Inhibition of the androgen receptor induces a novel tumor promoter, ZBTB46, for prostate cancer metastasis.

Current therapeutic regimens for prostate cancer focus on targeting androgen receptor (AR) signaling. However, the AR is a key factor in luminal epithelium differentiation and was shown to have a role as a tumor suppressor. Thus, its inhibition may activate oncogenic pathways that contribute to metastatic castration-resistant prostate cancer (CRPC). Herein, we report a novel tumor promoter, ZBTB46, which is negatively regulated by AR signaling via microRNA (miR)-1-mediated downregulation. ZBTB46 is associated with malignant prostate cancer and is essential for metastasis. Its overexpression can overcome the antitumor effects of miR-1 and promote androgen-independent proliferation. We demonstrated that ZBTB46 can transcriptionally regulate SNAI1, a key epithelial-to-mesenchymal transition (EMT) driver, which could contribute to induction of the EMT after androgen-deprivation therapy and metastasis. Our findings are supportive of the model that disruption of AR's function may predispose prostate cancer to progress to metastatic CRPC.

KLF4 functions as an activator of the androgen receptor through reciprocal feedback.

In prostate cancer, Krüppel-like factor 4 (KLF4) depletion occurs frequently, suggesting a role as suppressor tumor. KLF4 is a transcription factor associated with androgen receptor (AR) expression; however, its cellular functions and signaling regulation mechanism remain largely unknown. In this study, we demonstrated that activated AR binds to the KLF4 promoter and enhances KLF4 expression, which reciprocally targets the AR promoter, thus sustaining KLF4 activity. Ectopic KLF4 expression in androgen-independent prostate cancer cells induced AR expression and decreased cell proliferation, invasion and bone metastasis. We previously showed that increased microRNA (miR)-1 expression is associated with reduced bone metastasis of prostate cancer cells. Here we observed that KLF4 targets the primary miR-1-2 stem-loop promoter and stimulates miR-1 expression. In clinical prostate cancer specimens, KLF4 levels were positively correlated with miR-1 and AR levels. These data suggest that the loss of KLF4 expression is one mechanistic link between aggressive prostate cancer progression and low canonical AR output through miR-1 inactivation.

Pattern analysis and variations in the utilization of antihypertensive drugs in Taiwan: a six-year study.

BACKGROUND: In the last few years there have been changed in the pattern of consumption of antihypertensive drugs in other countries. Factors causing this variability include differences in the effectiveness of detection, guidelines for the management of hypertension, and differences in national health insurance systems among countries. AIM: The aim of this study was to reveal patterns in the use of antihypertensive drugs in Taiwan over a six year period (2001 to 2006) and compare these results with data from other countries. MATERIALS AND METHODS: This study performed descriptive analysis of data from the National Health Insurance Research Database (NHIRD) of Taiwan, and compared these findings with similar findings from around the world. Quantities were standardized using the defined daily dose (DDD) per 1000 inhabitants per day (DID) in accordance with WHO anatomical therapeutic classification and DDD measurement methodology. RESULTS: The total number of DDDs prescribed in Taiwan increased from 0.66 billion in 2001 to 1.08 billion in 2006, representing 80.6 and 129.2 DID in 2001 and 2006, respectively. This indicates a significant increase in the prescription of antihypertensive drugs in Taiwan over this period. The average annual increase ranged from 10.7% for calcium channel blockers (CCBs) to 22.1% for angiotensin II receptor blockers (ARBs). All of these patterns were statistically significant (p < 0.05). The rapid increase in the use of ARBs resulted in its surpassing ACEIs with the second highest DID (21.9) in 2006. Though the proportional use of CCBs and ARBs has increased significantly, the use of thiazide diuretics remains low. CONCLUSIONS: The consumption of antihypertension drugs in Taiwan increased during the period studied and the highest average annual increases were for ARBs and CCBs. Overall consumption of antihypertension drugs also increased in other countries, but differences in the relative increase for each class of drug suggest that further study may be required to clarify the origins and causes.

Association of CHRNA4 polymorphism with depression and loneliness in elderly males.

The cholinergic receptor, nicotinic, alpha 4 (CHRNA4) gene encodes the neuronal nicotinic acetylcholine receptor alpha-4 subunit. Recent research has shown that a variation in CHRNA4 (rs1044396) affects attention and negative emotionality in normal adults. To determine the link between CHRNA4 variation and cognitive function/depressed mood, this study conducted a genotype-phenotype correlation analysis between the common CHRNA4:rs1044396 variant and several baseline parameters of cognition and depressed mood in 192 elderly male subjects without major psychiatric disorders or dementia. Study findings identified a significant link between the CHRNA4:rs1044396 polymorphism and depression and loneliness in the aged. Compared to carriers of at least one T-allele, carriers of the homozygous C/C genotype described themselves as more depressed and lonely. This is the first evidence which may implicate CHRNA4 in depressed emotions in the elderly.

A closed shell structured eyeball model with application to radial keratotomy.

A closed shell structured eyeball model was developed for predicting the displacements and curvatures in an eyeball due to radial keratotomy. Both the cornea and sclera are modeled as an ellipsoidal cap, and the two caps are connected at the limbus to form a closed shell. The analysis of the number of corneal collagen laminae required for the tissue to be theoretically transversely isotropic was presented. The cornea, as well as the limbus and sclera, is considered as macroscopically homogeneous and isotropic in this study. A procedure to obtain the principal curvature at a point on the exterior surface was established. In the basic formulation, large displacements are contemplated. However, the FORTRAN computer program that was prepared to implement the procedure considers small displacements, and the resulting equations are linear. Although the results from this shell structured eyeball model are fairly good quantitatively, they do show vividly the following qualitative corneal behavior after the operation is performed: The opening of an incision has a V-shape, the radial displacements through the corneal thickness are nearly the same, and the largest in-plane displacement is only one-tenth of the largest radial displacement.

Detection and identification of toxigenic Vibrio cholerae O1 strains by a simplified polymerase chain reaction method.

The polymerase chain reaction (PCR) with three oligonucleotide primers was used to amplify both 184 bp and 425 bp DNA fragments of cholera toxin A subunit gene (ctxA) for detection and identification of toxigenic V. cholerae O1 strains in one step. For enhancing the sensitivity, we have used the chemiluminescent detection system for Southern hybridization. A total of 92 Vibrio strains were tested by both PCR and enzyme-linked immunosorbent assay (ELISA). Three E. coli (ETEC) strains, one toxigenic V. mimicus, and one toxigenic V. cholerae non-O1 were also tested for cross reactivities. Our results indicated that the correlation between the immunological ELISA method and the molecular biological PCR method were very well. The lowest detectable amount of the purified serotype Inaba chromosomal DNA by PCR is 2 pg and 0.4 pg by chemiluminescent detection system. In this work we report a PCR assay with a combination of three primers to detect and identify the ctxA of V. cholerae O1 in one step. The simplified and accurate method is useful for toxigenic V. cholerae O1 detection and identification.

A unique mathematic model of the geometry of the human eyeball.

The human eyeball was modeled as two intersecting ellipsoidal caps. Both the cornea and sclera were modeled as an ellipsoidal cap, and the two caps were connected at the limbus to form a completely closed shell. The shell coordinates and three Euler's angles were used, which uniquely defined the geometry of the eyeball. Computer programs were written to construct a geometric model of the human eyeball for radial keratotomy.

Production, Purification, and Characterization of alpha-Galactosidase from Monascus pilosus.

A Monascus pilosus strain was selected for production of intracellular alpha-galactosidase. Optimum conditions for mycelial growth and enzyme induction were determined. Galactose was one of the best enzyme inducers. The enzyme was purified by ammonium sulfate precipitation, gel filtration, and ion exchange chromatography and was demonstrated to be homogeneous by slab gel electrophoresis. The molecular weight of this enzyme, estimated by gel filtration, was about 150,000. The optimum conditions for the enzyme reaction was pH 4.5 to 5.0 at 55 degrees C. The purified enzyme was stable at 55 degrees C or below and in buffer at pH 3 to 8. The activity was inhibited by mercury, silver, and copper ions. The kinetics of this enzyme, with p-nitrophenyl-alpha-d-galactoside as substrate, was determined: K(m) was about 0.8 mM, and V(max) was 39 mumol/min per mg of protein. Enzymatic hydrolysis of melibiose, raffinose, and stachyose was analyzed by thin-layer chromatography.

Phase analysis of gated blood pool scintigraphic images to localize bypass tracts in Wolff-Parkinson-White syndrome.

The ability of radionuclide techniques to localize bypass tracts in patients with Wolff-Parkinson-White syndrome to sites around the atrioventricular (AV) ring using a three view triangulation method was investigated. In 17 patients with Wolff-Parkinson-White syndrome, phase images were generated from gated blood pool scans using the first Fourier harmonic of the time-activity curve of each pixel. In addition, the difference between left and right ventricular mean phase angles was calculated for each patient and for 13 control subjects. Bypass tracts were localized to one or more sites on a 10 site grid schematically superimposed on the AV ring (Duke grid) by electrophysiologic study in all patients and by intraoperative mapping in 7 of the 17 patients. These same 10 anatomic sites were projected onto three scintigraphic views and the site of earliest ventricular phase angle was located in each view. The 10 sites around the AV ring were divided into two anatomic groups: free wall and septal/paraseptal. Phase image locations correlated with electrophysiologic locations within one grid site in 11 of 11 patients with free wall tracts and were confirmed at surgery in 5 of the 11. In five of six patients with septal/paraseptal tracts, electrophysiologic study could not localize the bypass tract to one site, whereas phase images localized two of the five as free wall adjacent to the septum, one as paraseptal and two as true posteroseptal. One posteroseptal site was confirmed at surgery. In one patient, in whom phase image analysis and electrophysiologic study showed different sites, existence of both tracts was confirmed at surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence and clinical significance of the repetitive ventricular response during sinus rhythm in coronary disease patients.

The prevalence of the repetitive ventricular response (RVR) after single and double premature stimulation during sinus rhythm or a paced supraventricular rhythm at a rate of 85 bpm was assessed in 343 patients (group 1: 237 patients studied prospectively who were referred for coronary arteriography and ventriculography; group 2: 44 patients after recent acute myocardial infarction; group 3: 61 patients with documented ventricular tachycardia and/or fibrillation). In group 1 patients, RVR testing was performed from both the right ventricular apex (n = 237) and outflow tract (n = 190), whereas in the remaining patients only the apex was stimulated. In group 1, RVR after a single premature stimulus occurred in 21.9% and after two stimuli in 63.2%. In patients with normal left ventricular (LV) function (n = 63) the prevalence of RVR after a single stimulus was significantly less (9.5%) than in those with LV dysfunction (n = 174;26.4%,p less than 0.01). However, after double stimulation, there was no longer any difference. In group 2, the prevalence of RVR was 25% after one and 34.1% after two premature stimuli. In group 3 patients, RVR was observed in only 14.8% after one and in 41% of patients after two premature stimuli. Ventricular tachycardia (greater than or equal to 10 QRS) was induced in nine patients during a supraventricular rhythm. Two hundred thirty-seven patients of group 1, who were prospectively studied in order to assess the prognostic significance of the RVR, were followed for a mean period of 27.2 +/- 10.7 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of antiarrhythmic surgery on late ventricular potentials recorded by precordial signal averaging in patients with ventricular tachycardia.

In seven patients with documented ventricular tachycardia (VT) and prior myocardial infarction, late potentials (LP) were recorded at the end of or after the QRS complex from the body surface using high-gain amplification and the signal averaging technique (RC filter settings 100 to 300 Hz). In 6 to 7 patients VT could be initiated by programmed right ventricular stimulation; in one case, VT was inducible only from the left ventricle during surgery. Surgery was guided by epi- and endocardial mapping. In most cases besides resection of scar tissue, a partial or complete subendocardial encircling ventriculotomy was performed. Postoperatively, LPs were abolished in five cases, VT being no longer inducible. In the remaining two patients, LPs were still present. VT was still inducible in one of these two cases whereas in the other case, no programmed testing was done postoperatively. These data suggest that the abolition of LPs by surgery is closely related to the disappearance of the propensity to stimulus-induced VT. Thus, the averaging technique represents a new approach to the noninvasive control of the efficacy of surgery in patients with VT and prior myocardial infarction.

[Clinical-electrophysiological findings in patients following ventricular fibrillation]. / Klinisch-elektrophysiologische Befunde bei Patienten nach Kammerflimmern.

30 patients, successfully resuscitated from ventricular fibrillation outside acute myocardial infarction, were studied by programmed right-ventricular stimulation. The stimulation studies were carried out one week up to 1.5 years after the event (median two months). Mean age of the patients was 50.2 +/- 8.8 years, 27 were male. The majority of patients had coronary heart disease and/or localized or diffuse ventricular contraction abnormalities. In 26 patients the stimulation protocol included the application of premature single and double ventricular stimuli during sinus rhythm and a paced ventricular rhythm at cycle lengths of 500, 430, 370 and 330 msec until ventricular tachycardia, ventricular flutter or ventricular fibrillation were induced. 4 patients were studied only at a cycle length of 500 msec. Using this stimulation protocol, in 7 patients (26.9%) sustained ventricular tachycardia, in 5 patients (19.2%) ventricular flutter and in 7 patients (26.9%) ventricular fibrillation were induced. These arrhythmias were induced at a basic cycle length of 500 ms in 10 patients, at 430 ms in 3 patients, at 370 ms in 4 patients and at 330 ms in 2 patients. In the remaining patients, only ventricular echo beats (one to six) of the intra-ventricular reentry type were induced. Thus these results show a persistent increase in ventricular vulnerability in a high percentage of patients (73%), provided that appropriate stimulation techniques are used. These observations may have great importance for the management of these patients.

Prevalence of late potentials in patients with and without ventricular tachycardia: correlation with angiographic findings.

Late potentials occurring at the end of or after the QRS complex were searched for from the body surface using high gain amplification and signal averaging techniques with filter settings between 100 and 300 hertz. The number of repetitions of the averaging process ranged between 150 and 300. Two hundred thirty-six patients were studied. In 27 control subjects, no late potentials were recorded. Among 146 patients without ventricular tachycardia or fibrillation, late potentials were present in 49 (34 percent). The mean duration of late potentials was 31 +/- 15.3 ms (median 25). Of 63 patients with documented ventricular tachycardia or fibrillation, 45 (71 percent) had late potentials (mean duration 51 +/- 31.5 ms; median 50) (probability [p] greater than 0.001). There was a close correlation between the detection of late potentials and left ventricular function. Late potentials occurred more frequently in patients with than in those without ventricular akinesia or aneurysm and in patients with than in those without ventricular tachycardia or fibrillation. In conclusion, late potentials are a frequent finding in patients with regional contraction abnormalities, both in patients with and in those without documented ventricular tachycardia. The greater prevalence and longer duration of these signals in patients with ventricular tachycardia or fibrillation might be responsible for the greater susceptibility to ventricular tachycardia. Long-term follow-up studies will be necessary to assess the possible prognostic significance of late potentials in patients without previously documented ventricular tachycardia or fibrillation.

[Response of ventricular late potentials after surgical therapy of ventricular tachycardia]. / Verhalten ventrikulärer Spätpotentiale nach operativer Therapie ventrikulärer Tachykardien.

19 patients with either previously documented sustained ventricular tachycardia (VT) (n = 16) or only inducible VT (n = 3, one of whom had recurrent syncope), due to previous myocardial infarction were studied pre- and postoperatively. Mean age was 53 +/- 6 years, 16 were male, 3 female. In all but one, VT could be induced preoperatively by programmed right ventricular stimulation. Late potentials (LP) were recorded at the end of or after the QRS-complex from the body surface using high-gain amplification and the signal averaging technique (RC-filter settings 100 to 300 Hz). Indication for surgery was either intractable VT or bypass grafting and/or aneurysmectomy. Preoperatively, mean duration of late potentials was 54 +/- 37.7 ms, mean amplitude was 12 +/- 14.0 mean V. Surgery was guided by epi- and endocardial mapping. In 14 cases endomyocardial encircling ventriculotomy was the main procedure, whereas in 5 patients only aneurysmectomy and bypass grafting were performed. Postoperatively, late potentials were no longer detectable in 12 cases, whereas in 6 of 7 cases there was a decrease in duration, but no essential change in amplitude. A postoperative electrophysiological study was performed in 18 cases. In those 12 patients with abolition of LPs, the maximal number of inducible ventricular echo beats using an extended stimulation program from three right ventricular sites, ranged between 1 and 5 in 9 cases, between 10 and 11 VE in 2 cases, whereas VT was induced in only 1 case. In 6 patients in whom LPs were still detectable, ventricular tachycardia could still be induced in 2 cases and a maximal response of ten echo beats was observed in another patient. Abolition of LP by surgery is closely related to the disappearance of the propensity to stimulus-induced VT. Thus the averaging technique may provide a non-invasive procedure to assess the successful outcome after operation for ventricular tachycardia. If, however, LPs are still present, this does not exclude successful surgical abolition of the propensity to ventricular tachycardia.

[Electrophysiological findings and follow-up in patients with syncope (author's transl)]. / Elektrophysiologische Befunde und Langzeitbeobachtung bei Patienten mit Synkopen.

92 patients (mean age 54 +/- 14.7 years, 54 men) with unexplained syncopes were investigated by Holter monitoring, exercise testing and His-bundle-electrography (high-rate and programmed atrial stimulation). The diagnoses on 43 patients were sinus node dysfunction, in 32 cases atrio and/or intraventricular block, and in 6 patients idiopathic atrial fibrillation, whereas 8 patients had a history of ventricular tachycardia, 48 patients received a pacemaker (mean age 58 +/- 12.9 years), and 44 patients were discharged without a pacemaker (mean age 49 +2- 15.6 years). The mean duration of follow-up was 56 +2- 17.1 months. There were 13 deaths, 9 patients died from heart failure, 1 died suddenly, and 3 patients died from non-cardiac causes. 7 patients were lost to follow-up. 54 patients had no syncope any longer, while in 18 cases syncope was still present, 14 patients without pacemaker and 4 patients with pacemaker still had attacks. The cardiac mortality was 18.8% (with pacemaker) and 2.3% (without pacemaker). The only sudden cardiac death was observed in a patient with pacemaker. This study shows that pacemaker implantation bases on electrophysiologic study is able to improve symptoms in patients with syncope. However, the long-term prognosis of the patients is mainly depending on the severity of their underlying heart disease.

[Electrophysiological effects of flecainide on stimulus-inducible ventricular tachycardia]. / Elektrophysiologische Wirkungen von Flecainid (R 818) auf stimulusinduzierte ventrikuläre Tachykardien.

13 patients (54 +/- 11.8 years) with either spontaneously occurring ventricular tachycardia (N = 12) or recurrent syncope (n = 1) probably due to ventricular tachycardia were studied electrophysiologically. In all patients, ventricular tachycardia could be initiated by programmed right ventricular stimulation during the control study. Ventricular tachycardia was sustained in eleven patients and non-sustained in the remaining two. After several days of oral administration of flecainide (400 to 500 mg per day) sustained ventricular tachycardia could still be initiated in seven cases that had to be interrupted by overdrive stimulation in five cases, and by cardioversion in the remaining two. In six cases, short, self-terminating episodes of ventricular tachycardia were induced. In four patients, induction of ventricular tachycardia was unchanged or made easier, whereas in seven cases ventricular tachycardia was more difficult to induce (i.e. later during the step-like stimulation program). The mean rate of induced ventricular tachycardia decreased from 215 +/- 59.4/min (+/- S.D.) to 169 +/- 44.1/min during flecainide (p less than 0.025). The interval between the tachycardia-initiating beat and the first beat of tachycardia increased from 323 +/- 61.1 ms to 438 +/-148.3 ms (P less than 0.02). The effective refractory period of the right ventricle was prolonged from 240 +/- 20.5 ms t 279 +/- 37.3 ms (P less than 0.005). The plasma concentration of flecainide at the time of stimulation was 995 +/- 238 ng/ml. Thus, flecainide exerts a marked effect on the rate of induced ventricular tachycardia, whereas the mode of induction did not change considerably. The prophylactic effect of long-term therapy with flecainide in patients with recurrent ventricular tachycardia needs further studies.

The effects of treatment with antibiotics, laser and acupuncture upon chronic maxillary sinusitis in children.

UNLABELLED: In a clinical study we compared three different types of therapy in chronic maxillary sinusitis. 45 patients, 3-40 years old, were treated, 19 with antibiotics, 18 with acupuncture and 8 with Laser-acupuncture. There was no statistical difference of results between Laser-therapy and antibiotics (Chi-Square-Test). Compared to previous treatments with antibiotics, results and duration of improvement was significantly better after acupuncture. CONCLUSION: acute sinusitis, especially of frontal sinus and in younger children, will better be treated by antibiotics because of the danger of osteomyelitis and meningitis. Acupuncture should be tried in chronic and recurrent stages after exclusion of large adenoids in children or bone inhibition of sinus clearance, especially before an invasive operation like removal of sinus mucosa is carried out.