Improved tendon healing using bFGF, BMP-12 and TGFß1 in a rat model.

Several growth factors (GFs) are expressed as tendons heal, but it remains unknown whether their combined application enhances the healing process. This matter was addressed by applying a combination of basic fibroblast growth factor (bFGF), bone morphogenetic protein 12 (BMP-12) and transforming growth factor beta 1 (TGFß1) in a rat Achilles tendon transection model. GFs were applied in one of the three following ways: i) direct application of all three factors at the time of surgery; ii) sequential, tiered percutaneous injection of individual factors immediately after surgery, 48 h and 96 h later; iii) load of all three factors onto a collagen sponge implanted at the time of surgery. After 1, 2, 4 and 8 weeks, healing was assessed based on tendon length and thickness, mechanical strength, stiffness and histology. Best results were achieved when GFs were loaded onto a collagen sponge - with a rapid increase in mechanical strength (load to failure, 71.2 N vs. 7.7 N in controls), consistent tendon length over time (9.9 mm vs. 16.2 mm in controls) and faster tendon remodelling, as measured by histology - followed by tiered injection therapy over 96 h. In conclusion, implantation of a GF-loaded collagen sponge could provide a promising treatment, especially in high-performance athletes and revision cases prone to re-rupture. For conservative treatment, tiered percutaneous GF application could be an option for improving clinical outcome.

Novel insights into transcriptional dysregulation in colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Although CRC has been comprehensively characterized at the molecular level, the tumor heterogeneity hinders the identification of reliable diagnostic, prognostic and predictive biomarkers. Molecular stratification of CRC is based on prevalent gene mutations and transcription profiles but its significance for clinical practice remains obscure. Indeed, activating mutations in the genes KRAS, NRAS and BRAF are the only predictive biomarkers for anti-EGFR antibody therapy routinely tested the clinic for advanced stages of CRC. Gene expression signatures are important for clarifying the molecular mechanisms of CRC development and progression, but only two such tests for predicting recurrence risk are commercially available. The aim of our study was to propose a diagnostic approach based on mutation and gene expression analysis that can be routinely applied in the clinic for defining the most appropriate treatment strategy for each patient. We used qPCR to determine the presence of KRAS mutations and measure the transcription levels of a panel of 26 genes in 24 CRC patients. Statistical analyses were applied to check for associations between clinico-pathological and molecular parameters. Our results reveal novel data concerning CRC carcinogenesis: almost universal downregulation of EGFR; differential role of the pro-inflammatory cytokines TNF-α and IL-6; overexpression of the vitamin B12 transporter transcobalamin 1; tumor-suppressor function of SETD2, CA7 and GUCA2B. The practical application of these findings has yet to be clarified.

Low osmolality and shear stress during liposuction impair cell viability in autologous fat grafting.

BACKGROUND: Liposuction and subsequent autologous fat grafting have become essential techniques for fat augmentation in plastic surgery. However, standard harvesting techniques that ensure the survival of adipocytes and stromal vascular fraction (SVF) cells and thus preserve the transplanted fat volume are lacking. In particular, the effect of different parameters of the tumescent solution has not been studied in this context. We hypothesized that the osmolality of the tumescent solution could have a significant effect on the survival of adipocytes and SVF cells. METHODS: We developed two distinct in vitro models based on freshly harvested excision fat from patients undergoing surgical treatment. First, we investigated the effect of osmolality by incubating excision fat in different tumescent solutions and analyzed the total cell survival and the differentiation potential of SVF cells. Vital whole-mount staining, isolation yield of SVF cells, clonogenicity, and osteogenic and adipogenic differentiation capacities were analyzed. Second, we addressed the additional effect of mechanical stress by simulating a liposuction on pieces of excision fat after incubation with the tumescent solutions. RESULTS: Osmolality of the tumescent solution by itself did not have a significant effect on adipocyte and SVF viability or SVF differentiation. However, when osmolality was combined with liposuction, a significant trend toward lower viability and more lipid droplets with lower osmolality was observed. Especially, SVF viability was significantly lower after liposuction with a hypotonic (150 mOsm/kg) solution. CONCLUSION: This study demonstrates the considerable effect of osmolality during liposuction and may lead to the development of "cell-protective" tumescent solutions.

The association between childhood maltreatment, psychopathology, and adult sexual victimization in men and women: results from three independent samples.

BACKGROUND: Childhood maltreatment (CM) has consistently been linked with adverse outcomes including substance use disorders and adult sexual revictimization. Adult sexual victimization itself has been linked with psychopathology but has predominately been studied in women. The current investigation examines the impact of CM and co-occurring psychopathology on adult sexual victimization in men and women, replicating findings in three distinct samples. METHOD: We investigated the association between continuous CM factor scores and adult sexual victimization in the Childhood Trauma Study (CTS) sample (N = 2564). We also examined the unique relationship between childhood sexual abuse (CSA) and adult sexual victimization while adjusting for co-occurring substance dependence and psychopathology. We replicated these analyses in two additional samples: the Comorbidity and Trauma Study (CATS; N = 1981) and the Australian Twin-Family Study of Alcohol Use Disorders (OZ-ALC; N = 1537). RESULTS: Analyses revealed a significant association with CM factor scores and adult sexual victimization for both men and women across all three samples. The CSA factor score was strongly associated with adult sexual victimization after adjusting for substance dependence and psychopathology; higher odds ratios were observed in men (than women) consistently across the three samples. CONCLUSIONS: A continuous measure of CSA is independently associated with adult sexual trauma risk across samples in models that included commonly associated substance dependence and psychopathology as covariates. The strength of the association between this CSA measure and adult sexual victimization is higher in magnitude for men than women, pointing to the need for further investigation of sexual victimization in male community samples.

Evidence of CNIH3 involvement in opioid dependence.

Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 single-nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P=4.30E-9; odds ratio 0.64 (95% confidence interval 0.55-0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP's in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system.

[Surgical treatment of hepatic echinococcosis--10-year experience].

INTRODUCTION: Especially debatable remains the problem concerning the volume of the surgical treatment of hepatic echinococcosis. At present it varies from radical typical and atypical liver resections, through closed conservative approaches, to minimally invasive methods like PAIR or laparoscopic echinococcectomy. AIM: The aim of the present investigation is to elucidate the problems, occurring during surgical treatment of hepatic echinococcosis and to offer adequate treatment-diagnostic algorithm. This retrospective study summarizes our 10-year experience in a number of debatable topics, concerning the surgical treatment of this socially significant disease. RESULTS: To fulfill the aim, we performed a retrospective clinical study for a period of 10 years. One-hundred-forty-seven patients had been admitted to hospital and underwent surgical treatment for hepatic echinococcosis during that period. One-hundred were males (58%) and 47 (32%)--females. The age of the patients included in the retrospective study varies between 6 and 80 years--(mean age 39.1 +/- 8.9). In 19 patients we found multiple echinococcosis of the liver (2 to 7 cysts). Two cysts--in 7 patients, 3 cysts--in 6 patients, 4 cysts in 1 patient, 5 cysts in 2 patients, 6 cysts in 1 patient and 7 cysts in 2 patients. The right hepatic lobe is three times more frequently engaged than the left one--106 patients with right-sided localization (72.1%) compared to 41 with left-sided (27.9%). Combined echinococcosis is found in 14 patients. Concomitant engagement of liver and spleen is present in 2 patients, peritoneal dissemination--in 7 patients and accompanying lung cyst--in 6 patients. Echinococcectomy with capitonage of the residual cavity is performed in 126 patients, echinococcectomy with external drainage in 4 patients, atypical liver resection in 8 patients, echinococcectomy via thoracofrenectomy approach in 6 patients and combined surgical interventions with spleen removal in 3 patients. In their majority the complications are not serious and life-threatening or with permanent consequences to the patient. Severe complications demanding active surgical intervention occur in approximately 4% of the treated patients. Our results are comparable with the ones of leading national and foreign centers and confirm the correctness of our treatment. The average hospital stay is 12 days. We have no lethal cases for the study period. CONCLUSION: Based on our experience, we consider that echinococcectomy with capitonage of the residual cavity and invagination of the fibrous rims is the method of choice for hepatic localization of the parasite. The above-mentioned surgical technique is characterized with low percentage of post-surgical complications, is well-tolerated from patients and relatively atraumatic and shows excellent long-term results. We consider more radical surgical methods, like atypical liver resections, appropriate in selected patients, ones with multiple echinococcosis and vast fibrous-altered areas of liver parenchyma. We find reasonable the obligatory adjuvant post-surgical treatment with Albendazole under parasitologist control, especially in cases of multiple and/or recurrent echinococcosis.

[Swiss surgery: quo vadis? Reader and market analysis for strategic positioning of a specialty journal]. / Swiss Surgery: Quo vadis? Leser- und Marktanalyse zur strategischen Positionierung einer Fachzeitschrift.

UNLABELLED: Scientific journals currently face challenges including cost pressures caused by economic constraints, increasing rivalry among competitors, limited market potential of non-english speaking journals, increasing medical specialization with resulting market fragmentation, and internet-based competition. We therefore analyzed strategic opportunities of the journal Swiss Surgery on the basis of customer surveys and of a market analysis. RESULTS: Swiss surgeons expressed their interest in the continuation of the journal but also indicated their support for changes in its concept and for an increased use of electronic media. An international market analysis points-out the difficulties of national, non-english speaking journals in gaining impact points and in attracting authors and readers of scientific medical articles. Therefore, a journal such as Swiss Surgery should identify and use publication niches. RECOMMENDATION: The demand for a concept addressing surgical training including continuous postgraduate education was confirmed by the customers of Swiss Surgery. A corresponding offer does not presently exist in the area and could become the new focus of the journal. This change of concept may have a number of consequences: A journal focusing on surgical training and education should use the results of readers' surveys rather than impact point assignment to evaluate quality. The journal should increasingly use electronic services including data bases, pictures, videos and closed user groups to supplement the print version. At short term, however, the printed version should be continued and not be substituted by the electronic version in order to maintain the established brand "Swiss Surgery".

[Ambulatory long-term management of a left ventricular assist device. Current modality in terminal heart failure]. / Ambulante Langzeitbetreuung mit einem Linksherzunterstützungssystem. Eine zeitgemässe Modalität in der Behandlung der terminalen Herzinsuffizienz.

We report about the first use and successful outpatient therapy with an implantable pulsatile left ventricular assist device (LVAD, Novacor) in a patient with a combined dilative and ischemic cardiomyopathy in Switzerland. The patient, a 51 year old man (112 kg, 191 cm, blood type A) developed end-stage heart failure (New York Heart Association class (NYHA) IV) while he was awaiting orthotopic heart transplantation. Due to his profession as an independent graphic-designer the patient was afraid of a long-term temporary disablement with consecutive bankruptcy. Therefore we decided and performed the implantation of a Novacor-LVAD as a bridge to transplantation with the possibility to outpatient therapy in a favourable course. The patient was supported by the device for more than five months. His cardiac functional status returned to NYHA class I, and the patient was discharged 5 weeks after implantation. He returned into his normal life and started working at 100% again. Furthermore the LVAD enabled the patient to participate in almost all activities. Five months (151 days) after implantation a donor organ became available and the patient underwent orthotopic heart transplantation. The use and successful outpatient therapy with an implantable pulsatile left ventricular assist device in our patient has proved to be save, reliable, life-saving, quality of life improving and could be an important alternative for the economic burden in heart failure therapy.

The effect of prone positioning on intraocular pressure in anesthetized patients.

BACKGROUND: Ocular perfusion pressure is commonly defined as mean arterial pressure minus intraocular pressure (IOP). Changes in mean arterial pressure or IOP can affect ocular perfusion pressure. IOP has not been studied in this context in the prone anesthetized patient. METHODS: After institutional human studies committee approval and informed consent, 20 patients (American Society of Anesthesiologists physical status I-III) without eye disease who were scheduled for spine surgery in the prone position were enrolled. IOP was measured with a Tono-pen XL handheld tonometer at five time points: awake supine (baseline), anesthetized (supine 1), anesthetized prone (prone 1), anesthetized prone at conclusion of case (prone 2), and anesthetized supine before wake-up (supine 2). Anesthetic protocol was standardized. The head was positioned with a pinned head-holder. Data were analyzed with repeated-measures analysis of variance and paired t test. RESULTS: Supine 1 IOP (13 +/- 1 mmHg) decreased from baseline (19 +/- 1 mmHg) (P < 0.05). Prone 1 IOP (27 +/- 2 mmHg) increased in comparison with baseline (P < 0.05) and supine 1 (P < 0.05). Prone 2 IOP (40 +/- 2 mmHg) was measured after 320 +/- 107 min in the prone position and was significantly increased in comparison with all previous measurements (P < 0.05). Supine 2 IOP (31 +/- 2 mmHg) decreased in comparison with prone 2 IOP (P < 0.05) but was relatively elevated in comparison with supine 1 and baseline (P < 0.05). Hemodynamic and ventilatory parameters remained unchanged during the prone period. CONCLUSIONS: Prone positioning increases IOP during anesthesia. Ocular perfusion pressure could therefore decrease, despite maintenance of normotension.

[Reverse remodeling by surgery--fact or fiction?]. / "Reverse remodeling" durch Chirurgie induzierbar?

Mortality of chronic heart failure in industrial countries remains unacceptably high despite advances in medical therapy. Heart transplantation, the gold standard in the treatment of end-stage heart failure is reserved for only a few patients because of the shortage of donor hearts. Surgical alternatives to transplantation include dynamic cardiomyoplasty (CMP), mitral valve reconstruction, left ventricular reduction surgery (PLVR) and ventricular assist devices (VAD). Improved survival and objective physiologic improvement have not been documented for CMP in the treatment of dilative cardiomyopathy. Mitral valve reconstruction on the other hand shows promising results. PLVR is an innovative procedure in which the heart is surgically reduced in size and cardiac function is dramatically improved immediately after surgery. The presence of long-term effects is still unknown. VAD have been shown to be extremely effective as a short- and long-term "bridge" to heart transplantation. They are not approved for permanent support. A randomized trial in the U.S. is underway to compare the efficacy of these devices with the efficacy of medical therapy in NYHA functional class IV patients in quality of life, survival and costs.

Bias in proxies' reports of disability: data from the National Health Interview Survey on disability.

OBJECTIVES: These studies examined whether differences between self-reports and proxy reports of disabilities reflect proxy response biases or only respondent selection factors. METHODS: The data were from the National Health Interview Survey on Disability (1994-1995, phases 1 and 2). In study 1, reports of disabilities were regressed on respondent status, self vs proxy, and demographic factors. In study 2, the ratios of the proportions of self-reports and proxy reports of disabilities were regressed on independent lay ratings of observability of these disabilities and their "interactional" nature. In study 3, the disability reports for people who differed in respondent status in one phase but self-reported the same disability in the other phase were compared. RESULTS: In study 1, proxies under-reported disabilities for people aged 18 to 64 years but overreported for people 65 years or older. In study 2, the observability and interactional scores accounted for more than 60% of the variance of self and proxy differences in an inverse relationship, study 3 confirmed the basic findings of study 1. CONCLUSIONS: Use of proxies in representative surveys on disability introduces systematic biases, affecting national disability estimates.

Activation of host cell phosphatidylinositol 3-kinases by Trypanosoma cruzi infection.

Trypanosoma cruzi, the causative agent of Chagas' disease in humans, is an intracellular protozoan parasite with the ability to invade a wide variety of mammalian cells by a unique and remarkable process in cell biology that is poorly understood. Here we present evidence suggesting a role for the host phosphatidylinositol (PI) 3-kinases during T. cruzi invasion. The PI 3-kinase inhibitor wortmannin marked inhibited T. cruzi infection when macrophages were pretreated for 20 min at 37 degrees C before inoculation. Infection of macrophages with T. cruzi markedly stimulated the formation of the lipid products of the phosphatidylinositol (PI) 3-kinases, PI 3-phospate, PI 3,4-biphosphate, and PI 3,4,5-triphosphate, but not PI 4-phosphate or PI 4,5-biphosphate. This activation was inhibited by wortmannin. Infection with T. cruzi also stimulated a marked increase in the in vitro lipid kinase activities that are present in the immunoprecipitates of anti-p85 subunit of class I PI 3-kinase and anti-phosphotyrosine. In addition, T. cruzi invasion also activated lipid kinase activity found in immunoprecipitates of class II and class III PI 3-kinases. These data demonstrate that T. cruzi invasion into macrophages strongly activates separated PI 3-kinase isoforms. Furthermore, the inhibition of the class I and class III PI 3-kinase activities abolishes the parasite entry into macrophages. These findings suggest a prominent role for the host PI 3-kinase activities during the T. cruzi infection process.

Genetic analysis of the age at menopause by using estimating equations and Bayesian random effects models.

Multi-wave self-report data on age at menopause in 2182 female twin pairs (1355 monozygotic and 827 dizygotic pairs), were analysed to estimate the genetic, common and unique environmental contribution to variation in age at menopause. Two complementary approaches for analysing correlated time-to-onset twin data are considered: the generalized estimating equations (GEE) method in which one can estimate zygosity-specific dependence simultaneously with regression coefficients that describe the average population response to changing covariates; and a subject-specific Bayesian mixed model in which heterogeneity in regression parameters is explicitly modelled and the different components of variation may be estimated directly. The proportional hazards and Weibull models were utilized, as both produce natural frameworks for estimating relative risks while adjusting for simultaneous effects of other covariates. A simple Markov chain Monte Carlo method for covariate imputation of missing data was used and the actual implementation of the Bayesian model was based on Gibbs sampling using the freeware package BUGS.

Characterization of the myo-inositol transport system in Trypanosoma cruzi.

myo-inositol is a growth factor for mammalian cells as well as for the pathogenic protozoa Trypanosoma cruzi. Most of the cell surface molecules in this organism rely on myo-inositol as the biosynthetic precursor for phosphoinositides and glycosylated phosphatidylinositols. The aim of this work was to investigate the process of myo-inositol translocation across the parasite cell membrane. myo-Inositol uptake was concentration-dependent in the concentration range 0.1-10 microM with maximal transport obtained at 8 microM. Using sodium-free buffers, where Na+ was replaced by choline or K+, myo-inositol uptake was inhibited by 50%. Furosemide, an inhibitor of the ouabain-insensitive Na+-ATPase, inhibited the Na+-dependent and Na+-independent myo-inositol uptake by 68 and 33%, respectively. In contrast, ouabain, an (Na++/K+) ATPase inhibitor, did not affect transport. Part of the myo-inositol uptake is mediated by active transport as it was inhibited when energy metabolism inhibitors such as carbonyl cyanide p-(trifluoromethoxy)-phenylhydrazone (34%), 2,4-dinitrophenol (50%), KCN (71%) and NaN3 (69%) were added to the medium, or the temperature of the medium was lowered to 4 degrees C. The addition of glucose (5-50 mM) or mannose (10 mM) did not change the myo-inositol uptake, whereas the addition of 10 mM nonlabeled myo-inositol totally inhibited this transport, indicating that the transporter is specific for myo-inositol. Phloretin (0.3 mM) and phoridzin (5 mM), but not cytochalasin B, were efficient inhibitors of myo-inositol uptake. A portion of the accumulated myo-inositol is converted to inositol phosphates and phosphoinositides. These data show that myo-inositol transport in T. cruzi epimastigotes is mediated by at least two specific transporters - one Na+-dependent and the other Na+-independent.

Aberrant right pulmonary artery and double outlet ventricle: one-stage repair.

We report a 13-month-old male child with anomalous origin of the right pulmonary artery from the ascending aorta and a double outlet right ventricle. Aortic wall was used for elongation of the pulmonary artery and side-to-end connection to the pulmonary trunk. Special emphasis is made on this particular operative technique for strictly laterally originating right pulmonary artery that requires no prosthetic material, avoids extreme stretching, and may enable normal growth potential.

Linkage analysis for diseases with variable age of onset.

We present a method for the multivariate linkage analysis of the age of onset of a disease. The approach allows the incorporation of covariates for the study of gene by environment interactions. It is applicable to general pedigrees. The likelihood of the data is expressed as a function of the number of alleles identical by descent at a marker, the censored ages of onset and disease status, and environmental exposures. In a simulation study, we compare the power to detect linkage under different sampling schemes for either a dominant or recessive trait when approximately 10% of individuals are gene carriers. The majority of the linkage information from a sample of randomly selected sib pairs was retained when the analyses were limited to sibships with one sibling having early-onset disease (<59 years old). Incorporating parental phenotypes could improve the power to detect the gene. When the sample consists of affected sib pairs (ASPs) having variable age of onset, the likelihood ratio (LR) test had higher power than the means (t(2)) test for detecting a locus with a large genetic relative risk (R(g) = 20). However, the power of the two tests was similar when ASPs are selected so that the proband has an early onset of disease. Lastly, the LR test had more power than the t(2) test to detect linkage in the presence of gene by environment interactions.