Investigating epidemiologic trends and the geographic distribution of patients with anal squamous cell carcinoma throughout Canada.

Background: Anal cancer is a rare disease, constituting 0.5% of new cancer cases in the United States. The most common subtype is squamous cell carcinoma (scc). Studies in several developed nations have reported on an increasing incidence of anal cancer in recent decades, and various risk factors pertaining to the pathogenesis of the disease have been identified, including infection with the human papillomavirus, tobacco use, and immunosuppression. The epidemiology and distribution of anal scc throughout Canada remain poorly understood, however. Methods: Using 3 population-based cancer registries, a retrospective analysis of demographic data across Canada for 1992-2010 was performed. The incidence and mortality for anal scc was examined at the levels of provinces, cities, and the forward sortation area (FSA) component (first 3 characters) of postal codes. Results: During 1992-2010, 3720 individuals were diagnosed with anal scc in Canada; 64% were women. The overall national incidence rate was 6.3 cases per million population per year, with an average age at diagnosis of 60.4 years. The incidence increased over time, with significantly higher incidence rates documented in British Columbia and Nova Scotia (9.3 cases per million population each). Closer examination revealed clustering of cases in various urban centres and self-identified lgbtq communities in Toronto, Montreal, and Vancouver. Discussion: This study provides, for the first time, a comprehensive analysis of the burden of anal scc in Canada, identifying susceptible populations and shedding light onto novel avenues of research to lower the incidence of anal cancer throughout the country.

Meta-analysis: rectal indomethacin for the prevention of post-ERCP pancreatitis.

BACKGROUND: Despite initial evidence in the literature, nonsteroidal anti-inflammatory drugs (NSAIDs) have not been widely used to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). AIM: To complete a meta-analysis of high-quality RCTs that included the latest available literature published after past meta-analytical efforts METHODS: A comprehensive electronic literature search was carried out for RCTs comparing peri-procedural rectal indomethacin and placebo in preventing PEP. Methodological quality was assessed by the Cochrane risk of bias tool. Fixed model Mantel-Haenszel meta-analysis, Q test and I(2) index were used. Several subgroup and sensitivity analyses were planned. RESULTS: A total of four of 61 retrieved trials between 2007 and 2012 (n = 1470) were included. No significant publication bias existed. All studies used similar criteria to detect pancreatitis. The pooled proportion estimate of the rate of pancreatitis was 5.1% with indomethacin and 10.3% with placebo. After excluding the high-risk patients, the rates were 3.9% and 7.9% respectively. Fixed model meta-analysis showed that the rate of pancreatitis was significantly lower using indomethacin as compared with placebo [OR = 0.49(0.34-0.71); P = 0.0002]. Number needed to treat was 20. There was no significant statistical or clinical heterogeneity. In subgroup analysis, the difference remained unchanged for average-risk population [OR = 0.49(0.28-0.85); P = 0.01] or in preventing severe PEP [OR = 0.41(0.21-0.78); P = 0.007]. The result of the main outcome remained robust in multiple sensitivity analyses. CONCLUSIONS: Rectal indomethacin used immediately before or after ERCP significantly reduces the risk of PEP to half in both low- and high-risk patients, and with both statistically and clinically significant conclusions. These results suggest that a possible change in routine practice for patients at both low and high risk of developing PEP should be advocated.

What is the optimal management of dysphagia in metastatic esophageal cancer?

BACKGROUND: The palliation of dysphagia in metastatic esophageal cancer remains a challenge, and the optimal approach for this difficult clinical scenario is not clear. We therefore sought to define and determine the efficacy of various treatment options used at our institution for this condition. METHODS: We reviewed a prospective database for all patients managed in an esophageal cancer referral centre over a 5-year period. All patients receiving palliation of malignant dysphagia were reviewed for demographics, palliative treatment modalities, complications, and dysphagia scores (0 = none to 4 = complete). The Wilcoxon signed rank test was used to determine significance (p < 0.05). RESULTS: During 2004-2009, 63 patients with inoperable esophageal cancer were treated for palliation of dysphagia. The primary treatment was radiotherapy in 79% (brachytherapy in 18 of 50; external-beam in 10 of 50; both types in 22 of 50), and stenting in 21%. Mean wait time from diagnosis to treatment was 22 days in the stent group and 54 days in the radiotherapy group (p = 0.003). Mean duration of treatment was 1 day in the stent group and 40 days in the radiotherapy group (p = 0.001). In patients treated initially by stenting, dysphagia improved within 2 weeks of treatment in 85% of patients (dysphagia score of 0 or 1). However, 20% of patients presented with recurrence of dysphagia at 10 weeks of treatment. In the radiotherapy group, the onset of palliation was slower, with only 50% of patients palliated at 2 weeks (dysphagia score of 0 or 1). However, long-term palliation was more satisfactory, with 90% of patients remaining palliated after 10 weeks of treatment. CONCLUSIONS: In inoperable esophageal cancer at our centre, radiation treatment provided durable long-term relief, but came at a high price of a long wait time for initiation of treatment and a long lag time between initiation of treatment and relief of symptoms. On the other hand, endoluminal stenting provided more rapid and effective early relief from symptoms, but was affected by recurrence of dysphagia in the long-term. It is now time for a prospective randomized trial to assess the safety and efficacy of combined-modality treatment with both endoluminal stenting and radiation therapy compared with either treatment alone.

Blood viscosity modulates tissue perfusion: sometimes and somewhere.

Each organ possesses specific properties for controlling microvascular perfusion. Such specificity provides an opportunity to design transfusion fluids that target thrombo-embolic or vasospasm-induced ischemia in a particular organ or that optimize overall perfusion from systemic shock. The role of viscosity in the design of these fluids might be underestimated, because viscosity is rarely monitored or considered in critical care decisions. Studies linking viscosity-dependent changes of microvascular perfusion to outcome-relevant data suggest that whole blood viscosity is negligible as a determinant of microvascular perfusion under physiological conditions when autoregulation is effective. Because autoregulation is driven to maintain oxygen supply constant, the organism will compensate for changes in blood viscosity to sustain oxygen delivery. In contrast, under pathological conditions in the brain and elsewhere, increases of overall viscosity should be avoided - including all the situations where vascular autoregulatory mechanisms are inoperative due to ischemia, structural damage or physiologic dysfunction. As latter conditions are not to identify with high certainty, the risks that accompany therapeutic correction of blood viscosity are outweighing the benefits. The ability to bedside monitor blood viscosity and to link changes in viscosity to outcome parameters in various clinical conditions would provide more solid foundation for evidence-based clinical management.

Spatial learning induces predominant downregulation of cytosolic proteins in the rat hippocampus.

Spatial learning is known to depend on protein synthesis in the hippocampus. Whereas the role of the hippocampus in spatial memory is established, the biochemical and molecular mechanisms underlying this process are poorly understood. To comprehend the complex pattern of protein expression induced by spatial learning, we analyzed alterations in the rat hippocampus proteome after 7 days of spatial learning in the Morris water maze. Forty Wistar rats were randomized into two groups. Animals of group A learned to localize a hidden platform in the water maze. Animals of group B served as controls and spent exactly the same time in the water maze as animals of group A. However, no platform was used in this test and the rats could not learn to localize the target. After the last trial, hydrophilic proteins from the hippocampus were isolated. A proteome-wide study was performed, based on two-dimensional gel electrophoresis and mass spectrometry. Compared with non-learning animals, 53 (70%) proteins were downregulated and 23 (30%) proteins were upregulated after 7 days in rats with spatial learning. The overall changes in protein expression, as quantified by the induction factor, ranged from -1.62 (downregulation to 62%) to 2.10 (upregulation by 110%) compared with controls (100%). Most identified proteins exhibit known functions in vesicle transport, cytoskeletal architecture, and metabolism as well as neurogenesis. These findings indicate that learning in the Morris water maze has a morphological correlate on the proteome level in the hippocampus.

Volatile anesthetics evoke prolonged changes in the proteome of the left ventricule myocardium: defining a molecular basis of cardioprotection?

BACKGROUND: Volatile anesthetics can alter cardiac gene and protein expression. Of those underlying molecular changes in gene and protein expression in the myocardium after exposure to volatile anesthetics that have been identified, some of them have been related to cardioprotection. METHODS: We used two-dimensional gel electrophoresis and mass spectrometry to identify changes in the protein expression of the left ventricle myocardium of anesthesized rats. We maintained anesthesia for 3 h using isoflurane, sevoflurane or desflurane, respectively, at 1.0 minimum alveolar concentration (MAC) and dissected the left ventricular myocardium either immediately or 72 h after the end of anesthesia. RESULTS: We found changes of at least twofold in 106 proteins of the more than 1.600 protein spots discriminated in each gel. These differentially expressed proteins are associated with functions in glycolysis, mitochondrial respiration and stress response. No obvious difference could be observed between the patterns of differential expression of the three volatile anesthetics. CONCLUSION: We provide the first study of post-anesthetic protein expression profiles associated with three common volatile anesthetics. These volatile anesthetics promote a distinct change in the myocardial protein expression profile, whereby changes in the expression pattern still exist 72 h after anesthesia. These proteome changes are closely related to cardioprotection and ischemic preconditioning, indicating a common functional signaling of volatile anesthestics.

[Obturator nerve block for transurethral surgery. comparing ropivacaine 0.75 % vs. prilocaine 1 %]. / Vergleich der Motorblockade zwischen Ropivacain 0,75 % und Prilocain 1 % bei der direkten Obturatoriusblockade zur transurethralen Blasentumorresektion -- ein neuer Ansatz zur Bewertung des Motorblocks mit der MRC-Skala.

OBJECTIVE: Obturator nerve block is used for transurethral resection of lateral bladder wall tumors to prevent adductor muscle spasm and associated complications. Therefore, the local anesthetic applied should provide an adequate motor blockade. Ropivacaine 0.75 % was compared to prilocaine 1 % and motor blockade assessment performed by the Medical Research Council (MRC)-scale. METHODS: 40 patients (20 per group) scheduled for transurethral resection were randomized to either receiving 10 ml ropivacaine 0.75 % or prilocaine 1 % for direct obturator nerve block in a controlled user-blinded study. Motor block was assessed with the MRC-scale 5 and 10 minutes after local anesthetic injection followed by an assessment 120 and 180 minutes after surgery. Surgery was performed in equally distributed spinal or general anesthesia, intraoperative adductor spasm intensity was evaluated by surgeon's ranking. RESULTS: Motor blockade intensity was significantly higher with ropivacaine 0.75 % at all time points of assessment. Intraoperatively, severe spasm only occurred in the prilocaine 1 %-group. CONCLUSION: Ropivacaine 0.75 % is a more appropriate agent for direct obturator nerve block than prilocaine 1 %, providing a faster onset and a more intense and longer-lasting motor blockade. This may reduce surgical complications and facilitate early surgical re-intervention. In this study, MRC-scale was appropriate for motor blockade assessment in a peripheral nerve block.

Effects of chronic isovolaemic haemodilution on regional cerebral blood flow in conscious rats.

BACKGROUND AND OBJECTIVE: Acute isovolaemic haemodilution increases local and mean cerebral blood flow. It is not known whether a single haemodilution has a short-term effect only or whether it affects cerebral perfusion over a longer time period. In the present study, local and mean cerebral blood flow were determined in conscious rats after a 4, 24 and 48 h period following one-time haemodilution. METHODS: Thirty-six rats were randomized to three untreated sham groups and three groups of haemodilution (4, 24 or 48 h, n = 6 for each group). Isovolaemic haemodilution with albumin 5% aimed to a target haematocrit of 0.2. Local cerebral blood flow was measured in 38 brain regions by the iodo-[14C]antipyrine method in conscious normothermic rats. RESULTS: Isovolaemic haemodilution reduced haematocrit from 0.44 to 0.20. During the following 24 and 48 h periods, haematocrit remained low (0.22 and 0.21). Mean cerebral blood flow was similar in untreated sham groups (88 +/- 12 after 4 h, 92 +/- 11 after 24 h, 96 +/- 10 mL 100 g(-1) min(-1) after 48 h). Haemodilution increased mean cerebral blood flow after 4h (184 +/- 11 mL 100 g(-1) min(-1)), after 24h (153 +/- 13 mL 100 g(-1) min(-1)) and 48h (149 +/- 15 mL 100 g(-1) min(-1)) (P < or = 0.05). Local cerebral blood flow increased in all 38 structures after 4h haemodilution but decreased with time in six of 38 brain structures after 24h and in 15 regions after 48 h (P < or = 0.05). CONCLUSIONS: A single one-time haemodilution increased mean cerebral blood flow for 2 days. However, local adaptation of cerebral blood flow to a chronic low haematocrit occurred but was heterogeneous within the brain.

The mechanisms of prednisone inhibition of inflammation in Crohn's disease involve changes in intestinal permeability, mucosal TNFalpha production and nuclear factor kappa B expression.

BACKGROUND: The clinical course of Crohn's disease after the induction of remission with medical therapy is characterized by unpredictable relapse. AIM: To evaluate three surrogate markers, intestinal permeability, mucosal TNFalpha and nuclear factor (NF)-kappaB/IkappaBalpha expression, in order to determine the relationship of these parameters to clinical relapse. METHODS: Thirty patients with active Crohn's disease were treated with a 10 week course of prednisone using a tapering dosing regimen. Intestinal permeability (lactulose/mannitol [L/M ratio]) was determined at baseline and at the end of prednisone tapering. TNFalpha production and the levels of expression of NF-kappaB/IkappaBalpha were measured in colonic mucosal biopsies obtained after the induction of remission. RESULTS: Twenty-two patients (73%) achieved remission and 50% of patients experienced a clinical relapse during the ensuing 12 months. Treatment with prednisone resulted in a significant decrease in the L/M ratio. Of the patients that relapsed, 75% had a raised L/M ratio at the time of remission compared with 20% of patients with a normal L/M ratio (P < 0.008; hazard ratio = 6.094; CI 1.55, 17.43). Mucosal TNFalpha production was greater in relapsers compared with those who remained in remission. The levels of NF-kappaB in relapsers were significantly greater and levels of cytosolic IkappaBalpha were significantly lower compared with those measured in patients who remained in remission. CONCLUSIONS: These findings underscore the importance of incorporating biological parameters of inflammation in determining the clinical course of Crohn's disease.

Small volume resuscitation with 7.5% hypertonic saline solution--treatment of haemorrhagic shock in the tropics.

Rapid intravenous injection of 4 mL/kg body weight of a 7.5% hypertonic sodium chloride solution immediately increases intravascular osmotic pressure and intravascular volume after haemorrhage. This 'small volume resuscitation' rapidly improves blood pressure and microcirculatory perfusion in patients with hypovolaemic shock after large blood losses. Pathophysiological findings as well as practical application approaches are described. Small volume resuscitation is an effective and economic method in the first-line treatment of acute haemorrhagic shock.

Lack of hypercapnic increase in cerebral blood flow at high blood viscosity in conscious blood-exchanged rats.

BACKGROUND: The hypothesis of a compensatory dilation of cerebral vessels to maintain cerebral blood flow at a high blood viscosity was tested during hypercapnia in the study after replacement of blood by hemoglobin solutions of defined viscosities. If compensatory vasodilation exists at normocapnia at a high blood viscosity, vasodilatory mechanisms may be exhausted when hypercapnia is added, resulting in a lack of increase in cerebral blood flow at hypercapnia. METHODS: In conscious rats, blood was replaced by ultrapurified cross-linked hemoglobin solutions that had defined and shear rate-independent low or high viscosities (low- and high-viscosity groups). Blood viscosity differed threefold between both groups (1.2 vs. 3.6 mP x s). Thereafter, rats inhaled either a normal or an increased concentration of carbon dioxide in air. Cerebral blood flow was determined by the iodo[14C]antipyrine method. RESULTS: During normocapnia, global and local cerebral blood flows did not differ between both groups. With increasing degrees of hypercapnia, global and local cerebral blood flows were gradually elevated in the low-viscosity group (2.8 ml x mmHg(-1) CO2 x 100 g(-1) x min(-1)), whereas they remained unchanged in the high-viscosity group. CONCLUSIONS: Changes in blood viscosity do not result in changes of cerebral blood flow as long as cerebral vessels can compensate for these changes by vasodilation or vasoconstriction. However, such vascular compensatory adjustments may be exhausted in their response to further pathophysiologic conditions in blood vessels that have already been dilated or constricted as a result of changes in blood viscosity.

The use of spectral measures of heart rate variability to differentiate between male snorers and patients with sleep apnoea syndrome.

Snoring is a characteristic feature of habitual snorers and patients with sleep apnoea syndrome. However, unlike snorers, sleep apnoea patients have an increased peri-operative morbidity. Presently available methods to differentiate between these two groups are either expensive, invasive or time consuming. As cardiac reflexes are impaired in sleep apnoea syndrome, we tested whether heart rate variability could discriminate between snorers and patients with sleep apnoea syndrome. Heart rate variability measurement detects cardiac autonomic dysfunction non-invasively in an ambulatory setting. We studied 32 male patients undergoing polysomnography for suspected sleep apnoea. Total, low- and high-frequency power were measured using a Holter electrocardiogram. Differences in night- and daytime variability were then calculated. Differences between day and night values were more pronounced in the sleep apnoea group and related to the apnoea-hypopnoea-index and low oxygen saturation. Higher values in sleep apnoea patients resulted from increasing variability at night. Heart rate variability might thus help to differentiate between snorers and patients with severe sleep apnoea syndrome.

Oxygen delivery at high blood viscosity and decreased arterial oxygen content to brains of conscious rats.

We addressed the question to which extent cerebral blood flow (CBF) is maintained when, in addition to a high blood viscosity (Bvis) arterial oxygen content (CaO2) is gradually decreased. CaO2) was decreased by hemodilution to hematocrits (Hct) of 30, 22, 19, and 15% in two groups. One group received blood replacement (BR) only and served as the control. The second group received an additional high viscosity solution of polyvinylpyrrolidone (BR/PVP). Bvis was reduced in the BR group and was doubled in the BR/PVP. Despite different Bvis, CBF did not differ between BR and BR/PVP rats at Hct values of 30 and 22%, indicating a complete vascular compensation of the increased Bvis at decreased CaO2. At an Hct of 19%, local cerebral blood flow (LCBF) in some brain structures was lower in BR/PVP rats than in BR rats. At the lowest Hct of 15%, LCBF of 15 brain structures and mean CBF were reduced in BR/PVP. The resulting decrease in cerebral oxygen delivery in the BR/PVP group indicates a global loss of vascular compensation. We concluded that vasodilating mechanisms compensated for Bvis increases thereby maintaining constant cerebral oxygen delivery. Compensatory mechanisms were exhausted at a Hct of 19% and lower as indicated by the reduction of CBF and cerebral oxygen delivery.

Immune response to autologous transfusion in healthy volunteers: WB versus packed RBCs and FFP.

BACKGROUND: Storage of blood as packed RBCs and FFP is standard practice in allogeneic transfusion. Separation into components has been proposed for autologous transfusion, as well, but beneficial effects have not yet been shown. STUDY DESIGN AND METHODS: Twenty-four healthy male volunteers were randomly assigned to receive 1 unit of either autologous RBCs and FFP (RCP group) or WB (WB group) after 49 or 35 days of storage, respectively. The immune response was analyzed by ELISA for IL-6, C3a, terminal complement complex SC5b-9, TNF-alpha, and neopterin. Differential WBC counts and the phagocytosis of neutrophils and monocytes were measured by flow cytometry. RESULTS: Cell counts of monocytes (0.85 x 10(3) ng/microL) [corrected] and neutrophils (6.9 x 10(3) ng/microL) [corrected] increased 30 minutes after WB transfusion and then returned to close to the baseline values seen in the RCP group (0.47 and 2.9 x 10(3) ng/microL [corrected], respectively) throughout the monitored period (p<0.05). C3a (169 vs. 116 ng/microL) [corrected] and IL-6 (29 vs. 6 pg/mL) reached higher plasma concentrations in the WB group (n = 11) than in the RCP group (n = 10). Phagocytosis of opsonized Escherichia coli was increased in neutrophils and monocytes and lasted up to 7 days after the transfusion of whole blood. CONCLUSION: Autologous WB induces a modest immunomodulation, but this effect is not observed upon transfusion of autologous blood components.

Anaesthetic care for sickle cell disease.

Despite the high frequency of sickle cell disease in Europe, the disease is poorly managed. Critical periods are the hospital stays during which the anaesthesiologist plays an important role. Understanding the molecular basis of polymerization processes of haemoglobin S can help to avoid triggering a crisis. Differentiation of the various haemoglobin phenotypes helps to estimate the individual perioperative risk. Knowledge of the patient's history and the actual haemoglobin S level facilitates general anaesthesia, surgery and postoperative care. Damage to liver, spleen, eyes, bones, lung and central nervous system increases the perioperative risk. Preoperative preparation includes early admission, intravenous volume substitution, continuing pain therapy and prophylactic antibiotic medication. General anaesthesia seems to be better for patients with a high-risk profile rather than regional anaesthesia. Careful perioperative and postoperative monitoring should allow hypoxaemia, hypovolaemia, hypothermia, acidosis and overtransfusion to be avoided. Effective pain therapy includes a combination of opioids with peripherally acting analgesia.

Effects of xenon on cerebral blood flow and cerebral glucose utilization in rats.

BACKGROUND: The effects of xenon inhalation on mean and local cerebral blood flow (CBF) and mean and local cerebral glucose utilization (CGU) were investigated using iodo-[14C]antipyrine and [14C]deoxyglucose autoradiography. METHODS: Rats were randomly assigned to the following groups: conscious controls (n = 12); 30% (n = 12) or 70% xenon (n = 12) for 45 min for the measurement of local CBF and CGU; or 70% xenon for 2 min (n = 6) or 5 min (n = 6) for the measurement of local CBF only. RESULTS: Compared with conscious controls, steady state inhalation of 30 or 70% xenon did not result in changes of either local or mean CBF. However, mean CBF increased by 48 and 37% after 2 and 5 min of 70% xenon short inhalation, which was entirely caused by an increased local CBF in cortical brain regions. Mean CGU determined during steady state 30 or 70% xenon inhalation remained unchanged, although local CGU decreased in 7 (30% xenon) and 18 (70% xenon) of the 40 examined brain regions. The correlation between CBF and CGU in 40 local brain structures was maintained during steady state inhalation of both 30 and 70% xenon inhalation, although at an increased slope at 70% xenon. CONCLUSION: Effects of 70% xenon inhalation on CBF in rats are time-dependent. During steady state xenon inhalation (45 min), mean values of CBF and CGU do not differ from control values, and the relation of regional CBF to CGU is maintained, although reset at a higher level.

Influence of blood viscosity on blood flow in the forebrain but not hindbrain after carotid occlusion in rats.

That cerebral blood flow remains unchanged at an increased blood viscosity, as long as the vascular supply is not compromised, was tested. To induce a reduced blood supply of some parts of the brain and to keep the supply unchanged in others both carotid arteries were occluded in anesthetized, ventilated rats. By this procedure, blood supply to the rostral brain, but not to the brainstem and cerebellum, was compromised. Blood viscosity was increased by intravenous infusion of 20% polyvinylpyrrolidone (high viscosity group) or decreased by infusion of 5% albumin (low viscosity group). Cerebral blood flow was measured by the [14C]iodoantipyrine method in 50 complete coronal sections of the rostral brain and 22 complete coronal sections of the brainstem and cerebellum in each rat. In the high viscosity group, mean cerebral blood flow of the rostral brain was significantly lower (46 +/- 7 mL/100 g(-1) x min(-1)) than in the low viscosity group (82 +/- 18 mL/100 g(-1) x min(-1)). No differences could be observed in brainstem and cerebellum between both groups (162 +/- 29 mL/100 g(-1) x min(-1) vs. 156 +/- 18 mL/100 g(-1) x min(-1)). Local analysis of cerebral blood flow in different brain structures of the coronal sections showed the same identical results; i.e., in 29 of the 31 brain structures analyzed in rostral brain, local cerebral blood flow was lower in the high viscosity group, whereas no differences could be observed in the 11 brain structures analyzed in the brainstem and cerebellum. It is concluded that under normal conditions cerebral blood flow can be maintained at an increased blood viscosity by a compensatory vasodilation. When the capacity for vasodilation is exhausted by occlusion of supplying arteries, an increased blood viscosity results in a decrease of cerebral blood flow.