Mitochondrial DNA depletion and fatal infantile hepatic failure due to mutations in the mitochondrial polymerase γ (POLG) gene: a combined morphological/enzyme histochemical and immunocytochemical/biochemical and molecular genetic study.

Combined morphological, immunocytochemical, biochemical and molecular genetic studies were performed on skeletal muscle, heart muscle and liver tissue of a 16-months boy with fatal liver failure. The pathological characterization of the tissues revealed a severe depletion of mtDNA (mitochondrial DNA) that was most pronounced in liver, followed by a less severe, but still significant depletion in skeletal muscle and the heart. The primary cause of the disease was linked to compound heterozygous mutations in the polymerase γ (POLG) gene (DNA polymerase γ; A467T, K1191N). We present evidence, that compound heterozygous POLG mutations lead to tissue selective impairment of mtDNA replication and thus to a mosaic defect pattern even in the severely affected liver. A variable defect pattern was found in liver, muscle and heart tissue as revealed by biochemical, cytochemical, immunocytochemical and in situ hybridization analysis. Functionally, a severe deficiency of cytochrome-c-oxidase (cox) activity was seen in the liver. Although mtDNA depletion was detected in heart and skeletal muscle, there was no cox deficiency in these tissues. Depletion of mtDNA and microdissection of cox-positive or negative areas correlated with the histological pattern in the liver. Interestingly, the mosaic pattern detected for cox-activity and mtDNA copy number fully aligned with the immunohistologically revealed defect pattern using Pol γ, mtSSB- and mtTFA-antibodies, thus substantiating the hypothesis that nuclear encoded proteins located within mitochondria become unstable and are degraded when they are not actively bound to mtDNA. Their disappearance could also aggravate the mtDNA depletion and contribute to the non-homogenous defect pattern.

Changes in the FEV1/FVC ratio during childhood and adolescence: an intercontinental study.

In children, the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) is reportedly constant or falls linearly with age, whereas the ratio of residual volume (RV) to total lung capacity (TLC) remains constant. This seems counter-intuitive given the changes in airway properties, body proportions, thoracic shape and respiratory muscle function that occur during growth. The age dependence of lung volumes, FEV1/FVC and RV/TLC were studied in children worldwide. Spirometric data were available for 22,412 healthy youths (51.4% male) aged 4-20 yrs from 15 centres, and RV and TLC data for 2,253 youths (56.7% male) from four centres; three sets included sitting height (SH). Data were fitted as a function of age, height and SH. In childhood, FVC outgrows TLC and FEV1, leading to falls in FEV1/FVC and RV/TLC; these trends are reversed in adolescence. Taking into account SH materially reduces differences in pulmonary function within and between ethnic groups. The highest FEV1/FVC ratios occur in those shortest for their age. When interpreting lung function test results, the changing pattern in FEV1/FVC and RV/TLC should be considered. Prediction equations for children and adolescents should take into account sex, height, age, ethnic group, and, ideally, also SH.

Aromatic hydroxylation in nasal lavage fluid following ambient ozone exposure.

Ozone at ambient concentrations affects lung function and initiates an inflammatory response of the airways. However, the underlying mechanisms are poorly understood. In vitro studies have shown that ozone reacts with water to give reactive hydroxyl radicals capable of oxidizing a wide range of biomolecules. We conducted a study to determine if in vivo hydroxyl radical attack on human airways occurs under natural exposure to ozone. The relation of orthotyrosine to para-tyrosine as a measure of hydroxyl radical attack was analyzed in nasal lavage samples of 44 primary school children in an epidemiologic study. Repeated nasal lavages were performed between May and October 1991 both following "low" (daily half-hour maximum < 140 micrograms/m3, approximately 70 ppb) and "high" (daily half-hour maximum > 180 micrograms/m3, approximately 90 ppb) ozone exposure. Concomitantly, lung function tests were performed. On average, 11.6 (6-16) nasal lavages were performed for each of 24 study days (10 days following "low" ozone exposure and 14 days following "high" ozone exposure). Average ortho-tyrosine (median; 5-95% percentile) for each child was 0.037 mumol/L (0.016-0.064 mumol/L) and average para-tyrosine was 15.7 mumol/L (9.8-24.1 mumol/L). Ortho-tyrosine (as percentage of tyrosine) was significantly higher following days with "high" ozone exposure (0.18%) vs. days following "low" ozone exposure (0.02%; p = .0001). Ortho-tyrosine showed an inverse relationship with forced vital capacity (p = .01) but was not related to inflammation of the upper airways as assessed by cell counts of polymorphonuclear neutrophils. Hydroxyl radical attack subsequent to ambient ozone occurs in the upper airways of healthy children and is related to lung function decrements.

Influence of maternal smoking on variability of peak expiratory flow rate in school children.

Diurnal variability of peak expiratory flow rates (PEFRs) was assessed in 1,237 children. The PEFR was measured twice daily over a 1-week period. As an index of variability, the log of a week's mean of daily amplitude was calculated. Linear regression analyses revealed a significant positive association between maternal smoking and the variability of PEFR for nonasthmatic children. For these children, exposure to maternal smoking was associated with a 13.7 percent increase (confidence interval [CI], 3.8 to 24.7 percent) in PEFR variability. For asthmatic children an effect was found for nonatopic (54.7 percent increase; CI, 5.5 to 226.8 percent) but not for atopic children (-8.5 percent change; CI, -41.2 to 42.3 percent). In the latter group, there was evidence that mothers changed their smoking habits subsequent to the development of disease in their children. We conclude that exposure to maternal smoking can increase the variability of PEFR and thus might contribute to the development of asthma.

Lack of correlation between CFTR expression, CFTR Cl- currents, amiloride-sensitive Na+ conductance, and cystic fibrosis phenotype.

Cystic fibrosis (CF) is characterized by defective Cl- and enhanced Na+ conductance, both due to malfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in airway epithelial cells. In the present study we examined whether expression of CFTR mRNA (CFTR messenger ribonucleic acid) is different in airway epithelia derived from either CF patients or healthy volunteers. Moreover, we tried to correlate differences in epithelial Cl- and Na+ conductance with the level of CFTR mRNA expression and studied whether these properties correlate to the clinical phenotype of CF patients. To that end, CFTR mRNA was determined by means of quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and cyclic adenosine monophosphate (cAMP)-activated Cl- and epithelial Na+ conductances were examined in airway epithelial cells using microelectrode techniques. Complementary in vitro data were obtained from cultured CF and non-CF airway epithelial cell lines. Genotype and Shwachman score were assessed for each patient. We found variable levels of CFTR mRNA expression in airway cells of both CF patients and healthy volunteers. As expected, epithelial Na+ conductance was enhanced and CFTR Cl- conductance was absent in airway cells from CF patients. However, CFTR mRNA expression did not correlate with either electrophysiological properties or Shwachman scores obtained from CF patients. In addition, CFTR mRNA expression did not correlate to Cl- conductance in cultured CF and non-CF airway epithelial cells. These results indicate a lack of correlation between levels of CFTR mRNA and CFTR function, and that only small amounts of CFTR are required for expression of the CFTR Cl- conductance.

[Angiomatous dysplasia (Weber type) (author's transl)]. / Angiomatöse Dysplasie (Typ F.P. Weber).

A rare form of angiomatous dysplasia with hypotrophy of the left arm is described. Numerous haemodynamically significant arterio-venous fistulae could be demonstrated in the soft tissues and in bone. The venous and lymphatic systems were normal. The lacunar reticular-cystic changes in the spongiosa of the phalanges are pathognomonic of arterial angiodysplasia of the Weber type. In most cases this is associated with bone hypertrophy.

[CT diagnosis of chronic osteomyelitis (author's transl)]. / CT-Diagnostik der chronischen Osteomyelitis.

The CT findings in 20 patients with chronic osteomyelitis, mostly of post-traumatic origin, were compared with conventional radiographs and operative findings. CT diagnosed rather more sequestra than the conventional method. An important advantage of CT is the ability to demonstrate lesions in the medulla and infections in the soft tissues, eg. abscesses. CT should be reserved for cases where conventional methods with tomography leave unsolved problems, and in the present of fistulae.

[The radiological appearances of caustic burns in the upper intestinal tract (author's transl)]. / Das Röntgenbild kaustischer Veränderungen des oberen Intestinaltraktes

Seventy-three caustic burns of the upper gastrointestinal tract were divided into early and late effects; the radiological findings were analysed and, as far as possible, compared with the endoscopic results. The central role of radiology proved to be indisputable, particularly for the demonstration of a perforation, for the control of treatment by drugs or dilatation and before surgery. Endoscopy is of particular value in the diagnosis of caustic burns if the radiological findings are negative, for following treatment and for clarifying atypical late changes in order to exclude malignant degeneration.

[Air pollutant burden and bronchial asthma in school children]. / Luftschadstoffbelastung und Asthma bronchiale bei Schulkindern.

To examine the possibility of an effect of indoor and outdoor exposures on the prevalence of asthma in childhood we conducted a cross-sectional study in the area of Freiburg city and two communities in the Black Forest. The study group consists of 704 children aged 7 to 16 years. The children and their mothers took part in a standardized interview and a medical examination. Indoor exposures were assessed from information gathered in the interview by two different indices: (a) heating system and single room heating, and (b) the amount of indoor ventilation. The measurement of outdoor pollutants took into account weekly estimations of NO2 and combustion particles. The presence of asthma was recorded according to a previous medical diagnosis. Confounders were assessed during the interview (passive smoking, genetic predisposition to asthma etc.) or during the medical examination (cutaneous sensitization with a skin prick test). For the analysis of the data we applied logistic regression models and estimated odds-ratios. Only one of the four hypothesis variables displays a significant effect on the prevalence of asthma: Stoves as heating device carry a 4.8-fold relative risk for asthma compared to other types of heating. Among the confounding variables controlled for in the explanatory model, cutaneous reactions showed a relative risk of eight.

[The effect of immobilization on the number and function of osteoblasts]. / Der Einfluss der Immobilisation auf Zahl und Funktion der Osteoblasten.

The influence of immobilisation on the number and function of osteoblasts was determined by morphological examination of normal rabbit bone and that that had been inactivated through surgery. Contrary to earlier supposition, after inactivation not only the osteoclasts but also the osteoblasts increase distinctly. Even retardation of the parathyroid gland by magnesium does not lead to decrease of the osseous structure. Therefore, it can be concluded that disuse osteoporosis is normally produced in its first weeks by a considerable activity decrease of even more osteoblasts and less by increased function of osteoclasts. The increase in number of osteoblasts and their decreased activity after immobilisation indicate that the mechanical stimulus gives the essential impulse for full osteoblast function.

[The appendix stump insufficiency. Clinical appearance forms and treatment]. / Die Appendixstumpfinsuffizienz. Klinische Erscheinungsform und Behandlung.

Early manifestation of insufficiency of the appendiceal stump appearing as a diffuse peritonitis with a septicemic general state has led to the death of 6 of 10 patients treated here. One has to suppose that these complications have additional unknown causes. Insufficiency of the stump, with or without necrosis of the cecum, can only be discovered with active procedures and than treated in the appropriate way. Each of these patients has been lost when there has been no courage for reintervention or even an excuse for providing intensive medical treatment with respiration aid and hemodialysis. As a rule, the fecal fistula appears during postoperative days 5-8 without diffuse peritonitis and should be treated in a conservative way; spontaneous fading away should be expected and operative occlusion should not be started before a 3 month interval.

[Modification of osteomyelitis with free musculocutaneous transplants]. / Die Beeinflussung der Osteomyelitis durch freie myokutane Transplantate.

Twenty two latissimus dorsi free flaps transplanted with microsurgical techniques in infected regions are presented. The guarants of success are the end-end anastomosis, the venous drainage over the deep veins, the muscle with its skin coverage. The indications are: soft tissue infections, early infections after fractures, and the chronic osteitis. The economic, social and psychological effects of microsurgical tissue transfer elevate this technique to the procedure of choice.

[Clinical and epidemiological application of carbachol for the testing of bronchial hyperreactivity in school-age]. / Klinische und epidemiologische Anwendung von Carbachol zur Testung der bronchialen Reagibilität im Schulalter.

Airway reactivity was investigated by inhalation of the cholinergic agent carbachol. A standardized Carbachol challenge test (CCT) was carried out in a cumulative manner in 59 school-aged children as well as 10 not asthmatic individuals. The carbachol aerosol was delivered by jet nebulization. It was administered by inhalation of stepwise twofold increasing cumulative doses from a balloon taking tidal breaths. The inhalation was finished at the dose step eliciting a 100% increase in R(aw). Bronchial reactivity was derived by linear regression from the dose-response function. Bronchial sensitivity was registered by the threshold dose. Calculated on the bronchial reactivity of 57 asthmatics the asthma-related sensitivity of the CCT was 83%. The specificity was 90%. In 7 children the week-to-week reproducibility was tested: 6 children showed discrepancies of the threshold dose of less than two steps, in one case a shift of two steps was observed. In none of the probands a severe systemic side effect occurred. The carbachol challenge test is an appropriate method to distinguish asthmatic children from the normal population. The validity and good reproducibility as well as the feasibility in children makes the procedure valuable for pediatric investigations of bronchial hyperreactivity as a common feature in asthma.

Relevance of basophil histamine release changes during venom immunotherapy.

We investigated the effect of rush and long-term venom immunotherapy on histamine release parameters in bee venom allergic patients. Ten patients received rush venom immunotherapy, and histamine release data were obtained immediately before and after treatment. 17 patients were assessed by histamine release 24 to 63 months after termination of long-term venom immunotherapy. A control group of 10 non-allergic subjects was included in this study. Histamine released from whole blood was determined in a sensitive radio-enzymatic assay using a single isotope technique. Bee venom phospholipase A-induced histamine release from whole blood proved to be a test procedure of high specificity and sensitivity. Eight of 10 untreated patients and no control subject showed significant antigen-induced histamine release. Results obtained from patients immediately after successful rush venom immunotherapy showed an important decrease (mean 45.9%) of total histamine content of basophil leukocytes in all patients. Antigen-induced maximum histamine release was found to be increased in one, decreased in two and unchanged in seven patients. In patients who received long-term immunotherapy cell sensitivity to phospholipase A was significantly lower than in a group of untreated patients (P less than or equal to 0.002). These results suggest that even years after discontinuation of immunotherapy, histamine release parameters reflect patients' protection from systemic sting reactions as assessed by sting challenges. Histamine depletion of basophils induced by rush immunotherapy may play an important role in patients' protection immediately after termination of the rush regimen.

Anti-IgE- and complement-induced histamine release from peripheral leukocytes in normals and atopics.

Anti-IgE- and complement-induced histamine release from isolated basophils was compared in normal and atopic subjects. Activated complement was generated by incubation of a serum pool from normal donors with zymosan. Histamine was measured by a single-isotope radioenzymatic assay. In atopics, the mean histamine release induced by heterologous complement was significantly higher than in normals (p less than or equal to 0.01). Anti-IgE-mediated histamine release showed no differences between atopics and normals. Regarding the histamine release as a function of the age of the donor, we observed significantly higher complement-induced release values in normal children aged 1-10 years compared to those aged 10-20 and greater than 20 years (p less than or equal to 0.05). Anti-IgE-induced histamine release showed no age-related differences in normals or atopic patients. As a high complement-mediated leukocytic histamine release was more commonly found in atopics with heterologous complement, this phenomenon appears not to be due to a higher rate of complement activation in the serum of atopics, but rather to an intrinsic cell abnormality. Moreover, these results suggest that age-related releasability patterns might be considered when studying complement-induced histamine release. Differences between IgE- and complement-mediated histamine release indicated that parameters of releasability must be defined with respect to each stimulus.

[Respiratory symptoms in children with low birth weight with or without perinatal respiratory insufficiency]. / Respiratorische Symptome bei Kindern mit niedrigem Geburtsgewicht mit oder ohne perinatale respiratorische Insuffizienz.

We recorded prevalence of respiratory symptoms in 104 school children aged eight years (+/- 0.4 years) who were born with a weight below 2500 grams. Perinatal respiratory insufficiency (PRI) was observed in 18 children. Validation by medical records in 14 cases demonstrated that 7 children had been oxygen dependent over 1-5 days after birth, the other 7 children had required mechanical ventilation from 2 days up to 4 month. Children with a history of PRI did not suffer more frequently from "cough after exercise" (17%), "wheezing" (50%) or "frequent cough" (11%) than healthy children of low birthweight. Corresponding values were 26%, 38%, and 18% respectively. Multiple logistic regression analyses confirmed these observations. In children with a low birthweight PRI is not associated with respiratory symptoms at school age.

[Sensitization to 10 important air-borne allergens in school children]. / Sensibilisierung auf 10 wichtige Aeroallergene bei Schulkindern.

Sensitization patterns and frequencies for 10 important aeroallergens were tested in a cross-sectional study with 704 schoolchildren (7-16 years) using a standardized skin prick-test method and highly purified immunochemically characterized test-solutions. A ratio of allergen and histamine wheal diameter of 0.5 or more was classified as a positive skin test result. We found a positive skin prick-test to at least one of the aeroallergens in 242 (34.4%) of the children. Among these 39.6% showed monosensitization and 9.8% polysensitization to at least 6 allergens. The most common allergens were grasspollen (19.2%), birchpollen (14.8%), house-dust mite (13.4%), catdander (10.5%) and hazelpollen (9.7%). Monosensitized children reacted mainly to grasspollen and house-dust mite, whereas positive reactions to animal dander and moulds only occurred in polysensitized children more frequently. Reactivity of the tested allergens, measured by the wheal size, was strongest for grasspollen and house-dust mite and the weakest for cladosporium and alternaria. The high prevalence of sensitization to inhalant allergens is an important risk-factor for allergic disease in childhood.

[Accident and injuries situations in accidents at school and on the way to and from school]. / Das Unfall- und Verletzungsgeschehen bei Schulunfällen und Schulwegeunfällen.

In the Federal Republic of Germany, where accidents to schoolchildren are covered by the statutory accident insurance, a total of 991,947 accidents of this kind occurred in 1987, 133 of which were fatal. In this study, the accidents and injuries sustained by 1059 schoolboys and schoolgirls who received medical treatment in our clinics are analysed. We are concerned here with 887 accidents actually at school and 172 accidents on the way to or from school. In the case of accidents at school, the proportion of 6-, 7- and 8-year-olds affected was below 3% for each of these age groups. The percentage of children involved in accidents at school increased steeply with increasing age, reaching a peak in girls at 12 years of age, with 15.4%, and in boys at 13 years, with 14.5%. After this, the proportion in each individual age group lay between 10% and 12% up to 17 years of age and decreased to 7% in 19-year-olds. The proportion of accidents among 20- and 21-year-olds was less than 2%. Of the 887 accidents at school, 53% occurred during sports lessons, 28% during break times, 11% in the course of the general coming and going involved in attendance on the school premises, 3% during instruction in academic subjects and 3% during extracurricular activities, e.g. school outings. Each of these accident areas has its typical accident risks, and often its characteristic accident pattern in addition. Furthermore, there are age-specific and sex-specific features. The frequency of injuries to the upper extremities, including the hand, was 11% higher in girls than in boys.(ABSTRACT TRUNCATED AT 250 WORDS)