Tolerance to ischemia and hypoxia is reduced in aged human myocardium

BACKGROUND: Recovery of cardiac function after cardiac surgery and other interventional cardiac procedures in elderly patients is inferior to that in younger patients, suggesting that the aged myocardium is more sensitive to ischemia and other stresses. Although convincing data from animal studies of senescence now exist, there is a dearth of controlled in vitro studies that examine the specific response of aged human myocardium to the stress of hypoxia or ischemia. OBJECTIVE: We sought to determine the effect of age on the capacity of human atrial trabeculae to recover contractile function after in vitro hypoxic or ischemic stress. METHODS: Atrial pectinate trabeculae were dissected from the tip of 58 right atrial appendages harvested during an operation in patients aged between 34 and 89 years and electrically stimulated at 1 Hz in oxygenated Ringer's solution at 37 degrees C. Tissues experienced 30 minutes of either hypoxia (N(2) and perfusate) or simulated ischemia (humidified N(2) without perfusate) and were returned to normoxia for recovery of function for 30 minutes. Developed force and other contractile variables were determined during each period. RESULTS: Under normoxic conditions, no significant age difference was observed for any contractile function variable. However, after hypoxia, the old (70-89 years) and intermediate age groups (60-69 years) showed reduced recovery of developed force (48.5% +/- 22.2% [n = 11] and 44.9% +/- 19% [n = 12], respectively) compared with that found (66.4% +/- 19.7% [n = 15]) in the younger (34-59 years) group (mean +/- SD, P =.02). Similarly, after simulated ischemia, the groups of 70- to 89-year-old and 60- to 69-year-old subjects showed reduced recovery of developed force (35.7% +/- 17% [n = 5] and 51.1% +/- 11.8% [n = 9], respectively) compared with that found (68.2% +/- 10.4% [n = 6]) in the group of 34- to 59-year-old subjects (P =.01). Multivariable analysis, comparing 20 factors of surgical patient characteristics and recovery of developed force, found that only age (P =.01) and hypertension (P =.01) were predictors of reduced recovery of developed force after either hypoxia or simulated ischemia. CONCLUSIONS: In aged human atrial myocardium, the capacity to recover contractile function after in vitro hypoxia or simulated ischemia is reduced compared with the younger myocardium of mature adults. These findings suggest that enhanced myocardial protective strategies may be indicated for elderly patients undergoing cardiac surgery.     

Isolation and structure elucidation of new and unusual saxitoxin analogues from mussels

Chemical analyses of plankton and highly toxic mussel samples collected in eastern Canada during an intense bloom of the dinoflagellate Alexandrium tamarense established the presence of a complex mixture of paralytic shellfish poisoning (PSP) toxins. Application of a newly developed technique, hydrophilic interaction liquid chromatography-mass spectrometry, confirmed the identities of the known toxins and revealed the presence in the mussels of five saxitoxin analogues (M1-M5) that were not present in the plankton. Four of these compounds were isolated and their structures established by tandem mass spectrometry, 1D- and 2D-NMR spectroscopy, and chemical interconversion experiments. One of these was found to be 11beta-hydroxysaxitoxin (M2), while the other three were found to be new saxitoxin analogues, namely, 11beta-hydroxy-N-sulfocarbamoylsaxitoxin (M1), 11,11-dihydroxy-N-sulfocarbamoylsaxitoxin (M3), and 11,11-dihydroxysaxitoxin (M4). Compound M5 remains unidentified because of insufficient material for characterization.     

Pregnancy in uremic patients: an eventful journey

Renal damage, which can be caused by gestational anomalies such as pre-eclampsia, carries a risk of gestational complications; the greatest risk being in women who become pregnant while on hemodialysis or peritoneal dialysis. If this rare event occurs, there is a marked increase in the risk of pre-eclampsia, early uterine contractions and hydramnios, hypertensive crisis, preterm delivery and intrauterine growth retard. Furthermore, newborns are almost always of low birthweight. Patients who undergo renal transplantation are another high-risk category. In such cases, the pregnancy itself can compromise the success of the transplant and the immunosuppressive therapy correlated to it can become a threat to the course of the pregnancy and normal fetal growth. Therefore, in view of the lack of appropriate guidelines for the best possible approach to the treatment of women on dialysis or of those with a renal transplantation, it is best to advise these patients against becoming pregnant and/or to provide a valid counselling service illustrating the extreme difficulties and dangers involved in becoming pregnant.     

BOOST: a phase 3 trial of sorafenib vs. best supportive care in first line treatment of hepatocellular carcinoma in patients with deteriorated liver function

Aim: Only patients with good liver function {[Child-Pugh (CP)] A class} were eligible for trials testing sorafenib as first-line treatment of hepatocellular car...     

The pre-Vesalian kidney: Gabriele Zerbi, 1445-1505

Gabriel Zerbi was born in Verona in 1445 and died in Dalmatia in 1505. He was professor of philosophy in Padua at the age of 22, and moved to Bologna where he became professor of medicine and philosophy. In Rome at the time of Sixtus V and Innocentius VIII, he was archiater and professor of medicine. He completed his academic career in Padua where he worked from 1494 to 1505 with a salary of 600 florins a month. A man of vast culture, a philosopher, physician and professor of medicine, he wrote many books: (1) Questiones Metaphysicae; (2) Gerentocomia; (3) De Cautelis Medicorum; (4) Liber anatomiae corporis humani et singulorum membrorum illius; (5) De anatomia infantiis et porci ex traditione Cophonis, and (6) Libellus de preservatione corporum a passione calculosa. His contribution to anatomy was superb. Through him the discipline became the basis of modern medicine. The core of this article deals with some passages of Zerbi's chapters on the anatomy of the kidneys and bladder.     

Intravascular hemolysis in patients with new-generation prosthetic heart valves: a prospective study

OBJECTIVE: A prospective clinical study was designed to assess the frequency and severity of intravascular hemolysis in patients with new-generation, normally functioning prosthetic heart valves. METHODS: Hemolysis was evaluated in 172 patients with a mechanical prosthesis (53 CarboMedics and 119 Sorin Bicarbon) and in 106 patients with a bioprosthesis (15 St Jude Medical Toronto, 19 Baxter Perimount, and 72 Medtronic Mosaic) in the aortic position, mitral position, or both. Aortic valve replacement was performed in 206 patients, mitral valve replacement in 59 patients, and double valve replacement in 13 patients. The presence of hemolysis was assessed on the basis of the level of serum lactic dehydrogenase and serum haptoglobin and the presence and amount of reticulocytes and schistocytes in the peripheral blood. Severity of intravascular hemolysis was estimated on the basis of serum lactic dehydrogenase. Clinical, echocardiographic, and hematologic evaluations were performed 1, 6, and 12 months after discharge. RESULTS: None of the 278 patients experienced decompensated anemia, whereas at 12 months, mild subclinical hemolysis was identified in 49 patients, 44 (26%) with a mechanical prosthesis and 5 (5%) with a bioprosthesis (P <.001). At multivariate analysis, independent predictors of the presence of subclinical hemolysis were mitral valve replacement (P <.001), use of a mechanical prosthesis (P =.002), and double valve replacement (P =.02). Frequency of hemolysis in patients with stented aortic bioprostheses was 3%, whereas it was absent in those with stentless valves. Among mechanical valve recipients, double versus single valve replacement (P =.04) and mitral versus aortic valve replacement (P =.05) were correlated with the presence of hemolysis; double valve recipients also showed a more severe degree of hemolysis (P =.03). In patients with a Sorin Bicarbon prosthesis, hemolysis was less frequent (22% vs 34%, P =.09) and severe (P <.001) than in those with a CarboMedics prosthesis. CONCLUSIONS: In normally functioning prosthetic heart valves, subclinical hemolysis is a frequent finding. A low incidence of hemolysis is found in stented biologic prostheses, and it is absent in stentless aortic valves. Modifications of valve design may contribute to minimize the occurrence of hemolysis in mechanical prostheses.     

Oxidative stress, inflammation and cardiovascular disease in chronic renal failure

Traditional risk factors such as hypertension, diabetes, dyslipidemia, obesity and metabolic syndrome, as well as additional nontraditional risk factors, can damage the kidney directly and by promoting intrarenal atherogenesis. Evidence indicates that increased oxidative stress and inflammation may mediate most of the effects of risk factors on the kidney. Clinical studies have demonstrated a relationship between oxidative stress and inflammatory biomarkers, and a few studies indicate an inverse correlation of oxidative stress biomarkers with estimated glomerular filtration rate (eGFR). Further, surrogate indexes of atherosclerosis such as intima-media thickness and aortic pulse wave velocity have been demonstrated to be related to plasma concentrations of markers of endothelial activation, inflammation and fibrosis in patients with different stages of chronic kidney disease (CKD). Moreover, plasma concentrations of high-sensitivity C-reactive protein have been shown to be increased and related to left ventricular mass in CKD individuals having left ventricular hypertrophy. In contrast, in these patients, decreases in fetuin-A plasma levels have been reported. Considering the complex background of the pathophysiological changes characterizing CKD patients, we can consider cardiovascular disease a multifactorial complication of CKD.     

Elevated levels of HER-2/neu and androgen receptor in clinically localized prostate cancer identifies metastatic potential

BACKGROUND: In this study, we investigated the expression of HER-2/neu and AR in clinically organ-confined prostate cancer to determine whether alterations in these signaling pathways contribute to the development of metastatic disease. METHODS: HER-2/neu and AR immunoreactivity were evaluated in archived prostatic tissues obtained from 53 men with clinically organ-confined disease who underwent radical prostatectomy. Associations between AR and HER-2/neu immunostaining and disease outcome were determined. RESULTS: Seventy percent (37/53) of tumors exhibited high levels of HER-2/neu immunostaining and 68% (36/53) of tumors had elevated AR levels. Patients with high levels of both HER-2/neu and AR had the highest rate of PSA failure (56%, 15/27) compared with no PSA failures amongst seven patients with low levels of both HER-2/neu and AR (log rank statistic 7.69, P = 0.021). Concurrent high levels of HER-2/neu and AR expression were significantly associated with high pathological stage (P = 0.027) and development of metastatic disease (P = 0.022). CONCLUSIONS: These findings support the notion that both the HER-2/neu and AR signaling pathways may contribute to development of metastatic disease. The subset of prostate tumors with increased HER-2/neu and AR levels may benefit from treatment strategies that target both signaling pathways.     

Video-Assisted Thyroidectomy Significantly Reduces the Risk of Early Postthyroidectomy Voice and Swallowing Symptoms

Background Voice and swallowing symptoms are frequently reported after thyroidectomy even in absence of objective voice alterations. We evaluated the influence of the video-assisted approach on voice and swallowing outcome of thyroidectomy. Methods Sixty-five patients undergoing total thyroidectomy (TT) were recruited. Eligibility criteria were: nodule size ≤30 mm, thyroid volume ≤30 ml, no previous neck surgery. Exclusion criteria were: younger than aged 18 years and older than aged 75 years, vocal fold paralysis, history of voice, laryngeal or pulmonary diseases, malignancy other than papillary thyroid carcinoma. Patients were randomized for video-assisted (VAT) or conventional (CT) thyroidectomy. Videostrobolaryngoscopy (VSL), acoustic voice analysis (AVA), and maximum phonation time (MPT) evaluation were performed preoperatively and 3 months after TT. Subjective evaluation of voice (voice impairment score = VIS) and swallowing (swallowing impairment score = SIS) were obtained preoperatively, 1 week, 1 month, and 3 months after TT. Results Fifty-three patients completed the postoperative evaluation: 29 in the VAT group, and 24 in the CT group. No laryngeal nerves injury was shown at postoperative VSL. Mean postoperative MPT, F ₀, F _low, F _high, and the number of semitones were significantly reduced in the CT group but not in the VAT group. Mean VIS 3 months after surgery was significantly higher than preoperatively in CT group but not in the VAT group. Mean SIS was significantly decreased 1 and 3 months after VAT but not after CT. Conclusions The incidence and the severity of early voice and swallowing postthyroidectomy symptoms are significantly reduced in patients who undergo VAT compared with conventional surgery. Presented at the ISW2007—IAES free paper session, Montreal, Canada, August 26–30, 2007.     

High cysteine levels in renal transplant recipients: relationship with hyperhomocysteinemia and 5,10-MTHFR polymorphism

BACKGROUND: Long-term survival of renal transplant recipients seems to be influenced by the occurrence of thromboembolic complications and cardiovascular disease. Preliminary data available in the literature found high levels of cysteine (Cy) as a risk factor for deep venous thrombosis independently of high homocysteine (tHcy) levels, but no data are available about Cy levels in renal transplant recipients. METHODS: To investigate Cy, tHcy, and plasminogen activator inhibitor-1 (PAI-1) levels and the prevalence of 5,10-methylenetetrahydrofolate reductase (MTHFR) in renal transplantation, we studied 70 stable renal transplant recipients and 66 age- and sex-matched normal subjects as controls. RESULTS: Cy, tHcy, and PAI-1 levels were significantly higher in renal transplant recipients with respect to controls (Cy: 254 micromol/L [117-466] vs. 198 micromol/L [99-331], P<0.001; tHcy: 17.0 micromol/L [4.0-68] vs. 8.1 micromol/L [2.0-24.0], P<0.00001; PAI-1: 16.8 IU/ml [5.1-45.5] vs. 7.9 IU/ml [4.0-18.0], P<0.00001). High Cy levels were detected in 35.8% of patients. Hyperhomocysteinemia, both in the fasting state and postmethionine loading test, was diagnosed in 90% of cases. The odds ratios for Cy and tHcy levels within the fourth quartile with respect to the other quartiles were markedly increased in renal transplant recipients even after adjustment for prevalent cardiovascular risk factors, glomerular filtration rate, tHcy and, Cy, respectively (Cy: 29.0 micromol/L [95% CI 7.0-111]; tHcy: 29.9 micromol/L [95% CI 7.5-118.1]). Fasting tHcy levels correlated well with PAI-1 (r=0.65; P<0.0001) but not with Cy levels (r=0.10; P=0.4). The prevalence of the MTHFR 677TT genotype in renal transplant recipients was not significantly higher in patients than in controls (mutant allele frequency: 0.48 in patients and 0.47 in controls) and was associated with significantly higher fasting and postmethionine tHcy levels both in controls and patients. After 2 months of vitamin supplementation, tHcy (Pre: 17.0 micromol/L [4.0-68]; Post: 7.5 micromol/L [2.3-21.9]; P<0.0001) and PAI-1 levels (Pre: 16.8 IU/ml [5.1-45.5]; Post: 10 IU/ml [2.0-25]; P<0.001) were significantly decreased, whereas Cy levels showed a small decrease that did not reach statistical significance (Pre: 254 micromol/L [117-466]; Post: 209 micromol/L [168-300]; P=0.3). Patients with the MTHFR 677TT genotype had the major percentage of decrease of tHcy levels with respect to the other genotypes. CONCLUSION: In conclusion, this study demonstrates the presence of elevated Cy plasma levels in renal transplant recipients. Vitamin supplementation reduces tHcy but not Cy levels, and the amount of decrease seems to be influenced by the MTHFR genotype.