Tyrosine phosphorylation of Kv1.5 is upregulated in intrauterine growth retardation rats with exaggerated pulmonary hypertension.

Intrauterine growth retardation (IUGR) is associated with the development of adult-onset diseases, including pulmonary hypertension. However, the underlying mechanism of the early nutritional insult that results in pulmonary vascular dysfunction later in life is not fully understood. Here, we investigated the role of tyrosine phosphorylation of voltage-gated potassium channel 1.5 (Kv1.5) in this prenatal event that results in exaggerated adult vascular dysfunction. A rat model of chronic hypoxia (2 weeks of hypoxia at 12 weeks old) following IUGR was used to investigate the physiological and structural effect of intrauterine malnutrition on the pulmonary artery by evaluating pulmonary artery systolic pressure and vascular diameter in male rats. Kv1.5 expression and tyrosine phosphorylation in pulmonary artery smooth muscle cells (PASMCs) were determined. We found that IUGR increased mean pulmonary artery pressure and resulted in thicker pulmonary artery smooth muscle layer in 14-week-old rats after 2 weeks of hypoxia, while no difference was observed in normoxia groups. In the PASMCs of IUGR-hypoxia rats, Kv1.5 mRNA and protein expression decreased while that of tyrosine-phosphorylated Kv1.5 significantly increased. These results demonstrate that IUGR leads to exaggerated chronic hypoxia pulmonary arterial hypertension (CH-PAH) in association with decreased Kv1.5 expression in PASMCs. This phenomenon may be mediated by increased tyrosine phosphorylation of Kv1.5 in PASMCs and it provides new insight into the prevention and treatment of IUGR-related CH-PAH.

µSR investigation of a new diluted magnetic semiconductor Li(Zn,Mn,Cu)As with Mn and Cu codoping at the same Zn sites.

We report the successful synthesis and characterization of a new type I-II-V bulk form diluted magnetic semiconductor (DMS) Li(Zn,Mn,Cu)As, in which charge and spin doping are decoupled via (Cu,Zn) and (Mn,Zn) substitution at the same Zn sites. Ferromagnetic transition temperature up to ∼33 K has been observed with a coercive field ∼40 Oe for the 12.5% doping level. µSR measurements confirmed that the magnetic volume fraction reaches nearly 100% at 2 K, and the mechanism responsible for the ferromagnetic interaction in this system is the same as other bulk form DMSs.

Implantation of muscle satellite cells overexpressing myogenin improves denervated muscle atrophy in rats.

This study evaluated the effect of muscle satellite cells (MSCs) overexpressing myogenin (MyoG) on denervated muscle atrophy. Rat MSCs were isolated and transfected with the MyoG-EGFP plasmid vector GV143. MyoG-transfected MSCs (MTMs) were transplanted into rat gastrocnemius muscles at 1 week after surgical denervation. Controls included injections of untransfected MSCs or the vehicle only. Muscles were harvested and analyzed at 2, 4, and 24 weeks post-transplantation. Immunofluorescence confirmed MyoG overexpression in MTMs. The muscle wet weight ratio was significantly reduced at 2 weeks after MTM injection (67.17±6.79) compared with muscles injected with MSCs (58.83±5.31) or the vehicle (53.00±7.67; t=2.37, P=0.04 and t=3.39, P=0.007, respectively). The muscle fiber cross-sectional area was also larger at 2 weeks after MTM injection (2.63×10³±0.39×10³) compared with MSC injection (1.99×10³±0.58×10³) or the vehicle only (1.57×10³±0.47×10³; t=2.24, P=0.049 and t=4.22, P=0.002, respectively). At 4 and 24 weeks post-injection, the muscle mass and fiber cross-sectional area were similar across all three experimental groups. Immunohistochemistry showed that the MTM group had larger MyoG-positive fibers. The MTM group (3.18±1.13) also had higher expression of MyoG mRNA than other groups (1.41±0.65 and 1.03±0.19) at 2 weeks after injection (t=2.72, P=0.04). Transplanted MTMs delayed short-term atrophy of denervated muscles. This approach can be optimized as a novel stand-alone therapy or as a bridge to surgical re-innervation of damaged muscles.

Implantation of muscle satellite cells overexpressing myogenin improves denervated muscle atrophy in rats

This study evaluated the effect of muscle satellite cells (MSCs) overexpressing myogenin (MyoG) on denervated muscle atrophy. Rat MSCs were isolated and transfected with the MyoG-EGFP plasmid vector GV143. MyoG-transfected MSCs (MTMs) were transplanted into rat gastrocnemius muscles at 1 week after surgical denervation. Controls included injections of untransfected MSCs or the vehicle only. Muscles were harvested and analyzed at 2, 4, and 24 weeks post-transplantation. Immunofluorescence confirmed MyoG overexpression in MTMs. The muscle wet weight ratio was significantly reduced at 2 weeks after MTM injection (67.17±6.79) compared with muscles injected with MSCs (58.83±5.31) or the vehicle (53.00±7.67; t=2.37, P=0.04 and t=3.39, P=0.007, respectively). The muscle fiber cross-sectional area was also larger at 2 weeks after MTM injection (2.63×103±0.39×103) compared with MSC injection (1.99×103±0.58×103) or the vehicle only (1.57×103±0.47×103; t=2.24, P=0.049 and t=4.22, P=0.002, respectively). At 4 and 24 weeks post-injection, the muscle mass and fiber cross-sectional area were similar across all three experimental groups. Immunohistochemistry showed that the MTM group had larger MyoG-positive fibers. The MTM group (3.18±1.13) also had higher expression of MyoG mRNA than other groups (1.41±0.65 and 1.03±0.19) at 2 weeks after injection (t=2.72, P=0.04). Transplanted MTMs delayed short-term atrophy of denervated muscles. This approach can be optimized as a novel stand-alone therapy or as a bridge to surgical re-innervation of damaged muscles.

[Cloning, sequencing and in vitro expression of human RANTES gene].

An expected 276 bp fragment of the gene precursor encoding the signal peptide and mature protein of human beta-chemokine RANTES was amplified by reverse transcription-polymerase chain reaction (RT-PCR) from RNA of PHA-activated human peripheral blood lymphocytes. This putative interested gene was inserted directly into a T-vector and the ligation was confirmed by restriction enzyme digestion. The sequence data of the cloned fragment showed that it was almost identical with published sequences of RANTES gene, except for only one nucleotide substitution within the signal peptide region. The in vitro expressed recombinant RANTES protein was detected by the chemiluminescence enzyme-linked immune Dot blotting assay after combining the recombinant plasmid with the in vitro SP6/T7 transcription and translation system. The successful cloning and expression of RANTES gene should shed light on future's gene therapy of AIDS.

Dose findings of dihydroartemisinin in treatment of falciparum malaria.

Forty patients with uncomplicated P. falciparum malaria were respectively treated in an open randomized comparative study of dihydroartemisinin tablets given at total doses of 480 mg over 5 days and 640 mg over 7 days in a drug-resistant malaria endemic area in Hainan, China. The result showed that all patients were clinically cured. In 5-day and 7-day groups, the mean fever clearance times (FCT) were 26.1+/-10.2 and 21.1+/-11.8 hours respectively; the mean parasite clearance times (PCT) were 58.7+/-20.9 and 59.4+/-20.9 hours respectively, which showed no significant difference. 28-day follow-ups were accomplished on 39 and 37 cases respectively in two groups, the recrudescence rates were 20.5% (8/39) in 5-day group, while 2.7% (1/37) in 7-day group with significant difference (chi2=4.19, p<0.05). No clinical drug-related side effect was found in two groups during treatment.

Identification of Anoectochilus formosanus and Anoectochilus koshunensis species with RAPD markers.

RAPD (random amplified polymorphic DNA) markers were developed to distinguish Anoectochilus formosanus from Anoectochilus koshunensis and their putative hybrids. Morphological differentiation of these two species beyond the flowering period is difficult. RAPD markers provide a rapid and easy tool for identification of the two Anoectochilus species. In the study, forty arbitrary decamer primers were screened, and nineteen species-specific RAPD markers generated from polymerase chain reactions (PCR) with eight random primers were obtained. Nine were specific to A. formosanus and ten to A. koshunensis. Two primers, OPC-08 and OPL-07, produced two markers, one specific to A. formosanus and the other specific to A. koshunensis, which simultaneously appeared in the hybrids pattern. The RAPD markers can be applied both to identification of A. formosanus and A. koshunensis species and to assessment of the extent fo hybridization in hybrids between them. This information facilitates the breeding program process.

Nonlinear adaptive motion control for manipulators with compliant joints.

How to perform control and achieve stability of robotic manipulators with joint flexibility forms a problem of profound practical and theoretical interest. This paper is to investigate and to solve this problem without strict assumption on the joint stiffness. Here, an adaptive control scheme of a flexible-joint manipulator, which takes into account its full nonlinear dynamics, is presented. Without the knowledge of the system model, the developed control lams, requiring only the position and velocity information of the actuators and links, is capable of driving the link tracking errors asymptotically to zero, while maintaining the uniform boundedness of all signals in the closed-loop system. To demonstrate the effectiveness of the proposed control law, an example of a two-link flexible-joint manipulator is constructed and a number of computer simulations are performed which show quite satisfactory results.

The infectivity of gametocytes of Plasmodium falciparum from patients treated with artemisinin.

Twenty-seven patients with gametocytes of Plasmodium falciparum (PF) were divided into groups A, B, and C. A daily dose of 1200 mg artemisinin was given for 5 days to group A, a state dose of 750 mg of mefloquine to group B and a single dose of 750 mg mefloquine combined with 45 mg primaquine to group C. After treatment, the gametocyte count was taken daily, and infectivity of the gametocytes to Anopheles dirus via membrane feeding was also studied. Results showed that in group A, the density of gametocyte and infectivity were significantly reduced on days 4, 7, 14 and 21 after treatment; In group B, the gametocytes were significantly reduced on days 7, 14 and 21 and infectivity was significantly cut down on days 14 and 21 after medication. In group C, gametocytes disappeared in 5 out of 9 patients with failure of infecting mosquitoes in all 9 patients on day 4 after treatment. These indicate that artemisinin can effectively influence the infectivity of gametocytes of PF. Artemisinin is much better in blocking the transmission of PF malaria than mefloquine.

Clinical trials of artemisinin and its derivatives in the treatment of malaria in China.

Since 1979 several derivatives of artemisinin have been synthesized and studied in China. Artemisinin suppositories, artesunate (oral or parenteral), intramuscular artemether and dihydroartemisinin tablets have all proved rapidly effective. In all, 2352 patients (2150 with Plasmodium falciparum and 202 with P. vivax) have been included in clinical trials from our centre. All preparations have been well tolerated. These drugs have now replaced chloroquine and quinine for the treatment of malaria in China.

Pharmacokinetics of the combination pyrimethamine with sulfadoxine and mefloquine (FANSIMEF) in Chinese volunteers and the relative bioavailability of a lacquered tablet.

The oral single-dose pharmacokinetics and bioavailability of mefloquine (M) in combination with pyrimethamine (P) and sulfadoxine (S) from a single non-lacquered tablet (NL; M 250 mg, P 25 mg, S 500 mg) and two lacquered tablets (L; M 125 mg, P 12.5 mg, S 250 mg) were investigated in 6 healthy Chinese volunteers. The plasma concentrations of P and S were measured by high-performance liquid chromatography with UV detector over 11 days and the plasma concentrations of M were measured by gas chromatography with electron capture for 63 days. The pharmacokinetic evaluation of each of the three components was based on the assumption of an open linear one-compartment model. The model-independent pharmacokinetic parameters such as elimination half-life and total clearance of P and S in the present study were not appreciably different from those reported previously. The pharmacokinetic parameters of elimination half-life, total clearance and apparent volume of distribution of M were 11 days, 45.8 ml/h.kg, and 14.8 l/kg, respectively. Compared to previously published data on M in Thai patients, Caucasian, Brazilian and African subjects, it was found that the elimination half-life in Chinese subjects was similar to that in Thai patients, but different from Caucasian, Brazilian and African subjects. There were significant differences in total clearance and volume of distribution among Chinese subjects and Thai patients. The differences in pharmacokinetic behaviour of M between subject groups needs to be examined further. The relative bioavailability of P, S, and M in the lacquered and non-lacquered tablet formulations in the 6 subjects studied were not significantly different with values (mean +/- SD) of 0.98 +/- 0.06, 1.28 +/- 0.20 and 1.02 +/- 0.17, respectively.

[Comparative study of artemisinin suppositories and piperaquine phosphate in the treatment of falciparum malaria].

Artemisinin, developed by Chinese scientists, is a new type of anti-malarial drug with quick effect and low toxicity. Since its solubility in water or oil is very low, it cannot be made into a clear injection to be given intramuscularly or intravenously for emergency use. The artemisinin suppositories used in the study was provided by the institute of Chinese Materia Medica in 1982. Phase I and Phase II clinical trials of the drug were made by Guangzhou College of TCM. The results showed that the therapeutic effect of Artemisinin suppositories was satisfactory with no apparent side effects. The total dosage recommended was 2800-3200 mg. In 1986, fifty-six adults with falciparum malaria were treated with a total dose of 2800 mg Artemisinin suppositories for 3 days and randomly compared with a control group of Piperaquine phosphate in the Dongfang Town Hospital, Dongfang ( ) County of Hainan Island. The parasite clearance time in Artemisinin suppositories group (71.8 +/- 16.0 hrs) was significantly faster than that of Piperaquine phosphate group (100.3 +/- 20.3hrs), but recrudescence rate by 28 days (48.2%) was much higher than that of Piperaquine phosphate (17.0%). Artemisinin suppositories is simple to administrate and therefore it could be applied in endemic area of remote countryside and to the patients of incapable of oral dosing.

Double-blind dose finding study of mefloquine-sulfadoxine-pyrimethamine in children with acute falciparum malaria.

Three different doses of a combination of mefloquine-sulfadoxine-pyrimethamine (MSP), given double-blind as a single dose to 60 children, were evaluated for efficacy and tolerance. The children, 42 boys and 18 girls aged between 5 and 15 years, received a mefloquine dose equivalent to 1, 1.5, or 2 standard MSP (Fansimef) tablets. Radical cure was obtained in all patients with only mild to moderate side effects of nausea and vomiting, which were not worse in the higher dose groups. For children living in an endemic malarious area, a single dose of mefloquine 7.1-12.5 mg/kg, given in combination with sulfadoxine (14.3-25.0 mg/kg) and pyrimethamine (0.7-1.3 mg/kg), is a safe and effective treatment for uncomplicated chloroquine-resistant Plasmodium falciparum malaria. This dose of MSP is approximately 10 mg/kg, 20 mg/kg and 1.0 mg/kg respectively of mefloquine, sulfadoxine and pyrimethamine, which is equivalent to a single standard tablet of Fansimef (mefloquine, 250 mg; sulfadoxine, 500 mg; pyrimethamine, 25 mg) given to a child weighing 20-30 kg.

Randomised comparative study of mefloquine, qinghaosu, and pyrimethamine-sulfadoxine in patients with falciparum malaria.

A prospective trial in 80 patients randomly allocated to four antimalarial treatment regimens--mefloquine plus pyrimethamine-sulfadoxine ('Fansidar'); mefloquine plus qinghaosu; mefloquine, fansidar, and qinghaosu; and qinghaosu alone--was carried out on Hainan Island, China, in patients with chloroquine-resistant falciparum malaria. A radical cure with slight side-effects was obtained with mefloquine plus fansidar; the addition of qinghaosu greatly increased the rate of parasite clearance with no additional side-effects. Qinghaosu alone had a rapid rate of parasite clearance, no side-effects, but a high recrudescence rate. These antimalarial drugs seem to act at different stages of the asexual parasite cycle and their most efficient use may depend on when in the course of the disease they are given. Because of the continuing appearance of drug-resistant strains of Plasmodium falciparum combination drug therapy is now indicated, but which drugs and how best they should be used remains to be decided.