Citrin deficiency mimicking mitochondrial depletion syndrome.

BACKGROUND: Neonatal intrahepatic cholestasis caused by citrin deficiency (CD) is a rare inborn error of metabolism due to variants in the SLC25A13 gene encoding the calcium-binding protein citrin. Citrin is an aspartate-glutamate carrier located within the inner mitochondrial membrane. CASE PRESENTATION: We report on two siblings of Romanian-Vietnamese ancestry with citrin deficiency. Patient 1 is a female who presented at age 8 weeks with cholestasis, elevated lactate levels and recurrent severe hypoglycemia. Diagnosis was made by whole exome sequencing and revealed compound heterozygosity for the frameshift variant c.852_855del, p.Met285Profs*2 and a novel deletion c.(69 + 1_70-1)_(212 + 1_231-1)del in SLC25A13. The girl responded well to dietary treatment with a lactose-free, MCT-enriched formula. Her younger brother (Patient 2) was born 1 year later and also found to be carrying the same gene variants. Dietary treatment from birth was able to completely prevent clinical manifestation until his current age of 4.5 months. CONCLUSIONS: As CD is a well-treatable disorder it should be ruled out early in the differential diagnosis of neonatal cholestasis. Due to the combination of hepatopathy, lactic acidosis and recurrent hypoglycemia the clinical presentation of CD may resemble hepatic mitochondrial depletion syndrome.

Molecular and biochemical alterations in tubular epithelial cells of patients with isolated methylmalonic aciduria.

Methylmalonic acidurias (MMAurias) are a group of inherited disorders in the catabolism of branched-chain amino acids, odd-chain fatty acids and cholesterol caused by complete or partial deficiency of methylmalonyl-CoA mutase (mut(0) and mut(-) subtype respectively) and by defects in the metabolism of its cofactor 5'-deoxyadenosylcobalamin (cblA, cblB or cblD variant 2 type). A long-term complication found in patients with mut(0) and cblB variant is chronic tubulointerstitial nephritis. The underlying pathomechanism has remained unknown. We established an in vitro model of tubular epithelial cells from patient urine (hTEC; 9 controls, 5 mut(0), 1 cblB). In all human tubular epithelial cell (hTEC) lines we found specific tubular markers (AQP1, UMOD, AQP2). Patient cells showed disturbance of energy metabolism in glycolysis, mitochondrial respiratory chain and Krebs cycle in concert with increased reactive oxygen species (ROS) formation. Electron micrographs indicated increased autophagosome production and endoplasmic reticulum stress, which was supported by positive acridine orange staining and elevated levels of LC3 II, P62 and pIRE1. Screening mTOR signaling revealed a release of inhibition of autophagy. Patient hTEC produced and secreted elevated amounts of the pro-inflammatory cytokine IL8, which was highly correlated with the acridine orange staining. Summarizing, hTEC of MMAuria patients are characterized by disturbed energy metabolism and ROS production that lead to increased autophagy and IL8 secretion.

[Improvement in Phoneme Discrimination in Noise in Normal Hearing Adults]. / Trainierbarkeit der Diskrimination von Phonemen im Störgeräusch bei normalhörenden Erwachsenen.

Objective: The study's aim was to examine the possibility to train phoneme-discrimination in noise with normal hearing adults, and its effectivity on speech recognition in noise. A specific computerised training program was used, consisting of special nonsense-syllables with background noise, to train participants' discrimination ability. Material and Methods: 46 normal hearing subjects took part in this study, 28 as training group participants, 18 as control group participants. Only the training group subjects were asked to train over a period of 3 weeks, twice a week for an hour with a computer-based training program. Speech recognition in noise were measured pre- to posttraining for the training group subjects with the Freiburger Einsilber Test. The control group subjects obtained test and restest measures within a 2-3 week break. For the training group follow-up speech recognition was measured 2-3 months after the end of the training. Results: The majority of training group subjects improved their phoneme discrimination significantly. Besides, their speech recognition in noise improved significantly during the training compared to the control group, and remained stable for a period of time. Conclusions: Phonem-Discrimination in noise can be trained by normal hearing adults. The improvements have got a positiv effect on speech recognition in noise, also for a longer period of time.

[Phoneme discrimination training with experienced cochlear implant listeners]. / Training der Phonemdiskrimination mit erfahrenen Cochleaimplantatträgern.

BACKGROUND: Computer-based auditory training programmes seem to be a useful tool in the process of auditory rehabilitation after cochlear implantation (CI). Currently, little is known about the learning mechanism and efficiency of such programs. The aim of the study was to evaluate a specific auditory training programme for phoneme discrimination in experienced CI listeners. MATERIALS AND METHODS: A total of 15 CI adult listeners with more than 2 years' CI experience participated in the auditory training. Over a period of 3 weeks they were instructed to train their phoneme discrimination via computer twice a week. Training material consisted of special syllables for consonants (vCv) and vowels (cVc) discrimination. RESULTS: The discrimination abilities for consonants and vowels improved significantly over the training period for training group participants, whereas the changes for the consonants were higher. In addition, the improvement for voiced and unvoiced consonants was significant. CONCLUSION: Computerised auditory training with phonemes improves CI listeners' discrimination abilities for consonants and vowels.

Genus Erica: An identification aid version 4.00.

Species identification is fundamental to all aspects of biology and conservation. The process can be challenging, particularly in groups including many closely related or similar species. The problem is confounded by the absence of an up-to-date taxonomic revision, but even with such a resource all but professional botanists may struggle to recognise key species, presenting a substantial barrier to vital work such as surveys, threat assessments, and seed collection for ex situ conservation. Genus Erica: An Identification Aid is a tool to help both amateurs and professionals identify (using a limited number of accessible characteristics) and find information about the 851 species and many subspecific taxa of the genus Erica. We present an updated version 4.00, with new features including integrating distribution data from GBIF and iNaturalist, links to taxonomic resources through World Flora Online, and a probability function for identifications, that is freely available for PCs. It remains a work in progress: We discuss routes forward for collaboratively improving this resource.

Detecting flood-type-specific flood-rich and flood-poor periods in peaks-over-threshold series with application to Bavaria (Germany).

Previous studies suggest that flood-rich and flood-poor periods are present in many flood peak discharge series around the globe. Understanding the occurrence of these periods and their driving mechanisms is important for reliably estimating future flood probabilities. We propose a method for detecting flood-rich and flood-poor periods in peak-over-threshold series based on scan-statistics and combine it with a flood typology in order to attribute the periods to their flood-generating mechanisms. The method is applied to 164 observed flood series in southern Germany from 1930 to 2018. The results reveal significant flood-rich periods of heavy-rainfall floods, especially in the Danube river basin in the most recent decades. These are consistent with trend analyses from the literature. Additionally, significant flood-poor periods of snowmelt-floods in the immediate past were detected, especially for low-elevation catchments in the alpine foreland and the uplands. The occurrence of flood-rich and flood-poor periods is interpreted in terms of increases in the frequency of heavy rainfall in the alpine foreland and decreases of both soil moisture and snow cover in the midlands.

[Right-sided or left-sided donor nephrectomy-is this really relevant?] / Rechts- oder linksseitige Donornephrektomie ­ ist das wirklich relevant?

BACKGROUND: In the context of living donation, the protection of the donor and the outcome are very important aspects. However, the side selection of the donor nephrectomy is also decisive. In this work, the basics of side selection and the question of whether there are differences regarding the left-sided or right-sided donor nephrectomy are considered. MATERIALS AND METHODS: Living kidney donation data of our center between December 2004 and July 2019 were evaluated in terms of withdrawal side, complications and outcome, as well as the current literature in PubMed. Finally, the results from our center are compared with the current literature. RESULTS: During the investigation period, 152 live donations were carried out in our center. In these cases 66 patients had a left-sided and in 86 cases a right-sided donor nephrectomy. One transplant vein thrombosis occurred in each group. Complications and outcome were similar for the recipient in both groups. It was noticed in the current literature that generally more left-sided donor nephrectomies are performed, most likely due to the preference of the surgeon. Although a low significantly increased risk of transplant vein thrombosis after right-sided donor nephrectomy is described, all authors agree that right-sided donor nephrectomy is a safe procedure with good outcome. CONCLUSIONS: Our own results and the current literature show that the right-sided donor nephrectomy is a safe procedure with only a slightly increased risk of complications compared to the left side and therefore can be recommended. It is clearly safe for the donor and organ, with an equivalent outcome for the recipient. The results are also dependent on the experience of the surgeon.

Superpressure balloon flights in the tropical stratosphere.

Seven balloons were launched successfully from Ascension Island in January 1969. The balloons, flown at altitudes of 20 and 24 kilometers, will make possible a detailed analysis of the stratospheric circulation near the equator and will hopefully lead to an understanding of the quasi-biennial stratospheric oscillation in the tropics.

Trastuzumab therapy vs tetracycline controlled ERBB2 downregulation: influence on tumour development in an ERBB2-dependent mouse tumour model.

Trastuzumab (Herceptin) has improved therapy of breast cancer. Only patients overexpressing ERBB2 are treated with trastuzumab, whereas its use in tumours without ERBB2 expression is useless. This led to the concept that the subgroup of trastuzumab-sensitive tumours is 'ERBB2-dependent', meaning that ERBB2 signalling is indispensable for growth of these tumours. We used a mouse model that allows anhydrotetracycline (ATc)-controlled downregulation of ERBB2 in tumour tissue. ERBB2 mRNA and protein expression were downregulated below detection limit leading to a macroscopically complete tumour remission within 14 days. Tumour remission was accompanied by a strong decrease in proliferation, a moderate increase in apoptosis, as well as dephosphorylation of ERK1/2 and AKT/PKB. These data clearly indicate ERBB2 dependence. Therefore, a high sensitivity to trastuzumab may be suspected. Surprisingly, trastuzumab caused a much weaker effect compared to ATc-induced ERBB2 downregulation, although a decrease in ERBB2 membrane localisation was induced. Only a slight decrease in proliferation and a weak transient increase in apoptosis were observed. Interestingly, tumours responded to trastuzumab by a sharp fivefold increase in phosphorylated AKT/PKB as well as a 3.5- and 5.3-fold increase in AKT1 and AKT2 mRNA levels, respectively. In conclusion, 'ERBB2 dependence' is not sufficient to define trastuzumab-responsive tumours. The suboptimal effect of trastuzumab compared to the maximally possible effect induced by ATc demonstrates a high potential for improved ERBB2 blocking therapies.

Intention to quit smoking: is the partner's smoking status associated with the smoker's intention to quit?

BACKGROUND: Smoking behavior among couples is often similar. PURPOSE: The aim of the study was to examine the relationship between the partner's smoking status and the intention to stop smoking of the index person. METHOD: Cross-sectional data of 1,044 patients in a random sample of 34 general medical practices in northeastern Germany were analyzed. RESULTS: Among smokers with a non-smoking partner (SNP), more intended to quit smoking in the next six months (37.0% vs. 31.4%), compared to smokers with a smoking partner (SSP). Also, more SNP intended to quit in the next four weeks (4.7% vs. 2.7%) compared to SSP. SNP were more active in the use of self-change strategies than SSP. CONCLUSION: The data confirm that the partner's smoking status is related to the intention to quit smoking. Interventions should address the different needs of both smokers with a smoking partner and those with a non-smoking partner.

Postpartum smoking cessation and relapse prevention intervention: a structural equation modeling application to behavioral and non-behavioral outcomes of a randomized controlled trial.

The aim of the study was to test the effectiveness of a postpartum smoking cessation and relapse prevention intervention. Structural equation modeling techniques were applied to evaluate the impact of the intervention on smoking behavior and on non-behavioral variables derived from the Transtheoretical Model (TTM). Women were randomized to an intervention (I) and control group (C). Smoking status, TTM-variables, and control variables were assessed four weeks, six and 12 months postpartum. Membership in the intervention group significantly predicted non-smoking and higher self-efficacy six months, but not one year postpartum, after controlling for demographic, smoking, and postpartum risk variables.

[Diversity and accessibility of smoking cessation aids in the internet]. / Vielfalt und Auffindbarkeit von Hilfeangeboten zur Raucherentwöhnung im Internet.

AIM OF THE STUDY: Only a few smokers use smoking cessation aids. The Internet can act as a medium to improve the dissemination of traditional smoking cessation aids, but can also provide direct help by its own interactive capabilities. The purpose of this study is to give an overview of the different smoking cessation aids offered via the Internet and to categorise their contents. METHODS: Two different search strategies were used to find smoking cessation aids on the Internet. The first was a search with the search engine Google. Six search terms were previously generated by interviews with one hundred smokers. Using these terms, the Google search resulted in a list of 106 websites. The second strategy was a direct search on 31 websites of different health-related institutions. To classify the smoking cessation aids on the websites, a system of different categories was developed. RESULTS: The offers for smoking cessation on the Internet could be assigned to 11 categories. General information about smoking cessation was the most and interactive programs was the least represented category. The websites of the health-related institutions offered a larger variety of directly useable smoking cessation aids (39%) than the websites retrieved via Google (29%). CONCLUSION: Interactive smoking cessation aids which provide individual support are still underrepresented on the Internet. Direct search strategies on the pages of health-related institutions were more promising than the use of a search engine. The proactive promotion of quality-controlled Internet offers seems to be important to capitalise on the potential of the Internet.

[Radiation cystitis : Pathophysiology and treatment]. / Radiogen bedingte Zystitis : Pathophysiologie und Therapie.

Radiation cystitis (RC) is a common side-effect of radiation to the pelvis. Their clinical appearance as well as their degree of expression is manifold, as are the therapeutic options. However, in the absence of randomized examinations, recommendations are difficult. We differentiate between oral, systemic therapies, intravesical instillations and interventions as well as interventional, radiological and, as an ultima ratio, surgical treatments. This article provides an overview of the different treatment options with particular emphasis on the conservative-interventional therapy options.

Requirements for a Compton camera for in vivo range verification of proton therapy.

To ensure the optimal outcome of proton therapy, in vivo range verification is highly desired. Prompt γ-ray imaging (PGI) is a possible approach for in vivo range monitoring. For PGI, dedicated detection systems, e.g. Compton cameras, are currently under investigation. The presented paper deals with substantial requirements regarding hardware and software that a Compton camera used in clinical routine has to meet. By means of GEANT4 simulations, we investigate the load on the detectors and the percentage of background expected in a realistic irradiation and we simulate γ-ray detections subsequently used as input data for the reconstruction. By reconstructing events from simulated sources of well-defined geometry, we show that large-area detectors are favourable. We investigate reconstruction results in dependence of the number of events. Finally, an end-to-end test for a realistic patient scenario is presented: starting with a treatment plan, the γ-ray emissions are calculated, the detector response is modelled, and the image reconstruction is performed. By this, the complexity of the system is shown, and requirements and limitations regarding precision and costs are determined.

CFTR is a tumor suppressor gene in murine and human intestinal cancer.

This corrects the article DOI: 10.1038/onc.2015.483.

Smoking status, obesity and hypertension in a general population sample: a cross-sectional study.

BACKGROUND: In some studies, hypertension is more common in never and former smokers than in current smokers. AIM: To examine the associations between hypertension and smoking status, when divided into subgroups by overweight and obesity. DESIGN: Cross-sectional study. METHODS: We used data from a national health survey with a probability sample of the national population of Germany aged 18 to 79 (n = 6903 with complete data). Smoking status data were collected via questionnaire. Obesity and overweight were assessed by body mass index, hypertension by blood pressure measurement and by participants' statements about antihypertensive treatment. Analyses were adjusted for gender, age, history of coronary artery disease, serum cholesterol levels, alcohol drinking, exercise, and education. RESULTS: Obese former smokers who were abstinent for 3 or more years had an adjusted odds ratio (OR) 3.6 (95% confidence interval, CI 2.3-5.7) for mild hypertension (> or =140 mmHg systolic or > or =90 mmHg diastolic blood pressure) and an adjusted OR 6.5 (95%CI 3.6-11.8) for moderate or severe hypertension (> or =160 mmHg systolic or > or =100 mmHg diastolic). Normal weight never or former smokers did not differ from normal weight current smokers smoking > or =15 cigarettes/day with regard to likelihood of hypertension (normal weight never smokers, OR 1.1, 95%CI 0.8-1.5; normal weight former smokers, abstinent 3 or more years, OR 0.8, 95%CI 0.5-1.3). DISCUSSION: In this nationally representative sample, never or former smoking was unrelated to hypertension among normal weight individuals.

Mutational analysis of the H-ras oncogene in spontaneous C57BL/6 x C3H/He mouse liver tumors and tumors induced with genotoxic and nongenotoxic hepatocarcinogens.

The frequency and mutational profile of H-ras gene activation were determined in spontaneous liver tumors of male C57BL/6 x C3H/He mice and in tumors induced with the genotoxic hepatocarcinogen benzidine.2 HCl or the nongenotoxic hepatocarcinogens phenobarbital, chloroform, and ciprofibrate. DNA sequence analysis of the H-ras gene from representative tumors revealed that 32 of 50 (64%) spontaneous tumors and 13 of 22 (59%) benzidine.2 HCl-induced tumors contained a point mutation in codon 61. Tumors induced with the nongenotoxic agents had a much lower frequency of codon 61 mutations, i.e., phenobarbital, 1 of 15 (7%); chloroform, 5 of 24 (21%), and ciprofibrate, 8 of 39 (21%). No mutations were observed at codons 12, 13, and 117 in tumors from any of the groups. Only three base pair substitutions within codon 61 were found. The one most frequently detected in all of the groups was a C.G to A.T transversion at the first nucleotide position, occurring at a 59%, 85%, 100%, 80%, and 88% frequency in the spontaneous tumors and in the tumors induced with benzidine 2.Hcl, phenobarbital, chloroform, and ciprofibrate, respectively. In these same groups an A.T to G.C transition or an A.T to T.A transversion at the second nucleotide position occurred at a frequency of 34%, 8%, 0%, 0%, and 12%, and 6%, 8%, 0%, 20%, and 0%, respectively. The number of tumors carrying an activated H-ras gene in the nongenotoxic treatment groups is within the range that would be expected if those animals had not received any treatment. This indicates that the activation of the H-ras gene in those tumors is probably the result of a spontaneous event. The data suggest that these toxicologically and pharmacologically diverse nongenotoxic hepatocarcinogens increase the frequency of liver tumors but do not induce mutations in the H-ras gene. Instead these agents appear to interact with a population of cells that do not contain an activated H-ras gene. This suggests that the mechanisms of tumor development by these nongenotoxic carcinogens differ at least partially from the mechanisms responsible for the development of spontaneous tumors or those induced by a typical genotoxic agent.

From prompt gamma distribution to dose: a novel approach combining an evolutionary algorithm and filtering based on Gaussian-powerlaw convolutions.

Range verification and dose monitoring in proton therapy is considered as highly desirable. Different methods have been developed worldwide, like particle therapy positron emission tomography (PT-PET) and prompt gamma imaging (PGI). In general, these methods allow for a verification of the proton range. However, quantification of the dose from these measurements remains challenging. For the first time, we present an approach for estimating the dose from prompt γ-ray emission profiles. It combines a filtering procedure based on Gaussian-powerlaw convolution with an evolutionary algorithm. By means of convolving depth dose profiles with an appropriate filter kernel, prompt γ-ray depth profiles are obtained. In order to reverse this step, the evolutionary algorithm is applied. The feasibility of this approach is demonstrated for a spread-out Bragg-peak in a water target.

CFTR is a tumor suppressor gene in murine and human intestinal cancer.

CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid-base homeostasis. Cftr has been identified as a candidate driver gene for colorectal cancer (CRC) in several Sleeping Beauty DNA transposon-based forward genetic screens in mice. Further, recent epidemiological and clinical studies indicate that CF patients are at high risk for developing tumors in the colon. To investigate the effects of CFTR dysregulation on GI cancer, we generated Apc(Min) mice that carried an intestinal-specific knockout of Cftr. Our results indicate that Cftr is a tumor suppressor gene in the intestinal tract as Cftr mutant mice developed significantly more tumors in the colon and the entire small intestine. In Apc(+/+) mice aged to ~1 year, Cftr deficiency alone caused the development of intestinal tumors in >60% of mice. Colon organoid formation was significantly increased in organoids created from Cftr mutant mice compared with wild-type controls, suggesting a potential role of Cftr in regulating the intestinal stem cell compartment. Microarray data from the Cftr-deficient colon and the small intestine identified dysregulated genes that belong to groups of immune response, ion channel, intestinal stem cell and other growth signaling regulators. These associated clusters of genes were confirmed by pathway analysis using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA). We also conducted RNA Seq analysis of tumors from Apc(+/+) Cftr knockout mice and identified sets of genes dysregulated in tumors including altered Wnt ß-catenin target genes. Finally we analyzed expression of CFTR in early stage human CRC patients stratified by risk of recurrence and found that loss of expression of CFTR was significantly associated with poor disease-free survival.

No considerable long-term weight gain after smoking cessation: evidence from a prospective study.

The aim of the study was to analyse predictors of the body mass index (BMI) after smoking cessation. The sample included 4075 residents aged 18-64 years in a northern German area (participation rate 70.2%), drawn randomly from the resident registration files, among them 1545 current and 903 former daily smokers. The current smokers were followed up 36 months after baseline. Face-to-face in-home computer-aided interviews (Composite International Diagnostic Interview) including questions about body weight and height at baseline and postal questionnaires at follow-up were employed. The data reveal that the number of cigarettes smoked at time of peak consumption in life contributed substantially, and years of abstinence from daily smoking contributed marginally to the BMI in a general linear model. It is concluded that the contribution of smoking cessation to the BMI increase was practically negligible. Efforts to prevent weight gain after smoking cessation should focus especially on heavy smoking.