Showing papers by "Medical University of Graz published in 2006"

MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2.

Abstract: Mutations in mitofusin 2 (MFN2) have been reported in Charcot-Marie-Tooth type 2 (CMT2) families. To study the distribution of mutations in MFN2 we screened 323 families and isolated patients with distinct CMT phenotypes. In 29 probands, we identified 22 distinct MFN2 mutations, and 14 of these mutations have not been reported before. All mutations were located in the cytoplasmic domains of the MFN2 protein. Patients presented with a classical but rather severe CMT phenotype, since 28% of them were wheelchair-dependent. Some had additional features as optic atrophy. Most patients had an early onset and severe disease status, whereas a smaller group experienced a later onset and milder disease course. Electrophysiological data showed in the majority of patients normal to slightly reduced nerve conduction velocities with often severely reduced amplitudes of the compound motor and sensory nerve action potentials. Examination of sural nerve specimens showed loss of large myelinated fibres and degenerative mitochondrial changes. In patients with a documented family history of CMT2 the frequency of MFN2 mutations was 33% indicating that MFN2 mutations are a major cause in this population.

Brain tissue deforms similarly to filled elastomers and follows consolidation theory

Abstract: Slow, large deformations of human brain tissue—accompanying cranial vault deformation induced by positional plagiocephaly, occurring during hydrocephalus, and in the convolutional development—has surprisingly received scarce mechanical investigation. Since the effects of these deformations may be important, we performed a systematic series of in vitro experiments on human brain tissue, revealing the following features. (i) Under uniaxial (quasi-static), cyclic loading, brain tissue exhibits a peculiar nonlinear mechanical behaviour, exhibiting hysteresis, Mullins effect and residual strain, qualitatively similar to that observed in filled elastomers. As a consequence, the loading and unloading uniaxial curves have been found to follow the Ogden nonlinear elastic theory of rubber (and its variants to include Mullins effect and permanent strain). (ii) Loaded up to failure, the “shape” of the stress/strain curve qualitatively changes, evidencing softening related to local failure. (iii) Uniaxial (quasi-static) strain experiments under controlled drainage conditions provide the first direct evidence that the tissue obeys consolidation theory involving fluid migration, with properties similar to fine soils, but having much smaller volumetric compressibility. (iv) Our experimental findings also support the existence of a viscous component of the solid phase deformation. Brain tissue should, therefore, be modelled as a porous, fluid-saturated, nonlinear solid with very small volumetric (drained) compressibility.

Silver-coated dressing acticoat caused raised liver enzymes and argyria-like symptoms in burn patient.

Abstract: Background: Treatment of acute burn wounds with silver sulfadiazine (SSD) has raised concern about potential silver toxicity. Numerous adverse reactions and side effects have been reported and an increasing resistance to SSD, especially in Pseudomonas strains, have motivated researchers to search for an alternative wound dressing. Methods: Recently, a silver-coated wound dressing Acticoat (Smith & Nephew, Inc.) has become available for use in burn patients. It is a three-ply dressing, consisting of an inner rayon/ polyester absorptive core between two layers of silver-coated, high-density polyethylene mesh. In a moist environment, the nanocrystals of silver are released and improve the microbial control in the wound. Results: After 1 week of local treatment with Acticoat in a young, previously healthy 17-year-old boy with 30% mixed depth burns, hepatotoxicity and argyrialike symptoms, a grayish discoloration of the patient’s face, appeared. The silver levels in plasma (107 g/kg) and urine (28 g/kg) were clearly elevated, as well as the liver enzymes. As soon as the local application of Acticoat was aborted, the clinical symptoms and liver enzymes returned to the normal values. Conclusions: This is the first report on silver toxicity in a patient with 30% burns who received Acticoat for local treatment. Due to substantial experiences with adverse SSD reactions and side effects, it is appropriate to keep the possibility of a toxic silver effect in burn patients treated with Acticoat silver-coated wound dressing in mind. The silver levels in plasma and/or urine should be monitored.

Seizure control and treatment in pregnancy: Observations from the EURAP epilepsy pregnancy registry

Abstract: Objective: To analyze seizure control and treatment in pregnant women with epilepsy. Methods: Seizure control and treatment were recorded prospectively in 1,956 pregnancies of 1,882 women with epilepsy participating in EURAP, an international antiepileptic drugs (AEDs) and pregnancy registry. Results: Of all cases, 58.3% were seizure-free throughout pregnancy. Occurrence of any seizures was associated with localization-related epilepsy (OR: 2.5; 1.7 to 3.9) and polytherapy (OR: 9.0; 5.6 to 14.8) and for tonic-clonic seizures, with oxcarbazepine monotherapy (OR: 5.4; 1.6 to 17.1). Using first trimester as reference, seizure control remained unchanged throughout pregnancy in 63.6%, 92.7% of whom were seizure-free during the entire pregnancy. For those with a change in seizure frequency, 17.3% had an increase and 15.9% a decrease. Seizures occurred during delivery in 60 pregnancies (3.5%), more commonly in women with seizures during pregnancy (OR: 4.8; 2.3 to 10.0). There were 36 cases of status epilepticus (12 convulsive), which resulted in stillbirth in one case but no cases of miscarriage or maternal mortality. AED treatment remained unchanged in 62.7% of the pregnancies. The number or dosage of AEDs were more often increased in pregnancies with seizures (OR: 3.6; 2.8 to 4.7) and with monotherapy with lamotrigine (OR: 3.8; 2.1 to 6.9) or oxcarbazepine (OR: 3.7; 1.1 to 12.9). Conclusions: The majority of patients with epilepsy maintain seizure control during pregnancy. The apparently higher risk of seizures among women treated with oxcarbazepine and the more frequent increases in drug load in the oxcarbazepine and lamotrigine cohorts prompts further studies on relationships with pharmacokinetic changes. Risks associated with status epilepticus appear to be lower than previously reported.

Klebsiella oxytoca as a causative organism of antibiotic-associated hemorrhagic colitis.

Abstract: BACKGROUND Antibiotic-associated hemorrhagic colitis is a distinct form of antibiotic-associated colitis in which Clostridium difficile is absent. Although the cause is not known, previous reports have suggested a role of Klebsiella oxytoca. METHODS We studied 22 consecutive patients who had suspected antibiotic-associated colitis and who were negative for C. difficile. Patients underwent diagnostic colonoscopy, and among those who received a diagnosis of antibiotic-associated hemorrhagic colitis, stool samples were cultured for K. oxytoca. We isolated K. oxytoca strains and tested them for cytotoxin production using a tissue-culture assay. In addition, we also cultured stool samples obtained from 385 healthy subjects for K. oxytoca. An in vivo animal model for antibiotic-associated hemorrhagic colitis was established with the use of Sprague-Dawley rats. RESULTS Of the 22 patients, 6 had findings on colonoscopy that were consistent with the diagnosis of antibiotic-associated hemorrhagic colitis, and 5 of these 6 patients had positive cultures for K. oxytoca. No other common enteric pathogens were found in the five patients. Before the onset of colitis, all five were receiving penicillins, and two were also taking nonsteroidal antiinflammatory drugs (NSAIDs). All isolated K. oxytoca strains produced cytotoxin. K. oxytoca was found in 1.6% of the healthy subjects. In the animal model, K. oxytoca was found only in the colon of rats that received amoxicillin-clavulanate in addition to being inoculated with K. oxytoca. In these rats, infection with K. oxytoca induced a right-sided hemorrhagic colitis that was not observed in uninfected animals that received amoxicillin-clavulanate, indomethacin (an NSAID), or both. CONCLUSIONS Our fulfillment of Koch's postulates for cytotoxin-producing K. oxytoca suggests that it is the causative organism in at least some cases of antibiotic-associated hemorrhagic colitis. Infection with K. oxytoca should be considered in patients with antibiotic-associated colitis who are negative for C. difficile.

Dermoscopy in general dermatology.

Abstract: Dermoscopy improves the diagnostic accuracy in the clinical evaluation of pigmented skin lesions, but it is also useful for the assessment of vascular structures that are not visible to the naked eye. As a consequence, dermoscopy has been employed more and more for the differential diagnosis of nonpigmented skin disorders, including tumors but also inflammatory and infectious diseases. This article provides a review of the dermoscopic features seen in various nonpigmented tumoral and nontumoral skin lesions as well as the dermoscopic criteria used for monitoring skin reactions to various treatments.

The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis

Abstract: This multicenter, prospective study involving 26 242 participants examined associations between vitamin D receptor polymorphisms (Cdx2 promoter, FokI, BsmI, ApaI, and TaqI), bone mineral density (B...

Analysis of Dog Bites in Children Who Are Younger Than 17 Years

Abstract: OBJECTIVES. This study focuses on the pattern of incidence, mechanisms, and circumstances of accident and injury in a series of pediatric patients who sustained dog bites. METHODS. In our retrospective survey, the medical charts of all children who were younger than 17 years and sought medical attention after a dog bite between 1994 and 2003 were reviewed. To obtain the total number of each dog breed in the administrative district, we analyzed 5873 files from the community dog registers. For establishment of a risk index, the representation of a dog breed among the total canine population was divided by the frequency of dog bites from this breed. RESULTS. A total of 341 children (mean age: 5.9 years) were identified. The annual incidence of dog bites was 0.5 per 1000 children between 0 and 16 years of age. Incidence was highest in 1-year-old patients and decreased with increasing age. The relative risk for a dog attack by a German shepherd or a Doberman was ∼5 times higher than that of a Labrador/retriever or cross-breed. The vast majority (82%) of the dogs were familiar to the children. Most (322; 94%) of the children had injuries to 1 body region; in the remaining 19 (6%) children, up to 3 body regions were injured. Of 357 injuries, the face, head, and neck region was the leading site affected (50%). Inpatient treatment was required in 93 (27%) patients. CONCLUSIONS. Dog bites in children are frequent and influenced by the breed-related behavior of dogs, dog owners, children, and parents. Therefore, prevention strategies should focus on public education and training of dogs and their owners. Children who are younger than 10 years represent the high-risk group for dog attacks.

The European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life questionnaire cervical cancer module: EORTC QLQ-CX24.

Abstract: BACKGROUND The authors report on the development and validation of a cervical cancer module for the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life (QoL) questionnaire (QLQ), which was designed to assess disease-specific and treatment-specific aspects of QoL in patients with cervical cancer. METHODS The cervical cancer module (EORTC QLQ-CX24) was developed in a multicultural, multidisciplinary setting to supplement the EORTC QLQ-C30 core questionnaire. The QLQ-C30 and the cervical cancer module were administered to 346 patients with cervical cancer who underwent radical hysterectomy and received radiotherapy and chemotherapy. Psychometric analyses were performed by using data from 2 independent samples. RESULTS The QLQ-CX24 consists of 3 multiitem scales and 5 single-item scales. Multitrait scaling analyses revealed high internal consistencies for the subscales with Cronbach α coefficients ranging from .72 to .87 (Symptom Experience, .72; Body Image, .86; Sexual/Vaginal Functioning, .87). Convergent and discriminant validity were fulfilled with scaling errors below 3%. The QLQ-CX24 was capable of discriminating between clinical subgroups. All items exhibited good compliance with <3% missing values. Most patients completed the EORTC QLQ-C30 and the QLQ-CX24 in <15 minutes (86%), and many did not require any assistance to complete the questionnaires (65%). CONCLUSIONS The current psychometric analyses supported the content and construct validity and the reliability of the EORTC QLQ-CX24 module. This newly developed module is a useful instrument for assessing the QoL of patients who are treated for cervical cancer both in clinical trials and in clinical practice. Cancer 2006. © 2006 American Cancer Society.

Impact of TASK-1 in Human Pulmonary Artery Smooth Muscle Cells

Abstract: The excitability of pulmonary artery smooth muscle cells (PASMC) is regulated by potassium (K+) conductances. Although studies suggest that background K+ currents carried by 2-pore domain K+ channels are important regulators of resting membrane potential in PASMC, their role in human PASMC is unknown. Our study tested the hypothesis that TASK-1 leak K+ channels contribute to the K+ current and resting membrane potential in human PASMC. We used the whole-cell patch-clamp technique and TASK-1 small interfering RNA (siRNA). Noninactivating K+ current performed by TASK-1 K+ channels were identified by current characteristics and inhibition by anandamide and acidosis (pH 6.3), each resulting in significant membrane depolarization. Moreover, we showed that TASK-1 is blocked by moderate hypoxia and activated by treprostinil at clinically relevant concentrations. This is mediated via protein kinase A (PKA)-dependent phosphorylation of TASK-1. To further confirm the role of TASK-1 channels in regulation of resting membrane potential, we knocked down TASK-1 expression using TASK-1 siRNA. The knockdown of TASK-1 was reflected by a significant depolarization of resting membrane potential. Treatment of human PASMC with TASK-1 siRNA resulted in loss of sensitivity to anandamide, acidosis, alkalosis, hypoxia, and treprostinil. These results suggest that (1) TASK-1 is expressed in human PASMC; (2) TASK-1 is hypoxia-sensitive and controls the resting membrane potential, thus implicating an important role for TASK-1 K+ channels in the regulation of pulmonary vascular tone; and (3) treprostinil activates TASK-1 at clinically relevant concentrations via PKA, which might represent an important mechanism underlying the vasorelaxing properties of prostanoids and their beneficial effect in vivo.

Type 2 Diabetes Mellitus in Nursing Home Patients: Effects on Bone Turnover, Bone Mass, and Fracture Risk

Abstract: Context: Fractures are a major health burden in elderly institutionalized persons. Type 2 diabetes mellitus (DM) has a high prevalence in nursing home patients and has been associated with positive effects on bone mass in younger, community-dwelling elderly. Objective: The objective of this study was to investigate whether type 2 DM affects bone mass, bone turnover, or prospective fracture rates in frail, elderly women living in nursing homes. Design, Setting, and Participants: This study was a prospective cohort of 583 patients with type 2 DM and 1081 control (CTR) individuals above age 70 recruited from 95 nursing homes in Austria. Patients were enrolled and followed up by mobile study teams. Main Outcome Measures: We performed quantitative bone ultrasound measurements at the calcaneus, radius, and proximal third phalanx, measurements of quadriceps strength, and biochemical parameters of mineral metabolism and bone turnover. Patients were prospectively followed for hip and other nonvertebral fractures o...

Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes : the GENOMOS study

Abstract: Background Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes.

Sensitivity and specificity of confocal laser-scanning microscopy for in vivo diagnosis of malignant skin tumors

Abstract: BACKGROUND Melanoma and nonmelanoma skin cancer are the most frequent malignant tumors by far among whites. Currently, early diagnosis is the most efficient method for preventing a fatal outcome. In vivo confocal laser-scanning microscopy (CLSM) is a recently developed potential diagnostic tool. METHODS One hundred seventeen melanocytic skin lesions and 45 nonmelanocytic skin lesions (90 benign nevi, 27 malignant melanomas, 15 basal cell carcinomas, and 30 seborrheic keratoses) were sampled consecutively and were examined using proprietary CLSM equipment. Stored images were rated by 4 independent observers. RESULTS Differentiation between melanoma and all other lesions based solely on CLSM examination was achieved with a positive predictive value of 94.22%. Malignant lesions (melanoma and basal cell carcinoma) as a group were diagnosed with a positive predictive value of 96.34%. Assessment of distinct CLSM features showed a strong interobserver correlation (κ >0.80 for 11 of 13 criteria). Classification and regression tree analysis yielded a 3-step algorithm based on only 3 criteria, facilitating a correct classification in 96.30% of melanomas, 98.89% of benign nevi, and 100% of basal cell carcinomas and seborrheic keratoses. CONCLUSIONS In vivo CLSM examination appeared to be a promising method for the noninvasive assessment of melanoma and nonmelanoma skin tumors. Cancer 2006. © 2006 American Cancer Society.

Plasmapheresis reverses all side-effects of a cisplatin overdose – a case report and treatment recommendation

Abstract: Cisplatin is widely used as an antineoplastic agent since it is effective against a broad spectrum of different tumours. Nevertheless, it has several potential side effects affecting different organ systems and an overdose may lead to life-threatening complications and even death. We report on a 46-year old woman with non-small cell lung cancer who accidentally received 225 mg/m2 of cisplatin, which was threefold the dose as scheduled, within a 3-day period. Two days later, the patient presented with hearing loss, severe nausea and vomiting, acute renal failure as well as elevated liver enzymes. In addition, she developed a severe myelodepression. After plasmapheresis on two consecutive days and vigorous supportive treatment, the toxicity-related symptoms improved and the patient recovered without any sequelae. To date, no general accepted guidelines for the treatment of cisplatin overdoses are available. Along with the experience from other published cases, our report shows that plasmapheresis is capable of lowering cisplatin plasma and serum levels efficiently. Therefore, plasma exchange performed as soon as possible can ameliorate all side effects of a cisplatin overdose and be a potential tool for clinicians for treatment. However, additional intensive supportive treatment-modalities are necessary to control all occurring side effects.

Free Fatty Acids Are Independently Associated with All-Cause and Cardiovascular Mortality in Subjects with Coronary Artery Disease

Abstract: 0.002) and 1.83 (P 0.001), respectively. In persons with angiographic coronary artery disease (CAD), stable CAD, and unstable CAD, the predictive value of FFAs was similar to that in the entire cohort, but the association did not attain statistical significance in persons without CAD analyzed separately. FFA levels were not related to the presence of angiographic CAD but were elevated in subjects with unstable CAD, compared with probands with stable CAD. Furthermore, FFAs increased with the severity of heart failure and were positively correlated with N-terminal pro-B-type natriuretic peptide (P 0.001). Conclusions: FFA levels independently predict all-cause and cardiovascular mortality in subjects with angiographic CAD. A possible diagnostic use of FFAs warrants further studies, but our results may underline the importance of therapeutic approaches to influence FFA metabolism. (J Clin Endocrinol Metab 91: 2542–2547, 2006)

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus

Abstract: Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.

Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells

Abstract: Covalent modifications of histone proteins, in particular deacetylation of lysine residues, are important for the regulation of gene transcription both in normal and malignant cells. These processes are controlled by histone acetyltransferases and histone deacetylases (HDAC) and have up to now not been described in solid mesenchymal tumors. The present study shows differences in the HDAC1 and HDAC2 expression in endometrial stromal sarcomas (ESS) and a cognate cell line (ESS-1) compared with nonneoplastic endometrial stroma. We show for the first time that HDAC2 expression is consistently increased in ESS. In contrast, HDAC1 expression is generally lower than HDAC2 both in nonneoplastic stroma and in ESS, suggesting that these two proteins, although closely related, are regulated in different ways. In vitro experiments with an ESS cell line showed that valproate, an inhibitor of the class I HDACs, led to significant HDAC2 decrease and to cell differentiation. HDAC2 inhibition in ESS-1 cells caused significant changes in the cell cycle by inhibiting G1-S transition and influencing expression of p21WAF1 and cyclin D1. Moreover, in ESS-1 cells, increased expression of the p21WAF1 was associated with reduction of HDAC2 expression after transfection with small interfering RNA directed against HDAC2. Our results suggest that HDAC2 might be considered as potential drug target in the therapy of ESS and that HDAC inhibitors should be further evaluated in clinical trials in ESS.

Assessment of Bone Resorption After Secondary Alveolar Bone Grafting Using Three-Dimensional Computed Tomography: A Three-Year Study

Abstract: Objective: Secondary bone grafting plays an important role in the dental rehabilitation of patients with clefts of the lip, alveolus, and palate. A major complication of this surgical technique is resorption of the grafted bone transplant. Conventional two-dimensional radiographs are often inconclusive and do not demonstrate the true deficit. The main objective of this study was to evaluate the amount and exact location of bone loss on the basis of three-dimensional models over a period of 3 years. Design: Twenty-four patients with unilateral cleft palate were included in this prospective study. Axial computed tomography scans of all patients were taken immediately preoperatively, and 1, 2, and 3 years postoperatively. Volumetric analysis was performed on three-dimensional models of the cleft defects and the bone bridges using three-dimensional computed tomography. Interventions: All patients were treated by secondary alveolar bone grafting prior to eruption of the permanent canine. Results: Exte...

Age-related prevalence of dermoscopy patterns in acquired melanocytic naevi.

Abstract: Background Based on the dermoscopic classification of acquired melanocytic naevi, six different dermoscopic types can be distinguished by morphology (globular, globular-reticular, globular-homogeneous, reticular, reticular-homogeneous, homogeneous) and by pigment distribution (uniform, central hyperpigmentation, central hypopigmentation, peripheral hyperpigmentation, peripheral hypopigmentation, multifocal hyper/hypopigmentation). It has been suggested that most individuals harbour one predominant dermoscopic type among their naevi.

Permeability of injured and intact peripheral nerves and dorsal root ganglia.

Abstract: Background:Nerve injury that produces behavioral changes of allodynia and hyperalgesia in animals is associated with electrophysiologic changes in dorsal root ganglion (DRG) cells. The introduction of drugs into the DRG or the peripheral nerve that alter calcium, sodium, or potassium channel activit

Effect of extracorporeal liver support by MARS and Prometheus on serum cytokines in acute-on-chronic liver failure

Abstract: Cytokines are believed to play an important role in acute-on-chronic liver failure (ACLF). Extracorporeal liver support systems may exert beneficial effects in ACLF via removal of cytokines. At present, two systems are commercially available, the Molecular Adsorbent Recirculating System (MARS™) and Fractionated Plasma Separation, Adsorption and Dialysis (Prometheus™). The aim of this study was to compare the effects of MARS and Prometheus treatments on serum cytokine levels and their clearances. Eight patients with ACLF underwent alternating treatments with either MARS or Prometheus in a randomized cross-over design. Thirty-four treatments (17 MARS, 17 Prometheus) were available for analysis. Serum cytokines were measured before and after each treatment, and cytokine clearance was calculated from paired arterial and venous samples and effective plasma flow one hour after the start of treatment. Baseline serum levels of interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-α), and soluble TNF-α receptor 1 were significantly elevated in patients with ACLF. Measurable plasma clearances were detected for all cytokines tested, but no significant changes in serum levels of any cytokine were found after treatments with MARS or Prometheus. In MARS treatments, IL-10 was cleared from plasma more efficiently than IL-6. Clearance of IL-10 was higher in Prometheus than in MARS treatments. Cytokines are cleared from plasma by both MARS and Prometheus, but neither system is able to change serum cytokine levels. This discrepancy is probably due to a high rate of cytokine production in patients with ACLF.

A randomized multi-center phase II trial of the angiogenesis inhibitor Cilengitide (EMD 121974) and gemcitabine compared with gemcitabine alone in advanced unresectable pancreatic cancer

Abstract: Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer. A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m2 twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m2 for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients. Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa. There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent.

A randomized, double-blind, placebo-controlled trial of photopheresis in systemic sclerosis

Abstract: Background Systemic sclerosis is a multisystemic connective tissue disease with marked involvement of the skin and joints for which few effective evidence based therapies are available. To further investigate the efficacy of extracorporeal photochemotherapy on early aggresive cutaneous disease, a randomized, double-blind, placebo-controlled trial was performed. Objective Our aim was to evaluate the efficacy of photopheresis in the treatment of patients with systemic sclerosis (scleroderma). Methods This randomized, double-blind, placebo-controlled clinical trial was conducted at 16 investigational sites in the United States, Canada, and Europe. Sixty-four patients with typical clinical and histologic findings of scleroderma, of less than 2 years' duration, were studied. Patients did not receive any other concomitant treatment for scleroderma. Patients were randomized to receive either active or sham photopheresis treatment on two consecutive days monthly for 12 months. Severity of skin (skin scores assessed in 22 body regions) and joint involvement (60 joints examined for contractures) were assessed on a monthly basis. Results A statistically significant improvement in skin scores as compared with baseline was observed at 6 months (P = .0024) and 12 months (P = .008) among those who received active photopheresis, but not among those who received sham photopheresis. Comparison of skin scores between the two study arms did not achieve statistical significance because of the small sample size of the study arms. Joint involvement was also significantly improved after 6 months (P = .002) and 12 months (P = .001) of active photopheresis when compared with baseline. Limitations The study lacks sufficient statistical power to reveal a significant difference in skin and joint manifestations between the active and sham photopheresis arms. Conclusion Photopheresis induced significant improvement of skin and joint involvement in patients with scleroderma of recent onset; however, any effect when compared with sham treatment and a possible placebo effect may be modest.

The functional characterization of normal and neoplastic human enterochromaffin cells.

Abstract: Context: Neuroendocrine regulation of small intestinal (SI) function is poorly understood because pure neuroendocrine cells are unavailable, whereas the biological basis of SI carcinoid tumors is unknown because neoplastic human enterochromaffin (EC) cells are unavailable. Objective: The objective of this study was to define the secretory regulation and transcriptome of naive and neoplastic SI neuroendocrine cells. Design: EC cells from human ilea were isolated and purified, and a malignant EC cell carcinoid cell line (KRJ-I) was characterized. Methods: Human ilea from right hemicolectomies were pronase/collagenase digested and Nycodenz gradient centrifuged, and EC cells were fluorescence-activated cell sorting (FACS) sorted after acridine orange labeling. Enrichment was defined by immunostaining, gene expression, serotonin (5-HT) content, and real-time RT-PCR. Naive FACS-sorted EC and KRJ-I cells were cultured, and 5-HT secretion was measured after stimulation with forskolin, isoproterenol, acetylcholine...

Health-related quality of life of pediatric patients receiving allogeneic stem cell or bone marrow transplantation: results of a longitudinal, multi-center study

Abstract: The results of a 5-year longitudinal prospective study about the health-related quality of life (HRQL) of pediatric patients receiving allogeneic bone marrow or stem cell transplantation (BMT) are described. The patients' HRQL was assessed twice before, and five times after BMT, the end point being 1 year after BMT. For the measurement of HRQL, standardized questionnaires were completed by patients, parents and physicians. The final sample consisted of 68 patients aged 4-18 years, of which 19 were lost in the course of the study owing to relapse, transplant rejection and/or death. The worst HRQL was seen shortly after transplant and HRQL thereafter improved steadily, although the improvement was not always linear and not all patients drew benefit from this average positive evolution. Compromised emotional functioning, a high level of worry and reduced communication during the acute phase of treatment had a negative impact on HRQL 1 year after BMT. Nausea and pain during the acute phase of treatment did not have an effect on later HRQL. The interobserver agreement of HRQL reports between parents and their children was moderate to good, and generally better than child-physician and parent-physician agreement.

Corpus callosum atrophy is associated with mental slowing and executive deficits in subjects with age-related white matter hyperintensities. The LADIS study

Abstract: Background: Previous research has indicated that corpus callosum atrophy is associated with global cognitive decline in neurodegenerative diseases, but few studies have investigated specific cognitive functions. Objective: To investigate the role of regional corpus callosum atrophy in mental speed, attention and executive functions in subjects with age-related white matter hyperintensities (WMH). Methods: In the Leukoaraiosis and Disability Study, 567 subjects with age-related WMH were examined with a detailed neuropsychological assessment and quantitative magnetic resonance imaging. The relationships of the total corpus callosum area and its subregions with cognitive performance were analysed using multiple linear regression, controlling for volume of WMH and other confounding factors. Results: Atrophy of the total corpus callosum area was associated with poor performance in tests assessing speed of mental processing—namely, trail making A and Stroop test parts I and II. Anterior, but not posterior, corpus callosum atrophy was associated with deficits of attention and executive functions as reflected by the symbol digit modalities and digit cancellation tests, as well as by the subtraction scores in the trail making and Stroop tests. Furthermore, semantic verbal fluency was related to the total corpus callosum area and the isthmus subregion. Conclusions: Corpus callosum atrophy seems to contribute to cognitive decline independently of age, education, coexisting WMH and stroke. Anterior corpus callosum atrophy is related to the frontal-lobe-mediated executive functions and attention, whereas overall corpus callosum atrophy is associated with the slowing of processing speed.

Mobile phone-based surveillance of cardiac patients at home

Abstract: We tested the reliability, acceptability and feasibility of a home-monitoring system for cardiac patients. Each participant was equipped with a mobile phone, an automatic blood pressure device and a digital weight scale. In total, 20 patients (14 patients with chronic heart failure, six patients with hypertension; mean age 50 years, standard deviation [SD] 14) were monitored for 90 days each. They were asked to measure their blood pressure, pulse and body weight every day, and to transfer the data together with the dosage of medication to the telemonitoring server using wireless Internet technology in the mobile phone. The physician in charge received email alerts when reported data fell outside pre-defined limits. The patients' compliance with the system was high. During a cumulative monitoring period of 1735 days, there were 2040 data transfer sessions, a mean of 102 per patient (SD 43). The mean percentage of successful data transfers was 83% (SD 22). The stability of the telemonitoring system was 98%,...

p53 immunostaining in lichen sclerosus is related to ischaemic stress and is not a marker of differentiated vulvar intraepithelial neoplasia (d-VIN).

Abstract: Aim : To analyse p53 immunoreactivity in 207 biopsy specimens of lichen sclerosus (LS) and ‘differentiated vulvar intraepithelial neoplasia’ (d-VIN), a postulated precursor lesion for LS-associated vulvar squamous cell carcinoma (SCC), which is characterized by atypical basal keratinocyte proliferations with p53+ basal/suprabasal keratinocyte nuclei. Methods and results : Forty early, 78 classic, 30 hypertrophic vulvar LS, 26 paediatric vulvar and penile LS, 33 vulvar LS-associated SCC and 30 vulvar/penile control specimens were examined for p53 expression and the presence of d-VIN. Nuclear p53 staining was observed in 175/207 LS biopsy specimems. Eighty percent of early and 69% of paediatric LS showed discontinuous/continous p53 staining in basal keratinocytes. Classic LS showed no p53 staining in 17%, discontinuous basal keratinocyte staining in 20%, continuous basal keratinocyte staining in 58%, basal/suprabasal staining in 5%. Hypertrophic LS revealed basal keratinocyte staining in 32% and basal/suprabasal staining in 61%. p53 staining was associated with sclerosis of blood vessels and dermis, lymphoid infiltrates, vasculitis and hypertrophic LS. d-VIN was seen in 2% of LS alone and in 24% of LS-associated SCC. Conclusion : d-VIN in LS is rare, while p53 staining is common and best explained as an ischaemic stress response due to poor oxygenation, vasculitis and inflammation rather than as a marker of a precancerous lesion in LS.

Efferent-like roles of afferent neurons in the gut: Blood flow regulation and tissue protection.

Abstract: The maintenance of gastrointestinal mucosal integrity depends on the rapid alarm of protective mechanisms in the face of pending injury. To this end, the gastric mucosa is innervated by intrinsic sensory neurons and two populations of extrinsic sensory neurons: vagal and spinal afferents. Extrinsic afferent neurons constitute an emergency system that is called into operation when the gastrointestinal mucosa is endangered by noxious chemicals. The function of these chemoceptive afferents can selectively be manipulated and explored with the use of capsaicin which acts via a cation channel termed TRPV1. Many of the homeostatic actions of spinal afferents are brought about by transmitter release from their peripheral endings. When stimulated by noxious chemicals, these afferents enhance gastrointestinal blood flow and activate hyperaemia-dependent and hyperaemia-independent mechanisms of protection and repair. In the rodent foregut these local regulatory roles of sensory neurons are mediated by calcitonin gene-related peptide and nitric oxide. The pathophysiological potential of the neural emergency system is best portrayed by the gastric hyperaemic response to acid back-diffusion, which is governed by spinal afferent nerve fibres. This mechanism limits damage to the surface of the mucosa and creates favourable conditions for rapid restitution and healing of the wounded mucosa. Other extrinsic afferent neurons, particularly in the vagus nerve, subserve gastrointestinal homeostasis by signalling noxious events in the foregut to the central nervous system and eliciting autonomic, emotional-affective and neuroendocrine reactions. Under conditions of inflammation and injury, chemoceptive afferents are sensitized to peripheral stimuli and in this functional state contribute to the hyperalgesia associated with functional dyspepsia and irritable bowel syndrome. Thus, if GI pain is to be treated by sensory neuron-directed drugs it needs to be considered that these drugs do not inhibit nociception at the expense of GI mucosal vulnerability.