Journeys to tuberculosis treatment: a qualitative study of patients, families and communities in Jogjakarta, Indonesia

Background  

Many tuberculosis (TB) patients in Indonesia are diagnosed late. We seek to document patient journeys toward TB diagnosis and treatment and factors that influence health care seeking behavior.     

化学修饰小干扰RNA作为治疗药物的研究进展

化学修饰为小干扰RNA（siRNA）治疗面临的诸多挑战提供了解决方法。此综述考察现有的各种siRNA修饰方法,包括RNA和双链siRNA结构的各个方面。然后考察化学修饰siRNA的应用,重点关注其作用的专一性（消除免疫反应和杂交依赖性的脱靶作用）和转运方法,同时对酶稳定性和效价也进行了讨论。     

Dual modulation of urinary bladder activity and urine flow by prostanoid EP3 receptors in the conscious rat

Background and purpose:

Cyclooxygenase inhibitors function to reduce levels of prostaglandin E₂ (PGE₂) and are broadly efficacious in models of bladder overactivity. We therefore investigated a regulation of urinary bladder function in conscious rats by modulation of the EP₃ receptor for PGE₂.

Experimental approach:

The activity of the EP₃ receptor agonist GR63799X, and EP₃ receptor antagonists, CM9 and DG041, at recombinant EP₃ receptors was evaluated in vitro. In vivo, intraduodenal dosing during conscious, continuous-filling cystometry of spontaneously hypertensive rats was utilized to determine the urodynamic effect of EP₃ receptor modulation.

Key results:

GR63799X dose-dependently (0.001–1 mg·kg⁻¹) reduced bladder capacity, as indicated by a reduction in both the micturition interval and volume of urine per void. In contrast, CM9 (10 and 30 mg·kg⁻¹) and DG041 (30 mg·kg⁻¹) enhanced bladder capacity, as indicated by significantly longer micturition intervals and larger void volumes. CM9 and DG041 inhibited the responses to GR63799X supporting the in vivo activity of these pharmacological agents at the EP₃ receptor. In addition to its effect on bladder capacity, GR63799X increased endogenous urine production. Intra-arterial infusion of saline mimicked the enhancement of urine flow observed with GR63799X, and the response was inhibited by CM9.

Conclusions and implications:

These data support the EP₃ receptor as a modulator of urinary bladder activity in the conscious rat, and in addition, indicate a role for EP₃ receptor activity in regulating urine flow.     

Peripheral and central sites of action for the non-selective cannabinoid agonist WIN 55,212-2 in a rat model of post-operative pain

Background and purpose:

Activation of cannabinoid (CB) receptors decreases nociceptive transmission in inflammatory or neuropathic pain states. However, the effects of CB receptor agonists in post-operative pain remain to be investigated. Here, we characterized the anti-allodynic effects of WIN 55,212-2 (WIN) in a rat model of post-operative pain.

Experimental approach:

WIN 55,212-2 was characterized in radioligand binding and in vitro functional assays at rat and human CB₁ and CB₂ receptors. Analgesic activity and site(s) of action of WIN were assessed in the skin incision-induced post-operative pain model in rats; receptor specificity was investigated using selective CB₁ and CB₂ receptor antagonists.

Key results:

WIN 55,212-2 exhibited non-selective affinity and agonist efficacy at human and rat CB₁ versus CB₂ receptors. Systemic administration of WIN decreased injury-induced mechanical allodynia and these effects were reversed by pretreatment with a CB₁ receptor antagonist, but not with a CB₂ receptor antagonist, given by systemic, intrathecal and supraspinal routes. In addition, peripheral administration of both CB₁ and CB₂ antagonists blocked systemic WIN-induced analgesic activity.

Conclusions and implications:

Both CB₁ and CB₂ receptors were involved in the peripheral anti-allodynic effect of systemic WIN in a pre-clinical model of post-operative pain. In contrast, the centrally mediated anti-allodynic activity of systemic WIN is mostly due to the activation of CB₁ but not CB₂ receptors at both the spinal cord and brain levels. However, the increased potency of WIN following i.c.v. administration suggests that its main site of action is at CB₁ receptors in the brain.British Journal of Pharmacology (2009) 157, 645–655; doi:10.1111/j.1476-5381.2009.00184.x; published online 3 April 2009     

Increased exposure to hepatitis B virus infection in HIV-positive South African antenatal women

The prevalence of markers for hepatitis B virus (HBV) exposure and active infection in HIV-positive (n=710) and HIV-negative (n=710) pregnant South African women was investigated. The following statistically significant increases in the HIV-positive group were found: anti-hepatitis B core antigen (anti-HBc) (37.3% versus 28.6%; odds ratio [OR]: 1.49); anti-hepatitis B surface antigen (anti-HBs) (29.5% versus 20.1%; OR: 1.66); exposure based on hepatitis B surface antigen (HBsAg) and anti-HBc (39.2% versus 30.1%; OR: 1.49); and exposure based on anti-HBs, anti-HBc and HBsAg (37.1% versus 24.5%; OR: 1.82). However, there was no increase in active HBV infections, with 2.4% of the HIV positives and 2.2% of the HIV negatives being HBV DNA positive. Although the impact that HIV has had on the prevalence of HBV in this population group is not as pronounced as that found in areas of low endemicity (where up to seven-fold increases have been reported), there is a statistically significant increased exposure to HBV.     

Treatment with spironolactone for 24 weeks decreases the level of matrix metalloproteinases and improves cardiac function in patients with chronic heart failure of ischemic etiology

BACKGROUND:

The myocardial extracellular matrix is believed to be central to the remodelling that takes place following myocardial infarction. The contribution of markers of collagen metabolism to this process remains less well understood. The present study examined the contribution of some of the markers of collagen metabolism in cardiac remodelling, as well as the effect of spironolactone on the remodelling process.

OBJECTIVES:

To investigate the pathological contribution of markers of collagen metabolism, including matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), type I collagen carboxyterminal telopeptide (ICTP) and procollagen type I carboxyterminal propeptide (PICP), in cardiac remodelling following ischemic cardiomyopathy, and to examine the pharmacoregulatory effects of spironolactone on collagen metabolism.

METHOD:

Eighty-six consecutive patients (62 men and 24 women) with chronic heart failure of ischemic etiology (patient group) and 25 age-matched controls were enrolled in the study. The subjects in the patient group were randomly assigned into a spironolactone or nonspironolactone group. Plasma levels of MMP-9, TIMP-1, ICTP and PICP were measured using ELISA and radioimmunoassay techniques. Furthermore, left ventricular diastolic diameter and ejection fraction were assessed using two-dimensional and Doppler echocardiography.

RESULTS:

The plasma concentrations of MMP-9, TIMP-1 and the MMP-9 to TIMP-1 ratio, as well as ICTP, were significantly increased in the patient group. The PICP to ICTP ratio in the patient group was significantly lower than that in the age-matched control subjects. After a follow-up period of 24 weeks, the PICP to ICTP ratio increased, and MMP-9, TIMP-1 and the MMP-9 to TIMP-1 ratio decreased in the spironolactone subgroup.

CONCLUSIONS:

Biomarkers of collagen degradation were elevated and correlated with depressed heart function; spironolactone may partially reverse the dysregulation in collagen metabolism.     

Symptomatic and neuroprotective effects following activation of nigral group III metabotropic glutamate receptors in rodent models of Parkinson's disease

Background and purpose:

Increased glutamatergic innervation of the substantia nigra pars reticulata (SNpr) and pars compacta (SNpc) may contribute to the motor deficits and neurodegeneration, respectively, in Parkinson''s disease (PD). This study aimed to establish whether activation of pre-synaptic group III metabotropic glutamate (mGlu) receptors reduced glutamate release in the SN, and provided symptomatic or neuroprotective relief in animal models of PD.

Experimental approach:

Broad-spectrum group III mGlu receptor agonists, O-phospho-l-serine (l-SOP) and l-2-amino-4-phosphonobutyrate (l-AP4), were assessed for their ability to inhibit KCl-evoked [³H]-d-aspartate release in rat nigral prisms or inhibit KCl-evoked endogenous glutamate release in the SNpr in vivo using microdialysis. Reversal of akinesia in reserpine-treated rats was assessed following intranigral injection of l-SOP and l-AP4. Finally, the neuroprotective effect of 7 days'' supra-nigral treatment with l-AP4 was examined in 6-hydroxydopamine (6-OHDA)-lesioned rats.

Key results:

l-SOP and l-AP4 inhibited [³H]-d-aspartate release by 33 and 44% respectively. These effects were blocked by the selective group III mGlu antagonist (RS)-α-cyclopropyl-4-phosphonophenylglycine (CPPG). l-SOP also reduced glutamate release in the SNpr in vivo by 48%. Injection of l-SOP and l-AP4 into the SNpr reversed reserpine-induced akinesia. Following administration above the SNpc, l-AP4 provided neurochemical, histological and functional protection against 6-OHDA lesion of the nigrostriatal tract. Pretreatment with CPPG inhibited these effects.

Conclusions and implications:

These findings highlight group III mGlu receptors in the SN as potential targets for providing both symptomatic and neuroprotective relief in PD, and indicate that inhibition of glutamate release in the SN may underlie these effects.     

A systematic review of musculoskeletal disorders among dental professionals

Abstract:  Musculoskeletal problems have become a significant issue for the profession of dentistry and dental hygiene. This review provides a detailed examination and discussion regarding the prevalence of musculoskeletal disorders (MSD) in dental personnel and possible causative factors. All research studies or literature reviews, which have reported on the prevalence of musculoskeletal symptoms and/or potential risk factors for this problem in dentists, dental hygienists and dental students, were selected for inclusion. Our literature suggests that the prevalence of general musculoskeletal pain ranges between 64% and 93%. The most prevalent regions for pain in dentists have been shown to be the back (36.3–60.1%) and neck (19.8–85%), while the hand and wrist regions were the most prevalent regions for dental hygienists (60–69.5%). Interestingly, we found that studies on MSDs among dental and dental hygiene students are quite limited. Many risk factors have been identified, including static and awkward posture and work practices. Overall, the review suggests that musculoskeletal problems represent a significant burden for the dental profession. More research in the form of larger studies is urgently required, to help more clearly elucidate the development of this important issue for dental hygienists and dental hygiene students.