20(S)-Protopanaxatriol, one of ginsenoside metabolites, inhibits inducible nitric oxide synthase and cyclooxygenase-2 expressions through inactivation of nuclear factor-kappaB in RAW 264.7 macrophages stimulated with lipopolysaccharide

Ginsenosides from Panax ginseng are metabolized by human intestinal bacteria after oral administration of ginseng extract. 20(S)-Protopanaxatriol (PPT) is one of the major metabolites of ginsenosides. Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are important enzymes that mediate inflammatory processes. Improper up-regulation of iNOS and/or COX-2 has been associated with the pathogenesis of inflammatory diseases and certain types of human cancers. Here, we investigated whether PPT could modulate iNOS and COX-2 expressions in RAW 264.7 macrophages stimulated with the endotoxin lipopolysaccharide (LPS). We found that PPT blocked the increase in LPS-induced iNOS and COX-2 expressions through inactivation of nuclear factor-kappaB by preventing I-kappaBalpha phosphorylation and degradation. Thus, it may be possible to develop PPT as a useful agent for chemoprevention of cancer or inflammatory diseases.     

Transgenic mouse model for breast cancer: induction of breast cancer in novel oncogene HCCR-2 transgenic mice

Transgenic mice containing novel oncogene HCCR-2 were generated to analyse the phenotype and to characterize the role of HCCR-2 in cellular events. Mice transgenic for HCCR-2 developed breast cancers and metastasis. The level of p53 in HCCR-2 transgenic mice was elevated in most tissues including breast, brain, heart, lung, liver, stomach, kidney, spleen, and lymph node. We examined whether stabilized p53 is functional in HCCR-2 transgenic mice. Defective induction of p53 responsive genes including p21WAF1, MDM2, and bax indicates that stabilized p53 in HCCR-2 transgenic mice exists in an inactive form. These results suggest that HCCR-2 represents an oncoprotein that is related to breast cancer development and regulation of the p53 tumor suppressor.     

Response of pulmonary tuberculomas to anti-tuberculous treatment.

Pulmonary tuberculomas are well-circumscribed masses caused by Mycobacterium tuberculosis. However, the response of tuberculomas to anti-tuberculous (TB) treatment has not been well defined as yet. The response of pulmonary tuberculomas to anti-TB treatment was retrospectively reviewed in 45 patients diagnosed between January 1997 and December 2001. The areas of pulmonary tuberculomas were estimated by calculating products of the longest and their perpendicular short diameters on chest radiographs. The response to anti-TB treatment was categorised as "decreased" (> 25% reduction in area versus its initial area), "increased" (> 251% increase) and "no change" (the remainder). The mean of treatment duration was 11.5 +/- 3.6 months. Three months after treatment, 18 patients (40.0%) were categorised as decreased, 25 (55.6%) as no change and two (4.4%) as increased. Twelve months after treatment, out of 42 patients available for chest radiographs, 32 patients (76.2%) were categorised as decreased, nine (21.4%) as no change and one patient (2.4%) as increased. At the last follow-up (mean follow-up 27.0 +/- 10.2 months), 37 patients (82.2%) were categorised as decreased. The majority of pulmonary tuberculomas were decreased by anti-tuberculosis treatment during and even after treatment, although a transient enlargement during the early period of treatment was observed infrequently.     

Pharmacoeconomic analysis of thiopurine methyltransferase polymorphism screening by polymerase chain reaction for treatment with azathioprine in Korea

OBJECTIVES: To evaluate the value of genotype-based dosing by polymerase chain reaction (PCR)-based polymorphism screening in terms of cost-effectiveness for treatment with azathioprine in Korea. METHODS: Decision analysis was employed to compare a genotype-based dosing strategy with the conventional weight-based dosing strategy using a hypothetical cohort composed of rheumatoid arthritis and systemic lupus erythematosus patients. The time horizon was set up as 1 yr. Direct medical costs were used. Data used were obtained from previous reports, except for PCR and admission costs, which were from real cases. Cost-effectiveness analysis was conducted from a societal perspective. Outcomes were measured as a total expected cost and an incremental cost-effective ratio. RESULTS: In the base case model, total expected cost and the probability of not dropping out owing to serious adverse events of the conventional weight-based dosing and the genotype-based dosing strategy were 1339 x 10(3) Korean won (1,117 US dollars) and 1109 x 10(3) Korean won (926 US dollars), and 97.06 and 99.90%, respectively. CONCLUSIONS: Our model suggests that a genotype-based dosing strategy through PCR-based thiopurine methyltransferase (TPMT) polymorphism screening is less costly and more effective than the conventional weight-based dosing strategy in Korea, as it was associated with a marked reduction in the number of serious adverse events.     

Is slow nail growth a risk factor for onychomycosis?

This study was carried out to determine whether slow nail growth is a predisposing factor for onychomycosis or if onychomycosis results in slow nail growth. Forty-nine patients with unilateral onychomycosis of the great toenail were enrolled and classified in two groups according to the size of affected area, i.e. more than half or less than half of the toenail. The growth rates of affected and unaffected great toenails of all patients were measured. Before a normal appearance was reached, the growth rates of affected great toenails, when the affected area occupied more than half of total nail plate, was slower than that of the unaffected great toenails. After a normal appearance was achieved, there were no differences in growth rates between affected and unaffected great toenails. Therefore, this study of patients with unilateral toenail onychomycosis did not support the hypothesis that slow nail growth rate is a predisposing factor for onychomycosis.     

Differential coupling of the PAC1 SV1 splice variant on human colonic tumors to the activation of intracellular cAMP but not intracellular Ca2+ does not activate tumor proliferation

PAC1 is a recently cloned and characterized heptahelical, G protein-coupled receptor with high affinity to PACAP-27 and PACAP-38 and is differentially coupled to activate intracellular Ca2+ and cAMP. PAC1 is expressed as four major splice variants, each possessing differential coupling to inositol phosphates and intracellular Ca2+. PAC1 has been shown previously to be expressed and regulate the growth and proliferation of nonsquamous cell lung cancer cells, as well as breast cancer cell lines. PAC1 is expressed on the HCT8 human colon cancer cell line and is coupled to the activation of both intracellular cAMP and Ca2+ with consequent stimulation of growth. In the current study, we contrast the effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on the HCT8 colon cancer cell lines to the HCT116 and FET cell lines wherein PAC1 is expressed as the SV1 or HIP splice variant and is coupled to the activation only of cAMP but not of intracellular Ca2+. These data indicate that human colon tumor cells express PAC1 and are differentially coupled to intracellular signal transduction molecules. The ability to activate both cAMP and Ca2+ appears to be a prerequisite for activation of tumor proliferation, indicating a potentially important factor in how PACAP potentiates the growth of certain tumors.     

A novel polymerase gamma mutation in a family with ophthalmoplegia, neuropathy, and Parkinsonism

BACKGROUND: Mutations in polymerase gamma cause progressive external ophthalmoplegia and a variety of associated symptoms and signs, including neuropathy, ataxia, hypogonadism, hearing loss, muscle weakness, and psychiatric problems. Extrapyramidal signs have been rarely described. OBJECTIVE: To describe a family with a novel polymerase gamma mutation and autosomal dominant transmission of progressive external ophthalmoplegia, neuropathy, hypogonadism, and parkinsonism. DESIGN: Case report. PATIENTS: The proband, a 49-year-old woman with incipient parkinsonism, and her 59-year-old brother with overt parkinsonian features. MAIN OUTCOME MEASURES: Mutation in the proband by sequencing the polymerase gamma gene and in affected relatives by restriction fragment length polymorphism analysis. RESULTS: We found multiple mitochondrial DNA deletions in the proband's muscle and a novel missense mutation in the polymerase gamma gene (A2492G) in the proband and in her affected siblings. CONCLUSION: Parkinsonism was a prominent clinical feature in this family with autosomal dominant ophthalmoplegia, multiple mitochondrial DNA deletions, and a novel mutation in the polymerase gamma gene.     

Chronological alterations of neurofilament 150 immunoreactivity in the gerbil hippocampus and dentate gyrus after transient forebrain ischemia

In this study, we observed the chronological alterations of neurofilament 150 (NF-150) immunoreactivity in the gerbil hippocampus and dentate gyrus after 5 min transient forebrain ischemia. NF-150 immunoreactivity in the sham-operated group was mainly detected in mossy fibers and in the hilar region of the dentate gyrus. NF-150 immunoreactivity and protein contents of NF-150 and RT 97 (polyphosphorylation epitopes of neurofilament) were significantly decreased at 15 min after ischemic insult. Between 30 min and 12 h after ischemic insult, NF-150 immunoreactivity and protein content were significantly increased as compared with the sham-operated group. Thereafter, NF-150 immunoreactivity and protein content started to decrease. At 12 h after ischemic insult, unlike dentate gyrus, NF-150 immunoreactivity increased in pyramidal cells of the CA1 region. Thereafter, NF-150 immunoreactivity in the CA1 region started to decrease, and 4 days after ischemic insult, NF-150 immunoreactivity nearly was similar to that of the sham-operated group. These biphasic patterns of NF-150 immunoreactivity in the hippocampus and dentate gyrus are reverse correlated with that of the intracellular calcium influx. For calcium detection in the CA1 region, we also conducted alizarin red staining. Alizarin red positive neurons were detected in some neurons at 15-30 min after ischemic insult. At 12 h after ischemia, alizarin red positive neurons were decreased. Thereafter, alizarin red positive neurons started to decrease, but alizarin positive neurons were significantly increased in dying neurons 4 days after ischemia. These results suggest that ischemia-related changes of NF-150 expression may be caused by the calcium following transient forebrain ischemia.     

Hypothermia-induced changes of afferent sensory transmission to the VPM thalamus of rats and hamsters

Effects of hypothermia on the afferent somatosensory transmission to the ventroposteromedial (VPM) thalamus were determined in anesthetized rats and hamsters. Hamsters showed a gradual suppression of afferent sensory transmission during cooling (to 18 degrees C) and disinhibition during subsequent warming of body temperature (Tb). However, rats exhibited steep inhibition from Tb 26 degrees C to complete absence of sensory transmission at Tb 20 degrees C and abrupt disinhibition during subsequent warming. Species difference at thalamic level was quite similar to our previous results in the primary somatosensory (SI) cortex, suggesting that changes of sensory transmission observed in the SI cortex may have already occurred at thalamic level. Differences between the cortex and the thalamus were observed only during deep hypothermia in rat and during the final period of warming in hamster. Conduction latencies of thalamocortical system of both species were not influenced during Tb lowering until 24 degrees C (equivalent to brain temperature 25-26 degrees C). These results suggest inherently different adaptability to hypothermia in processing somatosensory information between hibernator and non-hibernator, but similar sustainability of sensory functions of the thalamocortical system during hypothermia in both species.