Effects of hemodynamic instability on brain death-induced prepreservation liver damage

BACKGROUND: Brain death (BD) is an important multifactorial variable contributing to donor-specific liver damage. Our study aimed at assessing the specific effects of hemodynamic instability on systemic and hepatic parameters of perfusion, bowel ischemia, and oxidative stress in a porcine model of BD. METHODS: BD was induced in 16 pigs (German Landrace, 18-28 kg) in two groups (hypotension-BD [HYPO-BD], n=8; normotension-BD [NORM-BD], n=8), which were compared with control animals/living donors (n=6) for a period of 2 hr. We analyzed systemic hemodynamic parameters, bowel ischemia (intramucosal pH in the stomach and colon, plasma endotoxin levels, and endotoxin-neutralizing capacity [ENC]), and oxidative stress (total glutathione levels in erythrocytes) and compared the findings with hepatic parameters of perfusion (hepatic arterial flow, portal venous flow, and microperfusion) and liver oxidative stress (reduced glutathione and oxidized glutathione levels in the liver). RESULTS: Independent of the hemodynamic stability, liver macrocirculation and microcirculation decreased (HYPO-BD, 79+/-6 to 69+/-10 mL/100 g/min; NORM-BD, 81+/-10 to 73+/-7 mL/100 g/min; P<0.05). Hepatocellular damage (aspartate aminotransferase: NORM-BD, 49+/-20 units/L; HYPO-BD, 170+/-140 units/L; P<0.01) and hepatic oxidative stress (reduced glutathione in the liver/oxidized glutathione in the liver: NORM-BD, 29.4+/-2.3 to 13.0+/-1.3; HYPO-BD, 29.4+/-2.3 to 9.05+/-0.81; P<0.001) increased in both BD groups. With dependence on systemic hemodynamic parameters, bowel ischemia increased (intramucosal pH in the colon, 7.22+/-0.01, P<0.01; ENC, 75+/-14 endotoxin-neutralizing units/mL, P<0.01; endotoxin levels, 7+/-2 to 43+/-10 pg/mL, P<0.01) in the HYPO-BD group but not in the NORM-BD group or the living donor group. Furthermore, systemic oxidative stress was increased in the HYPO-BD group only (total glutathione levels in erythrocytes, 2.65+/-0.25 to 0.15+/-0.25 mM; P<0.01). CONCLUSIONS: During BD, liver-specific parameters (portal venous flow, microperfusion, aspartate aminotransferase activity, ENC, and hepatic oxidative stress) were compromised, independent of the hemodynamic status. Therefore, the systemic hemodynamic status does not reflect the functional status of the liver during BD.     

Acute coronary syndrome following arteriovenous fistula creation in a post CABG patient: A steal phenomenon from coronary artery to subclavian artery

A 70‐year‐old man with a history of coronary artery bypass grafting 15 years back and arteriovenous (AV) fistula creation in the left arm 1 month back presented with acute coronary syndrome (ACS). He had not received dialysis before his referral. We felt the most likely etiology for these complaints was increased cardiac oxygen demand from an increased cardiac output related to the newly formed left AV fistula. Coronary angiography was done to detect any significant stenosis in the native or grafted vessels. This revealed that the left subclavian artery was totally occluded in the ostioproximal segment and the coronary arteries did not have occlusions to explain the ACS setting. CT angiography confirmed the angiographic findings of the totally occluded left subclavian artery followed by a well‐developed and patent left internal mammary artery to left anterior descending artery. This led to the consideration of a steal syndrome from the coronary artery by the subclavian artery distal to the occlusion. A successful percutaneous endovascular intervention on the left subclavian artery occlusion was performed. Subsequently, the patient became asymptomatic and experienced a dramatic increase in left ventricular ejection fraction.     

2-Chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide (CMV423), a new lead compound for the treatment of human cytomegalovirus infections

Human cytomegalovirus (HCMV) remains one of the major pathogens in immunocompromised patients (AIDS and transplants) and the main cause for congenital infections leading from slight cognitive defects up to severe mental retardation. The drugs that are currently available for the treatment of HCMV infections, i.e. ganciclovir, foscarnet and cidofovir, are all acting at the level of the viral DNA polymerase. Here we describe an entirely new molecule, the 2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide (CMV423), that shows very potent in vitro activity against HCMV. CMV423 is highly active against HCMV reference strains and clinical isolates, but also against those strains, isolated from patients or emerging after in vitro selection, that are resistant to either ganciclovir, foscarnet or cidofovir. CMV423 also showed activity in two ex vivo models, that are both highly relevant for the pathophysiology of HCMV, the retinal pigment epithelial and the bone marrow stromal cell assays. Viral antigen expression analysis by flow cytometry, as well as time of addition experiments, confirmed that CMV423 acts on a step of the viral replicative cycle that precedes the DNA polymerase step and, most likely, coincides with the immediate early (IE) antigen synthesis. Finally, CMV423 combined with either ganciclovir, foscarnet or cidofovir in checkerboard experiments demonstrated a highly synergistic activity.     

Kinematic investigations of the talocrural joint in human cadaver specimens. Basic studies for the development of a hinged fixator

To determine the specifications of a hinged fixator for the upper ankle joint, biomechanical investigations were performed on 20 human cadaver specimens and the talocrural axis was recorded by X-ray cinematography in all levels of the space.The results showed a medium variation of the axis in zero position (mean: 5.8 degrees ) from 3 degrees to 10 degrees in the anterior-posterior view. The span of the axis migration around zero position amounted to a minimum of 3 degrees and a maximum value of 10 degrees (mean: 7.2 degrees ). It could be ascertained that the axis kinetics does not move linearly in all cases. The talus rotation (the axle deviation from the sagittal plane) amounted to a minimum value of 2 degrees and a maximum value of 12 degrees (mean: 5.3 degrees ). In the transverse level, the axis kinetics was tracked by separate X-ray markings of the lateral and medial cortical of the talus in the zero point of the talocrural axis.The results were typical migration curves of the X-ray markings, demonstrating a ventral convex curve at the medial and lateral cortex. This migration of the cortex crossing point of the axis was geometrically entered in a coordinate system. The variance of the axis cortex crossing point at the medial cortical was X(M)=4.2 mm (min: 2 mm, max: 7 mm) and Y(M)=4.7 mm (2-7 mm), at the lateral cortical X(L)=3.7 mm (1-9 mm) and Y(L) =4.1 mm (1-8 mm). Regarding the clinical relevance for the development of a hinged fixator for the upper ankle joint, the results indicate that an external axis guidance of these axoids is not possible, but that an adjusted axis is necessary taking into consideration the values measured using ligamentotaxis.     

Soy protein supplementation increases serum insulin-like growth factor-I in young and old men but does not affect markers of bone metabolism

Recent studies suggest that soy protein (SP) protects bone in women; however, its effects on bone metabolism in men have not been investigated. Healthy men (59.2 +/- 17.6 y) were assigned to consume 40 g of either SP or milk-based protein (MP) daily for 3 mo in a double-blind, randomized, controlled, parallel design. Serum insulin-like growth factor-I (IGF-I), which is associated with higher rates of bone formation, was greater (P < 0.01) in men supplemented with SP than in those consuming MP. Serum alkaline phosphatase and bone-specific alkaline phosphatase activities, markers of bone formation, and urinary deoxypyridinoline excretion, a specific marker of bone resorption, were not different between the SP and MP groups. Furthermore, because substantial reductions in bone density occur in men at approximately 65 y of age, data were analyzed separately for men >/=65 y and those <65 y of age. The response to protein supplementation was consistent in the two age groups. The effects of SP on serum IGF-I levels suggest that SP may positively influence bone in men. Longer-duration studies examining the effects of SP or its isoflavones on bone turnover and bone mineral density and content in men are warranted.     

Interaction of high concentrations of riluzole with recombinant skeletal muscle sodium channels and adult-type nicotinic receptor channels

Riluzole is a neuroprotective drug that modulates glutamergic transmission but also blocks the inactivated state of voltage-gated neuronal sodium channels at very low concentrations (about 0.1 microM). After nausea, the most common adverse effect of riluzole is asthenia, which could be due to a block of muscle sodium channels or acetylcholine receptor channels. Using the patch-clamp technique, we applied riluzole on recombinant voltage-gated skeletal muscle sodium and adult nicotinic acetylcholine receptor channels expressed in a mammalian cell line (HEK 293). Riluzole blocked the inactivated state of voltage-gated skeletal muscle sodium channels, shifting the midpoint of the steady-state inactivation curve to more negative potentials, but only in comparatively high concentrations (> or = 0.1 mM). At these concentrations, riluzole also caused an open-channel block at acetylcholine receptor channels. We conclude that riluzole has only a mild blocking effect on the inactivated state of voltage-gated skeletal muscle sodium channels and nicotinic acetylcholine receptor channels. As the plasma concentration of riluzole in amyotrophic lateral sclerosis (ALS) patients approximates 2 microM, it seems unlikely that asthenia is caused by a block of skeletal muscle sodium channels or acetylcholine receptor channels by riluzole.     

Acute choroidal closure caused by hemodialysis accident in an amyloidosic patient

Background We report the case of a 43-year-old man haemodialysed for 20 years for systemic amyloidosis who underwent an acute choroidal occlusion after a haemodialysis accident.Case report The patient had cardiac, pulmonary, neurovegetative and renal localizations of amyloidosis. He complained during a haemodialysis session of uncomfort with abdominal pain, headache, bradycardia, vomiting, confusion and blurred vision. Acute haemolytic anemia was confirmed. In the following days, eyes were red and the vision was still altered.Results Examination showed decreased visual acuity (VA) to 20/80 OU, low intraocular pressure (IOP), major vitritis and pigmentary alterations of the fundus with yellow retinal deposits. Fluorescein and indocyanine green angiographies showed amyloid retinal deposits, pigmentary alterations, normal retinal perfusion and massive choroidal hypoperfusion persisting in the late sequence. Steroid therapy was tried unsuccessfully. The situation slowly improved within 3 months with complete clearing of the vitreous opacities and stabilisation of the pigmentary alterations. VA progressively recovered to 20/30, 1 year after the onset of the disease, but IOP remained low and choroidal perfusion did not improve 2 years after the accident.Conclusion Choroidal complications of amyloidosis have never been described so far. The acute occlusion observed here was the consequence of an intravascular haemolytic event that completed the preexisting amyloid vascular infiltration.     

Lower abdominal bulge after deep inferior epigastric perforator flap (DIEP) breast reconstruction

The etiology of lower abdominal bulge following breast reconstruction with the DIEP flap is uncertain. Most studies report an incidence that ranges from 0.7% to 5%. The purpose of this study was to review a set of factors that may predispose to a lower abdominal bulge. This was a retrospective review of 123 women who had breast reconstruction with the DIEP flap over a 4-year period. The reconstruction was unilateral in 93 women and bilateral in 30 women, totaling 153 flaps. Etiologic factors that were evaluated included patient age, diabetes mellitus, tobacco use, previous abdominal operations, unilateral or bilateral reconstruction, previous childbirth, aponeurotic plication to improve the natural abdominal contour, and use of Marlex mesh. A lower abdominal bulge occurred in 5 of the 123 women (4%), 2 following 30 bilateral reconstructions (6.6%) and 3 following 93 unilateral reconstructions (3.2%). Analysis of the factors for all women demonstrated diabetes mellitus in 1 (0.8%), tobacco use in 9 (7.3%), a prior abdominal operation in 55 (44.7%), previous childbirth in 95 (77%), aponeurotic plication in 49 (40%), and use of Marlex mesh in 4 (3.3%). Statistical analysis did not show any significant association between the explanatory factors and the occurrence of a lower abdominal bulge, except for a weak trend in women who had not been pregnant (P = 0.08). The results of this study demonstrate that the occurrence of a lower abdominal bulge following the DIEP flap is a random event that can occur in anyone. Pregnancy may confer a preventative effect as the collagen fibers strengthen to overcome the stretching forces. Techniques for prevention and treatment include intraoperative assessment of the anterior rectus sheath, use of an adjuvant material for reinforcement if unstable, and vertical plication for bulge repair.     

THE SOLID PHASE SYNTHESIS OF PORCINE SECRETIN WITH FULL BIOLOGICAL ACTIVITY

The solid phase synthesis of porcine secretin is described. The C-terminal residue was attached to a polymeric amino support and all the Boc-amino acids, including Boc-glutamine, were coupled by a modified carbodiimide method. A preliminary test synthesis showed that the couplings of several amino acids of the N-terminal section were unsatisfactory. This problem was overcome in the main synthesis by executing all the major reactions twice. Cleavage of the peptide from the resin as well as the removal of all the side chain protecting groups was achieved with liquid HF. The product was purified by ion-exchange chromatography on SP-Sephadex to obtain a highly purified heptacosapeptide amide with full biological activity.