Outcome, quality of life and cognitive function of patients with brain metastases from non-small cell lung cancer treated with whole brain radiotherapy combined with gefitinib or temozolomide. A randomised phase II trial of the Swiss Group for Clinical Cancer Research (SAKK 70/03)

Patients with brain metastases (BM) rarely survive longer than 6months and are commonly excluded from clinical trials. We explored two combined modality regimens with novel agents with single agent activity and radiosensitizing properties.

Multiple drug hypersensitivity: normal Treg cell function but enhanced in vivo activation of drug-specific T cells

Up to 10% of patients with severe immune-mediated drug hypersensitivity reactions have tendencies to develop multiple drug hypersensitivities (MDH). The reason why certain individuals develop MDH and the underlying pathomechanism are unclear. We investigated different T cell subpopulations in MDH patients and compared them with patients allergic to a single drug and with healthy controls (HC).

Structure and function of the glucose PTS transporter from Escherichia coli

The glucose transporter IICB of the Escherichia coli phosphotransferase system (PTS) consists of a polytopic membrane domain (IIC) responsible for substrate transport and a hydrophilic C-terminal domain (IIB) responsible for substrate phosphorylation. We have overexpressed and purified a triple mutant of IIC (mut-IIC), which had recently been shown to be suitable for crystallization purposes. Mut-IIC was homodimeric as determined by blue native-PAGE and gel-filtration, and had an eyeglasses-like structure as shown by negative-stain transmission electron microscopy (TEM) and single particle analysis. Glucose binding and transport by mut-IIC, mut-IICB and wildtype-IICB were compared with scintillation proximity and in vivo transport assays. Binding was reduced and transport was impaired by the triple mutation. The scintillation proximity assay allowed determination of substrate binding, affinity and specificity of wildtype-IICB by a direct method. 2D crystallization of mut-IIC yielded highly-ordered tubular crystals and made possible the calculation of a projection structure at 12Å resolution by negative-stain TEM. Immunogold labeling TEM revealed the sidedness of the tubular crystals, and high-resolution atomic force microscopy the surface structure of mut-IIC. This work presents the structure of a glucose PTS transporter at the highest resolution achieved so far and sets the basis for future structural studies.

Placebo effect characteristics observed in a single, international, longitudinal study in Huntington's disease

BACKGROUND Classically, clinical trials are based on the placebo-control design. Our aim was to analyze the placebo effect in Huntington's disease. METHODS Placebo data were obtained from an international, longitudinal, placebo-controlled trial for Huntington's disease (European Huntington's Disease Initiative Study Group). One-hundred and eighty patients were evaluated using the Unified Huntington Disease Rating Scale over 36 months. A placebo effect was defined as an improvement of at least 50% over baseline scores in the Unified Huntington Disease Rating Scale, and clinically relevant when at least 10% of the population met it. RESULTS Only behavior showed a significant placebo effect, and the proportion of the patients with placebo effect ranged from 16% (first visit) to 41% (last visit). Nondepressed patients with better functional status were most likely to be placebo-responders over time. CONCLUSIONS In Huntington's disease, behavior seems to be more vulnerable to placebo than overall motor function, cognition, and function

Consensus statement for inert gas washout measurement using multiple- and single- breath tests

Inert gas washout tests, performed using the single- or multiple-breath washout technique, were first described over 60 years ago. As measures of ventilation distribution inhomogeneity, they offer complementary information to standard lung function tests, such as spirometry, as well as improved feasibility across wider age ranges and improved sensitivity in the detection of early lung damage. These benefits have led to a resurgence of interest in these techniques from manufacturers, clinicians and researchers, yet detailed guidelines for washout equipment specifications, test performance and analysis are lacking. This manuscript provides recommendations about these aspects, applicable to both the paediatric and adult testing environment, whilst outlining the important principles that are essential for the reader to understand. These recommendations are evidence based, where possible, but in many places represent expert opinion from a working group with a large collective experience in the techniques discussed. Finally, the important issues that remain unanswered are highlighted. By addressing these important issues and directing future research, the hope is to facilitate the incorporation of these promising tests into routine clinical practice.

Severity of mucosal inflammation as a predictor for alterations of visceral sensory function in a rat model

Transient inflammation is known to alter visceral sensory function and frequently precede the onset of symptoms in a subgroup of patients with irritable bowel syndrome (IBS). Duration and severity of the initial inflammatory stimulus appear to be risk factors for the manifestation of symptoms. Therefore, we aimed to characterize dose-dependent effects of trinitrobenzenesulfonic acid (TNBS)/ethanol on: (1) colonic mucosa, (2) cytokine release and (3) visceral sensory function in a rat model. Acute inflammation was induced in male Lewis rats by single administration of various doses of TNBS/ethanol (total of 0.8, 0.4 or 0.2 ml) in test animals or saline in controls. Assessment of visceromotor response (VMR) to colorectal distensions, histological evaluation of severity of inflammation, and measurement of pro-inflammatory cytokine levels (IL-2, IL-6) using enzyme-linked immunosorbent assay (ELISA) were performed 2h and 3, 14, 28, 31 and 42 days after induction. Increased serum IL-2 and IL-6 levels were evident prior to mucosal lesions 2h after induction of colitis and persist up to 14 days (p<0.05 vs. saline), although no histological signs of inflammation were detected at 14 days. In the acute phase, VMR was only significantly increased after 0.8 ml and 0.4 ml TNBS/ethanol (p<0.05 vs. saline). After 28 days, distension-evoked responses were persistently elevated (p<0.05 vs. saline) in 0.8 and 0.4 ml TNBS/ethanol-treated rats. In 0.2 ml TNBS/ethanol group, VMR was only enhanced after repeated visceral stimulation. Visceral hyperalgesia occurs after a transient colitis. However, even a mild acute but asymptomatic colitis can induce long-lasting visceral hyperalgesia in the presence of additional stimuli.

A systematic review of the 5-year survival and complication rates of implant-supported single crowns

OBJECTIVES: The objective of this systematic review was to assess the 5-year survival of implant-supported single crowns (SCs) and to describe the incidence of biological and technical complications. METHODS: An electronic MEDLINE search complemented by manual searching was conducted to identify prospective and retrospective cohort studies on SCs with a mean follow-up time of at least 5 years. Failure and complication rates were analyzed using random-effects Poisson's regression models to obtain summary estimates of 5-year proportions. RESULTS: Twenty-six studies from an initial yield of 3601 titles were finally selected and data were extracted. In a meta-analysis of these studies, survival of implants supporting SCs was 96.8% [95% confidence interval (CI): 95.9-97.6%] after 5 years. The survival rate of SCs supported by implants was 94.5% (95% CI: 92.5-95.9%) after 5 years of function. The survival rate of metal-ceramic crowns, 95.4% (95% CI: 93.6-96.7%), was significantly (P=0.005) higher than the survival rate, 91.2% (95% CI: 86.8-94.2%), of all-ceramic crowns. Peri-implantitis and soft tissue complications occurred adjacent to 9.7% of the SCs and 6.3% of the implants had bone loss exceeding 2 mm over the 5-year observation period. The cumulative incidence of implant fractures after 5 years was 0.14%. After 5 years, the cumulative incidence of screw or abutment loosening was 12.7% and 0.35% for screw or abutment fracture. For supra-structure-related complications, the cumulative incidence of ceramic or veneer fractures was 4.5%. CONCLUSION: It can be concluded that after an observation period of 5 years, high survival rates for implants and implant-supported SCs can be expected. However, biological and particularly technical complications are frequent.

Early implant placement with simultaneous guided bone regeneration following single-tooth extraction in the esthetic zone: a cross-sectional, retrospective study in 45 subjects with a 2- to 4-year follow-up

BACKGROUND: The concept of early implant placement is a treatment option in postextraction sites of single teeth in the anterior maxilla. Implant placement is performed after a soft tissue healing period of 4 to 8 weeks. Implant placement in a correct three-dimensional position is combined with a simultaneous guided bone regeneration procedure to rebuild esthetic facial hard and soft tissue contours. METHODS: In this retrospective, cross-sectional study, 45 patients with an implant-borne single crown in function for 2 to 4 years were recalled for examination. Clinical and radiologic parameters, routinely used in implant studies, were assessed. RESULTS: All 45 implants were clinically successful according to strict success criteria. The implants demonstrated ankylotic stability without signs of a peri-implant infection. The peri-implant soft tissues were clinically healthy as indicated by low mean plaque (0.42) and sulcus bleeding index (0.51) values. None of the implants revealed a mucosal recession on the facial aspect as confirmed by a clearly submucosal position of all implant shoulders. The mean distance from the mucosal margin to the implant shoulder was -1.93 mm on the facial aspect. The periapical radiographs showed stable peri-implant bone levels, with a mean distance between the implant shoulder and the first bone-implant contact of 2.18 mm. CONCLUSIONS: This retrospective study demonstrated successful treatment outcomes for all 45 implants examined. The mid-term follow-up of 2 to 4 years also showed that the risk for mucosal recession was low with this treatment concept. Prospective clinical studies are required to confirm these encouraging results.

Correction of erosion after suburethral sling insertion for stress incontinence: results and related sexual function

BACKGROUND: Suburethral slings are commonly used for the surgical treatment of female stress incontinence; occasionally they can cause erosion and dyspareunia. OBJECTIVES: The primary aim of this study is to determine the outcome after reclosure of the vaginal epithelium for suburethral sling erosion. Sexual function was assessed before and after intervention using the Female Sexual Function Index (FSFI) questionnaire. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective case-controlled study in which, between December 2005 and December 2007, we included patients who were referred to the Department of Urogynaecology because of vaginal erosion after suburethral sling insertion for urinary stress incontinence. For evaluation of sexual function, all patients filled in an FSFI questionnaire before intervention and at follow-up. All patients underwent gynaecological examination including colposcopy, and the site and size of the defect were noted. INTERVENTION: The edge of the vaginal epithelium was trimmed, mobilized, and closed with interrupted vertical Vicryl mattress sutures in a single layer. MEASUREMENTS: FSFI questionnaire and clinical findings. RESULTS AND LIMITATIONS: Twenty-one patients were included in the study. Eighteen patients with larger defects were operated on, and three defects healed after topical application of estrogen cream. In 16 patients, the defect had healed at follow-up; two patients with persisting defects were brought back to surgery and the procedure was repeated, paying particular attention to tension-free adaptation of vaginal tissue. In one patient, partial sling removal was performed after the second failed intervention. The domains of desire (p<0.0001), arousal (p<0.0003), lubrication (p<0.0001), satisfaction (p<0.0130), and pain (p<0.0001) improved significantly. Orgasm remained unchanged (p=0.4130; all two-tailed t-test). CONCLUSION: Suburethral erosion can be treated effectively by resuturing. Sexual function is improved in regard to desire, arousal, lubrication, satisfaction, and pain, but not orgasm. In septic patients and patients with a history of radiation, grossly infected tissue, or severe pain, excision of the mesh needs to be considered.

Failures and complications in patients with birth defects restored with fixed dental prostheses and single crowns on teeth and/or implants

OBJECTIVES: To assess retrospectively, over at least 5 years, the incidences of technical and biological complications and failures in young adult patients with birth defects affecting the formation of teeth. MATERIAL AND METHODS: All insurance cases with a birth defect that had crowns and fixed dental prostheses (FDPs) inserted more than 5 years ago were contacted and asked to participate in a reexamination. RESULTS: The median age of the patients was 19.3 years (range 16.6-24.7 years) when prosthetic treatment was initiated. Over the median observation period of 15.7 years (range 7.4-24.9 years) and considering the treatment needs at the reexamination, 19 out of 33 patients (58%) with reconstructions on teeth remained free from all failures or complications. From the patients with FDPs and single unit crowns (SCs) on implants followed over a median observation period of 8 years (range 4.6-15.3 years), eight out of 17% or 47% needed a retreatment or repair at some point due to a failure or a complication. From the three groups of patients, the cases with amelogenesis/dentinogenesis imperfecta demonstrated the highest failure and complication rates. In the cases with cleft lip, alveolus and palate (CLAP) or hypodontia/oligodontia, 71% of the SCs and 73% of the FDPs on teeth (FDP T) remained complication free over a median observation period of about 16 years. Sixty-two percent of the SCs and 64% of the FDPs on implants remained complication free over 8 years. Complications occurred earlier with implant-supported reconstructions. CONCLUSIONS: Because healthy, pristine teeth can be left unprepared, implant-supported SCs and FDPs are the treatment choice in young adults with birth defects resulting in tooth agenesis and in whom the edentulous spaces cannot be closed by means of orthodontic therapy. However, the trend for earlier and more frequent complications with implant-supported reconstructions in young adults, expecting many years of function with the reconstructions, has to be weighed against the benefits of keeping teeth unprepared. In cases with CLAP in which anatomical conditions render implant placement difficult and in which teeth adjacent to the cleft require esthetic corrections, the conventional FDP T still remains the treatment of choice.

Prognostic clinical and radiological parameters for immediate facial nerve function following vestibular schwannoma surgery

OBJECTIVE: The paper aims to define the parameters available before surgery which could predict immediate facial nerve function after excision of a vestibular schwannoma (VS). METHODS: Ninety-nine patients with VS operated consecutively by a single surgeon using an identical surgical technique have been evaluated retrospectively. Data were collected regarding patients' sex, age at onset of symptoms and at surgery, initial symptoms, neurological status at presentation, early post-operative neurological status and complications. The main radiological parameters included in the study were tumour extension pattern, diameters, shape, and volume, as well as extent of bony changes of the internal auditory canal. RESULTS: As the tumour stage and volume increase, facial nerve function is worse after surgery (p < 0.001 and p < 0.05, respectively). Concomitantly, larger extra-meatal tumour diameters in three dimensions (sagittal, coronal and axial) led to worse function (p < 0.01). Anterior and/or caudal tumour extension (p = 0.001 and p = 0.004, respectively) had more significant correlation than posterior and/or cranial extension (p = 0.022 and p = 0.353, respectively). Polycyclic VS had the worst prognosis, followed by the tumours with oval shape. The extent of intra-meatal tumour growth does not correlate with immediate facial nerve outcome. The different angles, lengths and diameters of the internal auditory channel showed no significant correlation with facial nerve outcome. Patients with headache as an initial symptom and those with gait instability and/or pre-operative poor facial nerve function had significantly worse immediate facial nerve outcome. CONCLUSION: Our data suggests that the analysis of the radiological and neurological patient data prior to surgery could give reliable clues regarding the immediate post-operative facial nerve function.

Effect of urinary tract infection on reservoir function in patients with ileal bladder substitute

PURPOSE: We determined the functional consequences of urinary tract infection in patients with an ileal bladder substitute in terms of urinary continence, post-void residual and urinary retention. MATERIALS AND METHODS: A total of 48 patients with culture documented urinary tract infection (single organism, 10(5) or greater cfu) were retrospectively evaluated before, during and after the infection for changes in continence, post-void residual and urinary retention as well as for resolution of symptomatology after appropriate antibiotic therapy. RESULTS: Of the 48 patients 40 had a single infection while the remaining 8 had multiple urinary tract infection episodes. During daytime 27 of the 44 patients with previously good daytime continence experienced deterioration in their baseline voiding status while infected. Of the 40 patients who were previously continent at night 20 had incontinence while infected. There were 15 patients with documented post-void residual and urinary retention developed in 4 during the urinary tract infection. All patients returned to baseline continence status and reservoir function after appropriate antibiotic treatment based on objective and subjective assessments. CONCLUSIONS: Urinary tract infection may cause urinary incontinence in patients with ileal bladder substitutes. Therefore, when there are complaints of de novo urinary incontinence, a finding of post-void residual or an acute presentation of urinary retention, a urinary tract infection should be excluded. When the urinary tract infection is appropriately treated urinary continence and reservoir function return to their baseline status.

The role of common single-nucleotide polymorphisms on exon 9 and exon 12 skipping in nonmutated CFTR alleles

Classic cystic fibrosis (CF) is caused by two loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, whereas patients with nonclassic CF have at least one copy of a mutant gene that retains partial function of the CFTR protein. In addition, there are several other phenotypes associated with CFTR gene mutations, such as idiopathic chronic pancreatitis. In CFTR-associated disorders and in nonclassic CF, often only one CFTR mutation or no CFTR mutations can be detected. In this study, we screened 23 patients with CFTR-associated disorders for CFTR mutations by complete gene testing and quantitative transcript analysis. Mutations were found in 10 patients. In cells from respiratory epithelium, we detected aberrant splicing of CFTR mRNA in all investigated individuals. We observed a highly significant association between the presence of coding single-nucleotide polymorphisms (coding SNPs, or cSNPs) and increased skipping of exon 9 and 12. This association was found both in patients and in normal individuals carrying the same cSNPs. The cSNPs c.1540A>G, c.2694T>G, and c.4521G>A may have affected pre-mRNA splicing by changing regulatory sequence motifs of exonic splice enhancers, leading to lower amounts of normal transcripts. The analysis of CFTR exons indicated that less frequent and weak exonic splicing enhancer (ESE) motifs make exon 12 vulnerable to skipping. The number of splice variants in individuals with cSNPs was similar to previously reported values for the T5 allele, suggesting that cSNPs may enhance susceptibility to CFTR related diseases. In addition, cSNPs may be responsible for variation in the phenotypic expression of CFTR mutations. Quantitative approaches rather than conventional genomic analysis are required to interpret the role of cSNPs.

Probing the function of ionotropic and G protein-coupled receptors in surface-confined membranes

This article reports on recent electrical and optical techniques for investigating cellular signaling reactions in artificial and native membranes immobilized on solid supports. The first part describes the formation of planar artificial lipid bilayers on gold electrodes, which reveal giga-ohm electrical resistance and the insertion and characterization of ionotropic receptors therein. These membranes are suited to record a few or even single ion channels by impedance spectroscopy. Such tethered membranes on planar arrays of microelectrodes offer mechanically robust, long-lasting measuring devices to probe the influence of different chemistries on biologically important ionotropic receptors and therefore will have a future impact to probe the function of channel proteins in basic science and in biosensor applications. In a second part, we present complementary approaches to form inside-out native membrane sheets that are immobilized on micrometer-sized beads or across submicrometer-sized holes machined in a planar support. Because the native membrane sheets are plasma membranes detached from live cells, these approaches offer a unique possibility to investigate cellular signaling processes, such as those mediated by ionotropic or G protein-coupled receptors, with original composition of lipids and proteins.