Severe digital ischaemia treated with phosphodiesterase inhibitors

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miR-31 is consistently inactivated in EBV-associated nasopharyngeal carcinoma and contributes to its tumorigenesis

BACKGROUND: As a distinctive type of head and neck cancers, nasopharyngeal carcinoma (NPC) is genesis from the clonal Epstein-Barr virus (EBV)-infected nasopharyngeal epithelial cells accumulated with multiple genetic lesions. Among the recurrent genetic alterations defined, loss of 9p21.3 is the most frequent early event in the tumorigenesis of EBV-associated NPC. In addition to the reported CDKN2A/p16, herein, we elucidated the role of a miRNA, miR-31 within this 9p21.3 region as NPC-associated tumor suppressor. METHODS: The expression and promoter methylation of miR-31 were assessed in a panel of NPC tumor lines and primary tumors. Its in vitro and in vivo tumor suppression function was investigated through the ectopic expression of miR-31 in NPC cells. We also determined the miR-31 targeted genes and its involvement in the growth in NPC. RESULTS: Downregulation of miR-31 expression was detected in almost all NPC cell line, patient-derived xenografts (PDXs) and primary tumors. Both homozygous deletion and promoter hypermethylation were shown to be major mechanisms for miR-31 silencing in this cancer. Strikingly, loss of miR-31 was also obviously observed in the dysplastic lesions of nasopharynx. Restoration of miR-31 in C666-1 cells inhibited the cell proliferation, colony-forming and migratory capacities. Dramatic reduction of in vitro anchorage-independent growth and in vivo tumorigenic potential were demonstrated in the stable clones expressing miR-31. Furthermore, we proved that miR-31 suppressed the NPC cell growth via targeting FIH1 and MCM2. CONCLUSIONS: The findings provide strong evidence to support miR-31 as a new NPC-associated tumor suppressor on 9p21.3 region. The inactivation of miR-31 may contribute to the early development of NPC.published_or_final_versio

Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertension

Angiotensin receptor blockers (ARBs), also known as sartans, block the activation of angiotensin type 1 receptors and have a recognised role in the treatment of heart failure and nephropathy. Since 2002, there have been three major outcome trials of ARBs in hypertension. We performed a meta-analysis to evaluate the impact of ARB on major outcomes. Randomised controlled trials of ARBs in hypertensive subjects with an average follow-up of at least 2 years and at least 100 major cardiovascular events were included. For each trial, the ARB used, number and characteristics of subjects, baseline and change in blood pressure, cardiovascular and noncardiovascular outcomes were recorded. Three trials involving 29375 subjects were included in the meta-analysis. In Losartan Intervention For Endpoint (LIFE) and Study on Cognition and Prognosis in the Elderly (SCOPE) but not in Valsartan Antihypertensive Long-term Use Evaluation trial (VALUE), an ARB reduced the occurrence of the primary end point and stroke compared to control. Compared to other antihypertensive drugs, ARB treatment was associated with no significant change in all-cause mortality (relative risk ratio (RRR) 0.96, 95% CI: 0.88-1.06, P = 0.45). There was an increase in myocardial infarction (RRR, 1.12, 95% CI: 1.01-1.26, P = 0.041), but a decrease in new-onset diabetes mellitus (RRR, 0.80, 95% CI: 0.74-0.86, P < 0.0000001). In conclusion, the reduction in new-onset diabetes partly offsets any increase in the risk of myocardial infarction. Most hypertensive patients require more than one class of drugs. Small differences in treatment outcome should not over-ride the importance of good blood pressure control. © 2006 Nature Publishing Group. All rights reserved.link_to_subscribed_fulltex

Screening for fever by remote-sensing infrared thermographic camera

Background: Following the severe acute respiratory syndrome (SARS) outbreak, remote-sensing infrared thermography (IRT) has been advocated as a possible means of screening for fever in travelers at airports and border crossings, but its applicability has not been established. We therefore set out to evaluate (1) the feasibility of IRT imaging to identify subjects with fever, and (2) the optimal instrumental configuration and validity for such testing. Methods: Over a 20-day inclusive period, 176 subjects (49 hospital inpatients without SARS or suspected SARS, 99 health clinic attendees and 28 healthy volunteers) were recruited. Remotely sensed IRT readings were obtained from various parts of the front and side of the face (at distances of 1.5 and 0.5 m), and compared to concurrently determined body temperature measurements using conventional means (aural tympanic IRT and oral mercury thermometry). The resulting data were submitted to linear regression/correlation and sensitivity analyses. All recruits gave prior informed consent and our Faculty Institutional Review Board approved the protocol. Results: Optimal correlations were found between conventionally measured body temperatures and IRT readings from (1) the front of the face at 1.5 m with the mouth open (r = 0.80), (2) the ear at 0.5 m (r = 0.79), and (3) the side of the face at 1.5 m (r = 0.76). Average IRT readings from the forehead and elsewhere were 1°C to 2°C lower and correlated less well. Ear IRT readings at 0.5 m yielded the narrowest confidence intervals and could be used to predict conventional body temperature readings of ≥ 38°C with a sensitivity and specificity of 83% and 88% respectively. Conclusions: IRT readings from the side of the face, especially from the ear at 0.5 m, yielded the most reliable, precise and consistent estimates of conventionally determined body temperatures. Our results have important implications for walk-through IRT scanning/screening systems at airports and border crossings, particularly as the point prevalence of fever in such subjects would be very low.link_to_subscribed_fulltex

Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertension

Angiotensin receptor blockers (ARBs), also known as sartans, block the activation of angiotensin type 1 receptors and have a recognised role in the treatment of heart failure and nephropathy. Since 2002, there have been three major outcome trials of ARBs in hypertension. We performed a meta-analysis to evaluate the impact of ARB on major outcomes. Randomised controlled trials of ARBs in hypertensive subjects with an average follow-up of at least 2 years and at least 100 major cardiovascular events were included. For each trial, the ARB used, number and characteristics of subjects, baseline and change in blood pressure, cardiovascular and noncardiovascular outcomes were recorded. Three trials involving 29375 subjects were included in the meta-analysis. In Losartan Intervention For Endpoint (LIFE) and Study on Cognition and Prognosis in the Elderly (SCOPE) but not in Valsartan Antihypertensive Long-term Use Evaluation trial (VALUE), an ARB reduced the occurrence of the primary end point and stroke compared to control. Compared to other antihypertensive drugs, ARB treatment was associated with no significant change in all-cause mortality (relative risk ratio (RRR) 0.96, 95% CI: 0.88-1.06, P = 0.45). There was an increase in myocardial infarction (RRR, 1.12, 95% CI: 1.01-1.26, P = 0.041), but a decrease in new-onset diabetes mellitus (RRR, 0.80, 95% CI: 0.74-0.86, P < 0.0000001). In conclusion, the reduction in new-onset diabetes partly offsets any increase in the risk of myocardial infarction. Most hypertensive patients require more than one class of drugs. Small differences in treatment outcome should not over-ride the importance of good blood pressure control. © 2006 Nature Publishing Group. All rights reserved.link_to_subscribed_fulltex

Safety and systemic availability of intravenous and oral arsenic trioxide (As2O3) in children with relapsed / refractory neuroblastoma

Objective: We conducted a phase I study to evaluate the safety and bioavailability of intravenous (IV) and per oral (PO) As2O3 in children with neuroblastoma. Method: Eleven children with neuroblastoma were recruited (mean age 2.5 yrs [range 2.1 to 5 yrs, M:F=5:6]). All were previously treated with modified N6/N7 chemotherapy regimen, 3F8 immunotherapy, local irradiation plus auto-PBSCT (n=6), topotecan (n=2) & others (n=1). A maximum of 5 courses would be given and each consisted of 14 days of daily As2O3 alternated with 14 days of rest. In course one, 0.15mg/Kg As2O3 was given as 1 hour IV infusion and then shifted to PO route on Day 2, the rest of the course was by IV route. Blood samples for pharmacokinetic study were taken 0,1,2,4,6 & 8 hours on Days 1 & 2 and 0 hour on Day 3. Blood plasma and cellular fractions were freshly separated and arsenic concentrations were determined in duplicate by inductively coupled plasma-mass spectrometry. Results: A total of 33 courses of As2O3 were given (3 received 5 courses). The estimated 3 yrs progression free survival was 18% by Kaplan-Meier estimation (2/11 survived at 3yrs, median survival 11 months). In 5/11 tested, plasma and cell samples showed comparable area under the curve attributable to IV or PO dosing. However, the profile of concentrations (peak 400-600 nM) suggested that higher dosage is needed to achieve adequate anti-tumor effect based on in-vitro data for neuroblastoma (2000 nM). No significant side effects were found. Conclusions: Children could achieve similar plasma and cellular concentration of As2O3 by either IV or PO route. Using the current dosage, the peak and trough concentration of As2O3 were lower than anticipated concentrations required in-vitro