Growth Curves of Subependymal Giant Cell Tumors in Tuberous Sclerosis Complex.

BACKGROUND AND PURPOSE: Growth of subependymal giant cell tumor and subependymal nodules has not been well-characterized. The purpose of this study was to determine whether growth curves can differentiate subependymal giant cell tumors from subependymal nodules. MATERIALS AND METHODS: Brain MR imaging of patients with tuberous sclerosis complex were retrospectively reviewed from 2002 to 2018. All lesions in the region of the foramen of Monro were measured. Lesions were categorized on the basis of maximal diameter at the most recent scan: small lesions (<1 cm), indeterminate lesions (>1 cm), and resected lesions (>1 cm and surgically resected). Growth velocity and acceleration on serial imaging were analyzed, and growth rates were calculated between 0 and 20 years of age and compared among the 3 categories. RESULTS: Forty-one patients were analyzed. The average age at the earliest scan was 5.9 (SD = 5.7) years. One hundred twenty-six small, 27 indeterminate, and 10 resected lesions were measured. Subependymal giant cell tumors grew faster than indeterminate lesions between 6 and 15 years of age. Indeterminate lesions grew faster than small lesions at 0-10 years of age. Resected lesions showed increased velocity and acceleration of growth compared with indeterminate lesions and small lesions on serial imaging. CONCLUSIONS: Growth differentiates subependymal nodules and subependymal giant cell tumors within the first 20 years of life, and the use of velocity and acceleration of growth may refine the diagnostic criteria of subependymal giant cell tumors. Additionally, 6-15 years of age may be an important period to monitor subependymal giant cell tumors at the foramen of Monro because increased growth may help to identify subependymal giant cell tumors that will continue to grow and result in obstructive hydrocephalus.

Bone Involvement in Hyperphosphatemic Familial Tumoral Calcinosis: A New Phenotypic Presentation.

Mutations in FGF23, KL, and GALNT3 have been identified as the cause for the development of hyperphosphatemic familial tumoral calcinosis (HFTC). Patients with HFTC typically present in childhood or adolescence with periarticular soft tissue deposits that eventually progress to disrupt normal joint articulation. Mutations in the GALNT3 gene were shown to account for the hyperphosphatemic state in both HFTC and hyperostosis-hyperphosphatemia syndrome (HHS), the latter characterized by bone involvement. We present the case of a patient of a Druze ethnic origin with known HFTC that presented to our department with the first documented case of pathologic fracture occurring secondary to the disease. Our report introduces this new phenotypic presentation, suggests a potential role for prophylactic bone screening, and highlights the need for preconception genetic screening in selected populations.

Secukinumab-associated localized granuloma annulare (SAGA): a case report and review of the literature.

Granuloma annulare (GA) is a benign, usually self-limited inflammatory skin dermatosis characterized clinically by pink-red to brown dermal papules or annular plaques. The main histologic feature is the presence of palisading or interstitial granulomas composed of necrobiotic collagen, elastic fibers, and mucin surrounded by a lymphohistiocytic infiltrate. Granuloma annulare is commonly associated with trauma, infections, diabetes mellitus, dyslipidemia, malignancy, thyroid disease, and a variety of medications. Two cases of GA have been reported in association with the use of secukinumab, a monoclonal antibody directed against interleukin 17A (IL17A), for the treatment of moderate-to-severe plaque psoriasis. We report the third case of secukinumab-associated GA in a 52-year-old woman with a history of diabetes mellitus type II, dyslipidemia, and non-alcoholic steatohepatitis. After four months of therapy with secukinumab, she presented with pink papules coalescing to plaques involving the antecubital fossae. Histology demonstrated a lymphohistiocytic palisading granuloma with central necrobiotic collagen and mucin, consistent with GA. Physicians should be aware of the possibility of GA developing in patients receiving secukinumab, especially in those with predisposing factors for GA. A better understanding of secukinumab-associated GA may lead to discoveries in GA pathogenesis and reveal broader immunomodulatory effects of secukinumab.

High frequency jet ventilation for motion management during ablation procedures, a narrative review.

BACKGROUND: High frequency jet ventilation (HFJV) is a method of ventilation that has gained renewed interest over the recent years as it can reduce organ movement to near static conditions, thus enhancing surgical precision in minimal invasive procedures, for example, ablation procedures for atrial fibrillation and solid organ tumours. The aim of this review was to create a summary of the current evidence concerning the clinical use of HFJV for ablative procedures. METHOD: PubMed was searched for the key words high frequency ventilation and ablation January 1990-December 2016. RESULT: The search initially identified 34 papers, 14 met the inclusion criteria. Articles in other languages than English (n = 1), comments regarding other articles (n = 4) and articles that did not include HFJV or ablative procedures (n = 15) were excluded. Two articles were added from references in papers included from the primary search. Sixteen studies were finally included in the review; four updates/reviews and 12 papers with results from studies of HFJV on humans, with a total of 889 patients; 498 patients ventilated with HFJV and 391 controls. There were no randomised studies. The overall scientific quality of the studies was low. CONCLUSION: There is a lack of well-designed studies evaluating HFJV during ablation procedures. The available information, while sparse, supports the effect of less tissue movement, resulting in better surgical precision and outcome; such as shorter procedural time, fewer shock waves (ESWL) and less recurrence of atrial fibrillation. Randomised controlled studies are needed in this promising area of research to prove its superiority to standard ventilation.

The role of circulating platelet transcripts.

Our understanding of platelets, anucleate cells with a traditional role in hemostasis and inflammation, has developed greatly over the last decade. Platelets' role in the systemic response of the body to vascular injury, inflammation, and infection has expanded as has our understanding of their importance to the body's regulation of these processes. One recently explored mechanism by which platelets regulate the body's inflammatory and immune response is through its endogenous RNA. Platelets' messenger RNA (mRNAs) and microRNA (miRNAs) profiles have been shown to reflect disease and disease risk factors and have been correlated with select human clinical phenotypes. Developing an understanding of platelet transcripts in the circulation elucidates how platelets function in both their traditional thrombotic role and non-traditional functions and may have widespread implications in several fields including thrombosis, infection, cancer, and systemic inflammation.

Fate of necrotic volume after microwave ablation of multiple liver metastases.

BACKGROUND/AIMS: The aim of this study was to find the rate of shrinkage of necrosis and time of peak ablation volume after multiple microwave ablations in the treatment of multiple liver metastases of colorectal cancer. These factors are not known and are important in evaluation of treatment and identification of local recurrence, as microwave treatment is becoming more used thanks to improved technology in diagnostics and interventional therapy. METHODOLOGY: A retrospective analysis of non-cirrhotic patients with multiple liver only metastases of colorectal cancer, not suited for resection for this reason. Patients were selected for palliative microwave treatment at a liver multidisciplinary team conference. 68 ablations were made in six patients. Ablation volume was analysed with repeated imaging and computer analyses. RESULTS: The ablation volume peeks after 5-7 days where after reduction of the necrosis in the liver occurs logarithmically with a 60% reduction of ablation volume after 100 days and 80% after a year. DISCUSSION: Liver regeneration after microwave ablations occurs at a constant logarithmic rate after an initial expansion of the ablation volume during the first five days. Evaluation of ablation volume in comparison to tumour volume must take this into account so that follow-up imaging is properly timed.

A multiple microwave ablation strategy in patients with initially unresectable colorectal cancer liver metastases - A safety and feasibility study of a new concept.

AIMS: Resection for colorectal cancer liver metastases is indicated when an R0 resection with preservation of a sufficient future liver remnant (FLR) is achievable. Multimodality conversion of initially unresectable patients to resectable is possible in some patients. We present results of a downstaging strategy using microwave ablation (MWA). PATIENTS AND METHODS: In patients where resection was precluded by absence of a tumour-free FLR due to the extent of segmental tumour engagement, but with the potential to clear the whole liver with multiple local ablations, MWA was performed at laparotomy using ultrasound guidance or computer-assisted navigation. Mortality and morbidity was recorded and the overall and disease-free survival of the ablated patients was compared to data of two historic cohorts. RESULTS: Ten of twenty treated patients were alive at median follow-up 25 months. There was no perioperative mortality, with MWA-associated complications being mild to moderate. The MWA group showed a 4-year overall survival of 41%, compared to 70% for a historic cohort of primarily resected patients and 4% for patients with palliative treatment. CONCLUSION: Results of the multiple ablation strategy in the defined population suggest a survival benefit, compared to palliative chemotherapy alone with acceptable associated morbidity and no perioperative mortality.

Clinical trial: 2-L polyethylene glycol-based lavage solutions for colonoscopy preparation - a randomized, single-blind study of two formulations.

BACKGROUND: The 2-L polyethylene glycol (PEG) lavage solutions provide efficacy similar to that of standard 4-L PEG formulations in spite of the reduced volume. The comparative efficacy and tolerability of two formulations of 2-L PEG solution remain unknown. AIMS: To assess the efficacy, safety and tolerability of PEG + Bis compared with PEG + Asc, and to study the effect of bowel cleansing quality on adenoma detection rates. METHODS: Patients were randomized to receive either 2-L PEG with ascorbic acid (PEG + Asc) or 2-L PEG plus bisacodyl 10 mg (PEG + Bis). The primary endpoint was overall colon cleansing score, assessed by blinded investigators using a validated four-point scale. Secondary endpoints included adenoma detection rate, patient tolerability and compliance and adverse events. RESULTS: Fifty-two patients received PEG + Asc and 55 patients received PEG + Bis. Overall colon cleansing scores (+/-s.d.) were 1.40 +/- 0.69 and 1.75 +/- 0.70 (P < 0.003) in the PEG + Asc and PEG + Bis groups, respectively. Excellent and good ratings were recorded in 69% and 23% receiving PEG + Asc compared to 38% and 51% (P = 0.01) of patients receiving PEG + Bis. More adenomas were detected in colonoscopies performed with PEG + Asc (39%) than in those performed with PEG + Bis (20%) (P = 0.04). Patient tolerability and safety were similar with both preparations. CONCLUSION: The use of PEG + Asc resulted in better colon cleansing and higher adenoma detection rates compared with PEG + Bis.

Bariatric surgery reduces mortality in Swedish men.

BACKGROUND: Mortality is lower in obese patients who have undergone surgery for obesity than in those who have not. The majority of patients in these studies have been women. Perioperative mortality is known to be higher among men, and this may counterbalance the survival advantage seen after surgery. This cohort study compared mortality among operated obese patients, non-operated obese patients and a general control cohort of men. METHODS: The study was based on record linkage between Swedish registries. An operated obese, a non-operated obese and a general control cohort were created. The two non-operated cohorts were assigned pseudosurgery dates. Data regarding preoperative and postoperative morbidity were collected, as well as mortality data. RESULTS: Hazard ratios were calculated for mortality between the cohorts adjusting for preoperative morbidity and age. Comparison of all-cause mortality for the obese surgical and non-surgical cohorts gave an adjusted mortality risk of 0.7 (95 per cent confidence interval (c.i.) 0.5 to 1.0) (P = 0.039); the adjusted mortality risk was 1.5 (95 per cent c.i. 1.1 to 2.0) (P = 0.011) when the obese surgical cohort was compared with the general control cohort. CONCLUSION: Bariatric surgery reduces overall mortality in obese men.

A new role for the A2b adenosine receptor in regulating platelet function.

BACKGROUND: Activation of platelets is a critical component of atherothrombosis and plays a central role in the progression of unstable cardiovascular syndromes. Adenosine, acting through adenosine receptors, increases intracellular cAMP levels and inhibits platelet aggregation. The A2a adenosine receptor has already been recognized as a mediator of adenosine-dependent effects on platelet aggregation, and here we present a new role for the A2b adenosine receptor (A2bAR) in this process. METHODS AND RESULTS: As compared with platelets from wild-type controls, platelets derived from A2bAR knockout mice have significantly greater ADP receptor activation-induced aggregation. Although mouse megakaryocytes and platelets express low levels of the A2bAR transcript, this gene is highly upregulated following injury and systemic inflammation in vivo. Under these conditions, A2bAR-mediated inhibition of platelet aggregation significantly increases. Our studies also identify a novel mechanism by which the A2bAR could regulate platelet aggregation; namely, ablation of the A2bAR leads to upregulated expression of the P2Y1 ADP receptor, whereas A2bAR-mediated or direct elevation of cAMP has the opposite effect. Thus, the A2bAR regulates platelet function beyond mediating the immediate effect of adenosine on aggregation. CONCLUSIONS: Taken together, these investigations show for the first time that the platelet A2bAR is upregulated under stress in vivo, plays a significant role in regulating ADP receptor expression, and inhibits agonist-induced platelet aggregation.

A combinatorial mechanism for determining the specificity of E2F activation and repression.

Various studies have detailed the role of E2F proteins in both transcription activation and repression. Further study has shown that distinct promoter elements, but comprising the same E2F-recognition motif, confer positive or negative E2F control and that this reflects binding of either activator or repressor E2F proteins, respectively. We now show that the specificity of binding of an activator or repressor E2F protein is determined by adjacent sequences that bind a cooperating transcription factor. We propose that the functional E2F element is a module comprising not only the E2F-binding site but also the adjacent site for the cooperating transcription factor.

Supra-Tenon's capsule placement of a single-plate Molteno implant.

AIM: To describe clinical results of a new technique for inserting Molteno implants in a supra-Tenon's capsule location. DESIGN: Prospective interventional case study. PARTICIPANTS: 19 patients, 18 of whom had suffered previous filter or glaucoma implant failure. Seventeen had open-angle glaucoma, and two had neovascular glaucoma. Seventeen patients were black and two were Asian. INTERVENTION: All patients underwent supra-Tenon's capsule placement of a single-plate Molteno implant. Goldmann applanation tensions and Snellen visual acuities were determined before the operation and at the last follow-up visit. The numbers of preoperative and postoperative adjunctive drugs were compared before and after surgery. MAIN OUTCOME MEASURES: Success was defined as intraocular pressure < or = 18 mm Hg with or without anti-glaucoma drugs. RESULTS: Mean age was 62 years. Mean pressure before and after surgery was 31 and 16 mm Hg, respectively. Mean follow-up was 22 months (range 12-48). Vision returned to within 2 lines of preoperative vision, except in one patient who lost light perception. Surgery was regarded as a failure in four patients, including both patients with neovascular glaucoma. The difference between the median number of drugs used before (three) and after (one) the operation was significant (p<0.001). Complications were minimal, characterised by small choroidal effusions in three patients; all resolved spontaneously. CONCLUSION: Supra-Tenon's capsule placement of Molteno implants in eyes with previously failed glaucoma surgery is an effective method for controlling intraocular pressure.

Thrombin-triggered platelet apoptosis.

BACKGROUND: Thrombin is primarily known as a coagulation factor and as an inducer of platelet activation and aggregation. It has been reported that thrombin modulates apoptosis of nucleated cells. OBJECTIVES: The current study investigated whether thrombin can affect apoptosis in anucleated human platelets. METHODS: Using flow cytometry, we studied platelet apoptosis at the single-cell level, analyzing markers of mitochondrial and cytoplasmic apoptosis. Western blotting was also employed, in addition to flow cytometry, for determining the expression of Bcl-2 family proteins. RESULTS: We found that human alpha-thrombin induced four key manifestations of apoptosis in human platelets: (i) mitochondrial inner transmembrane potential (DeltaPsi m) depolarization; (ii) strong expression of pro-apoptotic Bax and Bak proteins but only weak expression of anti-apoptotic Bcl-2 protein; (iii) caspase-3 activation; and (iv) phosphatidylserine (PS) exposure. CONCLUSIONS: This study demonstrates that, aside from its 'classical' function as an inducer of platelet activation, thrombin can trigger platelet apoptosis, where it acts as a death ligand. These data indicate that thrombin triggers platelet apoptosis by impacting on several intracellular apoptotic targets, including shifting the balance between Bcl-2 regulatory proteins in a pro-apoptotic direction, depolarizing the inner mitochondrial membrane, activating the executioner caspase-3, and stimulating aberrant exposure of PS on the platelet surface.

Fibrinogen and von Willebrand factor-independent platelet aggregation in vitro and in vivo.

BACKGROUND: Fibrinogen (Fg) has been considered essential for platelet aggregation. However, we recently demonstrated formation of occlusive thrombi in Fg-deficient mice and in mice doubly deficient for Fg and von Willebrand factor (Fg/VWF(-/-)). METHODS AND RESULTS: Here we studied Fg/VWF-independent platelet aggregation in vitro and found no aggregation in citrated platelet-rich plasma of Fg/VWF(-/-) mice. Surprisingly, in Fg/VWF(-/-) plasma without anticoagulant, adenosine diphosphate induced robust aggregation of Fg/VWF(-/-) platelets but not of beta(3)-integrin-deficient (beta(3) (-/-)) platelets. In addition, beta(3) (-/-) platelets did not significantly incorporate into thrombi in Fg/VWF(-/-) mice. This Fg/VWF-independent aggregation was blocked by thrombin inhibitors (heparin, hirudin, PPACK), and thrombin or thrombin receptor activation peptide (AYPGKF-NH(2)) induced aggregation of gel-filtered Fg/VWF(-/-) platelets in 1 mm Ca(2+) PIPES buffer. Notably, aggregation in PIPES buffer was only 50-60% of that observed in Fg/VWF(-/-) plasma. Consistent with the requirement for thrombin in vitro, hirudin completely inhibited thrombus formation in Fg/VWF(-/-) mice. These data define a novel pathway of platelet aggregation independent of both Fg and VWF. Although this pathway was not detected in the presence of anticoagulants, it was observed under physiological conditions in vivo and in the presence of Ca(2+)in vitro. CONCLUSIONS: beta(3) integrin, thrombin, and Ca(2+) play critical roles in this Fg/VWF-independent aggregation, and both plasma and platelet granule proteins contribute to this process.

A provincial program of blood conservation: The Ontario Transfusion Coordinators (ONTraC).

PURPOSE: Although often life-saving, blood transfusions are associated with significant risk to the patient and escalating costs to the blood system and hospital. Transfusions are often given unnecessarily. Blood conservation represents the use of alternatives to transfusion. The ONTraC program attempts to enhance transfusion practice outside the blood transfusion laboratory, promote blood conservation in surgery patients, and reduce allogeneic red cell use. METHODS: In the first such large scale program, funding was obtained from the Ontario MOHLTC for a Transfusion Coordinator in 23 Ontario hospitals selected based on blood utilization and geography. At specific time periods, detailed anonymized information was collected in a defined number of all consecutive patients admitted for the three designated surgical procedures: knee arthroplasty (N=approximately 1200 at each time point), abdominal aortic aneurysm (AAA; N=300 at each time) and coronary artery bypass graft (CABG) surgery (N=300 at each time point). RESULTS: Considerable inter-institutional variation was observed in the proportion of patients and amount of blood transfused. At the 12 month analysis, most, although not all, hospitals had decreased use of allogeneic blood and there was an overall 24% reduction in blood use in patients undergoing knee surgery, 14% in AAA and 23% in CABG. In addition to reduction in proportion of patients transfused, transfused patients received fewer units of allogeneic blood. Patients who did not receive allogeneic transfusions had significantly lower postoperative infection rates (p<0.05) and length of stay (p<0.0001); multivariate analysis showed that allogeneic transfusion was an independent predictor of increased length of stay. Eighteen-month analysis indicates even greater reduction in allogeneic transfusion. The main measures of blood conservation employed were preoperative autologous donation and education, with recent increasing use of erythropoietin and the cell saver. These measures have been demonstrated to be very effective in avoiding allogeneic transfusion. CONCLUSIONS: The ONTraC have become leaders locally, nationally and internationally in blood conservation. The reduction in allogeneic transfusion associated with the implementation of the ONTraC program represents important savings in costs associated with blood components, hospital stay and work in transfusion laboratories and nursing units, as well as enhancing patient satisfaction and safety.

Vitronectin stabilizes thrombi and vessel occlusion but plays a dual role in platelet aggregation.

The role of vitronectin (Vn) in thrombosis is currently controversial; both inhibitory and supportive roles have been reported. To monitor directly the function of Vn in thrombotic events at the site of vascular injury, we studied Vn-deficient (Vn-/-) and wild-type (WT) control mice with two real-time intravital microscopy thrombosis models. In the mesenteric arteriole model, vessel injury was induced by ferric chloride. We observed unstable thrombi and a significantly greater number of emboli in Vn-/- mice. Vessel occlusion was also delayed and frequent vessel re-opening occurred. In the cremaster muscle arteriole model, vessel injury was induced by a nitrogen dye laser. We observed significantly fewer platelets, lower fibrin content, and unstable fibrin within the thrombi of Vn-/- mice. To define further the role of Vn in thrombus growth, we studied platelet aggregation in vitro. Consistent with our in vivo data, the second wave of thrombin-induced aggregation of gel-filtered platelets was abolished at a low concentration of thrombin in Vn-/- platelets. Interestingly, adenosine diphosphate (ADP)-induced platelet aggregation was significantly increased in Vn-/- platelet-rich plasma (PRP) and this effect was attenuated by adding purified plasma Vn. We also observed increased platelet aggregation induced by shear stress in Vn-/- whole blood. These data demonstrate that Vn is a thrombus stabilizer. However, in contrast to released platelet granule Vn which enhances platelet aggregation, plasma Vn inhibits platelet aggregation.

von Willebrand factor (VWF)-dependent human platelet activation: porcine VWF utilizes different transmembrane signaling pathways than does thrombin to activate platelets, but both require protein phosphatase function.

The interaction between von Willebrand factor (VWF) and glycoprotein (GP) Ib results in platelet agglutination and activation of many signaling intermediates. To determine if VWF-dependent platelet activation requires the participation of pivotal transmembrane signaling pathways, we analyzed VWF-dependent platelet activation profiles following inhibition of several transmembrane signaling intermediates. This was accomplished using porcine VWF, which has been shown to interact with human GPIb independently of shear stress or ristocetin. Platelet alpha (CD62) and lysozomal granule release (CD63), microparticle formation, and platelet agglutination/aggregation were evaluated. The ability of signaling inhibitors to prevent VWF-dependent platelet activation was compared to their ability to inhibit thrombin-dependent activation. The results demonstrate that VWF-dependent platelet activation can occur independently of the activities of protein kinase C (PKC), wortmannin-sensitive phosphatidylinositide 3-kinase, and phospholipase C, as well as independently of elevations in the concentration of intracellular calcium. In sharp contrast, these transmembrane signaling intermediates are required for thrombin-dependent platelet activation. In addition, thrombin-dependent but not VWF-dependent platelet activation was associated with elevations in the concentration of intracellular calcium under the conditions used. The family of signaling intermediates which appeared to be pivotal for both thrombin- and VWF-dependent platelet activation were the protein tyrosine phosphatases and the serine/threonine phosphatases. It is concluded that thrombin-dependent platelet activation relies on the activation of several transmembrane signaling pathways, whereas VWF-dependent platelet activation is dependent upon the activity of protein phosphatases. Inhibition of these phosphatases in vivo may provide a novel therapeutic approach for treating VWF-dependent platelet disorders such as thrombotic thrombocytopenic purpura or arterial thrombosis.

Concurrent measurement of the survival of two populations of rabbit platelets labeled with either two PKH lipophilic dyes or two concentrations of biotin.

BACKGROUND: To avoid radioisotopic labeling and permit comparison of the survival of two platelet populations concurrently in one animal, we compared simultaneous recoveries and survival times of homologous rabbit platelets labeled in vitro with the lipophilic dyes PKH26 (red fluorescing) and PKH67 (green fluorescing) and with two levels of biotin (low, 1 microg/ml; high, 10 microg/ml). METHODS: Blood samples were drawn up to 96 h postinfusion and analyzed by flow cytometry. Biotin-labeled samples were incubated with phycoerythrin-streptavidin before analysis. RESULTS: Recovery of PKH26-labeled platelets at 1 h was lower (37.5%) than that of PKH67-labeled platelets (47.3%; P < 0.001). Platelet survival times were 62.4 and 61.9 h. Recoveries at 1 h of platelets labeled with two levels of biotin were similar (86.6% and 84.6%) and greater than those of PKH-labeled platelets (P < 0.001). Survival of platelets labeled with biotin did not differ (low, 83.3 h; high, 85.2 h) and was longer than for PKH-labeled platelets (P < 0.01). Labeling methods did not activate platelets (measured by P-selectin expression), nor did they affect platelet responses to adenosine diphosphate (ADP), collagen, or thrombin. CONCLUSIONS: Labeling with two levels of biotin is superior to labeling with PKH dyes, and is useful for measuring concurrently the survival of two differing platelet populations.