A mitochondrial superoxide theory for oxidative stress diseases and aging

Fridovich identified CuZnSOD in 1969 and manganese superoxide dismutase (MnSOD) in 1973, and proposed ”the Superoxide Theory,” which postulates that superoxide (O₂^•−) is the origin of most reactive oxygen species (ROS) and that it undergoes a chain reaction in a cell, playing a central role in the ROS producing system. Increased oxidative stress on an organism causes damage to cells, the smallest constituent unit of an organism, which can lead to the onset of a variety of chronic diseases, such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis and other neurological diseases caused by abnormalities in biological defenses or increased intracellular reactive oxygen levels. Oxidative stress also plays a role in aging. Antioxidant systems, including non-enzyme low-molecular-weight antioxidants (such as, vitamins A, C and E, polyphenols, glutathione, and coenzyme Q₁₀) and antioxidant enzymes, fight against oxidants in cells. Superoxide is considered to be a major factor in oxidant toxicity, and mitochondrial MnSOD enzymes constitute an essential defense against superoxide. Mitochondria are the major source of superoxide. The reaction of superoxide generated from mitochondria with nitric oxide is faster than SOD catalyzed reaction, and produces peroxynitrite. Thus, based on research conducted after Fridovich’s seminal studies, we now propose a modified superoxide theory; i.e., superoxide is the origin of reactive oxygen and nitrogen species (RONS) and, as such, causes various redox related diseases and aging.     

Vibrotactile discriminative capacity is impacted in a digit-specific manner with concurrent unattended hand stimulation

A number of perceptual and neurophysiological studies have investigated the effects of delivering unilateral versus bilateral tactile sensory stimulation. While a number of studies indicate that perceptual discrimination degrades with opposite-hand stimulation, there have been no reports that examined the digit specificity of cross-hemispheric interactions to discriminative capabilities. The purpose of this study was to determine whether unattended hand (UH) stimulation significantly degraded or improved amplitude discriminative capacity on the attended hand (AH) in a digit-specific manner. The methods are based on a sensory perceptual task (vibrotactile amplitude discriminative capacity on the tips of the fingers D2 and D3 of the left hand) in the absence and presence of conditioning stimuli delivered to D2 and D3 of the right hand. Non-specific equal-amplitude stimulation to D2 and D3 of the UH significantly worsened amplitude discrimination (AD) performance, while delivering unequal-amplitude stimuli to D2 and D3 of the UH worsened task performance only under the condition in which the unattended stimuli failed to appropriately match the stimulus parameters on the AH. Additionally, delivering single-site stimuli to D2 or D3 of the UH resulted in degraded performance on the AD task when the stimulus amplitude did not match the amplitude of the stimulus applied to homologous digits of the AH. The findings demonstrate that there is a reduction in performance under conditions where UH stimulation least matched stimulation applied to the AH, while there was little or no change in performance when stimulus conditions on the homologous digit(s) of the contralateral sites were similar. Results suggest that bilateral interactions influence perception in a context-dependent manner that is digit specific.     

Mutation of Plekha7 attenuates salt-sensitive hypertension in the rat

PLEKHA7 (pleckstrin homology domain containing family A member 7) has been found in multiple studies as a candidate gene for human hypertension, yet functional data supporting this association are lacking. We investigated the contribution of this gene to the pathogenesis of salt-sensitive hypertension by mutating Plekha7 in the Dahl salt-sensitive (SS/JrHsdMcwi) rat using zinc-finger nuclease technology. After four weeks on an 8% NaCl diet, homozygous mutant rats had lower mean arterial (149 ± 9 mmHg vs. 178 ± 7 mmHg; P < 0.05) and systolic (180 ± 7 mmHg vs. 213 ± 8 mmHg; P < 0.05) blood pressure compared with WT littermates. Albumin and protein excretion rates were also significantly lower in mutant rats, demonstrating a renoprotective effect of the mutation. Total peripheral resistance and perivascular fibrosis in the heart and kidney were significantly reduced in Plekha7 mutant animals, suggesting a potential role of the vasculature in the attenuation of hypertension. Indeed, both flow-mediated dilation and endothelium-dependent vasodilation in response to acetylcholine were improved in isolated mesenteric resistance arteries of Plekha7 mutant rats compared with WT. These vascular improvements were correlated with changes in intracellular calcium handling, resulting in increased nitric oxide bioavailability in mutant vessels. Collectively, these data provide the first functional evidence that Plekha7 may contribute to blood pressure regulation and cardiovascular function through its effects on the vasculature.Hypertension is a complex disease that is characterized by increased blood pressure, renal damage, and vascular dysfunction which collectively increase risk of atherosclerosis, stroke, heart disease, and renal failure in one-quarter of all adults worldwide (1–3). Because there is strong evidence of heritability in hypertension (2, 4, 5), considerable effort has been put toward identifying novel candidate genes and their molecular mechanisms. Genome-wide association studies (GWAS) have identified many potential hypertension loci, which shed light on the genetic complexity of this disease (5–8) but have provided little mechanistic insight. As such, validation and elucidation of the functional roles and disease mechanisms for these gene candidates are the next important challenges (4).Because hypertension is a complex disease (i.e., multiple variants of small effect sizes contributing to disease risk), we hypothesized candidate gene targeting on a genetically sensitized background would reveal functional role(s) of genetic disease modifiers. The Dahl salt-sensitive (SS) rat is an inbred genetic model of salt-sensitive hypertension that displays hypertension-induced renal damage, cardiac hypertrophy and vascular dysfunction (9–11). These phenotypes are induced by exposing SS rats to a high-salt diet, which results in rapid induction of hypertensive phenotypes that closely resemble salt-induced hypertension seen in humans (12–15). Knockout of specific genes in this disease model using zinc-finger nuclease (ZFN) technology have revealed the importance of key mechanisms contributing to hypertension risk, such as the protection from salt-induced hypertension and renal injury by selective ablation of adaptive immune cells in the SS-Rag1^em1Mcwi and SS-Cd247^em1Mcwi knockout rats (16, 17) and reduced hypertension and renal injury in the SS-Ncf2^em1Mcwi (p67phox) null model exhibiting reduced medullary oxidative stress (18). Additionally, we have recently demonstrated multiple genes at a single hypertension GWAS-nominated locus (Agtrap-Plod1 locus) can have additive or subtractive effects on blood pressure and renal function when mutated in the SS rat (19). These previous studies highlight the utility of this model system for testing the roles of GWAS candidate human disease genes by disrupting their specific rat orthologs using ZFN technology (20).A single-nucleotide polymorphism (SNP) (rs381815, minor allele frequency 0.26) in intron 1 of the pleckstrin homology domain containing family A member 7 (PLEKHA7) gene, was identified by five independent GWAS to be associated with elevated systolic blood pressure and hypertension in multiple populations (5, 6, 8, 21, 22). The associated locus contains only the PLEKHA7 gene (5); however, the genetic mechanism(s) underlying this locus have not yet been functionally characterized. PLEKHA7 is highly expressed in the kidney and heart, where it may be involved in formation and maintenance of the apical junction complex of epithelial cells (23). However, limited data on PLEKHA7 function are available to extrapolate its potential role(s) in the pathogenesis of hypertension. Here we used ZFN mutagenesis to obtain the first evidence to our knowledge in any model system that Plekha7 has a functional role in several hypertension-associated phenotypes in the rat. We found that mutation of Plekha7 in the SS rat attenuated salt-induced hypertension, reduced renal damage, and improved cardiac function. We also show that Plekha7 modulates calcium handling and nitric oxide (NO) bioavailability, both of which are required for normal vascular health. Collectively, these studies provide significant mechanistic insight to the role of Plekha7 in salt-sensitive hypertension.     

Fresh-stored osteochondral allografts for the treatment of femoral head defects: surgical technique and preliminary results

Purpose

The purpose of this study was to present the preliminary clinical and radiographic outcomes of the treatment of femoral head osteochondral defects in eight consecutive symptomatic patients with fresh-stored osteochondral allografts via a trochanteric osteotomy.

Methods

This study included all consecutive patients treated in our department between 2008 and 2010 for worsening pain and mechanical symptoms of femoral head osteochondral defects. Each patient had preoperative routine hip radiographs and a preoperative magnetic resonance imaging study that determined and recorded the defect size and femoral head diameters. Allograft donors were identified through the Multiple Organ Retrieval and Exchange program (Ontario, Canada).

Results

The osteochondral defects were secondary to osteochondritis dissecans in four patients, avascular necrosis in three and femoral head fracture without dislocation in one. The patients’ average age at surgery was 23.7 (range 17–42), and the average follow-up was 41 months (range 24–54). Follow-up included clinical and radiographic examinations at standard intervals. The average Harris hip scores improved from 57.7 (range 50–65) points preoperatively to 83.9 (range 72–94) points at latest follow-up. Five patients had good-to-excellent clinical outcomes, and one had a fair outcome. One patient was converted to a total hip arthroplasty due to progression of arthritis. Another patient’s graft subsided and he underwent a successful repeat transplantation. An additional patient required the removal of the screws transfixing her trochanter due to persistent irritation.

Conclusions

These findings indicate that fresh-stored osteochondral allograft transplantation using a trochanteric slide and surgical dislocation is a viable treatment option for femoral head defects in young patients.     

A representative of arylcyanomethylenequinone oximes effectively inhibits growth and formation of hyphae in Candida albicans and influences the activity of protein kinases in vitro

In this study, we applied various assays to reveal new activities of phenylcyanomethylenequinone oxime-4-(hydroxyimino) cyclohexa-2,5-dien-1-ylidene](phenyl)ethanenitrile (4-AN) for potential anti-microbial applications. These assays demonstrated (a) the antimicrobial effect on bacterial and fungal cultures, (b) the effect on the in vitro activity of the kinase CK2, (c) toxicity towards human erythrocytes, the Caco-2 cancer cell line, and embryonic development of Zebrafish. We demonstrated the activity of 4-AN against selected bacteria and Candida spp. The MIC ranging from 4?µg/ml to 125?µg/ml proved effective in inhibition of formation of hyphae and cell aggregation in Candida, which was demonstrated at the cytological level. Noteworthy, 4-AN was found to inhibit the CK2 kinase with moderate potency. Moreover, at low concentrations, it did not exert any evident toxic effects on human erythrocytes, Caco-2 cells, or Zebrafish embryos. 4-AN can be a potential candidate as a novel drug against Candida infections.     

Sphenoid wing meningiomas: peritumoral brain edema as a prognostic factor in surgical outcome

Neurosurgical Review - Sphenoidal meningiomas constitute 18% of intracranial masses, and still present a difficult surgical challenge. PTBE has been associated with several complications and future...     

Total hip arthroplasty in patients with fibrous dysplasia: a modern update

BackgroundFibrous dysplasia (FD) results from an abnormality in lamellar bone formation and most frequently involves the proximal femur. This can lead to the development of osteoarthritis requiring total hip arthroplasty (THA). Such cases are challenging, and there is a lack of information guiding best management. As such, we devised a study assessing the outcomes and complications in patients with FD undergoing THA with modern implant technology, and we outlined our preferred surgical technique.MethodsA search of our institutional arthroplasty database was performed to identify patients who underwent THA for FD between January 2001 and July 2018 at Mount Sinai Hospital in Toronto, Canada. Data regarding implants used and the use of allograft material or metal augments or both were obtained. Complications and revision requirements were noted. Radiographic and clinical leg length discrepancies were assessed.ResultsA total of 10 hips in 9 patients who underwent THA for FD were identified. Mean follow-up time was 6.0 years (range 0.5 to 10.3 yr). The majority of patients underwent THA using uncemented femoral and acetabular components with large femoral heads on highly cross-linked polyethylene liners. Most cases (80% of hips) required allograft to the proximal femur. A single complication requiring revision was noted. In 90% of hip surgeries, the patient required transfusion of packed red blood cells. Mean radiographic and clinical leg length discrepancies were 0.9 cm (range −2.4 to 2.4 cm) and 0.9 cm (range −4 to 0 cm), respectively.ConclusionContrary to previous reports, low complication and revision rates were observed with cementless components and routine use of allograft material. The challenging nature of such cases warrants use of an experienced arthroplasty treatment team.     

Prospective evaluation of intra-observer variability of the hydronephrosis index in sonographic examination of 44 patients with acute renal colic

Purpose

The aim of our prospective designed study was to confirm the intra-observer agreement of assessments of the hydronephrosis index (HI) with a sonographic technique that potentially provides additional information in patients with acute renal colic (ARC).

Methods

Sonographic measurement of HI and valuation of common clinical criteria were performed in 44 consecutive patients presenting with unilateral stone-related ARC. HI of colic side was recorded twice in predefined time intervals. Intra-observer agreement was evaluated with the Spearman’s rank correlation/rho (ρ) for attributive-metric characteristics. Data of HI-measurement on the colic side were compared with data of the unaffected side using t test.

Results

Intra-observer agreement was significant for HI in the colic side (ρ = 0.918, p < 0.001) and in the unaffected side (ρ = 0.826, p < 0.001). The mean HI between colic and unaffected side differed significantly on the first evaluation (85.2 vs. 93.7, respectively; p < 0.001) and on the second evaluation (85.1 vs. 93.6, respectively; p < 0.001) as well.

Conclusions

The HI method is a slightly feasible examination method in patients presenting with stone-related renal colic. Moreover, it offers a solid discrimination between obstruction and non-obstruction. Our prospective trial illustrates HI as a reproducible method with a high-grade intra-observer agreement. However, potential change of values under medical expulsive therapy and coherency with the functionality of the obstructed kidney may lead to bias and therefore remain to be analyzed. Further studies to specify exact thresholds for this method and to state our findings are required.     

The Outcome of Modified Extended Trochanteric Osteotomy in Revision THA for Vancouver B2/B3 Periprosthetic Fractures of the Femur

We hypothesised that a modified ETO in patients undergoing revision total hip arthroplasty (THA) for treatment of Vancouver B2/B3 peri-prosthetic fractures would be associated with good clinical outcomes. A retrospective review was conducted of 34 patients (mean age 73 years). At mean follow-up of 57 months, the ETO had healed in all patients. Two patients had subsidence of the femoral stem at two and three years postoperatively requiring revision, and one patient had a dislocation 3 months after surgery. The mean Harris Hip Score at the time of the final follow-up was 76.9 (range, 46–95); 23/34 patients had an excellent result, 7/34 a good result, and 4/34 a poor result. We conclude that satisfactory outcomes can be obtained using this technique.