The levels of hormones regulating the cardiovascular system and metabolism were determined at rest and after graded maximal exercise and during exercise with constant submaximal workload. RESULTS: Submaximal exercise capacity increased significantly and peak oxygen consumption tended to improve by 12% in the training group. The plasma noradrenaline at rest tended to decrease by 19%. The plasma level of N-terminal pro atrial natriuretic peptide did not change. Serum cortisol, a catabolic hormone, was normal at baseline and remained unchanged. The serum levels of anabolic hormones, growth hormone and insulin, as well as dehydroepiandrosteronesulfate and free testosterone were within a normal range at baseline. They were not altered by training. The dehydroepiandrosteronesulfate/cortisol, and the free testosterone/cortisol ratios, reflecting anabolic/catabolic balance, did not change, either. Training resulted in a higher peak noradrenaline response during graded maximal exercise. The rise in serum cortisol during exercise tended to attenuate. CONCLUSION: Physical training, which improves exercise capacity, does not have an unfavourable effect on anabolic/catabolic balance or neurohumoral activation in patients with congestive heart failure. It decreases plasma noradrenaline at rest. Minor changes in hormonal responses during exercise emerged after physical training which unlikely contribute to the improved exercise capacity.

Aged↗
PubMed1996

Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells.

BACKGROUND & AIMS: Endothelin (ET) 1 could be involved in the regulation of hepatic microcirculation and in the development of portal hypertension. The expression and distribution of ET-1 in normal and cirrhotic liver tissue and its effects on hepatic stellate cells (HSCs), liver-specific pericytes, were investigated. METHODS: ET-1 expression in liver tissue was analyzed using in situ hybridization and immunohistochemistry. Secretion of ET-1 by HSC was evaluated by radioimmunoassay. Changes in intracellular Ca2+ concentration and cell contraction were studied using digital video imaging. Specific binding of ET-1 was evaluated using self- and cross-displacement curves. RESULTS: ET-1 expression was markedly enhanced in cirrhotic liver tissue, where activated HSCs were shown to be major sites of ET-1 synthesis, as confirmed by studies performed on cultured human HSC. ET-1 exerted several biological actions on HSC, including mitogenicity, activation of mitogen-activated protein kinase, and a rapid increase in intracellular Ca2+ coupled with reversible cell contraction. All these effects appeared to be mediated by ETA receptors. Finally, the relative prevalence of ETA and ETB binding sites changed with the progressive phenotypical modulation of HSC. CONCLUSIONS: ET-1 may act as a paracrine and autocrine factor for activated HSC and contribute to the increased resistance to portal flow in cirrhotic liver.

Adipocytes↗
PubMed2000

Activin A exerts both pro- and anti-inflammatory effects on human term gestational tissues.

There is a growing appreciation of the importance of activin as a modulator of immune function. The aim of the present study was to determine whether activin A exerts any effects on cytokine and prostaglandin (PG) production by the tissues of pregnancy. Explant cultures were established for amnion, choriodecidual and placental tissues derived from pregnancies delivered at term by Caesarean section (n=5 placentae). Explants were treated with activin A (0.5, 5 and 50 ng/ml) in serum-free Ham's F12/DME media for 24 h (n=3-4 replicates). Production rates of interleukin (IL)-1beta, IL-6, IL-8, tumour necrosis factor-alpha (TNF-alpha) and PGE(2)were determined using immunoassay. Differences between treatment groups were analysed by ANOVA followed by Dunnett's test;P< 0.05 was considered to be significant. Amnion IL-6 production exhibited biphasic responses to activin A: at 5 ng/ml activin A, IL-6 production was significantly stimulated (to 246+/-74.6 per cent of control (mean+/-sem), while at 50 ng/ml it was significantly inhibited (to 46+/-7.4 per cent of control). IL-8 and PGE(2)production by amnion showed significant responses to activin A that were similar to those of IL-6. No significant effects of activin A were observed on choriodecidual and placental IL-6, IL-8 and PGE(2)production. However, TNF-alpha production was significantly inhibited by 50 ng/ml activin A in both choriodecidual and placental explants (to 43+/-9.7 per cent and 51+/-6.7 per cent of control, respectively). Placental IL-1beta production was not altered by treatment with activin A at any concentration. These findings support the concept of activin as an immune modulator in tissues of pregnancy.

Activins↗
PubMed2000

Airway obstruction and chronic exertional dyspnoea in patients with persistent bronchial asthma.

In patients with COPD, flow limitation (FL) predicts chronic exertional dyspnoea (CED) better than routine spirometry. Whether, and to what extent, FL and CED are overlapping quantities in chronic asthma has not yet been defined. Forty consecutive clinically stable asthmatic patients without smoking history or cardiopulmonary disorders, were studied. In each subject respiratory function, including static and dynamic pulmonary volumes, was evaluated; maximal (MEFV) and partial (PEFV) expiratory V'-V curves and isovolumic partial to maximal flow ratio (M/P). FL was assessed in a seated patient by comparing tidal and PEFV curves; FL was detected when tidal flows were superimposed or exceeded those obtained during PEFV curves, and was expressed as a percentage of the expired control tidal volume (V(T)) affected by flow limitation (FL% VT). Dyspnoea was assessed by both MRC scale and Baseline Dyspnoea Index (BDI) focal score. Half of the patients were found to have FL. They were older, more dyspnoeic and more obstructed (P<0.03 - P<0.000005) than the non-FL group. FEV1, vital capacity (VC), age, body mass index, FL and M/P ratio were all related to dyspnoea scores. FL was significantly related to FEV1 (r = - 0.59). Multiple regression analysis showed that FEV1 (P=0.003, r2= 15-3% and P = 0.004, r2= 20.3%) and age (P = 0.0006, r2 = 26.8% and P = 0.016, r2 = 11%) independently predicted a part of the variance of MRC (P = 0.0001, r2 = 42.1%) and BDI (P = 0.0008, r2 = 31.3%), respectively. With dyspnoea scale being the gold standard, diagnostic accuracy (sensitivity and specificity) by ROC (receiver operating characteristics) analysis was similar for FEV1 and FL. The results indicate that FL may be present in this subset of asthmatics. CED may not be easily explained by abnormalities of routine spirometry or FL, the largest part of the CED variance remained unexplained. Thus, routine spirometry, FL and CED in patients with bronchial asthma are only partially overlapping quantities which need to be assessed separately.

Adolescent↗
PubMed2001

Acute exertional compartment syndrome in an athlete.

Acute exertional compartment syndrome is a rare condition, associated with strenuous, unaccustomed exercise. This report describes its onset in a professional footballer during a regular training session. It is often diagnosed late due to lack of awareness and patient stoicism. We illustrate the consequences of delay and reinforce the need for prompt and decisive fasciotomy if complications are to be avoided.

Acute Disease↗
PubMed2000

Does human betaA4 exert a protective function against oxidative stress in Alzheimer's disease?

The hypothesis is advanced that human betaA4--as opposed to rodent betaA4--may exert a protective function against the iron-induced oxidative stress associated with neurological diseases (notably Alzheimer's disease). Subsequent to its release by the host in response to oxidative injury, human betaA4 would interact with Cu(2+)ions whose level is correlatively elevated, adopting the 'aggregated' structure recently characterized by Atwood et al.(15). Then, depending on the oxidative state--hence the pH--of the medium, it might either return to its original structure if physiological pH is restored, or undergo site-specific copper-mediated oxidation and, finally, degradation. In this context, betaA4 pathogenicity could be due to an interfering mechanism preventing the degradation of the oxidized peptide, making its aggregation irreversible and inducing its final deposition. Coordination of side group oxygen donors of the oxidized peptide with 'hard' metal ions occurring in the physiological medium (notably Al(3+)) might be at the origin of this interference.

Alzheimer Disease↗
PubMed2000

Evolution of electromyographic signal, running economy, and perceived exertion during different prolonged exercises.

The purpose of this study was to compare the electromyographic (EMG) signal of the vastus lateralis muscle obtained during a run section of a triathlon and at the end of a prolonged run performed at the same running velocity. Seven subjects were studied on three occasions: a 2 h 15 min triathlon (30 min swimming, 60 min cycling, and 45 min treadmill running at 75% of the maximal aerobic speed), a 2 h 15 min run, where the last 45 min (Prolonged Run, PR) were run at the same speed as the Triathlon Run (TR) on a motorized treadmill, and a 45 min Isolated Run (IR) performed at the same TR and PR velocity. The three experimental trials were randomised. Oxygen uptake (VO2), heart rate (HR), and EMG data were recorded during the three run sections. The results confirm a greater VO2 and HR during PR compared with IR (P<0.01) and TR (P<0.05). Also the VO2 values obtained during TR were significantly greater compared to IR (P < 0.05). EMG signal, obtained from the vastus lateralis muscle during 4 sec of isometric contraction at 35 % of maximal voluntary contraction (MVC), showed that after PR the mean power frequency (MPF) shifted significantly to lower frequencies (P<0.01) compared with MPF recorded before the prolonged run. Moreover, the signal amplitude (RMS) was increased significantly after PR in comparison to pre-trial (P < 0.01). Similar results were obtained for the TR at P < 0.05. The integrated EMG flow, QIEMG (iEMG/burst duration), recorded during all run sections, was significantly increased near the end of PR (i.e. 2 h 10 min of running) compared with QiEMG recorded after 1 h 30 min of running. No significant increase in QiEMG was observed with TR and IR situations. The results suggest that a long exercise bout of running led to a greater increase in muscle fatigue compared with a triathlon or an isolated run performed at the same running speed. In addition it is suggested that the rating of perceived exertion recorded during isometric contractions is a good indice to approach the level of fatigue during prolonged exercises.

Adult↗
PubMed1983

Cortisol 21-mesylate exerts glucocorticoid action on the induction of milk protein synthesis in cultured mammary gland.

Cortisol 21-mesylate, an alkylating derivatives of cortisol, was previously shown to exert an anti-glucocorticoid action in rat hepatoma cell culture (Simons, Thompson and Johnson 1980). In this study the effect of cortisol 21-mesylate on milk protein synthesis induced in cultured mouse mammary gland by glucocorticoid, insulin, and prolactin was investigated. Addition of cortisol 21-mesylate at concentrations ranging from 10(-8) M to 10(-6) M produced no inhibition of casein synthesis that was induced by glucocorticoid, insulin and prolactin in mammary explants from midpregnant mice. On the other hand, cortisol 21-mesylate in combination with insulin and prolactin stimulated casein synthesis in cultured tissue. The potency of cortisol mesylate was about 1/10 to 1/30th of that of cortisol. Cortisol 21-mesylate, like cortisol, also augmented the accumulation of alpha-lactalbumin in midpregnant rat mammary tissue cultured in the presence of insulin and prolactin. A cell-free competition study of glucocorticoid receptors using cytoplasmic extracts from mouse mammary tissue showed that cortisol 21-mesylate competitively inhibited the binding of dexamethasone on glucocorticoid receptors. The apparent affinity of cortisol 21-mesylate for glucocorticoid receptors is about 1/10th of that of cortisol. These results indicate that cortisol 21-mesylate acts as a glucocorticoid but not as an antiglucocorticoid in the mammary gland.

Animals↗
PubMed1999

Substantial influence of level of endurance capacity on the association of perceived exertion with blood lactate accumulation.

Capillary blood lactate assessment is increasingly used by well-trained runners to monitor the intensity of endurance exercise. In order to examine the known association of exercise intensity with blood lactate accumulation also in less trained subjects, we analysed data from a standardized incremental maximal test on the treadmill of 319 men (age 22.9 +/- 5.5 years, [means +/- S.D.]) and 145 women (22.7 +/- 4.5 years) characterized by a wide variation in endurance capacity. Results showed that the running velocity eliciting a blood lactate concentration of 4 mmol/l did not correspond to the same exercise intensity in well endurance-trained vs poorly endurance-trained subjects. At 4 mmol/l blood lactate, the slowest decile of men (i.e. 32 out of 319) ran at 71 +/- 4.7% (corresponding to 2.9 +/- 0.3 m/s) of their maximal treadmill velocity attained during the test (4.1 +/- 0.4 m/s), indicating a rating of perceived exertion (RPE) of 12.3 +/- 1.8 points (Borg scale, range 6-20 points), while the fastest decile of men (n = 32) ran at 91 +/- 3.1% (corresponding to 5.4 +/- 0.2 m/s) of their maximal treadmill speed (5.9 +/- 0.2 m/s), indicating a RPE of 16.6 +/- 1.1 points. Very similar results were observed in women. There was a highly significant, positive correlation between running speed eliciting a blood lactate concentration of 4 mmol/l and RPE when running at this speed, with r = 0.64 in men and r = 0.55 in women. At the same proportional level of maximal running velocity, poorly endurance-trained athletes showed a 2-3 mmol/l higher capillary lactate concentration than well endurance-trained athletes, with both groups indicating the same RPE. These results suggest that fixed blood lactate concentrations not at all mean the same exercise intensity for well vs poorly endurance-trained subjects; this systemic trend should be considered when using blood lactate assessment for individual exercise counselling.

Adult↗
PubMed1998

Acute and chronic over-exertion: do depressed immune responses provide useful markers?

There are ethical objections to inducing cumulative muscle damage and associated decrements of performance deliberately in a healthy athlete. Available data on acute and chronic over-exertion thus include the changes of immune response observed following a single bout of exhausting exercise, sequential observations made on top-level competitors as they approach peak training periods, and longitudinal laboratory studies of heavy (but not necessarily damaging) bouts of training. In all three of these situations, subclinical muscle damage initiates an acute inflammatory response, with a resulting deterioration in physical performance. Although much smaller in degree and shorter in duration, the associated changes in immune function are similar to those seen in sepsis. There have been major advances in immunological technique over the past decade, and significant changes in a number of elements of the immune response can be identified in athletes during periods of heavy training. The most promising immunological marker of excessive training seems a decrease in salivary IgA concentration. However, no single change occurs with sufficient consistency to identify the individual competitor who is at risk of overtraining. Mechanisms can be conceived that convert a sequence of excessive training bouts into an acute and then a chronic inflammatory process, but the syndrome of overtraining has a complex overlay of biological and psychological influences. It remains more easily detected by decreases in physical performance and alterations in mood state than by changes in immune function.

Antibody Formation↗
PubMed1996

Alterations in plasma free tryptophan and large neutral amino acids do not affect perceived exertion and prolactin during 90 min of treadmill exercise.

It has been hypothesized that fatigue and prolactin (PRL) changes during endurance exercise are influenced by serotonin synthesis, and in turn, release. Such a change is thought to occur through an increase in blood free tryptophan (TRP) and a concomitant decrease in those large neutral amino acids (LNAA) which compete with free TRP for entry into the brain. For further investigation, 10 healthy athletes were randomly subjected to three test units (TU), each consisting of a treadmill run for 90 min. The speed was adjusted to a blood lactate level of 2 mmol/l. During the first 30 min of exercise infusions of 500 ml saline (TU I), 500 ml saline with amino acids (TU II) or 500 ml saline with 30 U heparin/kg following an oral soy oil solution given 1 h before (TU III) were administered. Rate of perceived exertion (RPE), heart rate and running speed were recorded during exercise. Venous blood samples were taken after a 10 h fast, at rest, after 10, 50 and 90 min of exercise as well as 10 and 30 min post-exercise. PRL, insulin, glucose, ammonia, lactate, triglycerides (TG), free fatty acids (FFA) and amino acids were determined in each sample. No significant differences were found in RPE. PRL increased (p < 0.01) in all TU. TG and heparin administration resulted in an increase (p <0.01) in FFA, which correlated (p < 0.01) with free TRP and the ratio of free TRP/TRP. Artificial increase in free TRP in TU III did not affect plasma PRL level. The amino acid infusion in TU II induced an increase in LNAA but had no significant effect on PRL. PRL and ammonia peaked at the end of exercise. We conclude that neither exercise-induced PRL secretion nor RPE are affected by changes in circulating free TRP and LNAA under the present conditions.

Adult↗
PubMed2002

House dust mite allergen exerts no direct proinflammatory effects on human keratinocytes.

BACKGROUND: Dermatophagoides pteronyssinus is a trigger of atopic dermatitis. Many D pteronyssinus allergens are proteases that can elicit airway inflammation by stimulating the release of cytokines and chemokines by bronchial epithelial cells. OBJECTIVE: We sought to investigate whether D pteronyssinus allergens can exert a similar activity on skin keratinocytes. METHODS: Primary cultures of keratinocytes from healthy subjects or patients with atopic dermatitis and normal human bronchial epithelial cells were compared for cytokine production in response to D pteronyssinus extract. RESULTS: Keratinocytes, but not bronchial epithelial cells, displayed a modest dose-dependent release of IL-1alpha and IL-1 receptor antagonist but no induction of their mRNA after exposure to D pteronyssinus. However, D pteronyssinus also degraded these cytokines. On the other hand, D pteronyssinus extract induced bronchial epithelial cells, but not keratinocytes, to increased expression of IL-8/CXCL8 and GM-CSF mRNA and protein. These effects were efficiently abrogated by a mixture of cysteine and serine protease inhibitors. Both IL-8 and GM-CSF were fully resistant to D pteronyssinus proteolytic attack. No induction of monocyte chemoattractant protein 1/CCL2, RANTES/CCL5, or IFN-gamma-induced protein of 10 kd/CXCL10 was detected in either cell type. Only bronchial epithelial cells expressed protease-activated receptor (PAR) 4 mRNA, whereas PAR-1, PAR-2, and PAR-3 mRNA was found in both cell types. D pteronyssinus did not affect PAR mRNA signals. CONCLUSIONS: Although D pteronyssinus can cause proteolysis-dependent release of cytokines from keratinocytes, it appears incapable of activating de novo expression of cytokines and chemokines, arguing against a direct proinflammatory activity of house dust mite on the skin.

Adult↗
PubMed2004

Identification of 4Ig-B7-H3 as a neuroblastoma-associated molecule that exerts a protective role from an NK cell-mediated lysis.

In this study, in an attempt to identify neuroblastoma-associated surface antigens, we generated mAbs against the ACN neuroblastoma cell line. A mAb was selected (5B14) that reacted with all neuroblastoma cell lines analyzed and allowed detection of tumor cell infiltrates in bone marrow aspirates from neuroblastoma patients. In cytofluorimetric analysis, unlike anti-disialoganglioside mAb, 5B14 mAb did not display reactivity with normal bone marrow hematopoietic cell precursors, thus representing a highly specific marker for identifying neuroblastoma cells. Molecular analysis revealed that the 5B14 mAb-reactive surface glycoprotein corresponded to the recently identified 4Ig-B7-H3 molecule. Remarkably, mAb-mediated masking of the 4Ig-B7-H3 molecule on cell transfectants or on freshly isolated neuroblastoma cells resulted in enhancement of natural killer-mediated lysis of these target cells. These data suggest that 4Ig-B7-H3 molecules expressed at the tumor cell surface can exert a protective role from natural killer-mediated lysis by interacting with a still undefined inhibitory receptor expressed on natural killer cells.

Animals↗
PubMed2006

p90 ribosomal S6 kinase 2 exerts a tonic brake on G protein-coupled receptor signaling.

G protein-coupled receptors (GPCRs) are essential for normal central CNS function and represent the proximal site(s) of action for most neurotransmitters and many therapeutic drugs, including typical and atypical antipsychotic drugs. Similarly, protein kinases mediate many of the downstream actions for both ionotropic and metabotropic receptors. We report here that genetic deletion of p90 ribosomal S6 kinase 2 (RSK2) potentiates GPCR signaling. Initial studies of 5-hydroxytryptamine (5-HT)(2A) receptor signaling in fibroblasts obtained from RSK2 wild-type (+/+) and knockout (-/-) mice showed that 5-HT(2A) receptor-mediated phosphoinositide hydrolysis and both basal and 5-HT-stimulated extracellular signal-regulated kinase 1/2 phosphorylation are augmented in RSK2 knockout fibroblasts. Endogenous signaling by other GPCRs, including P2Y-purinergic, PAR-1-thrombinergic, beta1-adrenergic, and bradykinin-B receptors, was also potentiated in RSK2-deficient fibroblasts. Importantly, reintroduction of RSK2 into RSK2-/- fibroblasts normalized signaling, thus demonstrating that RSK2 apparently modulates GPCR signaling by exerting a "tonic brake" on GPCR signal transduction. Our results imply the existence of a novel pathway regulating GPCR signaling, modulated by downstream members of the extracellular signal-related kinase/mitogen-activated protein kinase cascade. The loss of RSK2 activity in humans leads to Coffin-Lowry syndrome, which is manifested by mental retardation, growth deficits, skeletal deformations, and psychosis. Because RSK2-inactivating mutations in humans lead to Coffin-Lowry syndrome, our results imply that alterations in GPCR signaling may account for some of its clinical manifestations.

Amino Acid Sequence↗
PubMed2002

Pyrimethamine and WR99210 exert opposing selection on dihydrofolate reductase from Plasmodium vivax.

Plasmodium vivax is a major public health problem in Asia and South and Central America where it is most prevalent. Until very recently, the parasite has been effectively treated with chloroquine, but resistance to this drug has now been reported in several areas. Affordable alternative treatments for vivax malaria are urgently needed. Pyrimethamine-sulfadoxine is an inhibitor of dihydrofolate reductase (DHFR) that has been widely used to treat chloroquine-resistant Plasmodium falciparum malaria. DHFR inhibitors have not been considered for treatment of vivax malaria, because initial trials showed poor efficacy against P. vivax. P. vivax cannot be grown in culture; the reason for its resistance to DHFR inhibitors is unknown. We show that, like P. falciparum, point mutations in the dhfr gene can cause resistance to pyrimethamine in P. vivax. WR99210 is a novel inhibitor of DHFR, effective even against the most pyrimethamine-resistant P. falciparum strains. We have found that it is also an extremely effective inhibitor of the P. vivax DHFR, and mutations that confer high-level resistance to pyrimethamine render the P. vivax enzyme exquisitely sensitive to WR99210. These data suggest that pyrimethamine and WR99210 would exert opposing selective forces on the P. vivax population. If used in combination, these two drugs could greatly slow the selection of parasites resistant to both drugs. If that is the case, this novel class of DHFR inhibitors could provide effective and affordable treatment for chloroquine- and pyrimethamine-resistant vivax and falciparum malaria for many years to come.

Alleles↗
PubMed1983

Transcription modulation in vitro of the fibroin gene exerted by a 200-base-pair region upstream from the "TATA" box.

We have previously reported that the 5'-flanking sequence upstream from the "TATA" box modulates the faithful transcription initiation of the fibroin gene in a homologous whole cell extract prepared from the silk glands, whereas such a modulating effect is not observed in a HeLa cell extract. Subsequently we have determined that major signals responsible for the modulating effect are located within a 200-base-pair region upstream from the TATA box, mainly in a distal region between nucleotide positions -238 and -116 and in a proximal one between -73 and -53. Inversion of the sequence element -234 to -66 did not alter its modulating effect. A similar modulating effect by the upstream region of the sericin gene was also observed in the silk gland extract but not in the HeLa cell extract. In contrast, a modulating effect by the upstream region of the adenovirus 2 major late gene was observed in the HeLa cell extract but not in the silk gland extract. Thus, the modulating effect by the upstream regions of these genes is exerted only in their own homologous extracts.

Animals↗