Protective role of cyclooxygenase (COX)-2 in experimental lung injury: evidence of a lipoxin A4-mediated effect.

BACKGROUND: Polymorphoneutrophils (PMNs) are activated by inflammatory mediators following splanchnic ischemia/reperfusion (I/R), potentially injuring organs such as the lung. As a result, some patients develop respiratory failure following abdominal aortic aneurysm repair. Pulmonary cyclooxygenase (COX)-2 protects against acid aspiration and bacterial instillation via lipoxins, a family of potent anti-inflammatory lipid mediators. We explored the role of COX-2 and lipoxin A(4) in experimental I/R-mediated lung injury. MATERIALS AND METHODS: Sprague-Dawley rats were assigned to one of the following five groups: (1) controls; (2) aortic cross-clamping for 45 min and reperfusion for 4 h (I/R group); (3) I/R and SC236, a selective COX-2 inhibitor; (4) I/R and aspirin; and (5) I/R and iloprost, a prostacyclin (PGI(2)) analogue. Lung injury was assessed by wet/dry ratio, myeloperoxidase (MPO) activity, and bronchoalveolar lavage (BAL) neutrophil counts. BAL levels of thromboxane, PGE(2), 6-keto-PGF(1)α (a hydrolysis product of prostacyclin), lipoxin A(4), and 15-epi-lipoxin A(4) were analyzed by enzyme immunoassay (EIA). Immunostaining for COX-2 was performed. RESULTS: I/R significantly increased tissue MPO, the wet/dry lung ratio, and neutrophil counts. These measures were significantly further aggravated by SC236 and improved by iloprost. I/R increased COX-2 immunostaining and both PGE(2) and 6-keto-PGF(1α) levels in BAL. SC236 markedly reduced these prostanoids and lipoxin A(4) compared with I/R alone. Iloprost markedly increased lipoxin A(4) levels. The deleterious effect of SC236 and the beneficial effect of iloprost was associated with a reduction and an increase, respectively, in lipoxin A(4) levels. CONCLUSIONS: Lipoxin A(4) warrants further evaluation as a mediator of COX-2 regulated lung protection.

Electrical field stimulation promotes anastomotic healing in poorly perfused rat colon.

INTRODUCTION: Hypoperfusion of the bowel is a risk factor for anastomotic failure. Electrical field stimulation has been shown to improve repair in ischemic tissue, but its influence in hypoperfused colon has not been investigated. The hypothesis of this experimental animal study was that electrical field stimulation improves anastomotic healing in ischemic bowel. MATERIALS AND METHODS: Thirty rats were divided evenly into three groups: control, ischemia/placebo, and ischemia/test group. Ischemia was induced by ligation of the arterial supply to the proximal colon. The watershed area was identified and transected. Field stimulation was achieved by application of negatively charged diethylaminoethyl Sephadex beads in methylcellulose gel to the colonic epithelium prior to anastomosis. The placebo group had methylcellulose gel only applied and control animals had anastomosis only. Anastomotic strength was measured using anastomotic bursting pressure and hydroxyproline content. Systemic effect was investigated via interleukin-6 and vascular endothelial growth factor assay. RESULTS: The ischemia/electrical field stimulation (EFS) group had significantly increased bursting pressure and hydroxyproline content in comparison with the placebo group (P < 0.001). Serum cytokine levels were unaffected. CONCLUSION: Negatively charged EFS improves anastomotic healing in hypoperfused colon without induction of systemic cytokines and has potential as a local treatment in high-risk bowel anastomosis.

Treatment-resistant priapism associated with long-term low-molecular-weight heparin.

This case report summarises the case of a 56-year-old man with low-flow, ischaemic priapism requiring urgent insertion of a penile prosthesis following prophylactic anticoagulation with tinzaparin. Low-molecular-weight heparin (LMWH) has been proposed as a cause of ischaemic priapism, although reported cases of this are rare. This particular side effect of tinzaparin has been reported once in a case report in 2018, and there are scant other reports of LMWH-induced priapism. This case was refractory to the full treatment algorithm, including multiple aspirations, phenylephrine injection, cavernosal shunt and required transfer for implantation of a penile prosthesis. Only one other case of such a severe case of priapism has been documented, involving LMWH and warfarin. Documented evidence of possible causes of priapism are vital, given the rarity of this condition, the frequency of LMWH and the potentially devastating complications.

The evolving role of taurolidine in cancer therapy.

BACKGROUND AND DESIGN: Taurolidine consists of two taurinamide rings derived from the naturally occurring amino acid taurine. It has been utilized to prevent adhesions, as an antimicrobial, and as an anti-inflammatory agent. More recently, it has been found to exert antineoplastic activity. We reviewed the literature regarding taurolidine and its role in cancer treatment. RESULTS AND CONCLUSION: Taurolidine induces cancer cell death through a variety of mechanisms. Even now, all the antineoplastic pathways it employs are not completely elucidated. It has been shown to enhance apoptosis, inhibit angiogenesis, reduce tumor adherence, downregulate proinflammatory cytokine release, and stimulate anticancer immune regulation following surgical trauma. Apoptosis is activated through both a mitochondrial cytochrome-c-dependent mechanism and an extrinsic direct pathway. A lot of in vitro and animal data support taurolidine's tumoricidal action. Taurolidine has been used as an antimicrobial agent in the clinical setting since the 1970s and thus far appears nontoxic. The nontoxic nature of taurolidine makes it a favorable option compared with current chemotherapeutic regimens. Few published clinical studies exist evaluating the role of taurolidine as a chemotherapeutic agent. The literature lacks a gold-standard level 1 randomized clinical trial to evaluate taurolidine's potential antineoplastic benefits. However, these trials are currently underway. Such randomized control studies are vital to clarify the role of taurolidine in modern cancer treatment.

A randomized trial of photoselective vaporization of the prostate using the 80-W potassium-titanyl-phosphate laser vs transurethral prostatectomy, with a 1-year follow-up.

OBJECTIVE: To compare the potassium-titanyl-phosphate Greenlight(TM) 80-W laser ablation system for photovaporization of the prostate (PVP; Laserscope, San Jose, CA, USA) with transurethral resection of the prostate (TURP), as many technologies have been proposed as equivalent or superior to TURP without gaining widespread acceptance, due to lack of data from randomized trials. PATIENTS AND METHODS: In all, 120 patients were randomized to undergo either TURP or PVP after a full urological evaluation, which was repeated at 1, 3, 6 and 12 months after surgery. Irrigation use, duration of catheterization (DOC), length of hospital stay (LOS), blood loss, cost and operative time were also assessed. RESULTS: Both groups showed a significant increase in mean (sd) maximum urinary flow rate from baseline (P < 0.05); in the TURP group from 8.9 (3.0) to 19.4 (8.7) mL/s (154%), and in the PVP group from 8.8 (2.5) to 18.6 (8.2) mL/s (136%). The International Prostate Symptom Score (IPSS) decreased from 25.4 (5.7) to 10.9 (9.4) in the TURP group (53%), and from 25.3 (5.9) to 8.9 (7.6) in the PVP group (61%). The trends were similar for the bother and Quality of Life scores. There was no difference in sexual function as measured by Baseline Sexual Function Questionnaires. The DOC was significantly less in the PVP than the TURP group (P < 0.001), with a mean (range) of 13 (0-24) h vs 44.7 (6-192) h. The situation was similar for LOS (P < 0.001), with a mean (range) of 1.09 (1-2) and 3.6 (3-9) days in the PVP and TURP groups, respectively. Adverse events and complications were less frequent in the PVP group. Costs were also 22% less in the PVP group. CONCLUSIONS: This trial shows that PVP is an effective technique when compared to TURP, producing equivalent improvements in flow rates and IPSS with the advantages of markedly reduced LOS, DOC and adverse events. A long-term follow-up is being undertaken to ensure durability of these results.

Effect of pravastatin on experimental diabetic wound healing.

BACKGROUND: Impaired wound healing in diabetes has been associated with abnormalities in wound nitric oxide (NO) and nitric oxide synthase (NOS) availability. Efforts to alter the profile of NO expression in the wound microenvironment have proven to be successful in partially restoring wound healing deficits. We investigated the effects of pravastatin, a HMG Co A reductase inhibitor on endothelial nitric oxide synthase (eNOS) expression, NO production, and wound healing in a diabetic acute wound healing model. MATERIALS AND METHODS: Of 70 male Sprague Dawley rats injected with streptozocin, 62 were confirmed diabetic after 1 wk. Animals were randomized into two groups: (1) diabetic control and (2) diabetic treated with pravastatin. Pravastatin sodium was gavaged at 0.4 mg/kg/d for 5 d, after which all animals underwent dorsal incision with insertion of subcutaneous sponges. Breaking strengths and hydroxyproline were measured on days 1, 3, and 10 post-wounding. Wound fluid was analyzed for nitrate/nitrite production. Tissue samples were analyzed for eNOS expression. RESULTS: We demonstrated enhanced wound breaking strengths, hydroxyproline accumulation, an up-regulation in eNOS expression, and elevated NO levels in the pravastatin treated group. CONCLUSION: We have shown that pravastatin, in an experimental model of diabetes may through up-regulation of eNOS and NO expression improve wound healing.

Attenuation of lipopolysaccharide-mediated left ventricular dysfunction by glutamine preconditioning.

OBJECTIVE: Myocardial dysfunction is often seen during the inflammatory response to major surgery at 4 to 6h postoperatively. The aim of this study was to investigate the effect of glutamine pretreatment, as a means of preconditioning, on lipopolysaccharide-induced myocardial dysfunction. METHODS: C57BL/6 mice were randomized into four groups: Control; lipopolysaccharide; glutamine plus lipopolysaccharide; and Quercetin, an inhibitor of heat shock protein synthesis plus glutamine and lipopolysaccharide. Left ventricular function was assessed at 6h following lipopolysaccharide (LPS) insult by invasive hemodynamics. Heat shock protein (HSP)72 in heart tissue was determined by Western immunoblot at 12h after glutamine administration. RESULTS: Administration of lipopolysaccharide resulted in significant decrease in left ventricular end systolic pressure (LVESP) (69.1 +/- 2.52 mm Hg versus 106.3 +/- 3.36 mm Hg in controls), reduced dP/dtmax (4704.1 +/- 425.31 mm Hg/s versus 9389.8 +/- 999.4 mm Hg/s in controls), and the increase in left ventricular end diastolic pressure (LVEDP) (5.10 +/- 0.28 mm Hg versus 2.16 +/- 0.27 mm Hg in controls) (P < 0.05). Peritoneal injection of 25 g/kg of glutamine 12 h prior to lipopolysaccharide exposure induced HSP72 expression in heart tissues and attenuated lipopolysaccharide-induced left ventricular dysfunction: LVESP 85.94 +/- 3.8 mm Hg (P < 0.05), dP/dtmax 8331 +/- 425 mm Hg (P < 0.05), LVEDP 2.32 +/- 0.23 mm Hg (P < 0.01). Quercetin partially attenuated glutamine induced HSP72 expression and blocked the protective response of glutamine. CONCLUSION: These data demonstrate that cardioprotection with glutamine is associated with induction of HSP72 and may be an approach to activating the preconditioning response in the heart in clinical practise.

Contrast-induced nephrotoxicity: possible synergistic effect of stress hyperglycemia.

OBJECTIVE: Oxidative stress on the renal tubules has been implicated as a mechanism of injury in both stress hyperglycemia and contrast-induced nephrotoxicity. The purpose of this study was to determine whether the combination of these effects has a synergistic effect on accentuating renal tubular apoptosis and therefore increasing the risk of contrast-induced nephrotoxicity. MATERIALS AND METHODS: Dog kidney cells were incubated with 5- and 30-mmol/L glucose solutions and no glucose and then exposed for 2 hours to three types of contrast media-high osmolar (370 mg I/mL), low osmolar (300 mg I/mL), and isoosmolar (320 mg I/mL)-and a mannitol control solution. In an identical experiment, each group of cells was pretreated with an antioxidant-N-acetylcysteine or taurine-to evaluate the protective effect, if any. Apoptosis was assessed with fluorescence-activated cell sorter flow cytometry. RESULTS: The high-osmolar contrast medium was associated with significantly elevated levels of apoptosis compared with the mannitol control (percentage apoptosis, 27.98 +/- 1.08 vs 6.19 +/- 0.771; p < 0.001). This effect was less pronounced after incubation with the low-osmolar agent but was still significant (percentage apoptosis, 20.19 +/- 0.3665 vs 6.19 +/- 0.771; p < 0.001). The isosmolar agent did not have a significant effect. Both the high- and low-osmolar contrast media coupled with hyperglycemia (30-mmol/L glucose) were associated with a significantly increased level of apoptosis. In all contrast medium groups, taurine had a greater protective effect on attenuation of cell apoptosis than did N-acetylcysteine. CONCLUSION: The combination of contrast medium and an elevated glucose level has a synergistic effect on apoptosis. Taurine may be a more effective prophylactic antioxidant than the currently advocated antioxidant, N-acetylcysteine.

Taurine modulates neutrophil function but potentiates uropathogenic E. coli infection in the murine bladder.

Eradication of a urinary tract infection (UTI) appears to be related to a number of innate host defence mechanisms and their interactions with invading bacteria. Recurrent UTIs (rUTIs) pose a difficult problem in that these bacteria use both host and bacterial factors to evade elimination. Neutrophil bactericidal function is depressed, both systemically and in urine, in patients with a history of recurrent UTI. Taurine is a semi-essential amino acid and is successful in preserving neutrophil bactericidal function in urine. Taurine may preserve neutrophil function at the urothelium and thus aid UTI resolution. Adult female (6 weeks old) C57Bl/6 mice were randomised into three groups: a saline gavage only control group, a saline gavage + E. coli group, and a taurine gavage + E. coli group [21 g/70 kg taurine in 0.9% normal saline (N/S) for 5 days]. Whilst taurine gavage pre-treatment resulted in increased serum neutrophils respiratory burst activity, at the urothelial-endothelial interface it caused higher colony forming units in the urine and a higher incidence of E. coli invasion in the bladder wall with no evidence of increased bladder wall neutrophils infiltration on MPO assay of histological assessment. Histologically there was also evidence of reduced bladder inflammation and urothelial cell apoptosis. In conclusion, taurine effectively increases neutrophils activity but given its anti-inflammatory properties, at the expense of decreased urothelial-endothelial activation thus preventing clearance of active E. coli infection in the bladder. Despite the negative results, this study demonstrates the importance of modulating interactions at the urothelial interface.

Iodinated contrast media alter immune responses in pro-inflammatory states.

BACKGROUND: Hypertonic saline causes a transient elevation of blood osmolality and has been shown to alter cellular inflammatory responses in pro-inflammatory states. Intravascular administration of iodine contrast media also causes a transient elevation of blood osmolarity. PURPOSE: To investigate the effect of iodine contrast media on leukocyte-endothelial interaction in vivo using intravital microscopy. MATERIAL AND METHODS: Male Sprague-Dawley rats (n=36) were randomized into six groups and were treated with: saline, high osmolar contrast medium, low osmolar contrast medium, and endotoxin alone and in combination with the high and low osmolar contrast media. The effect on leukocyte-endothelial interaction in the post-mesenteric venules was observed using the technique of intravital microscopy. The sequence of leukocyte rolling velocity, leukocyte-endothelial cell adherence, and transmigration was recorded and analyzed at 10 min intervals to a maximum of 120 min. RESULTS: Endotoxin significantly decreased the rolling velocity and increased the adherence and transmigration of leukocytes in a time-dependent manner. Both types of iodine contrast media attenuated this pro-inflammatory response to endotoxin. This effect began between 60 and 70 min after the onset of the experiment. CONCLUSION: Hyperosmolar and lower osmolar iodine contrast media attenuate the pro-inflammatory leukocyte-endothelial response to endotoxin in vivo.

N-acetylcysteine protects striated muscle in a model of compartment syndrome.

BACKGROUND: To avoid ischemic necrosis, compartment syndrome is a surgical emergency treated with decompression once identified. A potentially lethal, oxidant-driven reperfusion injury occurs after decompression. N-acetylcysteine is an antioxidant with the potential to attenuate the reperfusion injury. QUESTIONS/PURPOSES: We asked whether N-acetylcysteine could preserve striated muscle contractility and modify neutrophil infiltration and activation after simulated compartment syndrome release. MATERIALS AND METHODS: Fifty-seven rats were randomized to control, simulated compartment syndrome, and simulated compartment syndrome plus N-acetylcysteine groups. We isolated the rodent cremaster muscle on its neurovascular pedicle and placed it in a pressure chamber. Chamber pressure was elevated above critical closing pressure for 3 hours to simulate compartment syndrome. Experiments were concluded at three times: 1 hour, 24 hours, and 7 days after decompression of compartment syndrome. We assessed twitch and tetanic contractile function and tissue myeloperoxidase activity. Ten additional rats were randomized to control and N-acetylcysteine administration after which neutrophil respiratory burst activity was assessed. RESULTS: The simulated compartment syndrome decreased muscle contractility and increased muscle tissue myeloperoxidase activity compared with controls. Treatment with N-acetylcysteine preserved twitch and tetanic contractility. N-acetylcysteine did not alter neutrophil infiltration (myeloperoxidase activity) acutely but did reduce infiltration at 24 hours, even when given after decompression. N-acetylcysteine reduced neutrophil respiratory burst activity. CONCLUSION: N-acetylcysteine administration before or after simulated compartment syndrome preserved striated muscle contractility, apparently by attenuating neutrophil activation and the resultant oxidant injury. CLINICAL RELEVANCE: Our data suggest a potential role for N-acetylcysteine in the attenuation of muscle injury after release of compartment syndrome and possibly in the prophylaxis of compartment syndrome.

GLUT-1 expression and response to chemoradiotherapy in rectal cancer.

Preoperative chemoradiotherapy is used in locally advanced rectal cancer to reduce local recurrence and improve operability, however a proportion of tumors do not undergo significant regression. Identification of predictive markers of response to chemoradiotherapy would improve patient selection and may allow response modification by targeting of specific pathways. The aim of this study was to determine whether expression of glucose transporter-1 (GLUT-1) and p53 in pretreatment rectal cancer biopsies was predictive of tumor response to chemoradiotherapy. Immunohistochemical staining for GLUT-1 and p53 was performed on 69 pretreatment biopsies and compared to tumor response in the resected specimen as determined by the tumor regression grade (TRG) scoring system. GLUT-1 expression was significantly associated with reduced response to chemoradiotherapy and increasing GLUT expression correlated with poorer response (p=0.02). GLUT-1 negative tumors had a 70% probability of good response (TRG3/4) compared to a 31% probability of good response in GLUT-1 positive tumors. GLUT-1 may be a useful predictive marker of response to chemoradiotherapy in rectal cancer.

Intravenous glutamine enhances COX-2 activity giving cardioprotection.

BACKGROUND: Preconditioning, a highly evolutionary conserved endogenous protective response, provides the most powerful form of anti-infarct protection known. We investigated whether acute intravenous glutamine, through an effect on cyclooxygenase (COX)-2 and heat shock protein (HSP) 72, might induce preconditioning. MATERIALS AND METHODS: Male New Zealand white rabbits (n = 28) received either 0.5 g/kg glutamine in 0.9% saline or saline only in divided doses for 3 d. The large marginal branch of the left coronary was occluded for 30 min; cardiac function was assessed during 3 h of reperfusion, and infarct size was measured. 6-Keto-PGF-1alpha, nitrate, and malonaldehyde serum levels were determined. Hearts were taken from a further group of pretreated rabbits (n = 10) to assess myocardial COX-2 and HSP72 levels. RESULTS: Glutamine pretreatment resulted in a 39% reduction in infarct size (30.7 +/- 2.0% versus 50.4 +/- 2.1% controls; P < 0.01). Myocardial COX-2 levels were significantly elevated with pretreatment (P < 0.05) and were mirrored by higher serum 6-keto-PGF-1alpha levels prior to ischemia (69 +/- 13 versus 18 +/- 21 pg/mL in controls, P = 0.027). There was no significant difference in myocardial HSP72 or serum nitrate levels following pretreatment, or malonaldehyde levels during reperfusion. CONCLUSIONS: Glutamine pretreatment confers anti-infarct protection through up-regulation of COX-2, a key mediator of delayed preconditioning protection. Previous confirmation of its clinical safety profile at these doses suggests an acceptable strategy for inducing preconditioning for perioperative protection.

Should incidental asymptomatic angiographic stenoses and occlusions be treated in patients with peripheral arterial disease?

PURPOSE: The clinical importance of angiographically detected asymptomatic lower-limb stenoses and occlusions is unknown. This study aims to (i) assess the clinical outcome of asymptomatic lesions in the lower limb, (ii) identify predictors of clinical deterioration, and (iii) determine which asymptomatic lower-limb lesions should be treated at presentation. MATERIALS AND METHODS: All 918 patients undergoing peripheral angiography with or without angioplasty over a period of 7.5 years (January 1999 through June 2006) at a single institution were retrospectively evaluated. One hundred twenty-two patients (54% men; mean age, 70.3 years; age range, 41-91 y) with angiographic stenoses (> or =50%) or occlusions on the asymptomatic leg were included. The composite endpoint of interest was major adverse clinical outcome (MACO) of the asymptomatic limb at clinical follow-up, which was defined as the development of intermittent claudication (IC), critical limb ischemia (CLI), or need for subsequent endovascular or surgical revascularization. Actuarial freedom from MACO was assessed with Kaplan-Meier curves and multivariable Cox proportional-hazards regression. RESULTS: During a 4.2-year mean follow-up in 122 patients with significant concomitant asymptomatic disease, 32.8% of patients developed symptoms (13.9% with IC, 18.9% with CLI); 42.5% of these cases required revascularization. Cox regression revealed two independent predictors of MACO on the asymptomatic side: contralateral below-knee amputation (BKA; hazard ratio, 2.93; 95% CI, 1.21-7.10; P = .01) and statin treatment (hazard ratio, 3.56; 95% CI, 1.56-8.13; P = .003). CONCLUSIONS: Asymptomatic peripheral angiographic stenoses and occlusions become symptomatic in one third of patients, necessitating treatment in 13.9% overall. Previous contralateral BKA and statin use were independent predictors of adverse outcome in this population. Close clinical follow-up and appropriate risk factor modification are recommended.

Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia.

Vascular endothelial growth factor (VEGF) is produced by most tumour types and stimulates the growth of new blood vessels in the tumour. The expansion of a solid tumour ultimately leads to the development of hypoxic regions, which increases VEGF production and further angiogenesis. In this study, we examined the role of VEGF in the survival of breast tumour cells under hypoxia. Murine 4T1 and human MDA-MB-231 tumour cells were cultured under normoxic and hypoxic growth conditions in the presence or absence of VEGF neutralising antibodies. Apoptosis was assessed in addition to changes in expression of the anti- and pro-apoptotic proteins, Bcl-2 and Bad, respectively. The effect of hypoxia on the novel VEGF receptor, NP1 (neuropilin-1) and the role of the PI3K (phosphatidylinositol-3-kinase) signalling pathway in response to VEGF were examined. VEGF blockade resulted in direct tumour cell apoptosis of both tumour cell lines under normoxia and hypoxia. While blocking VEGF resulted in a downregulation of hypoxia-induced Bcl-2 expression, there was a significant increase in the pro-apoptotic protein Bad relative to cells cultured under hypoxia alone. Both hypoxia and VEGF phosphorylated Akt. Neutralising antibodies to VEGF abrogated this effect, implicating the PI3K pathway in VEGF-mediated cell survival of mammary adenocarcinoma cells. This study demonstrates that VEGF acts as a survival factor not only for endothelial cells as previously thought, but also for some breast tumour cells, protecting them from apoptosis, particularly under hypoxic stress. The data presented provide an additional rationale for combining anti-VEGF strategies with conventional anti-cancer therapies such as chemotherapy and radiotherapy.

The Tromped: a solution for flight-related deep vein thrombosis?

Flight-related deep vein thrombosis (DVT) is well recognized. Reduced venous return occurs during immobility. This alteration in venous hemodynamics may contribute to DVT development. A prototype design of an in-flight exercise device to stimulate ambulatory bloodflow while seated has been developed, consisting of a foot pedal attached to a base by a hinge mechanism. Four devices of differing resistance were evaluated. Calf muscle pump function was assessed by air plethysmography in 10 healthy volunteers. Ejection volume fraction and RVF were determined in the standing position (control values) and were compared with those achieved by depression of the 4 devices while seated. Similar EVF and RVF values were achieved by the control and 2 of the devices. Plantar flexion against a predetermined resistance can effectively activate the calf muscle pump while seated and may reduce the incidence of flight-related DVT.

Testicular torsion in a patient with Ehlers-Danlos syndrome.

We present a 19-year-old man with a diagnosis of Ehlers-Danlos syndrome (EDS) and a delayed presentation of testicular torsion. EDS is a rare and heterogeneous condition affecting collagen synthesis and presents multiple difficulties in a surgical setting. Management of this case of testicular torsion was complicated by impaired cognition of the patient, difficulty with intubation, a contralateral undescended testis and postoperative bleeding. We discuss the specific challenges faced in this case of testicular torsion with longstanding ischaemia and perioperative considerations of EDS.

Two-week treatment with pravastatin improves ventriculo-vascular haemodynamic interactions in young men with type 1 diabetes.

Young patients with diabetes but without established vascular disease have altered conduit and resistance artery reactivity. Early endothelial dysfunction is an initial step in atherogenesis: reductions in nitric oxide (NO) production in these vascular beds are implicated. The study aim was two-fold: first, to detect baseline abnormalities in cardiac function, conduit vessels and the microcirculation using applanation tonometry, brachial artery ultrasound and laser Doppler fluximetry, respectively; and second, to investigate any modification in these parameters with the use of pravastatin. Nine young men with diabetes and normoalbuminuria were randomised in a double-blind cross-over fashion to placebo or pravastatin (40 mg) treatment for two weeks. They underwent scans on three separate occasions. Control patients (n=12) underwent a baseline scan but were not given any drug treatment. It was found that patients with diabetes had significantly higher systolic and diastolic blood pressures, heart rate and Buckberg index (propensity to myocardial ischaemia). Brachial artery reactivity and microcirculatory dilation were both reduced. Levels of von Willebrand Factor, a marker of endothelial damage, were also elevated. Pravastatin treatment restored these sub-clinical abnormalities towards normal levels. In conclusion, pravastatin improves vascular abnormalities in young male patients with diabetes through alterations in microcirculation and conduit vessel function, with secondary myocardial effects. This may be of benefit in preventing end-organ injury.

Modulation of the glycemic response using insulin attenuates the pulmonary response in an animal trauma model.

BACKGROUND: Hyperglycemia has been shown to be an independent prognostic indicator of poor outcome in the traumatized patient. The role of insulin and the prevention of hyperglycemia in the trauma patient have as yet not been fully explored. We hypothesized that the systemic inflammatory response to trauma could be modified by modulating the glycemic response to trauma using insulin. METHODS: A rodent model of end- organ (lung) injury in trauma was chosen. Two groups underwent bilateral femur fracture and 15% blood loss. The third group was anesthetized only. The treatment group immediately received subcutaneous insulin according to a sliding scale. The control groups received normal saline subcutaneously. The animals were maintained under anesthesia for 4 hours from injury. Blood samples were then taken. Bronchoalveolar lavage was performed for neutrophil content and total protein estimation. The left lower lobe was harvested for wet:dry lung weight ratios as a measure of end-organ tissue edema. RESULTS: Measures of end-organ injury, wet:dry lung weight ratios, and bronchoalveolar lavage neutrophil content were significantly reduced in the insulin-treated animals compared with in the controls (p < 0.05). Neutrophil respiratory burst activity was increased in insulin-treated animals compared with in controls (p < 0.05). CONCLUSIONS: Insulin reduces leukocyte lung sequestration and end-organ (lung) edema, indicating an endothelial protective effect in this injured-animal model without attenuating neutrophil function. This work confirms that modifying the glycemic response to trauma using insulin may have a role in reducing adult respiratory distress syndrome rates in injured patients and thereby lead to improved outcomes.

Oncological implications of hypoxia inducible factor-1alpha (HIF-1alpha) expression.

Solid tumours contain regions of hypoxia, which may be a prognostic indicator and determinant of malignant progression, metastatic development and chemoradio-resistance. The degree of intra-tumoural hypoxia has been shown to be positively correlated with the expression of the transcription factor hypoxia-inducible factor 1. HIF-1 is composed of 2 sub-units, namely HIF-1alpha and HIF-1beta. The production of hypoxia inducible factor 1-alpha has been identified as a key element in allowing cells to adapt and survive in a hostile hypoxic environment via a variety of pathways. HIF-1alpha is stabilised by hypoxia at the protein level, and also by the oncogenes HER2neu, v-src and ras. There are over 60 target genes for HIF-1, many of which are activated in cancers in comparison to equivalent normal tissues. Chemotherapeutic modulation of HIF-1 pathways has shown promise for patients with chemo-radio resistant or recurrent tumours in Phase II clinical trials. We herein review the existing literature on hypoxia inducible factor-1alpha, particularly its role in carcinogenesis and clinical implications of its over-expression.