Increased plasma concentration of macrophage migration inhibitory factor (MIF) and MIF mRNA in mononuclear cells in the obese and the suppressive action of metformin

The objective of the study was to determine whether plasma migration inhibitor factor (MIF) concentration and mononuclear cell (MNC) mRNA are elevated in obesity and whether treatment with metformin reduces plasma MIF concentration. Forty obese subjects [body mass index (BMI), 37.5 +/- 4.9 kg/m(2)] and 40 nonobese healthy subjects (BMI, 22.6 +/- 3.4 kg/m(2)) had their plasma MIF, glucose, insulin, free fatty acids (FFAs) and C-reactive protein (CRP) concentrations measured. Sixteen obese patients and 16 nonobese healthy subjects had RNA prepared from MNCs. Eight obese subjects with normal glucose concentration were treated with metformin 1 g (Glucophage XR; 1000 mg twice daily) twice daily for 6 wk. Eight obese subjects were used as controls. Plasma concentration of glucose, insulin, FFAs, and MIF was measured by appropriate assays. mRNA for MIF was measured by real-time PCR. Forty obese subjects had a fasting concentration of MIF of 2.8 +/- 2.0 ng/ml, whereas 40 nonobese subjects had a fasting MIF concentration of 1.2 +/- 0.6 ng/ml (P < 0.001). Plasma MIF concentrations were significantly related to BMI (r = 0.52; P < 0.001). mRNA for MIF was correlated to plasma FFAs (r = 0.40; P < 0.05) and plasma CRP (r = 0.42; P < 0.05) concentrations. Eight obese subjects had their fasting blood samples taken before and after taking a slow-release preparation of metformin at 1, 2, 4, and 6 wk. The mean plasma concentration fell from 2.3 +/- 1.4 to 1.6 +/- 1.2 ng/ml at 6 wk (P < 0.05). Obese subjects not on treatment with metformin showed no change. During the period of treatment with metformin, the body weight did not change and the plasma concentration of glucose, insulin, and FFAs did not alter. We conclude that: 1) plasma MIF concentrations and MIF mRNA expression in the MNCs are elevated in the obese, consistent with a proinflammatory state in obesity; 2) these increases in MIF are related to BMI, FFA concentrations, and CRP; 3) metformin suppresses plasma MIF concentrations in the obese, suggestive of an antiinflammatory effect of this drug; and 4) this action of metformin may contribute to a potential antiatherogenic effect, which may have implications for the reduced cardiovascular mortality observed with metformin therapy in type 2 diabetes mellitus.     

Evidence for a potent antiinflammatory effect of rosiglitazone

We have recently demonstrated a potent antiinflammatory effect of troglitazone, an agonist of peroxisome proliferator-activated receptor gamma (PPARgamma) and a partial agonist of PPARalpha in both the nondiabetic obese and diabetic obese subjects. We have now investigated the antiinflammatory actions of rosiglitazone, a selective PPARgamma agonist. Eleven nondiabetic obese subjects and 11 obese diabetic subjects were each given 4 mg of rosiglitazone daily for a period of 6 wk. Fasting blood samples were obtained at 0, 1, 2, 4, 6, and 12 wk (6 wk after the cessation of rosiglitazone). Eight obese subjects and five obese diabetic subjects were also included in the study as control groups. Fasting blood samples were obtained from the control groups at 0, 1, 2, 4, and 6 wk only. Nuclear factor kappaB (NFkappaB)-binding activity in mononuclear cells, plasma monocyte chemoattractant protein-1 (MCP-1), TNF-alpha, soluble intercellular adhesion molecule-1, C-reactive protein (CRP), and serum amyloid A (SAA) were measured. Blood glucose concentration changed significantly at 6 wk only in the obese diabetic subjects after rosiglitazone treatment for 6 wk, whereas insulin concentration decreased significantly at 6 wk in both groups. NFkappaB-binding activity in mononuclear cell nuclear extract fell in both obese and obese diabetic subjects (P < 0.02). Rosiglitazone treatment resulted in a reduction in plasma MCP-1 and CRP in both groups (P < 0.05). Plasma TNF-alpha and SAA concentrations were inhibited significantly in the obese group (P < 0.05) but not in the obese diabetic subjects. NFkappaB-binding activity and plasma MCP-1, CRP, SAA, and TNF-alpha did not change in the obese and obese diabetic control groups. We conclude that rosiglitazone, a selective PPARgamma agonist, exerts an antiinflammatory effect at the cellular and molecular level, and in plasma. These observations may have implications for atherogenesis in the long term in subjects treated with rosiglitazone and possibly other thiazolidinediones.     

Acetaminophen inhibits neuronal inflammation and protects neurons from oxidative stress

Background  

Recent studies have demonstrated a link between the inflammatory response, increased cytokine formation, and neurodegeneration in the brain. The beneficial effects of anti-inflammatory drugs in neurodegenerative diseases, such as Alzheimer's disease (AD), have been documented. Increasing evidence suggests that acetaminophen has unappreciated anti-oxidant and anti-inflammatory properties. The objectives of this study are to determine the effects of acetaminophen on cultured brain neuronal survival and inflammatory factor expression when exposed to oxidative stress.     

Systemic adjuvant therapy for breast cancer.

Systemic therapy for operable breast cancer can delay the time to recurrence. Recurrence of breast cancer can follow a variable clinical course but will lead to death in virtually all cases. This delay is reflected in an accompanying improvement in overall survival with treatment. Almost 35 years have passed since the introduction of adjuvant chemotherapy, whereas adjuvant tamoxifen trials were begun 17 years ago. In that time, only in a minority of patients has a clear consensus emerged on the appropriate use of adjuvant therapies. Overview analysis from large numbers of controlled clinical trials has produced a much larger data base for examining the effects of hormonal and cytotoxic therapy on the outcome of patients with early-stage breast cancer and provides greater statistical power to detect small differences in particular subgroups of patients, which may not have been apparent in individual studies. Patients with involved lymph nodes are now routinely treated with chemotherapy if they are premenopausal and with tamoxifen if they are postmenopausal, especially if their tumors contain estrogen receptor. More recent trials attempt to examine the use of these therapies outside of these prescribed groups as well as the introduction of new chemotherapeutic agents and dosage regimens, some of which are based on biologic principles of alternating, non-cross-resistant therapy and dose responsiveness. Treatment of node-negative breast cancer remains controversial. Small but real differences in odds of relapse have emerged with adjuvant treatment, although the nature of the risks and benefits remains to be defined.     

Tarlov cysts: a report of two cases

Perineural cysts are common and usually detected incidentally during magnetic resonance imaging of the lumbosacral spine. Treatment is indicated only when the cyst is symptomatic. We report one such patients presented with cauda equina syndrome and another with low back pain with claudication. They underwent excision and duraplasty; both motor and sensory fibres were carefully separated from the cyst wall using a nerve root retractor and penfield. There was no nerve root damage or neural deficit. Symptoms were relieved postoperatively.     

A biomechanical evaluation of a spacer with integrated plate for treating adjacent-level disease in the subaxial cervical spine

Background contextAdjacent level degeneration (ALD) has been reported as one of the long-term consequences of anterior discectomy and fusion despite its clinical success in treating cervical pathologies. Traditionally, ALD is treated by replacing the previously implanted plate with a longer plate, which can lead to postoperative complications. The biomechanics of SIP in the adjacent level has not been investigated.PurposeTo evaluate the multidirectional stability of a spacer with integrated plate (SIP) in comparison to a traditional spacer and plate (TSP).Study designTo evaluate the biomechanical stability of a spacer with integrated plate adjacent to a traditional spacer and plate construct in a human cervical cadaveric model.MethodsEight fresh human cervical (C2–C7) cadaver spines were mounted on a six degree-of-freedom spine simulator. The sequence of test constructs was: 1) Intact; 2) TSP (C4–C6) with SIP (C3–C4); and 3) TSP (C3–C6). An unconstrained moment of ±1.5 Nm was used in flexion-extension, lateral bending, and axial rotation. Range of motion (ROM) was measured by a digital motion analysis system. Statistical analysis was performed using ANOVA repeated measures.ResultsAll instrumented constructs significantly reduced ROM compared to the intact condition. No statistically significant difference was observed between the two-level TSP with an adjacent SIP construct and three-level TSP construct in all loading modes.ConclusionThe biomechanical study shows that adding a spacer with integrated plate adjacent to a two-level anterior plate demonstrates equivalent stability to a three-level anterior plate. The spacer with integrated plate, which preserves the originally plated fusion levels, may overcome the complications associated with the traditional technique of replacing the original plate with a longer plate. However, prospective clinical studies are required to address the clinical benefits and challenges, if any.