Effects of bone marrow or mesenchymal stem cell transplantation on oral mucositis (mouse) induced by fractionated irradiation.

BACKGROUND AND PURPOSE: Oral mucositis is a severe and dose limiting early side effect of radiotherapy for head-and-neck tumors. This study was initiated to determine the effect of bone marrow- and mesenchymal stem cell transplantation on oral mucositis (mouse tongue model) induced by fractionated irradiation. MATERIAL AND METHODS: Daily fractionated irradiation (5 × 3 Gy/week) was given over 1 (days 0-4) or 3 weeks (days 0-4, 7-11, 14-18). Each protocol was terminated (day 7 or 21) by graded test doses (5 dose groups, 10 animals each) in order to generate complete dose-effect curves. The incidence of mucosal ulceration, corresponding to confluent mucositis grade 3 (RTOG/EORTC), was analyzed as the primary, clinically relevant endpoint. Bone marrow or mesenchymal stem cells were transplanted intravenously at various time points within these fractionation protocols. RESULTS: Transplantation of 6 × 10(6), but not of 3 × 10(6) bone marrow stem cells on day - 1, + 4, + 8, + 11 or + 15 significantly increased the ED50 values (dose, at which an ulcer is expected in 50 % of the mice); transplantation on day + 2, in contrast, was ineffective. Mesenchymal stem cell transplantation on day - 1, 2 or + 8 significantly, and on day + 4 marginally increased the ED50 values. CONCLUSION: Transplantation of bone marrow or mesenchymal stem cells has the potential to modulate radiation-induced oral mucositis during fractionated radiotherapy. The effect is dependent on the timing of the transplantation. The mechanisms require further investigation.

Mutation of ATF4 mediates resistance of neuronal cell lines against oxidative stress by inducing xCT expression.

Selecting neuronal cell lines for resistance against oxidative stress might recapitulate some adaptive processes in neurodegenerative diseases where oxidative stress is involved like Parkinson's disease. We recently reported that in hippocampal HT22 cells selected for resistance against oxidative glutamate toxicity, the cystine/glutamate antiporter system x(c)(-), which imports cystine for synthesis of the antioxidant glutathione, and its specific subunit, xCT, are upregulated. (Lewerenz et al., J Neurochem 98(3):916-25). Here, we show that in these glutamate-resistant HT22 cells upregulation of xCT mediates glutamate resistance, and xCT expression is induced by upregulation of the transcription factor ATF4. The mechanism of ATF4 upregulation consists of a 13 bp deletion in the upstream open reading frame (uORF2) overlapping the ATF4 open reading frame. The resulting uORF2-ATF4 fusion protein is efficiently translated even at a low phosphorylation levels of the translation initiation factor eIF2α, a condition under which ATF4 translation is normally suppressed. A similar ATF4 mutation associated with prominent upregulation of xCT expression was identified in PC12 cells selected for resistance against amyloid ß-peptide. Our data indicate that ATF4 has a central role in regulating xCT expression and resistance against oxidative stress. ATF4 mutations might have broader significance as upregulation of xCT is found in tumor cells and associated with anticancer drug resistance.

Efficacy of a targeted cognitive-behavioral treatment program for cannabis use disorders (CANDIS).

AIMS: To examine the efficacy, 3- and 6-month follow-up effects of a psychological treatment for older adolescents and adults with DSM-IV cannabis use disorders. The program was tailored to the needs of this patient population. EXPERIMENTAL PROCEDURES: A randomized controlled clinical trial of 122 patients aged 16 to 44 years with DSM-IV cannabis dependence as the main substance use diagnosis was conducted. Patients were randomly assigned to either Active Treatment (AT, n = 90) or a Delayed Treatment Control group (DTC, n = 32). Treatment consisted of 10 sessions of therapy, detailed in a strictly enforced manual. Assessments were conducted at baseline, during each therapy session, at post treatment and at follow-up assessments at 3 and 6 months. RESULTS: The treatment retention rate was 88%. Abstinence was achieved in 49% of AT patients and in 13% of those in DTC (p < 0.001; intend-to-treat (ITT) analysis). Further, AT patients improved significantly (p < = 0.001) in the frequency of cannabis use per week, addiction severity, number of disability days, and overall level of psychopathology. Program effects were maintained over a 3-month- (abstinence rate: 51%) and 6-month follow-up (45%) period. CONCLUSION: The treatment program is effective in obtaining abstinence as well as reducing cannabis use and improves the associated social and mental health burden.

Cannabis use patterns and their association with DSM-IV cannabis dependence and gender.

AIMS: To investigate the gender differences in the patterns of cannabis use (CU), namely frequency, times of day, social context and methods and in their association with DSM-IV cannabis dependence. METHODS: A sample of 3,904 students from German universities was recruited via an internet survey. Logistic regressions and associated areas under the ROC curve (AUC) were calculated among current cannabis users (at least once a month, n = 843). RESULTS: CU using a water pipe was more often reported by males (50 vs. 34.6%). Usual CU 'before going to sleep at night' was more often reported by females (47.3 vs. 35.7%). Most CU patterns showed a similar association with DSM-IV cannabis dependence in both genders. The association of CU 'with strangers' was stronger in females (AUC 0.68 vs. AUC 0.56). Slightly different multiple models were found (females AUC 0.86, males AUC 0.77). CONCLUSIONS: There are considerable gender differences in the CU patterns and, thus, in the way CU functions. In the association of CU patterns with cannabis dependence, the similarities are rather great. Examining the CU patterns might make a considerable contribution to the better detection of high-risk population segments for prevention and early intervention in both genders.

Entropic analysis of quantum phase transitions from uniform to spatially inhomogeneous phases.

We propose a new approach to study quantum phase transitions in low-dimensional fermionic or spin models that go from uniform to spatially inhomogeneous phases such as dimerized, trimerized, or incommensurate phases. It is based on studying the length dependence of the von Neumann entropy and its corresponding Fourier spectrum for finite segments in the ground state of finite chains. Peaks at a nonzero wave vector are indicators of oscillatory behavior in decaying correlation functions and also provide significant information about certain relevant features of the excitation spectrum; in particular, they can identify the wave vector of soft modes in critical models.

Strongly correlated fermions after a quantum quench.

Using the adaptive time-dependent density-matrix renormalization group method, we study the time evolution of strongly correlated spinless fermions on a one-dimensional lattice after a sudden change of the interaction strength. For certain parameter values, two different initial states (e.g., metallic and insulating) lead to observables which become indistinguishable after relaxation. We find that the resulting quasistationary state is nonthermal. This result holds for both integrable and nonintegrable variants of the system.

Creation and destruction of a spin gap in weakly coupled quarter-filled ladders.

We investigate weakly coupled quarter-filled ladders with model parameters relevant for NaV(2)O(5) using density-matrix renormalization group calculations on an extended Hubbard model coupled to the lattice. NaV(2)O(5) exhibits super-antiferroelectric charge order with a zigzag pattern on each ladder. We show that this order causes a spin dimerization along the ladder and is accompanied by a spin gap of the same magnitude as that observed experimentally. The spin gap is destroyed again at large charge order due to a restructuring of the spins. An analysis of an effective spin model predicts a recreation of the gap by interladder singlets when the charge order increases further.

Phase diagram of the two-channel kondo lattice model in one dimension.

Employing the density matrix renormalization group method and strong-coupling perturbation theory, we study the phase diagram of the SU(2)xSU(2) Kondo lattice model in one dimension. We show that, at quarter filling, the system can exist in two phases depending on the coupling strength. The weak-coupling phase is dominated by RKKY exchange correlations, while the strong-coupling phase is characterized by strong antiferromagnetic correlations of the channel degree of freedom. These two phases are separated by a quantum critical point. For conduction-band fillings of less than one-quarter, we find a paramagnetic metallic phase at weak coupling and a ferromagnetic phase at moderate to strong coupling.

Estimation of available energy of dietary fibres by indirect calorimetry in rats.

BACKGROUND: Knowledge of energetic availability of dietary fibres is important for human nutrition. But up to now results are often different and depend on the methods used. Estimation of metabolisable energy of dietary fibres (mainly by balance technique) is a time-consuming procedure and needs special technical effort. AIM OF THE STUDY: Validation of the experimental design for short-term studies by using indirect calorimetry with feeding below maintenance requirement to evaluate the energetic availability of dietary fibres and their influence on absorption velocity of carbohydrates (CHO). METHODS: Energy expenditure and CHO oxidation (including short-chain fatty acids as fermentation products) were estimated in Wistar rats over 23 h after being fed a basal diet for the first day (300 KJ/kg0.75, 20% protein, 3% fat, 77% CHO) followed by supplementation with either microcrystalline cellulose, the soluble rye fibre arabinoxylan, apple pectin, amylomaize starch (with 48% of resistant starch) or gelatinised wheat starch (200 KJ/kg0.75 each) as control for the following days. Energetic availability was determined by comparing the increase of CHO oxidation after addition of gelatinised wheat starch with that of the dietary fibres tested. RESULTS: In comparison to wheat starch (100%), the following energetic availability of the dietary fibres was found: microcrystalline cellulose 14%, arabinoxylan 33%, pectin 39%, amylomaize starch 62%. The time-course of CHO oxidation indicated that microcrystalline cellulose enhances, whereas the soluble rye fibre slows down the velocity of CHO absorption due to the different consistency of the intestinal contents modified by the kind and properties of the used dietary fibres. After intake of arabinoxylan or pectin, CHO oxidation remained at a higher level during the experimental period elucidating an increased activity of fermentation to short-chain fatty acids. CONCLUSIONS: Short-term experiments in rats using indirect calorimetry are a suitable method for comparative estimation of the energetic availability of dietary fibres. Results are partly in agreement with values estimated by long-term in vivo methods.

Modification of oral mucositis by keratinocyte growth factor: single radiation exposure.

PURPOSE: The aim was to quantify the effect of recombinant human keratinocyte growth factor (rhKGF) on acute oral mucositis induced by a single radiation dose, simulating accidental radiation exposure. MATERIAL AND METHODS: Tongue epithelium of the C3H/Neu mouse was irradiated with graded single doses of 25 kV X-rays to a 3 x 3 mm2 area in the centre of the lower tongue surface. Acute mucosal ulceration, as a clinically relevant reaction, was used as the quantal endpoint for dose response analyses by probit analysis. As a secondary endpoint the time-course, i.e. time to first diagnosis of ulcer (latent time) and individual ulcer duration, was analysed. KGF was applied before, after or in combination before and after radiation exposure. RESULTS: Administration of KGF in all protocols resulted in a significant reduction of the incidence of oral mucosal ulceration, as illustrated by an increase in iso-effective dose from 10.9 to 24.9 Gy; the corresponding dose-modification factors ranged between 1.7 and 2.3. The effect was most pronounced when KGF was applied after irradiation. In all protocols where KGF was given after irradiation, a significant shortening of the latent time to ulceration from 11 to 6-8 days was observed. CONCLUSIONS: The mechanisms underlying the amelioration of the oral mucosal response to single-dose irradiation remain unclear. However, KGF represents a promising approach for the effective management of acute radiation reactions in oral, gastrointestinal and cutaneous epithelia after radiation exposure.

Dielectric catastrophe at the Mott transition.

We study the Mott transition as a function of interaction strength in the half-filled Hubbard chain with next-nearest-neighbor hopping t' by calculating the response to an external electric field using the density matrix renormalization group. The electric susceptibility chi diverges when approaching the critical point from the insulating side. We show that the correlation length xi characterizing this transition is directly proportional to fluctuations of the polarization and that chi approximately xi2. The critical behavior shows that the transition is infinite order for all t', whether or not a spin gap is present, and that hyperscaling holds.

Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group.

OBJECTIVE: To determine the effect of orlistat, a new lipase inhibitor, on long-term weight loss, to determine the extent to which orlistat treatment minimizes weight regain in a second year of treatment, and to assess the effects of orlistat on obesity-related risk factors. RESEARCH METHODS AND PROCEDURES: This was a 2-year, multicenter, randomized, double-blind, placebo-controlled study. Obese patients (body mass index 28 to 43 kg/m2) were randomized to placebo or orlistat (60 or 120 mg) three times a day, combined with a hypocaloric diet during the first year and a weight maintenance diet in the second year of treatment to prevent weight regain. Changes in body weight, lipid profile, glycemic control, blood pressure, quality of life, safety, and tolerability were measured. RESULTS: Orlistat-treated patients lost significantly more weight (p<0.001) than placebo-treated patients after Year 1 (6.6%, 8.6%, and 9.7% for the placebo, and orlistat 60 mg and 120 mg groups, respectively). During the second year, orlistat therapy produced less weight regain than placebo (p = 0.005 for orlistat 60 mg; p<0.001 for orlistat 120 mg). Several obesity-related risk factors improved significantly more with orlistat treatment than with placebo. Orlistat was generally well tolerated and only 6% of orlistat-treated patients withdrew because of adverse events. Orlistat leads to predictable gastrointestinal effects related to its mode of action, which were generally mild, transient, and self-limiting and usually occurred early during treatment. DISCUSSION: Orlistat administered for 2 years promotes weight loss and minimizes weight regain. Additionally, orlistat therapy improves lipid profile, blood pressure, and quality of life.

Validation of a self-administered food-frequency questionnaire administered in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study: comparison of energy, protein, and macronutrient intakes estimated with the doubly labeled water, urinary nitrogen, and repeated 24-h dietary recall methods.

BACKGROUND: The validation of dietary assessment instruments is critical in the evaluation of diet as a chronic disease risk factor. OBJECTIVE: The objective was to assess the validity of a self-administered food-frequency questionnaire by comparison with dietary recall, urinary nitrogen excretion, and total energy expenditure data. DESIGN: Over a 1-y period, data from twelve 24-h dietary recalls, a food-frequency questionnaire, and four 24-h urine samples were obtained from 134 study participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) Study in Potsdam, Germany. In a substudy of 28 participants, total energy expenditure from doubly labeled water measurements was assessed. RESULTS: Energy-adjusted, deattenuated correlation coefficients between the questionnaire and the recalls ranged from 0.54 for dietary fiber to 0.86 for alcohol. Cross-classification of quintiles of nutrient intakes from the questionnaire and recalls indicated severe misclassification to be <4%. Reported protein intake correlated with estimated protein excretion (r = 0.46). Energy intake and total energy expenditure were also significantly correlated (r = 0.48); however, all but one subject underreported their energy intake. The magnitude of underreporting varied considerably, by 22% on average, and increased slightly with increasing energy intake. A similar pattern of underreporting was observed when energy intakes from the 24-h dietary recalls were compared with total energy expenditure. CONCLUSIONS: These data indicate an acceptable relative validity of the food-frequency questionnaire in this study population. Compared with measurements of total energy expenditure and protein excretion, however, only moderate agreement with both the food-frequency questionnaire and the 24-h dietary recalls was observed.

[Diagnosis and therapy of Lyme borreliosis in children. Practice guideline of the German Society for Pediatric Infectious Diseases]. / Diagnostik und Therapie der Lyme-Borreliose im Kindesalter. Empfehlung der Deutschen Gesellschaft für Pädiatrische Infektiologie.

Lyme borreliosis is the most frequent tickborne++ disease of man in the Northern hemisphere. A variety of systems may be involved. The most frequent manifestations in childhood include erythema migrans, meningitis, cranial nerve palsy and arthritis. Erythema migrans usually is easily recognised and determination of antibodies to Borrelia burgdorferi should not be performed. Childhood neuroborreliosis is characterised mostly by aseptic meningitis with or without cranial nerve palsy, in most cases facial palsy. Basic CSF findings often show a combined evidence of lymphocytic pleocytosis, IgM-class dominance in intrathecal humoral immune++ response, and blood-CSF barrier dysfunction. Calculation of the Borrelia burgdorferi specific antibody index (according to Reiber) proved to be the most sensitive method for detecting intrathecal synthesis of specific antibodies. Lyme arthritis presents initially as episodic oligoarthritis, mostly involving the knee joint, and may turn into chronic monoarthritis of the knee; usually high titers of IgG antibodies to Borrelia burgdorferi are found. The rarer manifestations encephalomyelitis, chronic arthritis, carditis and inflammatory eye disease may be difficult to diagnosis due to clinical ambiguity and problems in the interpretation of serological results. Antibodies to Borrelia burgdorferi found by sensitive Elisa must always be confirmed by immunoblot analysis, but sometimes immunoblot analysis is more sensitive than Elisa. Treatment is by antibiotics, amoxicillin or doxyciclin for erythema migrans, and i.v. third generation cephalosporins for all other manifestations. Even after successful antibiotic therapy, antibodies may persist for months and years and no further antibiotic treatment is necessary in the absence of attributable clinical manifestations. The differentiation between a persisting immune response and a persisting infection therefore has to be based upon the clinical symptoms, non-specific laboratory data and the development of the antibody titers.

Multicenter, randomized, double-blind comparison of erythromycin estolate versus amoxicillin for the treatment of acute otitis media in children. AOM Study Group.

Erythromycin is frequently prescribed in Germany for acute otitis media, but well-designed clinical trials under present epidemiological conditions are lacking. Therefore, a double-blind, randomized, multicenter trial was performed to compare the clinical efficacy and safety of erythromycin estolate versus amoxicillin in children with acute otitis media and to identify the risk factors associated with clinical failure. Investigators from 19 centers throughout Germany recruited 302 children with clinical, otoscopic, and tympanometric evidence of acute otitis media. In a double-blind fashion, patients were allocated randomly to a 10-day course of erythromycin estolate at 40 mg/kg/day in two divided doses or amoxicillin at 50 mg/kg/day in two divided doses. Clinical examinations, otoscopy, and tympanometry were performed at baseline, day 3-5, day 9-11, and at 5 weeks. Clinical outcome was assessed on day 9-11. Two-hundred eighty children were evaluable for efficacy (erythromycin group, 141; amoxicillin group, 139). Both groups were comparable with respect to demographic data and severity of disease at entry. Treatment was successful in 94% of the erythromycin-treated patients and in 96% of the amoxicillin-treated patients. Clinical outcome was statistically equivalent between groups within a range of 7 percentage points. Clinical recurrence was seen in eight erythromycin-treated children (5.7%) and in seven amoxicillin-treated children (5.0%) (P=0.81). Patients with bilateral disease at entry were at higher risk of unfavourable outcome, whereas age and presence/absence of otorrhea at entry were not associated with outcome. Treatment-related adverse events were recorded in eight (5.3%) of 151 erythromycin-treated patients and in 11 (7.3%) of 151 amoxicillin-treated patients. In this study in an outpatient setting in Germany, erythromycin estolate was as safe and effective as amoxicillin in the treatment of acute otitis media. Both drugs can be administered in a convenient twice-daily dosage schedule.