Increased response of renal perfusion to the antioxidant vitamin C in type 2 diabetes.

BACKGROUND: Reactive oxygen species play a major role in the development of endothelial dysfunction. It is as yet unspecified whether increased oxidative stress contributes to endothelial dysfunction of the renal vasculature in patients with type 2 diabetes. METHODS: Renal haemodynamics were studied in 20 patients with type 2 diabetes and arterial hypertension (age 62 +/- 5 years) and 20 non-diabetic hypertensive patients at baseline and following infusions of the nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA; 4.25 mg/kg); the substrate of nitric oxide synthase, L-arginine (100 mg/kg); and the antioxidant, vitamin C (3 g, co-infused with L-arginine 100 mg/kg). RESULTS: The response of renal plasma flow (RPF) to L-NMMA (-54 +/- 62 and -45 +/- 42 ml/min/1.73 m(2); P = NS) and L-arginine (+46 +/- 36 and +49 +/- 25 ml/min/1.73 m(2); P = NS) was not different between diabetic and non-diabetic patients. In contrast, vitamin C induced a more pronounced increase in RPF in diabetic than in non-diabetic patients when co-infused with L-arginine (+71+/-47 and +43+/-33 ml/min/1.73 m(2); P<0.05). CONCLUSIONS: The difference in the response of renal perfusion to an antioxidant suggests increased formation of reactive oxygen species and thereby reduced nitric oxide bioavailability in the renal vasculature of patients with type 2 diabetes.     

Single breath-hold extended free-breathing navigator-gated three-dimensional coronary MRA

PURPOSE: To acquire the center of k-space while extending three-dimensional free-breathing navigator-gated coronary magnetic resonance (MR) angiography by an initial single breath-hold. MATERIALS and METHODS: This approach was successfully applied in eight healthy adult subjects. Resulting images were compared with conventionally acquired free-breathing navigator-gated MR angiograms. RESULTS: The acquisition of k-space center during the single breath-hold resulted in a 26% increase (P < 0.05) of signal-to-noise ratio. Visible length of the right coronary artery, as well as contrast-to-noise ratio between the blood and the myocardial muscle, were identical. CONCLUSION: The breath-hold extension was shown to be a valuable technique that may be combined with first-pass contrast-enhanced MR imaging.     

Tacrolimus or cyclosporine: which is the better partner for mycophenolate mofetil in heart transplant recipients?

BACKGROUND: The aim of this single-center study was to investigate whether trough level adjusted mycophenolate mofetil (MMF) is more efficacious in combination with tacrolimus (TAC) or cyclosporine (CsA) and to evaluate the impact of either drug on MMF dosage. METHODS: Sixty patients (TAC, n = 30; CsA, n = 30) undergoing heart transplantation were randomized into a prospective, open-label, controlled trial. Immunosuppression consisted of TAC or CsA in combination with MMF and corticosteroids. Target blood trough levels of TAC, CsA, and mycophenolic acid (MPA) were in the range of 10 to 15 ng/mL, 100 to 300 ng/mL, and 1.5 to 4.0 microg/mL, respectively. Acute rejection episodes (ARE); survival data; and adverse events with a special emphasis on infections, diabetes, hypertension, hypercholesterolemia, and the development of graft vessel disease (GVD) were recorded. RESULTS: Baseline characteristics were well balanced. All patients were successfully withdrawn from corticosteroids within 6 months of transplant. Freedom from acute rejection was significantly higher (P = 0.0001) and the incidence of ARE per 100 patient days significantly lower in the TAC-MMF group than in the CsA-MMF group (0.03 vs. 0.15; P = 0.00007). Overall patient survival during follow-up was similar (93% vs. 90%). To achieve the targeted MPA blood levels, a significantly lower dose of MMF was required for TAC versus CsA patients. After a follow-up time of 2 years, the mean GVD score was 1.85 +/- 3.18 in the TAC-MMF group and 3.95 +/- 4.8 in the CsA-MMF group (P = 0.08). CONCLUSIONS: At the selected doses and target levels for TAC and CsA used in this study, trough level adjusted MMF was more efficacious in combination with TAC for prevention of ARE. Furthermore, CsA patients need significantly more MMF to achieve similar MPA levels.     

Polysialylation and lipopolysaccharide‐induced shedding of E‐selectin ligand‐1 and neuropilin‐2 by microglia and THP‐1 macrophages

Microglia are tissue macrophages and mediators of innate immune responses in the brain. The protein‐modifying glycan polysialic acid (polySia) is implicated in modulating microglia activity. Cultured murine microglia maintain a pool of Golgi‐confined polySia, which is depleted in response to lipopolysaccharide (LPS)‐induced activation. Polysialylated neuropilin‐2 (polySia‐NRP2) contributes to this pool but further polySia protein carriers have remained elusive. Here, we use organotypic brain slice cultures to demonstrate that injury‐induced activation of microglia initiates Golgi‐confined polySia expression in situ. An unbiased glycoproteomic approach with stem cell‐derived microglia identifies E‐selectin ligand‐1 (ESL‐1) as a novel polySia acceptor. Together with polySia‐NRP2, polySia‐ESL‐1 is also detected in primary cultured microglia, in brain slice cultures and in phorbol ester‐induced THP‐1 macrophages. Induction of stem cell‐derived microglia, activated microglia in brain slice cultures and THP‐1 macrophages by LPS, but not interleukin‐4, causes polySia depletion and, as shown for stem cell‐derived microglia, a metalloproteinase‐dependent release of polySia‐ESL‐1 and polySia‐NRP2. Moreover, soluble polySia attenuates LPS‐induced production of nitric oxide and proinflammatory cytokines. Thus, shedding of polySia‐ESL‐1 and polySia‐NRP2 after LPS‐induced activation of microglia and THP‐1 macrophages may constitute a mechanism for negative feedback regulation. GLIA 2016 GLIA 2016;64:1314–1330     

One-screw fixation provides similar stability to that of two-screw fixation for type II dens fractures

Background

Anterior screw fixation has been widely adopted for the treatment of Type II dens fractures. However, there is still controversy regarding whether one- or two-screw fixation is more appropriate.

Questions/Purposes

We addressed three questions: (1) Do one- and two-screw fixation techniques differ regarding shear stiffness and rotational stiffness? (2) Can shear stiffness and rotational stiffness after screw fixation be restored to normal? (3) Does stiffness after screw fixation correlate with bone mineral density (BMD)?

Methods

We randomly assigned 14 fresh axes into two groups (seven axes each): one receiving one-screw fixation and another receiving two-screw fixation. Shear and torsional stiffness were measured using a nondestructive low-load test in six directions. A transverse osteotomy then was created at the base of the dens and fixed using one or two screws. Shear and torsional stiffness were tested again under the same testing conditions.

Results

Mean stiffness in all directions after screw fixation was similar in both groups. The stiffness after one- and two-screw fixation was not restored to normal: the mean shear stiffness restored ratio was less than 50% and the mean torsional stiffness restored ratio was less than 6% in both groups. BMD did not correlate with mean stiffness after screw fixation in both groups.

Conclusions

One- and two-screw fixation for Type II dens fractures provide similar stability but neither restores normal shear or torsional stiffness.

Clinical Relevance

One-screw fixation might be used as an alternative to two-screw fixation. Assumed BMD should not influence surgical decision making.     

Low-dose cyclosporine mediates donor hyporesponsiveness in a fully mismatched rat kidney transplant model

Tolerance induction protocols have been successfully tested in animal models, yet their compatibility with immunosuppressive drugs remains to be fully elucidated. Our own previous data have indicated that cyclosporine A (CsA) affects the balance of effector and regulatory mechanisms with low-dose CsA doses promoting hyporesponsiveness. Here, we present a fully mismatched rat kidney model in which low-dose CsA treatment induces donor hyporesponsiveness to secondary renal allografts. Lewis recipients of DA kidney grafts received low, medium or high doses of CsA × 10 days. By 30 days, the primary transplant was removed and a second transplant of donor origin was engrafted. Following low-dose CsA, but not high-dose CsA treatment of the primary recipient, secondary transplants were accepted long-term in the absence of immunosuppression. Regulatory T-cell function was unimpaired and independent of the CyA dosage. Of note, low-dose CsA significantly reduced alloantibody titers in primary recipients. Adoptive transfer of graft infiltrating cells or splenocytes from hyporesponsive recipients supported long-term acceptance of donor kidney allografts. These results demonstrate a dose-dependent and transferable "pro-tolerogenic" effect of low-dose CsA treatment. This model is of clinical relevance to test the interference of CsA with tolerance induction in the absence of additional immunosuppression.     

Poor experience with a hinged endoprosthesis (WEKO) for the metacarpophalangeal joints: all 28 prostheses removed within 2 years in 8 patients having rheumatoid arthritis

We prospectively assessed the outcome of implanting a hinged prosthesis in destroyed metacarpophalangeal (MCP) joints (Larsen stage III-V). We implanted 28 cementless, axis-coupled total endoprostheses with hinging (WEKO prosthesis, Implant-Service GmbH, Hamburg, Germany) in 8 women (mean age 62 (47-80) years) suffering from rheumatoid arthritis. The mean follow-up period was 15 (12-18) months, and the evaluation was based on objective criteria, including joint motion, ulnar deviation of the long fingers, grip strength, radiographic migration and torsion of the prostheses, as well as the patients' subjective satisfaction. 12 months postoperatively, the mean arc of flexion was 30 (22-35) degrees, and the mean extension lag was 43 (40-48) degrees. Although no ulnar deviation was seen in 2 fingers, it was < 10 degrees in 3, between 10 degrees and 20 degrees in 7 of the fingers, and more than 20 degrees in 16. None of the patients could clench their fist firmly. We found prosthesis migration in 20 and torsion in 19 fingers. 2 years postoperatively, we had to remove all of the prostheses due to functional failure.     

Assessment of thoracic aortic dimensions in an experimental setting: comparison of different unenhanced magnetic resonance angiography techniques with electrocardiogram-gated computed tomography angiography for possible application in the pediatric population

PURPOSE: To compare different unenhanced magnetic resonance angiography (MRA) techniques for quantitative evaluation of vessel lumen in an experimental setting in young pigs whose dimensions allow for a comparison with a pediatric population. MATERIAL AND METHODS: Magnetic resonance imaging was performed in 5 healthy ventilated pigs at 1.5 T. Three different electrocardiogram (ECG)-triggered sequences were applied for MRA: [TSE-Db] T2-weighted dark-blood TurboSpinEcho (2.0 x 1.1 x 4 mm3); [trueFISP] 2D-steady-state-free-precession (2.2 x 1.8 x 2 mm3); [NAV] respiratory-gated, T2-prepared 3D-trueFISP (1.3 x 1.3 x 1.3 mm3). ECG-gated-CT angiography (CTA) (16-row CT, 1 mm collimation) served as the standard of reference. The vessel lumen was measured at 7 positions perpendicularly angulated to the vessel wall on multiplanar reformations: ascending aorta (P1), the aortic arch before (P2) and after (P3) the origin of the first supraaortic branch, the aortic arch after the origin of the second supraaortic branch (P4), the descending aorta at the level of the diaphragm (P5), and the first and second supraaortic branches (P6, P7). RESULTS: Percentage differences in the vessel area determined by MRA reformation compared with CTA-reformation were 10% +/- 20% and 35% +/- 27% (TSE-Db), -4% +/- 13% and 20% +/- 24% (trueFISP), and -3% +/- 13% and -10% +/- 19% (NAV), for positions P1 to P5 and P6 to P7, respectively. A significant difference from CTA was found for TSE-Db at all positions, and for trueFISP only at positions P6 and P7. CONCLUSIONS: Unenhanced MRA techniques allow for a reliable assessment of the dimensions of the thoracic aorta compared with CTA as the standard of reference. Using ECG-gating and navigator techniques, the free-breathing approach showed the best agreement with CTA. This technique may therefore be the most useful in the pediatric age group allowing for true 3D data acquisition with its inherent postprocessing possibilities.     

Four nonfatal and six fatal cases of opiate use: utility of morphine, its metabolites, and their ratios in blood specimens

Four nonfatal and six fatal cases of opiate use are presented with careful toxicological analysis. Levels of morphine (M), 6-monoacetylmorphine (6-MAM), morphine-6-glucuronide (M6G), and morphine-3-glucuronide (M3G) in blood specimens were measured by the sophisticated method of liquid chromatography (LC)-electrospray ionization (ESI)-tandem mass spectrometry (MS-MS). Fatal cases were characterized by much higher levels of free M than the nonfatal cases; this caused lower ratios of M6G/M and M3G/M in the fatal cases when compared with the nonfatal cases. Among the six fatal cases, the M6G/M ratios were especially low in four cases, in which rapid deaths were estimated. The present data are compared with data previously reported by other groups, and we discuss the utility of the levels of M, M6G, and M3G in blood and their ratios for estimating the antemortem status of each individual.