Minimally invasive lateral foraminotomy with partial lateral facetectomy for lumbar radiculopathy-An evaluation of facet integrity and description of the procedure.

Foraminal stenosis causing nerve root compression and radiculopathy is a relatively common pathology in the lumbar spine. The treatment of choice, when surgery is indicated, is foraminal decompression at the affected level, usually through a conventional midline open foraminotomy. Minimally invasive lateral foraminotomy with partial lateral facetectomy is a potentially effective surgical alternative when such a surgery is warranted. The evaluation of the efficacy and benefits of this approach for treatment of radiculopathy; an assessment of facet integrity; and, a detailed description of the procedure are also provided. Patients with predominantly unilateral lower limb radiculopathy, who had persistent symptoms despite conservative therapy, underwent a minimally invasive lumbar lateral foraminotomy (through tubular retractors) with partial lateral facetectomy. The Oswestry disability index (ODI) and the visual analog scale (VAS) for back and leg pain were evaluated preoperatively, postoperatively, and at the latest follow-up. Facet integrity was evaluated with postoperative computed tomography (CT) scans. Between 2013 and 2014, in the 12 patients who underwent this procedure and were evaluted after a minimum follow up of 1 year, there was significant improvement in the ODI, VAS based back pain, and VAS based leg pain. A minimally invasive, lateral foraminotomy with partial lateral facetectomy is an effective alternative technique for treatment of radiculopathy due to foraminal stenosis in a carefully selected subgroup of patients. A larger study would possibly highlight the effectiveness of this procedure.

Lymphoblastic lymphoma presenting as bilateral renal enlargement diagnosed by percutaneous kidney biopsy: Report of three cases.

Renal involvement by lymphoma can be a diagnostic challenge. Acute kidney injury (AKI) is an unusual manifestation of lymphomatous infiltration in the kidneys. We report three cases of lymphoblastic lymphoma, a very rare form of lymphoma, presenting with AKI and bilateral enlargement of kidneys, diagnosed by percutaneous kidney biopsy. Lymphomatous infiltration should be suspected with such clinical presentation. Kidney biopsy is a valuable diagnostic tool, to establish the correct diagnosis and subtype of lymphoma for timely initiation of therapy for these aggressive hematological malignancies.

IgA dominant postinfectious glomerulonephritis: Report of two cases.

Immunoglobulin A (IgA) dominant postinfectious glomerulonephritis (IgA PIGN) is a distinct clinical entity increasingly recognized in adult. It usually presents with reduced glomerular filtration rate, heavy proteinuria, and has unfavorable prognosis. Immunofluorescence study of renal biopsy specimens have IgA as dominant or codominant antibody. We encountered two cases of IgA dominant PIGN recently presenting as rapidly progr essive glomerulonephritis and managed conservatively. Both the patients are on follow-up and do not have complete recovery of renal function till date. Long-term follow-up is needed to assess the progression of the disease in these patients.

Perianal Basal cell carcinoma-an unusual site of occurrence.

Basal cell carcinoma is the most common nonmelanoma skin cancer. Its occurrence in the perianal region is very rare. Awareness of its benign behavior in this region, in contrast to the earlier reports, is vital in its management. Local excision seems to provide adequate control. We are herewith reporting an extremely rare case of a 69-year-old male with basal cell carcinoma treated adequately with local excision.

Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia.

During ischemia and heart failure, there is an increase in cardiac glycolysis. To understand if this is beneficial or detrimental to the heart, we chronically elevated glycolysis by cardiac-specific overexpression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) in transgenic mice. PFK-2 controls the level of fructose-2,6-bisphosphate (Fru-2,6-P2), an important regulator of phosphofructokinase and glycolysis. Transgenic mice had over a threefold elevation in levels of Fru-2,6-P2. Cardiac metabolites upstream of phosphofructokinase were significantly reduced, as would be expected by the activation of phosphofructokinase. In perfused hearts, the transgene caused a significant increase in glycolysis that was less sensitive to inhibition by palmitate. Conversely, oxidation of palmitate was reduced by close to 50%. The elevation in glycolysis made isolated cardiomyocytes highly resistant to contractile inhibition by hypoxia, but in vivo the transgene had no effect on ischemia-reperfusion injury. Transgenic hearts exhibited pathology: the heart weight-to-body weight ratio was increased 17%, cardiomyocyte length was greater, and cardiac fibrosis was increased. However, the transgene did not change insulin sensitivity. These results show that the elevation in glycolysis provides acute benefits against hypoxia, but the chronic increase in glycolysis or reduction in fatty acid oxidation interferes with normal cardiac metabolism, which may be detrimental to the heart.

Altering and analyzing glucose metabolism in perfused hearts of transgenic mice.

Glucose metabolism plays an important role in cardiac bioenergetics that changes under various stress conditions including hypertrophy, diabetic cardiomyopathy, and ischemia-reperfusion injury. To understand the role of glycolysis under these conditions, we have altered several steps of the glycolytic pathway specifically in the heart. In this chapter, we describe methods used to produce cardiac-targeted transgenic mice and procedures for measuring various glucose metabolites including glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-bisphosphate, and glycogen. Also, we describe methods for measuring glucose transport and glycolysis in perfused mouse hearts. Using these methods, we show that mice over-expressing cardiac-specific kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (Mykd-PFK-2) show reduced glucose transport and reduced glycolysis when compared with control. The metabolites glucose-6-phosphate, fructose-6-phosphate, and glycogen were elevated, whereas fructose-1,6-bisphosphate was reduced in the transgenic Mykd-PFK-2 mouse hearts.

Cardiomyocyte dysfunction in models of type 1 and type 2 diabetes.

Cardiomyopathy is a major cause of mortality for both type 1 and 2 diabetic patients. However, experimental analysis of diabetic cardiomyopathy has focused on type 1 diabetes and there are few reports on cardiomyocyte dysfunction in the widely used type 2 diabetic model, db/db. In the current study, we assessed function in isolated ventricular myocytes from type 1 diabetic OVE26 mice and from type 2 diabetic db/db mice. When compared with their respective control strains, both diabetic models showed significant impairment in contractility, as assessed by percent peak shortening, maximal rate of contraction, and maximal rate of relaxation. The calcium decay rate was also significantly reduced in both types of diabetes, but the decrement was much greater in OVE26 myocytes, approx 50% vs only 20% in db/db myocytes. To understand the basis for slow calcium decay in diabetic myocytes and to understand the molecular basis for the quantitative difference between calcium decay in OVE26 and db/db myocytes, we measured cardiac content of the SERCA2a calcium pump. SERCA2a was significantly decreased in OVE26 diabetic myocytes but not reduced at all in db/db myocytes. The reduction of SERCA2a in OVE26 myocytes was completely prevented by overexpression of the antioxidant protein metallothionein, confirming that oxidative stress is an important component of diabetic cardiomyopathy. The current results demonstrate that though contractility is impaired in individual myocytes of db/db hearts and deficits are similar to what is seen in a severe model of type 1 diabetes, impairment in calcium reuptake is less severe, probably as a result of maintenance of normal levels of SERCA2a.

Overexpression of hexokinase protects hypoxic and diabetic cardiomyocytes by increasing ATP generation.

Cardiac glucose metabolism is critical to hypoxic cardiac function and hypoxia is known to stimulate glucose metabolism. This increases generation of ATP when mitochondrial respiration is inhibited. In diabetes, cardiac glucose metabolism declines and this may contribute to diabetic cardiomyopathy. The first step in committing glucose to metabolism is glucose phosphorylation catalyzed by hexokinase. But the potential role of hexokinase in the hypoxic or diabetic heart is uncertain. This study is designed to assess the ability of hexo-kinase and elevated ATP to protect cardiomyocyte contractility from hypoxia and diabetes. We used cardiomyocytes from the transgenic mouse Mh, which has cardiac specific expression of yeast hexokinase, to investigate the importance of glucose phosphorylation in the myocyte response to hypoxia and diabetes. Cardiomyocytes were isolated from FVB control and Mh hearts to assess the effects of 2 h of hypoxia on myocyte contractility and ATP content. The protective effect of hexokinase on diabetes was assessed in myocytes from the OVE26 Type I diabetic mouse and in OVE26Mh diabetic mice that carry the hexokinase gene. Overexpression of hexokinase had no effect during aerobic culture, but during hypoxia, hexokinase improved ATP content by 44% and this restored contractility almost to normal levels. In myocytes from diabetic mice, tested under both aerobic and hypoxic conditions, the hexokinase gene significantly improved ATP content and this significantly improved contractility. These results demonstrate that elevating hexokinase activity can be beneficial to hypoxic or diabetic cardiomyocytes secondary to improving myocyte ATP levels.

Is there a need for resident general surgical cover in small peripheral hospitals?

AIM: To assess the need for resident general surgical cover in a small peripheral hospital. PATIENTS AND METHODS: The total number of admissions to Caerphilly District Miners' Hospital in the year 2001 was noted along with the admission criterion for elective general and vascular surgical patients. RESULTS: Among the 10,608 in-patients only 120 (1.13%) developed general surgical/vascular problems that merited surgical referral and out of these 30 (0.28%) patients were transferred to neighbouring larger hospitals for specialist care. CONCLUSIONS: A resident staff grade surgeon is not required in a small peripheral hospital and this service could be provided by the resident on-call surgical SpR in a neighbouring larger hospital.

Cardiac expression of kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase inhibits glycolysis, promotes hypertrophy, impairs myocyte function, and reduces insulin sensitivity.

Glycolysis is important to cardiac metabolism and reduced glycolysis may contribute to diabetic cardiomyopathy. To understand its role independent of diabetes or hypoxic injury, we modulated glycolysis by cardiac-specific overexpression of kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (kd-PFK-2). PFK-2 controls the level of fructose 2,6-bisphosphate (Fru-2,6-P(2)), an important regulator of glycolysis. Transgenic mice had over 2-fold reduced levels of Fru-2,6-P(2). Heart weight/body weight ratio indicated mild hypertrophy. Sirius red staining for collagen was significantly increased. We observed a 2-fold elevation in glucose 6-phosphate and fructose 6-phosphate levels, whereas fructose 1,6-bisphosphate was reduced 2-fold. Pathways branching off of glycolysis above phosphofructokinase were activated as indicated by over 2-fold elevated UDP-N-acetylglucosamine and glycogen. The kd-PFK-2 transgene significantly inhibited glycolysis in perfused hearts. Insulin stimulation of metabolism and Akt phosphorylation were sharply reduced. In addition, contractility of isolated cardiomyocytes was impaired during basal and hypoxic incubations. The present study shows that cardiac overexpression of kinase-deficient PFK-2 reduces cardiac glycolysis that produced negative consequences to the heart including hypertrophy, fibrosis, and reduced cardiomyocyte function. In addition, metabolic and signaling responses to insulin were significantly decreased.

Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes.

Many diabetic patients suffer from a cardiomyopathy that cannot be explained by poor coronary perfusion. Reactive oxygen species (ROS) have been proposed to contribute to this cardiomyopathy. Consistent with this we found evidence for induction of the antioxidant genes for catalase in diabetic OVE26 hearts. To determine whether increased antioxidant protection could reduce diabetic cardiomyopathy, we assessed cardiac morphology and contractility, Ca(2+) handling, malondialdehyde (MDA)-modified proteins, and ROS levels in individual cardiomyocytes isolated from control hearts, OVE26 diabetic hearts, and diabetic hearts overexpressing the antioxidant protein catalase. Diabetic hearts showed damaged mitochondria and myofibrils, reduced myocyte contractility, slowed intracellular Ca(2+) decay, and increased MDA-modified proteins compared with control myocytes. Overexpressing catalase preserved normal cardiac morphology, prevented the contractile defects, and reduced MDA protein modification but did not reverse the slowed Ca(2+) decay induced by diabetes. Additionally, high glucose promoted significantly increased generation of ROS in diabetic cardiomyocytes. Chronic overexpression of catalase or acute in vitro treatment with rotenone, an inhibitor of mitochondrial complex I, or thenoyltrifluoroacetone, an inhibitor of mitochondrial complex II, eliminated excess ROS production in diabetic cardiomyocytes. The structural damage to diabetic mitochondria and the efficacy of mitochondrial inhibitors in reducing ROS suggest that mitochondria are a source of oxidative damage in diabetic cardiomyocytes. We also found that catalase overexpression protected cardiomyocyte contractility in the agouti model of type 2 diabetes. These data show that both type 1 and type 2 diabetes induce damage at the level of individual myocytes, and that this damage occurs through mechanisms utilizing ROS.

Elevated hexokinase increases cardiac glycolysis in transgenic mice.

OBJECTIVE: Cardiac glucose metabolism is critical to normal and pathological function. The significance of the first committed metabolic step, glucose phosphorylation, has not been established. In this study a new transgenic model was developed in order to investigate the importance of this enzymatic step in cardiac glycolysis. METHODS: Transgenic mice were produced that overexpress yeast hexokinase B under the control of a cardiac specific promoter. Yeast hexokinase B is a high affinity enzyme that is not inhibited by glucose-6-phosphate. Hexokinase enzyme activity was measured by a modified radiometric procedure. Cardiac glucose metabolism and contractility were measured in the Langendorff mode. Cardiac glycogen content and glucose-6-phosphate independent glycogen synthase activity were also determined. RESULTS: In transgenic hearts hexokinase activity was significantly elevated and increased glucose metabolism, particularly in the presence of insulin and during cardiac reperfusion. However during ischemic perfusion the effect of the transgene on glycolysis was minimal. Under all conditions tested there was no effect of hexokinase on contractility. Glycogen content of transgenic hearts was elevated 2-fold and glucose-6-phosphate independent glycogen synthase was also increased. CONCLUSION: These results demonstrate that glucose phosphorylation is a key step in determining cardiac glucose metabolism under oxidative conditions.

Overexpression of metallothionein reduces diabetic cardiomyopathy.

Many diabetic patients suffer from cardiomyopathy, even in the absence of vascular disease. This diabetic cardiomyopathy predisposes patients to heart failure and mortality from myocardial infarction. Evidence from animal models suggests that reactive oxygen species play an important role in the development of diabetic cardiomyopathy. Our laboratory previously developed a transgenic mouse model with targeted overexpression of the antioxidant protein metallothionein (MT) in the heart. In this study we used MT-transgenic mice to test whether an antioxidant protein can reduce cardiomyopathy in the OVE26 transgenic model of diabetes. OVE26 diabetic mice exhibited cardiomyopathy characterized by significantly altered mRNA expression, clear morphological abnormalities, and reduced contractility under ischemic conditions. Diabetic hearts appeared to be under oxidative stress because they had significantly elevated oxidized glutathione (GSSG). Diabetic mice with elevated cardiac MT (called OVE26MT mice) were obtained by crossing OVE26 transgenic mice with MT transgenic mice. Hyperglycemia in OVE26MT mice was indistinguishable from hyperglycemia in OVE26 mice. Despite this, the MT transgene significantly reduced cardiomyopathy in diabetic mice: OVE26MT hearts showed more normal levels of mRNA and GSSG. Typically, OVE26MT hearts were found to be morphologically normal, and elevated MT improved the impaired ischemic contractility seen in diabetic hearts. These results demonstrate that cardiomyocyte-specific expression of an antioxidant protein reduces damage to the diabetic heart.