Alveolar progenitor cells and the origin of lung cancer.

Lung Cancer is the leading cause of cancer-related deaths worldwide. This is mainly due to late diagnosis and therefore advanced stage of the disease. Understanding the cell of origin of cancer and the processes that lead to its transformation will allow for earlier diagnosis and more accurate prediction of tumour type, ultimately leading to better treatments and lower patient morbidity. In this review, we focus on alveolar type 2 (AT2) cells as the cell of origin of lung adenocarcinoma (LUAD), the most common type of lung cancer. We first elaborate on the different oncogenes that are associated with LUAD and other lung cancers. After, we lay out in detail what is known about AT2 biology, to further delve into AT2 cells as cell of origin for adenocarcinoma. Understanding the precursors of LUAD and identifying the molecular changes during its progression will allow for earlier detection and better molecular targeting of the disease in early stages.

H3K9 methyltransferases and demethylases control lung tumor-propagating cells and lung cancer progression.

Epigenetic regulators are attractive anticancer targets, but the promise of therapeutic strategies inhibiting some of these factors has not been proven in vivo or taken into account tumor cell heterogeneity. Here we show that the histone methyltransferase G9a, reported to be a therapeutic target in many cancers, is a suppressor of aggressive lung tumor-propagating cells (TPCs). Inhibition of G9a drives lung adenocarcinoma cells towards the TPC phenotype by de-repressing genes which regulate the extracellular matrix. Depletion of G9a during tumorigenesis enriches tumors in TPCs and accelerates disease progression metastasis. Depleting histone demethylases represses G9a-regulated genes and TPC phenotypes. Demethylase inhibition impairs lung adenocarcinoma progression in vivo. Therefore, inhibition of G9a is dangerous in certain cancer contexts, and targeting the histone demethylases is a more suitable approach for lung cancer treatment. Understanding cellular context and specific tumor populations is critical when targeting epigenetic regulators in cancer for future therapeutic development.

Liquid-state carbon-13 hyperpolarization generated in an MRI system for fast imaging.

Hyperpolarized (HP) tracers dramatically increase the sensitivity of magnetic resonance imaging (MRI) to monitor metabolism non-invasively and in vivo. Their production, however, requires an extra polarizing device (polarizer) whose complexity, operation and cost can exceed that of an MRI system itself. Furthermore, the lifetime of HP tracers is short and some of the enhancement is lost during transfer to the application site. Here, we present the production of HP tracers in water without an external polarizer: by Synthesis Amid the Magnet Bore, A Dramatically Enhanced Nuclear Alignment (SAMBADENA) is achieved within seconds, corresponding to a hyperpolarization of ∼20%. As transfer of the tracer is no longer required, SAMBADENA may permit a higher polarization at the time of detection at a fraction of the cost and complexity of external polarizers. This development is particularly promising in light of the recently extended portfolio of biomedically relevant para-hydrogen-tracers and may lead to new diagnostic applications.

Blood pressure regulation determined by ambulatory blood pressure profiles in children and adolescents with type 1 diabetes mellitus: Impact on diabetic complications.

BACKGROUND: The combination of high blood pressure and hyperglycemia contributes to the development of diabetic complications. Ambulatory monitoring of blood pressure (ABPM) is seen as standard to assess blood pressure (BP) regulation. OBJECTIVE: We evaluated 24-hour BP regulation in 3529 children with type 1 diabetes, representing 5.6% of the patients <20 years of age documented in the DPV registry, and studied the influence of BP parameters including pulse pressure (PP) and blood pressure variability (BPV) on microalbuminuria (MA) and diabetic retinopathy (DR). RESULTS: BP was increased in this selected cohort of children with diabetes compared to healthy German controls (standard deviation score (SDS) day: systolic BP (SBP) +0.06, mean arterial pressure (MAP) +0.08, PP +0.3; night: SBP +0.6, diastolic BP +0.6, MAP +0.8), while daytime diastolic BP (SDS -0.2) and dipping of SBP and MAP were reduced (SBP -1.1 SDS, MAP 12.4% vs 19.4%), PP showed reverse dipping (-0.7 SDS). Children with microvascular complications had by +0.1 to +0.75 SDS higher BP parameters, except of nocturnal PP in MA and diurnal and nocturnal PP in DR. Reverse dipping of PP was more pronounced in the children with MA (-5.1% vs -0.8%) and DR (-2.6% vs -1.0%). BP alteration was stronger in girls and increased with age. CONCLUSION: There is an early and close link between 24-hour blood pressure regulation and the development of diabetic complications not only for systolic, diastolic, and mean arterial BP but also for the derived BP parameter PP and BPV in our selected patients.

Outbreak of hot-foot syndrome - caused by Pseudomonas aeruginosa.

Infections with Pseudomonas aeruginosa can cause the hot-foot syndrome, presenting with painful plantar erythematous nodules. Particularly, the mechanically stressed areas of the foot are affected after contact with contaminated water from saunas, swimming pools, hot tubs, etc. We report an outbreak of hot-foot syndrome caused by Pseudomonas in 10 patients. The therapeutic regimens applied reached from local antiseptic therapy to systemic antibiotics.

[Frequency and influencing factors of ketoacidosis at diabetes onset in children and adolescents--a long-term study between 1995 and 2009]. / Häufigkeit und Einflussfaktoren der Ketoazidose bei Diabetesmanifestation im Kindes- und Jugendalter--eine Langzeitstudie von 1995 bis 2009.

BACKGROUND: Diabetic ketoacidosis (DKA) is a frequent acute complication at onset of type 1 diabetes. It is assumed that increased public awareness about diabetes symptoms may reduce DKA rate at diabetes onset. To investigate the time-dependent trend in DKA prevalence we analysed the frequency and determinants of DKA at disease onset over 15 years in pediatric patients. PATIENTS AND METHODS: The prevalence of DKA at disease onset was analysed in individuals aged ≤18 years treated for the first time from 1995-2009 within 7 days after diagnosis in pediatric centers. Simple and multiple logistic regression analysis was performed to investigate influencing factors on DKA prevalence. Change of the probability of ketoacidosis over years were modelled in the logistic regression as linear trend. RESULTS: 16 562 individuals from 170 institutions were studied with a mean age of 9.2 ± 4.2 years. DKA (pH <7.3) was present in 20.8% of patients without a significant trend between 1995 and 2009 (p=0.222). DKA prevalence was higher in children ≤5 years (26.3%) and in the age group 10-15 years (21.7%) than in individuals aged 5-10 years (16.4%) and 15-18 years (16.9%, p<0.001). Girls had DKA more often than boys (21.2% vs. 19.3%, p=0.002). DKA frequency was increased in individuals with migration background (26.5% vs. 19.2%, p<0.001). CONCLUSIONS: DKA prevalence at diabetes onset was constant at about 21% during the last 15 years. Very young children, pubertal adolescents, girls and individuals with migration background are at higher risk for DKA at diagnosis. To prevent DKA earlier diagnosis of type 1 diabetes is warranted especially in these patient groups.

10-year-old girl with severe edema caused by adder bite.

We report a case of acute hemorrhagic edema in a 10-year-old girl caused by adder bite. Therapy consisted of analgesics, antihistamines, corticosteroids. Antivenum serum was applied in a single dose due to severe spreading of the edema. The patient recovered almost completely after 10 days of treatment.

Down's syndrome in diabetic patients aged <20 years: an analysis of metabolic status, glycaemic control and autoimmunity in comparison with type 1 diabetes.

AIMS/HYPOTHESIS: Intellectual impairment in individuals with Down's syndrome and diabetes mellitus potentially limits the quality of diabetic control. In addition, these patients are at risk of having immunological abnormalities. The present study compared metabolic status and concomitant diseases in young (<20 years old) Down's syndrome patients with diabetes vs young type 1 diabetic patients. METHODS: The Diabetes-Patienten-Verlaufsdaten is a longitudinal follow-up database, which collects data from 298 German and Austrian diabetes centres. Data available on diabetic patients aged <20 years were analysed statistically. RESULTS: We compared data for 159 Down's syndrome patients with diabetes and 41,983 type 1 diabetic patients. The former used less insulin, but showed better glycaemic control (HbA1c). Diabetes onset during the first 3 years of life occurred in 18.9% of Down's syndrome patients with diabetes and in 6.4% of type 1 diabetic patients. Antibody titres indicative of coeliac disease and thyroid peroxidase antibodies were more frequent in Down's syndrome patients with diabetes. No significant differences were found regarding the beta cell autoantibodies studied. CONCLUSIONS/INTERPRETATION: The age-of-onset distribution showed a shift towards younger ages and was bimodal in the Down's syndrome group. The better metabolic control found, despite intellectual impairment, in young Down's syndrome patients with diabetes cannot be conclusively explained by our data, but is likely to be due to a less complex lifestyle. Our data provide further confirmation that coeliac and thyroid antibodies are more prevalent in Down's syndrome. The presence of beta cell autoantibodies supports an autoimmune cause of diabetes in some children with Down's syndrome.

Exposure to inhalable dust and its cyclohexane soluble fraction since the 1970s in the rubber manufacturing industry in the European Union.

OBJECTIVES: As exposures to airborne particulates in the European rubber industry might still be causing genotoxic risks, it is important to assess trends in levels of inhalable dust and its cyclohexane soluble fraction (CSF) between the 1970s and 2003. METHODS: 13 380 inhalable and 816 respirable dust and 5657 CSF measurements, collected within the framework of the European Union Concerted Action EXASRUB, were analysed. Hierarchical mixed effects models were applied to assess exposure trends, taking into account between-factory, between-worker/location and day-to-day variances. RESULTS: Geometric mean levels of inhalable dust and CSF exposure changed by -4% (range -5.8 to +2.9%) and -3% (range -8.6 to 0%) per year, respectively. Significant reductions in inhalable dust concentrations were found in all countries for handling of crude materials and mixing and milling (-7% to -4% per year), as well as for miscellaneous workers (-11% to -5% per year), while significant CSF exposure reductions were found in curing (-8.6% per year) and maintenance and engineering departments (-5.4% per year). CONCLUSION: These analyses suggest that on average exposure levels of inhalable dust and its CSF in the European rubber manufacturing industry have steadily declined. Most likely genotoxic risks have also lessened over time since exposure levels have decreased and the most toxic chemicals have been replaced. In addition to differences in exposure reductions and levels among various stages of the production process, large differences across countries were noted. These patterns should be taken into account in retrospective assessment of exposure for epidemiological studies assessing cancer risk in the rubber industry.

Shorter remission period in young versus older children with diabetes mellitus type 1.

BACKGROUND: The initial period of diabetes type 1 is of great importance, since early metabolic adjustment has profound impact on long term control. The majority of pediatric centers in Germany participate in a national quality initiative, providing longitudinal data for central analysis. PATIENTS: 104543 anonymous data sets were obtained from 6123 pediatric patients under 18 years who were treated in 157 pediatric centers and monitored for 36 months at the same center starting from diagnosis. RESULTS: Partial remission (insulin <0.5 U/kg/d and HbA1c < or = 7.0%) was present in 1992 children (32.5%) within the first 3 months after diagnosis. Remission phase lasted in average for 0.74 +/- 0.77 years and was significantly shorter in children below 10 years of age at onset of diabetes compared to the older patients. The remission period was significantly longer in boys, particularly in children under 10 years (p=0.0039). Multiple regression analysis showed a longer remission phase in children with pubertal diabetes onset. The children entering remission were younger, more often boys and had a lower initial HbA1c level. CONCLUSION: These data from a large multicenter group of children with diabetes type 1 emphasize the influence of gender, pubertal stage and age at manifestation on the amount of insulin required, and therefore the clinical remission, during the first three years of the disease.

[Malaria in Afghanistan]. / Maliariia v Afganistane.

Malaria is endemic throughout the country at altitudes below 1500 m. The annual number of malaria cases is estimated to be 2-3 million. A total of 395,581 were officially reported in 1999. Plasmodium falciparum is responsible for 11.2% of the total microscopically confirmed cases. Voluntary repatriation for Afghan refugees from Iran has started since April 2000. WHO is negotiating with UNHCR the issue of providing special groups with insecticide-impregnated bednets (ITNs). Malaria control activities during 1999 focused on the better quality of diagnosis and treatment, implementation of selective and sustainable preventive measures, epidemic readiness and response, and a strengthened surveillance system. Community participation was well demonstrated in using bednets and gambusia fish programs. During 1999, the number of PHC structures involved in malaria diagnosis and treatment and recording tripled as compared to those in 1998. A total of 62,507 ITNs were distributed nationwide. Other 39,601 bednets distributed in 1998 were reimpregnated. Urban and periurban malaria control was initiated in two provinces by using larvicides, biological and environmental management methods. A national prevalence survey was conducted in 20 out of 31 provinces of Afghanistan. Malaria Committees were established in the western, northern, and northeastern regions of the country in January-February 2000. The total number of such committees in the country increased to 7. An RBM task force including key stakeholders was set up to initiate the Roll Back Malaria partnership in Afghanistan.

Exposure to rubber fume and rubber process dust in the general rubber goods, tyre manufacturing and retread industries.

This study assesses the current patterns and levels of exposure to rubber fume and rubber process dust in the British rubber industry and compares and contrasts the data obtained from the general rubber goods (GRG), retread tire (RT) and new tire (NT) sectors. A total of 179 rubber companies were visited and data were obtained from 52 general rubber goods, 29 retread tire and 7 new tire manufacturers. The survey was conducted using a questionnaire and included a walk-through inspection of the workplace to assess the extent of use of control measures and the nature of work practices being employed. The most recent (predominantly 1995-97) exposure monitoring data for rubber fume and rubber process dust were obtained from these companies; no additional sampling was conducted for the purpose of this study. In addition to the assessment of exposure data, evaluation of occupational hygiene reports for the quality of information and advice was also carried out.A comparison of the median exposures for processes showed that the order of exposure to rubber fume (E, in mg m(-3)) is: E(moulding) (0.40) approximately E(extrusion) (0.33)>E(milling) (0.18) for GRG; E(press) (0. 32)>E(extrusion) (0.19)>E(autoclave) (0.10) for RT; and E(press) (0. 22) approximately E(all other) (0.22) for NT. The order of exposure to rubber fume between sectors was E(GRG) (0.40)>E(RT) (0.32)>E(NT) (0.22). Median exposures to rubber process dust in the GRG was E(weighing) (4.2)>>E(mixing) (1.2) approximately E(milling) (0.8) approximately E(extrusion) (0.8) and no significant difference (P=0. 31) between GRG and NT sectors. The findings compare well with the study carried out in the Netherlands [Kromhout et al. (1994), Annals of Occupational Hygiene 38(1), 3-22], and it is suggested that the factors governing the significant differences noted between the three sectors relate principally to the production and task functions and also to the extent of controls employed. Evaluation of occupational hygiene reports indicated a number of shortcomings including lack of suitable and sufficient information with regard to sampling and analytical methods in use, poor sampling strategy, lack of appreciation regarding true rubber process dust, and a poor understanding of the principles of control for substances assigned maximum exposure limits.

Practical aspects of managing preschool children with type 1 diabetes.

Day-to-day variations in diet and physical exercise, large variations in the glucose response to small changes in insulin doses, and high insulin sensitivity are characteristic of preschool children with diabetes. Hence, difficulties in achieving adequate metabolic control and stable glycaemia in preschool children are common. In addition, hypoglycaemic episodes tend to be frequent and severe in this age group. Problems identifying and treating hypoglycaemia present an additional challenge for the diabetes team and for the family caring for the young child with diabetes. Specific glucose targets are provided for this age group: premeal levels of 6-12 mmoll(-1)(110-220 mg dl(-1)) with bedtime levels above 8 mmoll(-1)(140 mg dl(-1)). It is important to note that children who suffer severe hypoglycaemic events at a young age show evidence of subtle cognitive deficits when tested during adolescence. The question of whether or not the years before pubertal onset contribute less towards the development of diabetes-related microvascular complications than do the years starting with the onset of puberty remains controversial. Twice-daily or multiple insulin injections, dietary adjustments and considerations, home blood-glucose monitoring, family education, support groups and 24-h hotline information facilities can help to achieve good metabolic control without severe hypoglycaemia in the preschool child. In general, good metabolic control without severe hypoglycaemia can be achieved using frequent counselling and a caring team approach.

Improvements and new potentials in pharmacological therapy of diabetes mellitus in children and adolescents.

Subcutaneous insulin substitution is not physiological. Despite the many attempts using intensified insulin regimens to render current insulin substitution protocols more physiological, a nondiabetic circulating insulin profile cannot be simulated in patients with type 1 diabetes. Despite many efforts, the pharmacological treatment of type 1 diabetes consists of an unphysiological attempt to substitute only one of the hormones which are lost after beta-cell destruction, namely insulin. It is therefore mandatory to search for additional means to achieve physiological regulation of glucose homeostasis and overall metabolic status. Peptides which are being developed as additional new therapeutic compounds for type 1 diabetes include, for example, IGF-I, leptin, C-peptide and amylin. In addition, the application of insulin analogues has already been introduced into clinical practice. However, so far none of these pharmaceutical compounds has been shown to offer real clinical benefits and substantially improve metabolic control in patients with type 1 diabetes. The results of long-term clinical trials using the peptide compounds listed above for the treatment of type 1 diabetes are still not available.

A novel immunosuppressive factor in bovine colostrum blocks activation of the interleukin 2 gene enhancer at the NFAT site.

A factor in bovine colostrum (colostrum inhibitory factor, CIF) inhibits interleukin 2 (IL2) production in activated T helper cells by blocking the accumulation of IL2 mRNA. To determine whether CIF blocks at the level of IL2 transcription, we introduced reporter plasmids into the human T leukemia cell line Jurkat by transient transfection. These contained the luciferase gene under the control of either the human IL2 upstream enhancer region (segments -326 to +45) or three repeats of the NFAT element contained within it (segments -255 to -285). Expression of luciferase in these cells was induced by phorbol myristate acetate plus a calcium ionophore. CIF inhibited induction of either construct as did cyclosporine, which is known to block activation of the NFAT element. CIF failed to inhibit several other enhancer elements. The NFAT-controlled luciferase gene system distinguishes CIF from other T cell inhibitory activities present in colostrum, in particular, TGF beta 1 and TGF beta 2 and the glucocorticoids. Stably transfected Jurkat cells behaved similarly to the transiently transfected ones with respect to inhibition by CIF and cyclosporine. The NFAT-luc assay is a useful technique for the rapid, sensitive measurement of CIF or other immunosuppressants with a similar mode of action.

A European meeting held to discuss dermal exposure monitoring and related issues, Brussels, Belgium, 21-23 June 1994.

Recognizing the significance of dermal exposure, the European Commission funded and convened a consultative meeting on dermal exposure and related issues, with the objectives of identifying gaps in knowledge, discussing future research requirements and exploring the possibility of establishing a research network for the purpose of stimulating collaborative European R&D projects. The meeting began with a series of keynote review lectures covering a range of issues associated with dermal exposure. Participants from the United States outlined the prevailing situation and likely future developments in dermal exposure assessment in the United States, and representatives of participating European states then presented a brief summary of regulatory position regarding dermal exposure in their respective countries. The prevailing position in skin and surface contamination monitoring was discussed and gaps in knowledge identified; areas of work which would result in the development of standardized methodologies were debated. The meeting resulted in the formation of five syndicate groups, these include: (i) occupational exposure assessment-risk assessment; (ii) biological monitoring; (iii) skin and surface contamination; (iv) in vitro models (skin penetration); and (v) source apportionment (dermal vs air exposure). Each syndicate group discussed and identified the R&D requirements in its area of interest and reported its findings to the meeting. There was a consensus that a need exists for the establishment of a European network on dermal exposure to co-ordinate efforts in this field. Preparatory work for the establishment of the network is currently underway.