Photoirradiation therapy of experimental malignant glioma with 5-aminolevulinic acid

OBJECT: Accumulation of protoporphyrin IX (PPIX) in malignant gliomas is induced by 5-aminolevulinic acid (5-ALA). Because PPIX is a potent photosensitizer, the authors sought to discover whether its accumulation might be exploited for use in photoirradiation therapy of experimental brain tumors, without injuring normal or edematous brain. METHODS: Thirty rats underwent craniotomy and were randomized to the following groups: 1) photoirradiation of cortex (200 J/cm2, 635-nm argon-dye laser); 2) photoirradiation of cortex (200 J/cm2) 6 hours after intravenous administration of 5-ALA (100 mg/kg body weight); 3) cortical cold injury for edema induction; 4) cortical cold injury with simultaneous administration of 5-ALA (100 mg/kg body weight) and photoirradiation of cortex (200 J/cm2) 6 hours later; or 5) irradiation of cortex (200 J/cm2) 6 hours after intravenous administration of Photofrin II (5 mg/kg body weight). Tumors were induced by cortical inoculation of C6 cells and 9 days later, magnetic resonance (MR) images were obtained. On Day 10, animals were given 5-ALA (100 mg/kg body weight) and their brains were irradiated (100 J/cm2) 3 or 6 hours later. Seventy-two hours after irradiation, the brains were removed for histological examination. Irradiation of brains after administration of 5-ALA resulted in superficial cortical damage, the effects of which were not different from those of the irradiation alone. Induction of cold injury in combination with 5-ALA and irradiation slightly increased the depth of damage. In the group that received irradiation after intravenous administration of Photofrin II the depth of damage inflicted was significantly greater. The extent of damage in response to 5-ALA and irradiation in brains harboring C6 tumors corresponded to the extent of tumor determined from pretreatment MR images. CONCLUSIONS: Photoirradiation therapy in combination with 5-ALA appears to damage experimental brain tumors selectively, with negligible damage to normal or perifocal edematous tissue.     

Late oesophageal perforation after intraoperative transoesophageal echocardiography

Serious haemodynamic instability occurred during emergency surgeryfor a perforated duodenal ulcer in a 72-year-old man with acutemyocardial infarction. Intraoperative transoesophageal echocardiographywas crucial for diagnosis of the location of myocardial infarctionin the right ventricle and the subsequent haemodynamic management.Postoperatively, a thrombus in the right coronary artery wasremoved by coronary angiography. The patient’s tracheawas extubated on the fourth postoperative day. Another 4 dayslater a leak in the lower oesophagus was suspected because ofpleural empyema, and verified. The patient’s trachea hadto be re-intubated and an oesophageal stent was inserted. Thepatient was discharged, fully recovered, 2 months after theoperation. Br J Anaesth 2002: 88: 595–7     

Understanding the dose–response relationship of allopurinol: predicting the optimal dosage

Aims

The aim of the study was to identify and quantify factors that control the plasma concentrations of urate during allopurinol treatment and to predict optimal doses of allopurinol.

Methods

Plasma concentrations of urate and creatinine (112 samples, 46 patients) before and during treatment with various doses of allopurinol (50–600 mg daily) were monitored. Non-linear and multiple linear regression equations were used to examine the relationships between allopurinol dose (D), creatinine clearance (CL_cr) and plasma concentrations of urate before (U_P) and during treatment with allopurinol (U_T).

Results

Plasma concentrations of urate achieved during allopurinol therapy were dependent on the daily dose of allopurinol and the plasma concentration of urate pre-treatment. The non-linear equation: U_T = (1 – D/(ID₅₀ + D)) × (U_P – U_R) + U_R, fitted the data well (r² = 0.74, P < 0.0001). The parameters and their best fit values were: daily dose of allopurinol reducing the inhibitable plasma urate by 50% (ID₅₀ = 226 mg, 95% CI 167, 303 mg), apparent resistant plasma urate (U_R = 0.20 mmol l⁻¹, 95 % CI 0.14, 0.25 mmol l⁻¹). Incorporation of CL_cr did not significantly improve the fit (P = 0.09).

Conclusions

A high baseline plasma urate concentration requires a high dose of allopurinol to reduce plasma urate below recommended concentrations. This dose is dependent on only the pre-treatment plasma urate concentration and is not influenced by CL_cr.     

Neurogenic and Sympathoexcitatory Actions of NaCl in Hypertension

Excess dietary salt intake is a major contributing factor to the pathogenesis of salt-sensitive hypertension. Strong evidence suggests that salt-sensitive hypertension is attributed to renal dysfunction, vascular abnormalities, and activation of the sympathetic nervous system. Indeed, sympathetic nerve transections or interruption of neurotransmission in various brain centers lowers arterial blood pressure (ABP) in many salt-sensitive models. The purpose of this article is to discuss recent evidence that supports a role of plasma or cerebrospinal fluid hypernatremia as a key mediator of sympathoexcitation and elevated ABP. Both experimental and clinical studies using time-controlled sampling have documented that a diet high in salt increases plasma and cerebrospinal fluid sodium concentration. To the extent it has been tested, acute and chronic elevations in sodium concentration activates the sympathetic nervous system in animals and humans. A further understanding of how the central nervous system detects changes in plasma or cerebrospinal fluid sodium concentration may lead to new therapeutic treatment strategies in salt-sensitive hypertension.     

Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes

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Defining Quality for Distal Pancreatectomy: Does the Laparoscopic Approach Protect Patients from Poor Quality Outcomes?

Introduction

Established systems for grading postoperative complications do not change the assigned grade when multiple interventions or readmissions are required to manage a complication. Studies using these systems may misrepresent outcomes for the surgical procedures being evaluated. We define a quality outcome for distal pancreatectomy (DP) and use this metric to compare laparoscopic distal pancreatectomy (LDP) to open distal pancreatectomy (ODP).

Methods

Records for patients undergoing DP between January 2006 and December 2009 were reviewed. Clavien–Dindo grade IIIb, IV, and V complications were classified as severe adverse—poor quality—postoperative outcomes (SAPOs). II and IIIa complications requiring either significantly prolonged overall lengths of stay including readmissions within 90 days or more than one invasive intervention were also classified as SAPOs.

Results

By Clavien–Dindo system alone, 91 % of DP patients had either no complication or a low/moderate grade (I, II, IIIa) complication. Using our reclassification, however, 25 % had a SAPO. Patients undergoing LDP demonstrated a Clavien–Dindo complication profile identical to that for SDP but demonstrated significantly shorter overall lengths of stay, were less likely to require perioperative transfusion, and less likely to have a SAPO.

Conclusions

Established systems undergrade the severity of some complications following DP. Using a procedure-specific metric for quality, we demonstrate that LDP affords a higher quality postoperative outcome than ODP.     

Vortical ciliary flows actively enhance mass transport in reef corals

The exchange of nutrients and dissolved gasses between corals and their environment is a critical determinant of the growth of coral colonies and the productivity of coral reefs. To date, this exchange has been assumed to be limited by molecular diffusion through an unstirred boundary layer extending 1–2 mm from the coral surface, with corals relying solely on external flow to overcome this limitation. Here, we present direct microscopic evidence that, instead, corals can actively enhance mass transport through strong vortical flows driven by motile epidermal cilia covering their entire surface. Ciliary beating produces quasi-steady arrays of counterrotating vortices that vigorously stir a layer of water extending up to 2 mm from the coral surface. We show that, under low ambient flow velocities, these vortices, rather than molecular diffusion, control the exchange of nutrients and oxygen between the coral and its environment, enhancing mass transfer rates by up to 400%. This ability of corals to stir their boundary layer changes the way that we perceive the microenvironment of coral surfaces, revealing an active mechanism complementing the passive enhancement of transport by ambient flow. These findings extend our understanding of mass transport processes in reef corals and may shed new light on the evolutionary success of corals and coral reefs.A scleractinian coral is often described as a holobiont (1), harboring a complex consortium of microorganisms, including, in particular, photosynthetic algal symbionts living within the coral’s tissue. For this holobiont to thrive, the coral animal must support the metabolic requirements of its symbionts by supplying nutrients and eliminating toxic byproducts, such as excess oxygen accumulated as a byproduct of the symbionts’ photosynthetic activity (2–4). The algal symbionts, in return, provide the coral with organic carbon (2, 5), and their activity underpins the calcification and skeletal growth that is at the basis of the coral reef ecosystem (6, 7). These processes and other key metabolic processes involve the continuous exchange of nutrients, inorganic carbon and dissolved oxygen between the coral and the surrounding seawater. Identifying and quantifying the processes controlling mass transport at the coral surface are, therefore, paramount to the prediction of coral sustainability and coral reef development (8), particularly in the face of changing environmental conditions (9, 10).Corals are simple multicellular organisms, lacking the circulatory and respiratory organs (11) used by higher animals to ensure elevated rates of mass transport (12). Accordingly, corals are generally viewed as oxyconformers (7, 13), with metabolic processes involving the exchange of oxygen or other dissolved molecules being limited by molecular diffusion through an unstirred mass transport boundary layer. To enhance this exchange, corals have been assumed to depend entirely on ambient flow, which by compression of the coral’s boundary layer (14), shortens the distance that molecules must traverse. Indeed, increased ambient flow is known to positively affect essential physiological processes, including nutrient uptake (15), photosynthesis (2), respiration (16), growth (17, 18), and calcification (18, 19).Many corals, however, frequently experience extended periods of weak ambient flow. Such conditions occur on a daily basis on reefs where flow is dominated by tidal cycles (20, 21) and in sheltered areas within lagoons or on leeward parts of the reef (18, 22, 23). Furthermore, ambient flow is significantly reduced within densely branched corals, where parts of the colony experience over 90% reduction in fluid flow compared with conditions outside the colony (18, 23, 24). At such places and times, mass transport enhancement due to ambient flow is restricted and may even jeopardize coral survival (17, 25).Here, we show that reef-building corals are not solely dependent on ambient flow to overcome mass transport limitations. Instead, corals can actively mix a layer of water extending up to ∼2 mm from the coral surface by means of vortical flows produced by the coordinated beating of the coral’s epidermal cilia. This stirring action considerably enhances mass transport, particularly under conditions of weak ambient flow, and thus, seems to represent a vital adaptation to the reef environment.