[A prospective cohort study on blood pressure control and risk of ischemic stroke in patients with hypertension].

Objective: To explore the association between blood pressure control and risk of ischemic stroke (IS) in patients with hypertension. Methods: A total of 5 488 patients with hypertension from 60 communities were randomly selected from 101 communities in 8 streets of Nanshan District in Shenzhen City by using two-stage sampling method. The social demographic characteristics, behavior and life style, coronary heart disease and diabetes were collected and the physical condition, blood pressure and blood biochemical indexes were measured. From April 1, 2010 to August 31, 2017 as the follow-up period, the incidence of IS was annually collected by using telephone survey. Cox proportional hazard regression model was used to analyze the relationship between blood pressure control, systolic blood pressure (SBP), diastolic blood pressure (DBP) and the risk of IS. Results: The age of all patients was (58.50±12.14) years old, including 2 712 males (49.42%) and 3 112 patients with well-controlled blood pressure (56.71%). During the follow-up period, 358 new cases of IS were confirmed, and the incidence density was 1 346.27/100 000 person-years. Cox proportional hazard regression model analysis showed after adjusting for confounding factors, unstable blood pressure control, SBP≥150 mmHg (1 mmHg=0.133 kPa; compared with SBP<120 mmHg), and DBP≥95 mmHg (compared with DBP<80 mmHg) were associated with risk of IS. The HR (95%CI) was 1.29 (1.04, 1.59), 2.00 (1.26, 3.17) and 1.52 (1.01, 2.64), respectively. Subgroup analyses showed these associations only existed in female patients with hypertension. The HR (95%CI) was 1.39 (1.05, 1.85), 2.53 (1.41, 4.56) and 1.73 (1.00, 3.36), respectively. Conclusion: Unstable blood pressure control increases the risk of IS in female patients with hypertension.

A new mouse mutant of the Cdh23 gene with early-onset hearing loss facilitates evaluation of otoprotection drugs.

We report a novel mutation (erlong, erl) of the cadherin 23 (Cdh23) gene in a mouse model for DFNB12 characterized by progressive hearing loss beginning from postnatal day 27 (P27). Genetic and sequencing analysis revealed a 208 T >C transition causing an amino-acid substitution (70S-P). Caspase expression was upregulated in mutant inner ears. Hearing was preserved (up to 35-dB improvement) in pan-caspase inhibitor Z-VAD-FMK-treated mutants compared with untreated mutants (P<0.05). Outer hair cell (OHC) loss in the cochleae of Z-VAD-FMK-treated mutants was significantly reduced compared with those of untreated mice. Thus, the erl mutation can lead to hearing loss through apoptosis. This is the first genetic mouse model of hearing loss shown to respond to otoprotective drug therapy. The short interval from initial hearing loss to deafness (P27-P90) makes this model ideal for screening and validating otoprotective drugs.

Transdermal testosterone gel increases serum testosterone levels in hypogonadal men in Taiwan with improvements in sexual function.

A randomized, double-blind, placebo-controlled trial was conducted to (1) evaluate efficacy and safety of transdermal testosterone gel (AndroGel) for hypogonadal men in Taiwan, and (2) observe improvements in sexual function through international index of erectile function (IIEF) scores. Eligible hypogonadal men were randomized to receive 50 mg/day transdermal testosterone gel (TTG) or placebo for 3 months. Primary end point was change from baseline in total testosterone (TT) and free testosterone (FT). Secondary end points were change from baseline in serum hormone levels (such as dihydrotestosterone (DHT), estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex-hormone-binding globulin (SHBG)) and changes in IIEF scores. Safety evaluations included adverse events (AEs) and skin irritation assessment. Compared with baseline, the TTG group (n=20) had statistically significant increases in mean TT levels at month 1 (P=0.024) and month 2 (P=0.025), but no significant changes at month 3. TT levels in the placebo group (n=18) showed no statistically significant change at any visit. Changes in FT levels paralleled changes in TT levels in both groups. TTG group IIEF scores were significantly increased at month 3 (P=0.01), compared with a decline in placebo scores. No drug-related AEs occurred in the TTG group; the placebo group had 2 AEs (mild skin rash). In conclusion, TTG effectively restores serum TT and FT levels to a normal physiological range for hypogonadal men in Taiwan and improves sexual function.

Characterisation and molecular epidemiology of extended-spectrum beta-lactamase-producing Enterobacter cloacae isolated from a district teaching hospital in Taiwan.

Enterobacter cloacae (n = 110) isolates from a district hospital in Taiwan were screened for extended-spectrum beta-lactamases (ESBLs). In total, 17 ESBL-producers were identified, based on the combination-disk synergy test using cefotaxime and ceftazidime +/- clavulanic acid. Investigation of ESBL genes in 33 ceftazidime-resistant isolates revealed the SHV-12 gene in the same 17 ESBL-producers. In addition, one isolate also carried the CTX-M-3 gene, and two isolates also carried the CTX-M-9 gene. No major epidemic clone of ESBL-producers was identified by pulsed-field gel electrophoresis. Routine screening for the ESBL phenotype, focusing on ceftazidime-resistant E. cloacae, should be undertaken in this area.

Combined use of androgen and sildenafil for hypogonadal patients unresponsive to sildenafil alone.

To investigate the therapeutic effect of androgen on hypogonadal patients unresponsive to sildenafil alone. In total, 32 hypogonadal patients with erectile dysfunction (ED), initially had an inadequate response to sildenafil (100 mg). Oral testosterone undecanoate (Restandol, 80 mg, bid or tid) alone was supplied for 2 months, and if patients could not achieve a satisfactory erection, combined use of testosterone and sildenafil was continued thereafter. Total testosterone (TT), free testosterone (FT), and the parameters of the International Index of Erectile Function (IIEF), International Prostate Symptom Score (IPSS), and uroflow rate (UFR) were assessed. Eleven patients (34.3%) achieved satisfactory erectile function after testosterone replacement only. Another 12 (37.5%) patients experienced satisfactory intercourse after combined therapy. Serum TT and FT levels significantly increased after the use of testosterone alone (415+/-163 vs 220+/-101 ng/dl, P<0.01; 10.4+/-4.6 vs 5.1+/-1.9 ng/dl; P<0.01, respectively) and the combined use of testosterone and sildenafil (498+/-178 vs 220+/-101 ng/dl, P<0.01; 11.7+/-4.6 vs 5.1+/-1.9 ng/dl, P<0.001, respectively); as did the IIEF score (14.8+/-6.8 vs 12.6+/-7.5, P<0.01, 17.5+/-5.2 vs 12.6+/-7.5, P<0.001, respectively). However, no statistical differences were demonstrated for IPSS or UFR. In conclusions, one-third of hypogonadal patients with ED who failed to respond to sildenafil, responded to testosterone alone, another third responded to sildenafil again after normalization of testosterone. So, in hypogonadal patients with ED, androgen supplementation is first-line therapy. If patients are unresponsive to androgen alone or sildenafil alone, combined use may improve erectile function and enhance the therapeutic effect of PDE-5 inhibitors.

Hormone levels in middle-aged and elderly men with and without erectile dysfunction in Taiwan.

The change in sexual hormones with age in middle-aged and elderly Chinese men, with and without erectile dysfunction (ED), was investigated. Total testosterone (TT), free testosterone (FT), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG) were determined from fasting serum samples by radioimmunoassay in 627 middle-aged and elderly ethnic Chinese men with and without ED. Calculated FT was derived from TT and SHBG. Patients with ED were subdivided into groups having low serum TT (<2.7 ng/ml) and normal TT (> or =2.7 ng/ml). FT and DHEAS declined and SHBG rose with age in both normal patients and in patients with ED. TT and SHBG were lower in patients with ED than in normal subjects at all ages. In contrast to findings in previous studies, levels of FT were higher in patients with ED than in normal subjects. Hormonal changes in this Chinese population generally mirrored those in previously studied ethnic populations, except for higher FT in patients with ED. This suggests that hormonal levels in patients with ED may vary in different populations. The significance and reproducibility of this finding remains to be determined.

Identification of a novel cephalosporinase (DHA-3) in Klebsiella pneumoniae isolated in Taiwan.

A strain of Klebsiella pneumoniae resistant to cefoxitin and oxyimino-cephalosporins, but susceptible to cefepime, was isolated from an adult patient hospitalised in Taichung, Taiwan. Isoelectric focusing revealed three beta-lactamases with isoelectric points of 5.4, 8.2 and 7.9, respectively. Following PCR with plasmid DNA templates and gene sequencing, these enzymes were shown to correspond to TEM-1, SHV-5 and a novel DHA-1-like enzyme (designated DHA-3). The bla genes for TEM-1 and SHV-5 were transferable, but the bla(DHA-3) gene was non-self-transferable in conjugation experiments. All three bla genes were successfully introduced by electrotransformation into an Escherichia coli recipient (DH5alpha), resulting in a similar resistance profile to that observed in the original donor strain. Other K. pneumoniae strains producing DHA-1-like enzymes have been identified previously in Taiwan, and this report suggests that DHA-type beta-lactamases are continuing to emerge in this country.

Regulation of colony-stimulating factor 1 receptor signaling by the SH2 domain-containing tyrosine phosphatase SHPTP1.

SHPTP1 (PTP1C, HCP, SHP) is an SH2 domain-containing tyrosine phosphatase expressed predominantly in hematopoietic cells. A frameshift mutation in the SHPTP1 gene causes the motheaten (me/me) mouse. These mice are essentially SHPTP1 null and display multiple hematopoietic abnormalities, most prominently hyperproliferation and inappropriate activation of granulocytes and macrophages. The me/me phenotype suggests that SHPTP1 negatively regulates macrophage proliferative pathways. Using primary bone marrow-derived macrophages from me/me mice and normal littermates, we examined the role of SHPTP1 in regulating signaling by the major macrophage mitogen colony-stimulating factor 1 (CSF-1) (also known as macrophage colony-stimulating factor). Macrophages from me/me mice hyperproliferate in response to CSF-1. In the absence of SHPTP1, the CSF-1 receptor (CSF-1R) is hyperphosphorylated upon CSF-1 stimulation, suggesting that SHPTP1 dephosphorylates the CSF-1R. At least some CSF-1R-associated proteins also are hyperactivated. SHPTP1 is associated constitutively, via its SH2 domains, with an unidentified 130-kDa phosphotyrosyl protein (P130). P130 and SHPTP1 are further tyrosyl phosphorylated upon CSF-1 stimulation. Tyrosyl-phosphorylated SHPTP1 binds to Grb2 via the Grb2 SH2 domain. Moreover, in me/me macrophages, Grb2 is associated, via its SH3 domains, with several tyrosyl phosphoproteins. These proteins are hyperphosphorylated on tyrosyl residues in me/me macrophages, suggesting that Grb2 may recruit substrates for SHPTP1. Our results indicate that SHPTP1 is a critical negative regulator of CSF-1 signaling in vivo and suggest a potential new function for Grb2.

Differential regulation of the alpha/beta interferon-stimulated Jak/Stat pathway by the SH2 domain-containing tyrosine phosphatase SHPTP1.

Interferons (IFNs) induce early-response genes by stimulating Janus family (Jak) tyrosine kinases, leading to tyrosine phosphorylation of Stat transcription factors. Previous studies implicated protein-tyrosine phosphatase (PTP) activity in the control of IFN-regulated Jak/Stat signaling, but the specific PTPs responsible remained unidentified. We have found that SH2 domain-containing PTP1 (SHPTP1; also called PTP1C, HCP, or SHP) reversibly associates with the IFN-alpha receptor complex upon IFN addition. Compared with macrophages from normal littermate controls, macrophages from motheaten mice, which lack SHPTP1, show dramatically increased Jak1 and Stat1 alpha tyrosine phosphorylation, whereas Tyk2 and Stat2 activation is largely unaffected. These findings correlate with selectively increased complex formation on a gamma response element, but not an IFN-stimulated response element, in motheaten macrophages. Our results establish that SHPTP1 selectively regulates distinct components of Jak/Stat signal transduction pathways in vivo.