Evaluation of the efficacy, safety and tolerability of valdecoxib gel (1%) in adult patients with painful inflammatory joint disease

Valdecoxib, a COX-2 inhibitor, has recently been introduced as a gel formulation. The present study was conducted to evaluate the efficacy, safety and tolerability of valdecoxib gel in adult patients with painful inflammatory joint conditions. The present study was a 10-day prospective, open, multicentric (6 centres) trial. Patients with clinical and radiological diagnosis of painful inflammatory joint conditions were treated with valdecoxib gel (1%). Efficacy was assessed by visual analogue scale (VAS), patient's and physician's global assessment of pain relief. Grading of associated clinical manifestations such as stiffness, swelling, tenderness and restriction of mobility was done. Tolerability and safety was assessed by physical examination, laboratory parameters and evaluation of adverse events. There was a statistically significant decrease in the mean pain visual analogue score (p<0.05). Onset of pain relief was within 15 minutes. There was a reduction of 58.8%, 57.2%, 65.4% and 60.2% in mean scores of stiffness, swelling, tenderness and mobility respectively from the baseline which was statistically significant. The laboratory values were within normal limits. The drug was well tolerated. There was no report of any hypersensitivity reaction. This study confirms that valdecoxib gel (1%) is an effective and safe option for the management of painful inflammatory joint conditions.     

Minimally invasive procedures for disorders of the lumbar spine

In the past decade, there has been a substantial increase in interest in minimally invasive procedures in all areas of medicine, particularly for spinal disorders. Some of these techniques represent notable advances in spinal care and have major roles in the care of patients with back-related symptoms. Other techniques appear to offer no benefit and in some cases may be less effective than conventional treatments. Percutaneous lumbar diskectomy techniques hold considerable promise; however, lumbar microdiskectomy is the gold standard for surgical treatment of lumbar disk protrusion with radiculopathy. Intradiskal electrothermal therapy is emerging as a useful option for selected patients with intractable mechanical back pain whose only other option historically has been a spinal fusion. Percutaneous fusion techniques are in their infancy and may prove to be beneficial for these patients as well. Percutaneous vertebral augmentation, including vertebroplasty and kyphoplasty, has become the treatment of choice for many patients with intractable back pain secondary to vertebral insufficiency fractures. Spinal injections are important for evaluating and managing spinal pain and can be extremely useful diagnostically and therapeutically. This multidisciplinary review outlines the status of these procedures and offers suggestions for their use in patient care.     

Nociceptin inhibits cough in the guinea-pig by activation of ORL(1) receptors

We studied the central and peripheral antitussive effect of ORL(1) receptor activation with nociceptin/orphanin FQ in conscious guinea-pigs. In guinea-pig cough studies, nociceptin/orphanin FQ (10, 30, and 90 microg) given directly into the CNS by an intracerebroventricular (i.c.v.) route inhibited cough elicited by capsaicin exposure by approximately 23, 29 and 52%, respectively. The antitussive activity of nociceptin/orphanin FQ (90 microg, i.c.v.) was blocked by the selective ORL(1) antagonist [Phe(1)gamma(CH(2)-NH)Gly(2)]nociceptin-(1-13)-NH(2) (180 microg, i.c.v.) and J113397 (10 mg kg(-1), i.p.) but not by the opioid antagonist, naltrexone (3 mg kg(-1), i.p.). Furthermore, intravenous (i.v.) nociceptin/orphanin FQ (1.0 and 3.0 mg kg(-1)) also inhibited cough approximately by 25 and 42%, respectively. These findings indicate that selective ORL(1) agonists display the potential to inhibit cough by both a central and peripheral mechanism, and potentially represent a novel therapeutic approach for the treatment of cough.     

Killing of brain tumor cells by hypoxia-responsive element mediated expression of BAX

The presence of radioresistant hypoxic cells in human brain tumors limits the overall effectiveness of conventional fractionated radiation therapy. Tumor-specific therapies that target hypoxic cells are clearly needed. We have investigated the expression of suicide genes under hypoxia by a hypoxia-responsive element (HRE), which can be activated through hypoxia-inducible factor-1 (HIF-1). We transfected plasmids containing multiple copies of HRE into U-87 MG and U-251 MG-NCI human brain tumor cells and tested their ability to induce LacZ gene expression under anoxia. Gene expression under anoxia versus oxia was increased about 12-fold for U-87 MG cells and about fourfold for U-251 MG-NCI cells. At intermediate hypoxic conditions, increased LacZ gene expression in U-87 MG cells was induced by the plasmid that contained three HREs, but not by the plasmid with two HREs. Lastly, when we placed a suicide gene BAX under the control of HREs, cells transfected with the BAX plasmids were preferentially killed through apoptosis under anoxia. Our studies demonstrate that HRE-regulated gene expression is active in brain tumor cells, and that the amount of increased gene expression obtained is dependent on the cell line, the HRE copy number, and the degree of hypoxia.     

奥美拉唑与脑卒中相关性肺炎的关系研究

目的探讨无法进食经鼻饲的急性脑卒中患者给予奥美拉唑后胃液pH值、胃腔细菌定植情况以及对应激性消化道溃疡、卒中相关性肺炎（SAP）的影响。方法90例患者依据奥美拉唑应用时间随机分为三组,每8小时抽取胃液,测pH值及潜血试验。留取胃液、深部痰行细菌培养。结果三组胃液pH值、各组SAP发生率差异有统计学意义：三组应激性溃疡的发生率差异无统计学意义。90例患者中31例发生胃腔细菌定植,三组差异有统计学意义。胃腔细菌定植患者pH值与无细菌定植患者胃液pH值差异有统计学意义;发生胃腔细菌定植细菌主要为革兰阴性杆菌;17例SAP患者痰细菌培养主要为革兰阴性杆菌。17例SAP患者pH值与非SAP患者胃液pH值差异有统计学意义;急性脑卒中鼻饲患者,应用奥美拉唑时间延长,胃液pH增加,胃腔细菌定植增多,SAP发生率增加,应激性溃疡发生率下降。结论对于急性脑卒中患者应选择应用奥美拉唑时间,需监测胃液pH值,使胃液pH值保持适当范围。     

Use of verbal autopsy to determine mortality patterns in an urban slum in Kolkata, India

Objective

To define mortality patterns in an urban slum in Kolkata, India, in the context of a cholera and typhoid fever project.

Methods

In a well-defined population that was under surveillance for 18 months, we followed a dynamic cohort of 63 788 residents whose households were visited monthly by community health workers to identify deaths. Trained physicians performed verbal autopsies and experienced senior physicians assigned the primary cause of death according to the International classification of diseases, 10th edition. We tabulated causes of death in accordance with Global Burden of Disease 2000 categories and assessed overall and cause-specific mortality rates per age group and gender.

Findings

During 87 921 person–years of follow-up, we recorded 544 deaths. This gave an overall mortality rate of 6.2 per 1000 person–years. We assigned a cause to 89% (482/544) of the deaths. The leading causes of death, in descending order, were cardiovascular diseases (especially among adults aged over 40 years), cancer, respiratory ailments and digestive disorders. Most deaths in children under 5 years of age were caused by tuberculosis, respiratory infections and diarrhoeal diseases.

Conclusion

Although the most common causes of death in children were infectious, non-communicable diseases were predominant among adults. There is a need for continuing interventions against infectious diseases in addition to new and innovative strategies to combat non-infectious conditions.     

Long-term effectiveness against cholera of oral killed whole-cell vaccine produced in Vietnam

We assessed the long-term protection afforded by a killed whole-cell oral cholera vaccine produced in Vietnam. A mass immunization of children and adults with the killed whole-cell oral cholera vaccine was undertaken in half of the communes of Hue, Vietnam, in 1998; the remaining communes were immunized in 2000. No cholera was observed in Hue until 2003, when an outbreak of El Tor cholera made it possible to conduct a case-control study. The overall vaccine effectiveness 3-5 years after vaccination was 50% (9-63%). This low-cost, easily administered vaccine should be considered as a tool for the control of cholera.     

Role for angiotensin II in an overt functional proteinuria

A partial renal vein constriction (RVC) was induced acutely in Munich-Wistar rats. RVC caused a marked reduction in glomerular plasma flow rate, and rises in glomerular transcapillary hydraulic pressure difference and efferent arteriolar resistance. These changes were associated with a marked increase in urinary protein excretion, on average from a baseline level of 8 to approximately 120 mg/24 hrs per kidney. Infusion of saralasin, an angiotensin II (AII) antagonist, largely normalized these indices, including urinary protein excretion (to approximately 35 mg/24 hrs per kidney), despite continued RVC. In separate rats, fractional clearances of neutral [125I]dextrans (molecular radii = 18-60 A) (CDEX/CIN) were measured. RVC caused a significant increase in CDEX/CIN for large dextrans (greater than or equal to 44A), but not small dextrans (less than or equal to 42A). Saralasin infusion led to a partial return toward baseline values of CDEX/CIN for the large dextrans. On the basis of the heteroporous membrane theory for glomerular filtration, the glomerular sieving defect during RVC was attributed to an increase in the relative fluid flux through a group of large non-selective pores. A marked alteration in glomerular microcirculatory pattern induced by enhanced action of endogenous AII in turn seemed to account largely, although not entirely, for the impairment of glomerular size-selectivity during RVC.     

Effect of alpha-difluoromethylornithine on 1,3-bis(2-chloroethyl)-1-nitrosourea and cis-diamminedichloroplatinum(II) cytotoxicity, DNA interstrand cross-linking, and growth in human brain tumor cell lines in vitro

The polyamine biosynthesis inhibitor alpha-difluoromethylornithine (DFMO) has been shown to potentiate the cytotoxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in 9L rat brain tumor cells and in non-central nervous system human cancer cells in vitro, but the effects on a human brain tumor cell line have not been reported. Because BCNU is one of the main chemotherapeutic agents used clinically for the treatment of brain tumors, the effect of DFMO treatment on cell growth and potentiation of cytotoxicity was studied in vitro in U-251 MG and SF-126 cells, human tumor cell lines derived from malignant glioma tissue. Pretreatment of U-251 MG with 1 mM DFMO depleted cells of putrescine and spermidine within 48 h but did not sensitize cells to BCNU treatment even after a pretreatment of 72 h. DFMO treatment had no effect on the number of interstrand cross-links formed in BCNU-treated cells. Even treatment with 5 mM DFMO for 72 h caused only the suggestion of potentiation of BCNU cell kill. In contrast, a 72-h pretreatment with 1 mM DFMO decreased the cytotoxic effect of cis-diammine-dichloroplatinum(II) and caused a 38% decrease in the number of DNA interstrand cross-links formed. The glutathione content and cell cycle distribution of U-251 MG cells were not affected by DFMO pretreatment. Because Phase II clinical trials with DFMO and BCNU have shown promise for the treatment of anaplastic astrocytomas in humans, a second brain tumor cell line, SF-126, was studied. In this cell line a consistent potentiation of BCNU cytotoxicity (dose enhancement of 1.2 at the 10% survival level) was observed in cells pretreated with 1 mM DFMO for 72 h.