Effect of MG132 on proteasome activity and prooxidant/antioxidant status of rat liver subjected to ischemia/reperfusion injury.

Aim: Previous studies have shown that proteasome inhibitors exerted protective effects against ischemia/reperfusion injury (IRI) of brain, heart, kidney and intestine. The aim of the present study was to investigate: (i) whether the proteasome inhibitor MG132 protects rat liver against IRI; and (ii) whether MG132 modulates prooxidant/antioxidant status of rat liver subjected to warm IRI. Methods: The left lateral and medial lobes (approximately 70% of the total liver volume) of livers of male Wistar rats were subjected to 30-min ischemia followed by 60-min reperfusion. Lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels were measured in the plasma. Proteasome chymotryptic-like (ChT-L) activity, levels of thiobarbituric acid-reactive substances (TBARS), protein carbonyls (PC) and glutathione (GSH), as well as superoxidase dismutase (SOD), catalase (CAT), glutathionine peroxidase and glutathionine reductase activities were measured in liver fractions. Results: Thirty-min ischemia followed by 60-min reperfusion increased liver TBARS and PC, CAT and SOD activities, but decreased GSH level. Ischemia/reperfusion-induced oxidative stress was exacerbated in mitochondria, indicating that these organelles are the preferential target of IRI. Plasma LDH and AST levels were decreased by MG132 during both ischemia and reperfusion, while ALT values were decreased only after 30 min of reperfusion. MG132 did not significantly affect liver TBARS and GSH levels, but it increased PC and decreased ChT-L activity; the activities of CAT and SOD were also decreased. Conclusions: MG132 exerts a protective effect during the early phase of reperfusion and it modulates prooxidant/antioxidant status of rat liver subjected to warm IRI.     

Safety and Tolerability of Tapentadol Extended Release in Moderate to Severe Chronic Osteoarthritis or Low Back Pain Management: Pooled Analysis of Randomized Controlled Trials

Introduction

This analysis of pooled data from four randomized, controlled-dose adjustment, phase 3 studies (three 15-week, double-blind, placebo- and active-controlled studies and a 1-year, open-label, active-controlled safety study) in patients with chronic osteoarthritis hip or knee pain or low back pain evaluated the safety and tolerability of tapentadol extended release (ER) for the management of moderate to severe, chronic pain.

Methods

In the three 15-week studies, patients were randomized (1:1:1) to twice-daily (bid) doses of placebo, tapentadol ER (100–250 mg), or oxycodone hydrochloride (HCl) controlled release (CR; 20–50 mg). In the 1-year safety study, patients were randomized (4:1) to tapentadol ER (100–250 mg bid) or oxycodone HCl CR (20–50 mg bid). Adverse events (AEs) and discontinuations were recorded in each study; pooled results were analyzed by treatment group.

Results

In the placebo (n = 993), tapentadol ER (n = 1,874), and oxycodone CR (n = 1,224) groups, respectively, 40.7%, 48.4%, and 62.3% of patients discontinued treatment prematurely and 58.7%, 79.0%, and 86.6% of patients experienced ≥1 treatment-emergent AE (TEAE). Incidences of gastrointestinal TEAEs in the placebo, tapentadol ER, and oxycodone CR groups, respectively, were 26.6%, 47.3%, and 65.4%; incidences of nervous system TEAEs were 22.5%, 42.6%, and 45.1%, respectively. Moderate or severe gastrointestinal TEAEs were reported for 10.9% of patients who received placebo, 25.3% of patients who received tapentadol ER, and 42.3% of patients who received oxycodone CR, and moderate or severe nervous system TEAEs were reported for 10.6%, 22.1%, and 25.2% of patients, respectively. In the placebo, tapentadol ER, and oxycodone CR groups, respectively, incidences of gastrointestinal TEAEs leading to study discontinuation were 2.1%, 8.3%, and 24.1%; incidences of nervous system TEAEs leading to discontinuation were 1.4%, 7.9%, and 16.3%, respectively.

Conclusion

Results from this large patient population showed that tapentadol ER (100–250 mg bid) had improved gastrointestinal tolerability compared with oxycodone CR, based on the overall incidence of gastrointestinal TEAEs, the incidence of moderate or severe gastrointestinal TEAEs, and the incidence of gastrointestinal TEAEs leading to discontinuation.     

The TRPS1 transcription factor: androgenic regulation in prostate cancer and high expression in breast cancer

TRPS1 mRNA is more highly expressed in androgen-dependent lymph node carcinoma of prostate-fast growing colony (LNCaP-FGC) compared with androgen-independent lymph node carcinoma of prostate-lymph node original (LNCaP-LNO) prostate cancer cell lines. Furthermore, TRPS1 mRNA expression is down-regulated by androgens in LNCaP-FGC cells, a process mediated by the androgen receptor (AR). Here, we present TRPS1 protein expression in human prostate cancer material derived from a panel of six androgen-dependent and eight androgen-independent human prostate cancer xenografts. TRPS1 protein is expressed in all androgen-dependent xenografts, which also express AR and prostate-specific antigen (PSA). Androgen withdrawal by castration resulted in an increase in TRPS1 protein in two androgen-dependent xenografts, indicating relieved repression by action of AR. TRPS1 protein is expressed in four androgen-independent xenografts and is low or absent in the other four androgen-independent xenografts. Androgen withdrawal by castration demonstrates that TRPS1 protein levels remain the same in 1 androgen-independent xenograft, most likely due to the lack of AR expression. These data show that TRPS1 protein expression is regulated by androgens via the AR in human prostate cancer xenografts. Analysis of TRPS1 mRNA expression in normal and tumour tissue of the prostate and 18 other human tissues, showed that TRPS1 had the highest mRNA expression levels in normal and tumour tissues of breast. In addition, high TRPS1 mRNA and protein expression levels were observed in four out of five human breast cancer cell lines. In conclusion, TRPS1 protein expression is down-regulated by androgens in human prostate cancer, and analysis of TRPS1 mRNA expression levels in several human tissues showed that the highest levels were observed in normal and tumour breast tissue.     

Development of spontaneous arthritis in beta2-microglobulin-deficient mice without expression of HLA-B27: association with deficiency of endogenous major histocompatibility complex class I expression

OBJECTIVE: Mice deficient in beta2-microglobulin (beta2m), but expressing the human major histocompatibility complex (MHC) class I molecule HLA-B27, have been reported to develop spontaneous inflammatory arthritis (SA). We sought to determine whether, under certain conditions, beta2m deficiency alone was sufficient to cause SA, and if this might be a result of class I deficiency. METHODS: The following types of mice were produced: mice of the MHC b haplotype genetically deficient in beta2m (beta2m(0)) on several genetic backgrounds (C57BL/6J [B6], BALB/cJ, SJL/J, MRL/MpJ, and B6,129), mice deficient in the transporter associated with antigen processing (TAP1(0)) on a B6,129 background, and HLA-B27-transgenic beta2m(0) mice on a B6 background. Cohorts were transferred from specific pathogen-free (SPF) to conventional (non-SPF) animal rooms, and evaluated clinically and histologically for the development of SA. RESULTS: SA occurred in TAP1(0) and beta2m(0)/class I-deficient mice with a mixed B6,129 genome at a frequency of 30-50%, while 10-15% of B6, SJL/J, and BALB/cJ beta2m(0) mice developed this arthropathy. MRL/ MpJ beta2m(0) mice were unaffected. Expression of B27 did not increase the frequency of SA in B27-transgenic B2m(0) B6 mice compared with that in beta2m(0) B6 controls. CONCLUSION: Class I deficiency is sufficient to cause SA in mice. The frequency of disease, as well as B27-specific SA, is markedly dependent on a non-MHC genetic background. These results suggest that class I deficiency in a genetically susceptible mouse can mimic B27-associated arthropathy.     

Coronary stenting using the radial approach in two women with situs viscerum inversus and acute myocardial infarction

A situs inversus with dextrocardia (DC) is a rare condition in adults. Usually, patients have structurally normal hearts and normal life expectancy. The incidence of coronary artery disease in this setting is similar to that in the general population.Coronary revascularization may present potential difficulties related to the unusual anatomy. Although the radial artery is a safe and effective site of access for coronary interventions, some anatomical variations may make this procedure more complicated. We describe two cases of patients with situs viscerum inversus and acute myocardial infarction who underwent successful transradial percutaneous coronary intervention (PCI). We will show that coronary angioplasty with stent application via the radial approach in patients with DC is feasible and effective also in emergency and urgent care.     

Lymphoplasmacyte-rich meningioma mimicking idiopathic hypertrophic pachymeningitis.

A 24-year-old man presented with long-term headache and progressive visual loss. Neuro-ophthalmic manifestations included finger counting acuity in both eyes, weakly reactive pupils, pale optic discs, and increased deep tendon reflexes. Brain MRI showed meningeal thickening that involved the optic nerves and chiasm and enveloped and displaced the brainstem as far caudally as the foramen magnum. The diffuse extensive nature of the lesion suggested an inflammatory process such as idiopathic hypertrophic pachymeningitis (IHP), but anterior temporal brain biopsy disclosed a relatively high proportion of meningothelial cells with islands of polyclonal inflammatory reaction consistent with a diagnosis of lymphoplasmacyte-rich meningioma (LRM), a rare variant. Among the 19 reported cases of LRM, none has shown as extensive a mass as seen in our patient. Distinguishing between LRM and IHP is important because these entities are treated differently.     

Pitfalls in the diagnosis of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes.

We describe a patient with genetically- and biochemically-proven mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) who was initially misdiagnosed as having had multiple ischemic strokes in part because the clinical presentation appeared to be acute, the MRI of lesions showed restricted diffusion, and the brain biopsy showed features suggestive of stroke. This report emphasizes the pitfalls in the diagnosis of MELAS and points out the similarities and differences between MELAS and ischemic stroke.     

Fragile X syndrome: An overview and update of the FMR1 gene

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and the leading form of the monogenic cause of autism. Fragile X mental retardation type 1 (FMR1) gene premutation is the first single‐gene cause of primary ovarian failure (Fragile X‐associated primary ovarian insufficiency [FXPOI]) and one of the most common causes of ataxia (fragile X‐associated tremor/ataxia syndrome [FXTAS]), multiple additional phenotypes such as fibromyalgia, hypothyroidism, migraine headaches, sleep disturbances, sleep apnea, restless legs syndrome, central pain syndrome, neuropathy and neuropsychiatric alterations has been described. Clinical involvement in men and women carrying the FMR1 premutation currently constitutes a real health problem in the society that should be taken into account. It is important to highlight that while in FXS there is a loss‐of‐function of the FMR1 gene, in premutation associated disorders there is a gain of FMR1 mRNA function. To date, the tremendous progress achieved in the understanding of the pathophysiology of FXS, has led to the development of several targeted therapies aimed at preventing or improving the neurological manifestations of the disease. This review is an update of the diseases associated with the FMR1 gene.