The role of cell death and myofibrillar damage in contractile dysfunction of long-term cultured adult cardiomyocytes exposed to doxorubicin

In failing hearts cardiomyocytes undergo alterations in cytoskeleton structure, contractility and viability. It is not known presently, how stress-induced changes of myofibrils correlate with markers for cell death and contractile function in cardiomyocytes. Therefore, we have studied the progression of contractile dysfunction, myofibrillar damage and cell death in cultured adult cardiomyocytes exposed to the cancer therapy doxorubicin. We demonstrate, that long-term cultured adult cardiomyocytes, a well-established model for the study of myofibrillar structure and effects of growth factors, can also be used to assess contractility and calcium handling. Adult rat ventricular myocytes (ARVM) were isolated and cultured for a total of 14 days in serum containing medium. The organization of calcium-handling proteins and myofibrillar structure in freshly isolated and in long-term cultured adult cardiomyocytes was studied by immunofluorescence and electron microscopy. Excitation contraction-coupling was analyzed by fura 2 and video edge detection in electrically paced cardiomyocytes forming a monolayer, and cell death and viability was measured by TUNEL assay, LDH release, MTT assay, and Western blot for LC3. Adult cardiomyocytes treated with Doxo showed apoptosis and necrosis only at supraclinical concentrations. Treated cells displayed merely alterations in cytoskeleton organization and integrity concomitant with contractile dysfunction and up-regulation of autophagosome formation, but no change in total sarcomeric protein content. We propose, that myofibrillar damage contributes to contractile dysfunction prior to cell death in adult cardiomyocytes exposed to clinically relevant concentrations of anthracyclines.

Diastolic dysfunction of the cardiac allograft and maximal exercise capacity

BACKGROUND: Peak oxygen uptake (peak Vo(2)) is an established integrative measurement of maximal exercise capacity in cardiovascular disease. After heart transplantation (HTx) peak Vo(2) remains reduced despite normal systolic left ventricular function, which highlights the relevance of diastolic function. In this study we aim to characterize the predictive significance of cardiac allograft diastolic function for peak Vo(2). METHODS: Peak Vo(2) was measured using a ramp protocol on a bicycle ergometer. Left ventricular (LV) diastolic function was assessed with tissue Doppler imaging sizing the velocity of the early (Ea) and late (Aa) apical movement of the mitral annulus, and conventional Doppler measuring early (E) and late (A) diastolic transmitral flow propagation. Correlation coefficients were calculated and linear regression models fitted. RESULTS: The post-transplant time interval of the 39 HTxs ranged from 0.4 to 20.1 years. The mean age of the recipients was 55 +/- 14 years and body mass index (BMI) was 25.4 +/- 3.9 kg/m(2). Mean LV ejection fraction was 62 +/- 4%, mean LV mass index 108 +/- 22 g/m(2) and mean peak Vo(2) 20.1 +/- 6.3 ml/kg/min. Peak Vo(2) was reduced in patients with more severe diastolic dysfunction (pseudonormal or restrictive transmitral inflow pattern), or when E/Ea was > or =10. Peak Vo(2) correlated with recipient age (r = -0.643, p < 0.001), peak heart rate (r = 0.616, p < 0.001) and BMI (r = -0.417, p = 0.008). Of all echocardiographic measurements, Ea (r = 0.561, p < 0.001) and Ea/Aa (r = 0.495, p = 0.002) correlated best. Multivariate analysis identified age, heart rate, BMI and Ea/Aa as independent predictors of peak Vo(2). CONCLUSIONS: Diastolic dysfunction is relevant for the limitation of maximal exercise capacity after HTx.

Transalveolar maxillary sinus floor elevation using osteotomes with or without grafting material. Part II: Radiographic tissue remodeling

OBJECTIVES: To evaluate the pattern of tissue remodeling after maxillary sinus floor elevation using the transalveolar osteotome technique with or without utilizing grafting materials. METHODS: During the period of 2000-2005, 252 Straumann dental implants were inserted using the transalveolar sinus floor elevation technique in a group of 181 patients. For 88 or 35% of those implants, deproteinized bovine bone mineral with a particle size of 0.25-1 mm was used as the grafting material, but for the remaining 164 implants, no grafting material was utilized. Periapical radiographs were obtained with a paralleling technique and digitized. Two investigators, who were blinded to whether grafting material was used or not, subsequently evaluated the pattern of tissue remodeling. RESULTS: The mean residual bone height was 7.5 mm (SD 2.2 mm), ranging from 2 to 12.7 mm. The mean residual bone height for implants placed with grafting material (6.4 mm) was significantly less compared with the implants installed without grafting material (8.1 mm). The implants penetrated on average 3.1 mm (SD 1.7 mm) into the sinus cavity. The measured mean radiographic bone gain using the transalveolar technique without grafting material was significantly less, 1.7 mm (SD 2 mm) compared with a mean bone gain of 4.1 mm (SD 2.4 mm), when grafting material was used. Furthermore, the probability of gaining 2 mm or more of new bone was 39.1% when no grafting material was used. The probability increased to 77.9% when the implants were installed with grafting material. CONCLUSION: When the transalveolar sinus floor elevation was performed without utilizing grafting material, only a moderate gain of new bone could be detected mesial and distal to the implants. On the other hand, when grafting material was used, a substantial gain of new bone was usually seen on the radiographs.

Maxillary sinus floor elevation using the (transalveolar) osteotome technique with or without grafting material. Part I: Implant survival and patients' perception

OBJECTIVES: To analyze the survival and success rates of implants installed utilizing the (transalveolar) osteotome technique, to compare peri-implant soft tissue parameters and marginal bone levels of osteotome-installed implants with implants placed using standard surgical procedures, and to evaluate patient-centered outcomes. MATERIAL AND METHODS: During 2000 to 2005, 252 Straumann dental implants were inserted in 181 patients. The surgical technique was a modification of the original osteotome technique presented by Summers. In addition to the clinical examination, the patients were asked to give their perception of the surgical procedure, utilizing a visual analogue scale. RESULTS: The cumulative survival rate of the osteotome-installed implants after a mean follow-up time of 3.2 years, was 97.4% (95% confidence intervals: 94.4-98.8%). From the 252 implants inserted, three were lost before loading and another three were lost in the first and second year. According to residual bone height the survival was 91.3% for implant sites with < or =4 mm residual bone height, and 90% for sites with 4 mm and 5 mm, when compared with that of 100% in sites with bone height of above 5 mm. According to implant length the survival rates were 100% for 12 mm, 98.7% for 10 mm, 98.7% for 8 mm and only 47.6% for 6 mm implants. Soft tissue parameters (pocket probing depth, probing attachment level, bleeding on probing and marginal bone levels) did not yield any differences between the osteotome-installed and the conventionally placed implants. More than 90% of the patients were satisfied with the implant therapy and would undergo similar therapy again if necessary. The cost associated with implant therapy was considered to be justified. CONCLUSION: In conclusion, the osteotome technique was a reliable method for implant insertion in the posterior maxilla, especially at sites with 5 mm or more of preoperative residual bone height and a relatively flat sinus floor.

Displacement of a dental implant into the maxillary sinus: report of an unusual complication when performing staged sinus floor elevation procedures

Grafting of the maxillary sinus in both one- and two-stage protocols has become a highly predictable surgical technique for site development and for the placement of implants to support dentures. However, despite the predictability and high success rates reported for dental implants placed either simultaneously with or after a sinus floor elevation (SFE) procedure, complications have been reported. The aim of the following case report is to present an uncommon complication in a staged SFE procedure: the displacement of a dental implant into the maxillary sinus during insertion. As implant dentistry is becoming more and more popular among practitioners, and ever more demanding procedures for initial site development in jaws with bony deficiencies are being introduced into daily practice, the displacement of dental implants into the maxillary sinus during implant placement may become a more frequent complication. Management of this complication is presented, discussed, and evaluated in light of the current literature.

Comparative study of the neuropeptide-Y sympathetic nerves in endometriotic involved and noninvolved sacrouterine ligaments in women with pelvic endometriosis

STUDY OBJECTIVE: To show the relationship between the neuropeptide-Y pelvic sympathetic nerves and neoangiogenesis in the development of endometriosis DESIGN: Prospective study. SETTING: Academic community teaching hospital. PATIENTS: Fifteen consecutive women with unilateral endometriotic infiltration of the sacrouterine ligaments. INTERVENTIONS: A laparoscopic excision/biopsy of involved and noninvolved parts of the sacrouterine ligaments were taken. The sections were incubated with the neuronal marker rabbit polyclonal anti-protein gene product 9.5 and rabbit polyclonal anti-neuropeptide-Y. We made a comparative study on the distribution of nerve fibers and their relationship to the vessels on intact and endometriotic involved tissue. MEASUREMENTS AND MAIN RESULTS: The results show that a large amount of nerves are present around the blood vessels in the endometriosis samples, and a large number of these nerves are neuropeptide-Y sympathetic nerves. Adrenergic fibers are also present in the intact control subjects, however, in significantly smaller amounts. CONCLUSION: This finding shows a strong relationship between the neuropeptide-Y sympathetic pelvic nerves and the neoangiogenesis required for the development of endometriosis.

Loss of alpha10beta1 integrin expression leads to moderate dysfunction of growth plate chondrocytes

Integrin alpha10beta1 is a collagen-binding integrin expressed on chondrocytes. In order to unravel the role of the alpha10 integrin during development, we generated mice carrying a constitutive deletion of the alpha10 integrin gene. The mutant mice had a normal lifespan and were fertile but developed a growth retardation of the long bones. Analysis of the skeleton revealed defects in the growth plate after birth characterized by a disturbed columnar arrangement of chondrocytes, abnormal chondrocyte shape and reduced chondrocyte proliferation. Electron microscopy of growth plates from newborn mice revealed an increased number of apoptotic chondrocytes and reduced density of the collagen fibrillar network compared to these structures in control mice. These results demonstrate that integrin alpha10beta1 plays a specific role in growth plate morphogenesis and function.

Human internal thoracic arteries from diabetic patients are resistant to endothelial dysfunction

The aim of this analysis was to compare vasoreactive properties of internal thoracic arteries (ITA) grafts from diabetic (DM) to those of non-diabetic (ND) patients. Ring segments of ITA, taken from patients undergoing coronary artery bypass grafting, were suspended in organ bath chambers filled with modified Krebs-Henseleit solution and contractile responses to potassium chloride (KCl), noradrenaline (NA), endothelin-1 (ET-l), and endothelium-dependent relaxant responses to acetylcholine (ACH) were recorded isometrically. The receptor-mediated agonists NA and ET-1 stimulated ITA from both groups within similar concentration ranges while ITA from DM patients proved to be significantly more sensitive to KCl than ITA from ND. Furthermore, maximal contractile responses indicated that KCl (3.79 +/- 0.30 g, n = 7 in DM and 2.50 +/- 0.23 g, n = 29 in ND, P < 0.05) evoked significantly higher responses in ITA from DM as compared to the ND control group while both NA and ET-l stimulated ITA from both groups with similar efficacies. Endothelium-dependent relaxant responses to ACH proved to be similar in both groups when expressed as percentages of the pre-existing tone. The present data support the contention that in comparison to ND controls arteries from DM patients are more sensitive to depolarization but endothelial dysfunction is less frequent in human ITA than expected from observations in systemic vascular beds.

Primary pelvic pyomyositis in a neonate

Primary pyomyositis is a bacterial infection occurring in skeletal muscle with no obvious local or adjacent cause. It is classically an infection of the tropics, although it is reported in temperate climates with increasing frequency. Tropical pyomyositis occurs predominantly in children aged between 2 and 5 and in adults aged between 20 and 45 years, whereas most temperate pyomyositis cases occur in adults. Using a magnetic resonance imaging scan, we made the diagnosis of staphylococcal pelvic pyomyositis in a Swiss term-born infant with an initial working diagnosis of septic hip osteoarthritis.

Nervous system dysfunction in Henoch-Schonlein syndrome: systematic review of the literature

OBJECTIVE: CNS or peripheral nervous system dysfunction sometimes occurs in Henoch-Schönlein patients. METHODS: We review all Henoch-Schönlein cases published after 1969 with CNS dysfunction without severe hypertension and neuroimaging studies (n = 35), cranial or peripheral neuropathy (n = 15), both CNS and peripheral nervous system dysfunction without severe hypertension (n = 2) or nervous system dysfunction with severe hypertension (n = 2). Forty-four of the 54 patients were <20 years of age. RESULTS: In patients with CNS dysfunction without or with severe hypertension the following presentations were observed in decreasing order of frequency: altered level of consciousness, convulsions, focal neurological deficits, visual abnormalities and verbal disability. Imaging studies disclosed the following lesions: vascular lesions almost always involving two or more vessels, intracerebral haemorrhage, posterior subcortical oedema, diffuse brain oedema and thrombosis of the superior sagittal sinus. Following lesions were noted in the subjects with cranial or peripheral neuropathy without severe hypertension: peroneal neuropathy, peripheral facial palsy, Guillain-Barré syndrome, brachial plexopathy, posterior tibial nerve neuropathy, femoral neuropathy, ulnar neuropathy and mononeuritis multiplex. Persisting signs of either CNS (n = 9) or peripheral (n = 1) nervous system dysfunction were sometimes reported. CONCLUSIONS: In Henoch-Schönlein syndrome, signs of nervous system dysfunction are uncommon but clinically relevant. This review helps clinicians managing Henoch-Schönlein syndrome with nervous system dysfunction.

Sexual dysfunction in multiple sclerosis

Multiple sclerosis is a chronic disease that commonly affects young adults who may be sexually active. Sexual dysfunction is a significant, but often underestimated, symptom of multiple sclerosis, affecting 50-90% of men and 40-80% of women. The types of sexual dysfunction can be categorized in terms of the normal sexual response cycle: sexual interest/desire dysfunction (reduced libido), sexual arousal dysfunction (including erectile dysfunction) and ejaculatory and orgasmic dysfunction. Sexual dysfunction may not only be due to lesions affecting the neural pathways involved in physiological function (primary dysfunction), but also result from general physical disabilities (secondary dysfunction) or psychological and emotional issues (tertiary dysfunction). Comprehensive management should address all these possible contributing problems. Specific pharmacotherapy is only currently available for erectile dysfunction. This review summarizes the available information about sexual dysfunction in men and women with multiple sclerosis.