Favorable NK cell activity after haploidentical hematopoietic stem cell transplantation in stage IV relapsed Ewing's sarcoma patients.

Natural killer (NK) cell activity has been shown to have potential activity against Ewing's sarcoma (EWS) especially in tumors with low HLA I expression and high NKG2D expression. Two patients with metastatic relapsed and primary metastatic stage IV EWS who had received two courses of high dose chemotherapy with autologous stem cell rescue were transplanted from a haploidentical parental stem cell donor. Patients are alive in ongoing CR for 10.2 and 3.4 years now. Post transplant local second and first relapses were treated successfully in both patients. In vivo IL-2 stimulation not only increased the number and activity of effector cells in one patient but was also associated with severe GvHD. In vitro studies demonstrated high NK cell activity against K562 and relevant activity against EWS cell line A673 post transplant. NK activity was enhanced by cytokine prestimulation as well as by EWS targeting anti-GD2 Ab. Haploidentical hematopoietic stem cell transplantation (HSCT) might contribute to long-term survival by NK cell-mediated effect exerted by donor-derived NK cells. Local tumor recurrence was manageable in both high-risk patients indicating systemic immune control preventing subsequent metastasizing. The efficacy of haploidentical HSCT, cytokine application and tumor targeting antibodies for the use of Ab-dependent cellular cytotoxicity needs evaluation in clinical trials.

[Orthopaedic Treatment for Patients with Myelomeningocele]. / Orthopädische Behandlung bei Myelomeningozele.

BACKGROUND: Due to prenatal diagnostic and folic acid prophylaxis less children with myelomeningocele are now being born. But they become older and need increasingly more orthopaedic care. The orthopaedic care is aimed at the improvement or the preservation of function. METHOD: In this review the current knowledge from the literature and our approach are presented. This is done in the context of the functional aspects within certain periods of life. Treatment Concept: In the first two years of life, the mobility of MMC children is supported by physiotherapy and orthoses irrespective of the level of the lesion. Afterwards, the optimal orthoses are chosen depending on the muscle power, emerging bone deformities, associated CNS malformation, shunt revisions, obesity and limitations in perception as well as the child's motivation. At school age, it is paramount to encourage independence. Orthotic treatment should be continued as long as the children benefit from it. Orthopaedic operations serve the orthosis fitting and the avoidance of pressure sores. Pathological fractures are common. They should be rapidly recognised in order to avoid further bony deformities. CONCLUSION: The aim of any orthopaedic treatment consists of the avoidance of musculoskeletal deformities in order to support the patient's self employment.

[Pilot study on a modular outpatient treatment programme following public order placements because of endangerment in patients with psychotic disorders]. / Pilot-Anwendung eines modularen ambulanten Therapieprogramms im Anschluss an PsychKG-Unterbringungen wegen Fremdgefährdung bei Patienten mit Psychose-Erkrankungen.

Patients with psychotic disorders who were detained by public order because of endangerment, can be regarded as a population at risk of further endangerment, public order placements and a forensic course. Concepts of specific aftercare for this subgroup are lacking thus far. The present pilot study explores the feasibility of a modular therapeutic outpatient programme that is tailored to specific subgroup needs and is applied over six months. Readmission rates during the intervention period are regarded exploratively.Consecutive screening of all patients placed in general psychiatry by public order during 05 to 11/2012. Included patients received baseline measurements followed by six-month intervention. Individual utilisation of treatment modules and number of readmissions, differentiated according to legal bases were assessed.Inclusion rate: 17.4 % of all screened subjects (115) and 57 % of all potentially includable subjects, dropout rate: 15 %. Mean utilisation rate: 23.5 therapeutic contacts per 6 months. Readmission rate: 50 %, of these 60 % on voluntary legal basis.Study inclusion, mean utilisation and dropout rates attest the feasibility and acceptance of the intervention in the population under study. A preponderance of voluntary vs. compulsory readmissions to hospital during the intervention indicates that in the majority of patients a higher degree of therapeutic cooperativeness can be reached. Further study on reduction of compulsory readmissions and on avoidance of a forensic course by application of the here introduced intervention in combination with methods of risk assessment in a consecutive main project seems justified.

Compartments of the foot: topographic anatomy.

Recent publications have renewed the debate regarding the number of foot compartments. There is also no consensus regarding allocation of individual muscles and communication between compartments. The current study examines the anatomic topography of the foot compartments anew using 32 injections of epoxy-resin and subsequent sheet plastination in 12 cadaveric foot specimens. Six compartments were identified: dorsal, medial, lateral, superficial central, deep forefoot, and deep hindfoot compartments. Communication was evident between the deep hindfoot compartment and the superficial central and deep central forefoot compartments. In the hindfoot, the neurovascular bundles were located in separate tissue sheaths between the central hindfoot compartment and the medial compartment. In the forefoot, the medial and lateral bundles entered the deep central forefoot compartment. The deep central hindfoot compartment housed the quadratus plantae muscle, and after calcaneus fracture could develop an isolated compartment syndrome.

[Oral anticoagulation after major hip or knee replacement surgery: a process-driven managerial pharmacoeconomic analysis in German hospitals]. / Orale Antikoagulation bei Hüft- und Kniegelenkersatzpatienten: Prozessanalyse in Akut- und Rehabilitationskliniken.

BACKGROUND: The thrombin inhibitor dabigatranetexilat is used for prophylaxis of venous thromboembolism after total hip or knee replacement surgery (THR/TKR). Patients can take it orally in hospitals. METHOD: In a managerial pharmacoeconomic analysis of six German acute-care hospitals and six German rehabilitation hospitals, the use of dabigatranetexilat was compared with the use of low-molecular-weight heparins. RESULTS: The analysis showed that the new drug led to an economic advantage for an acute-care hospital of 2.43 euro per patient per day. In a rehabilitation hospital, the use of dabigatranetexilat led to an economic advantage of 1.40 euro per patient per day. CONCLUSION: These results have direct implications for drug decisions in hospitals. To demonstrate that fact, the price difference between dabigatranetexilat and low-molecular-weight heparins was derived to lead exactly to their"economic neutrality" from the hospital's point of view.

Self-reported health-related quality of life in children and adolescents with myelomeningocele.

The aim of the study was to investigate self-reported health-related quality of life (HRQOL) in children and adolescents with myelomeningocele (MMC) and to examine the impact of clinical impairments and limitations in activities of daily living (ADL). Fifty patients (28 females, 22 males) between 8 and 16 years of age (mean age 12y 1mo [SD 2y 4mo]) with MMC from three German paediatric centres and their mothers completed standardized measures on HRQOL (KINDL-R) and limitations in ADL (Childhood Health Assessment Questionnaire). Lesion level was thoracic in nine, sacral in 25, and lumbosacral in 11 patients. Twenty-one patients were community walkers, 17 were able to walk in the home, and seven used a wheelchair. Two-thirds had health problems related to the central nervous system causing current difficulties (eight patients had a shunt, six had hydrocephalus, and 10 had a tethered cord). Patients in the study group reported diminished overall HRQOL compared with norm data, specifically in the dimensions of emotional well-being, self-esteem, and peer relations. Adolescents reported diminished HRQOL in the dimension of peer relations. Most medical parameters as well as limitations in ADL were not significantly associated with HRQOL. Our findings confirm the results of studies which dispute a linear inverse association between condition severity and HRQOL and emphasize the importance of peer relations in young patients with MMC.

Long-term nonsurgical management of Barrett's esophagus with high-grade dysplasia.

BACKGROUND & AIMS: Surgical resection of the esophagus is frequently recommended for Barrett's high-grade dysplasia (HGD) without cancer. METHODS: During a 20-year period, patients were diagnosed and observed through an organized surveillance program at the Hines Veterans Affairs Hospital. The program was supported by Hines VA and organized and managed by 2 endoscopists using preestablished endoscopic criteria. RESULTS: Barrett's esophagus was diagnosed in 1099 patients, and 36,251 esophageal mucosal specimens were reviewed. Seventy-nine of 1099 patients (7.2%) initially had HGD (34 prevalent) or subsequently developed HGD (45 incident) without evidence of cancer. Of the 75 HGD patients who remained without detectable cancer after the 1 year of intensive searching, 12 developed cancer (16%) during a mean 7.3-year surveillance period: 11 of the 12 who were compliant were considered cured with surgical or ablation therapy. Cancer did not develop in the remaining 63 HGD patients during the surveillance period. CONCLUSIONS: HGD without cancer in Barrett's esophagus follows a relatively benign course in the majority of patients. In the patients who eventually progress to cancer during regular surveillance, surgical resection is curative. Surveillance endoscopies with biopsy is a valid and safe follow-up strategy for Barrett's patients who have HGD without cancer.

Lower limb muscle activity in ambulatory children with cerebral palsy before and after the treatment with Botulinum toxin A.

Purpose: The study investigated the effect of Botulinum toxin A on the gait and lower limb muscle activity of ambulatory CP children. Methods: 19 spastic diplegic and 4 left hemiparetic CP children were injected with a mean dose of 23.5 units of Botulinum toxin A/kg body weight into the gastrocnemius and hamstring muscles. Muscle tone and gait analysis including the kinesiological electromyogram of the shank and thigh muscles were assessed before and four weeks after injection and compared with the help of a multivariate analysis (p < 0.05). Results: Botulinum toxin A caused a definite reduction of plantarflexor, knee and hip hypertonia in 21 children, resulting in a more plantar grade and erect gait in 17 children four weeks after injection. Gait analysis showed a statistically significant improvement in peak ankle dorsi-flexion and knee extension during stance, and the length of the force point of action under both feet increased. Electromyography revealed sig-nificantly less co-contraction of the lower leg muscles, due to a more phasic instead of a tonic activity of the tibialis anterior muscle, and an improved activation pattern of the left rectus and biceps femoris muscles. Conclusions: The present study demonstrated that the injection of Botulinum toxin A resulted in a more mature muscle activation pattern of CP children. Most of the children walked more plantigrade and erect, the functional gait parameters, however, did not change.

A common mutation (epsilon1267delG) in congenital myasthenic patients of Gypsy ethnic origin.

OBJECTIVE: Mutation analysis of the acetylcholine receptor (AChR) epsilon subunit gene in patients with sporadic or autosomal recessive congenital myasthenic syndromes (CMS). BACKGROUND: The nicotinic AChR of skeletal muscle is a neurotransmitter-gated ion channel that mediates synaptic transmission at the vertebrate neuromuscular junction. Mutations in its gene may cause congenital myasthenic syndromes. A recently described mutation in exon 12 of the AChR epsilon subunit (epsilon1267delG) disrupts the cytoplasmic loop and the fourth transmembrane region (M4) of the AChR epsilon subunit. METHODS: Forty-three CMS patients from 35 nonrelated families were clinically classified as sporadic cases of CMS (group III according to European Neuromuscular Centre consensus) and were analyzed for epsilon1267delG by PCR amplification and sequence analysis. RESULTS: The authors report the complete genomic sequence and organization of the gene coding for the epsilon subunit of the human AChR (accession number AF105999). Homozygous epsilon1267delG was identified in 13 CMS patients from 11 independent families. All epsilon1267delG families were of Gypsy or southeastern European origin. Genotype analysis indicated that they derive from a common ancestor (founder) causing CMS in the southeastern European Gypsy population. Phenotype analysis revealed a uniform pattern of clinical features including bilateral ptosis and mild to moderate fatigable weakness of ocular, facial, bulbar, and limb muscles. CONCLUSIONS: The mutation epsilon1267delG might be frequent in European congenital myasthenic syndrome patients of Gypsy ethnic origin. In general, patients (epsilon1267delG) were characterized by the onset of symptoms in early infancy, the presence of ophthalmoparesis, positive response to anticholinesterase treatment, and the benign natural course of the disease.

Occurrence of polychlorinated terphenyls (PCTs) in indoor particulate matter.

In the course of a routine investigation concerned with polychlorinated biphenyl (PCB) contamination of dust collected in classrooms of a junior high school, a group of electron capture detector (ECD)-sensitive compounds with high boiling points were found in addition to PCBs. Using gas chromatographic-mass spectrometric techniques, these compounds were identified as polychlorinated terphenyls (PCTs). Additional measurements indicated that the PCTs were present only in particulate matter collected from the tops of fluorescent light frames but not in air samples obtained concomitantly in the classrooms. Attempts to identify the PCT emission source were unsuccessful. A survey of the literature revealed that PCTs are ubiquitously distributed environmental contaminants, although no data on their indoor occurrence have been reported to date. In view of the toxic effects of PCTs, which seem to be as important as those of PCBs, further attention should be given to the possible presence of PCTs in indoor environments.

Comparison of three immunoassays for diagnosing sensitization to latex in children with spina bifida.

As natural rubber latex (latex) has become more widespread in our environment, physicians have become increasingly aware of the problem of possible allergic reactions. Many fatal and near-fatal incidents have been reported (mainly during surgery) (1-3) and data has been published on groups frequently exposed to latex, such as patients with spina bifida (4-9), healthcare professionals (10-12) and occupationally exposed persons (13). The incidence of latex allergy in children seems to be increasing (14). Tests are therefore needed which can reliably detect sensitization to latex. Our aim was to compare the diagnostic accuracy of three commercial immunoassays for measuring specific IgE in serum to latex.

Risk factors for latex allergy in patients with spina bifida.

OBJECTIVE AND METHODS: In order to study risk factors for latex allergy in patients with spina bifida, we investigated 165 patients with spina bifida (mean age 9 years). Besides answering a questionnaire, patients underwent skin-prick testing and determination of specific serum IgE to latex as well as a screening test for specific IgE to environmental allergens. A total of 80 patients (49%) were sensitized to latex according to the presence of specific IgE to latex. RESULTS: Skin-prick tests (SPT) with high ammonia latex milk were performed in 81 of our patients with spina bifida and were positive in 36 patients (46%). Concordance of SPT with specific IgE in serum was good. Nineteen out of 165 patients suffered from a clinically relevant latex allergy: five patients had a history of systemic reactions to latex (e.g. severe bronchospasm, anaphylactic reactions), mostly during surgery. Fourteen patients reported clinical symptoms while inflating a balloon; all these 19 patients were sensitized to latex. Number of operations ranged from one to 26 (mean 5 operations). Concentration of specific IgE to latex in serum correlated well with increasing numbers of operations. Some 32/76 patients (41%) with spina bifida who were sensitized to latex showed an atopic disposition, while 21 out of 81 latex-negative patients (26%) were atopic. Of 300 consecutive sera (mean age of patients 9 years) sent to our laboratory for routine determination of specific IgE, 144 (48%) were positive in terms of specific IgE to environmental allergens, of which 247144 (17%) were sensitized to latex. CONCLUSIONS: From our data we conclude that in order to minimize risk of severe systemic clinical reactions, all patients with spina bifida should be screened for their individual risk of latex allergy to plan preventive measures before operations. Main risk factors for latex allergy seem to be: more than five operations, atopic predisposition, history of clinical symptoms while inflating a balloon, and a sensitization with a CAP-class of > or = 4.

Valproate (VPA) metabolites in various clinical conditions of probable VPA-associated hepatotoxicity.

Of a cohort of 470 epileptic patients in whom valproate (VPA) serum metabolites had been measured, 170 subjects without symptoms or signs of hepatic side effects were chosen as a reference group to establish the usual metabolic pattern. A wide interindividual variation of VPA metabolite concentrations was noted. Infants receiving VPA monotherapy and comedication with other antiepileptic drugs (AEDs) showed lower concentrations of the potential hepatotoxin 4-ene-VPA than did older children. In 11 patients with early symptoms and signs of possible fatal VPA-associated hepatotoxicity, the following spectrum of benign clinical conditions was observed: unusually severe side effect during initiation of VPA therapy (1 patient), high VPA dosage (2 patients), reversible impairment of coagulation with bleeding manifestations in association with a slight increase in transaminase levels (1 child), and reversible liver dysfunction associated with febrile illness (7 patients). Reversible or irreversible fulminant liver failure had occurred in 5 children. Three of the 4 children with a fatal outcome had massive lactic acidosis. In all patients with probable VPA-associated hepatotoxicity, some aspects of VPA metabolism differed distinctly from that of the reference group, but the inter-individual profile of metabolites varied considerably, even in the subgroup of 4 children who died. Impairment of VPA beta-oxidation and increase of metabolites of alternative metabolic pathways (omega- and omega 1-hydroxylation, dehydrogenation reactions) were the most frequent findings. Increased values of 2-n-propyl-4-pentenoic acid metabolite of VPA (4-ene-VPA), could be detected only in 1 of the 5 patients with fulminant liver failure and in one other child with a slight hepatic dysfunction, indicating that this VPA metabolite is not the decisive hepatotoxin or indicator of hepatotoxicity. Because we cannot distinguish between benign and life-threatening hepatic adverse reactions on the basis of VPA metabolites, all identified changes are considered secondary to an as-yet-unknown primary metabolic event. The most toxic compound could be VPA itself, which may unmask an inborn or an acquired metabolic defect in the processing of fatty acids.

[Irreversible valproate-associated liver failure]. / Irreversibles valproatassoziiertes Leberversagen.

A very severely retarded infant with a Dandy-Walker malformation was treated with valproate since the age of 6 months on account of infantile spasms. Three weeks after start of therapy dexamethasone was applied additionally because valproate was ineffective. Seventy-six days after initiation of valproate therapy the infant died with the clinical signs of fulminant valproate-associated hepatotoxicity despite the discontinuation of valproate. In combination with a febrile otitis media the child had been periodically restless and lethargic during the last week prior to liver coma. Activity of liver enzymes remained within normal limits up to two days before coma occurred. Analysis of valproate metabolites by gas chromatography/mass spectrometry yielded unusually high concentrations of the di-unsaturated metabolite E,E-2,3'-dien-valproate before and during liver failure. The concentrations of the main metabolites E-2-en-valproate und 3-keto-valproate remained within the usual range found during valproate therapy at steady state. The oxydation products 4-en-valproate and E-2,4-dien-valproate which are formed by alternative pathways and are considered to be hepatotoxic were detected in very low concentrations only. The application of carnitine, of antioxidants thought to improve the capacity of the free radical scavenger system (selen, vitamin E), and of N-acetylcysteine which can detoxify reactive drug metabolites could not prevent the fatal outcome.

Prevalence of oesophagitis in asthmatics.

The exact relation between gastro-oesophageal reflux and asthma remains poorly understood. To determine whether gastro-oesophageal reflux in asthmatics results in oesophagitis, endoscopy and oesophageal biopsy were performed on 186 consecutive adult asthmatics. The presence or absence of reflux symptoms was not used as a selection criterion for asthmatics. Endoscopy was performed by two endoscopists using predefined criteria. All asthmatics had discrete wheezing and either a previous diagnosis of asthma or documented reversible airways obstruction of at least 20%. The oesophageal mucosa was graded as normal if no erosions or ulcerations were present in the tubular oesophagus; as oesophagitis if a mucosal break with exudate (erosions and/or ulcerations) was present; and as Barrett's if specialised (intestinal) columnar epithelium was present. A hiatal hernia was diagnosed if greater than or equal to 2 cm of gastric mucosa appeared above the diaphragm during endoscopy. Thirty nine per cent of the patients with asthma had oesophagitis or Barrett's oesophagus, or both. There was no difference in the oesophageal mucosal status between asthmatics who required and those who did not require bronchodilators. Fifty eight per cent of asthmatics had a hiatal hernia. It is concluded that oesophagitis is common and independent of the use of bronchodilator therapy in asthmatics.

The importance of hiatal hernia in reflux esophagitis compared with lower esophageal sphincter pressure or smoking.

The characteristics of gastroesophageal reflux disease have not been adequately defined. To determine the influence on the esophageal mucosa of hiatal hernia, lower esophageal sphincter pressure, acid reflux, and cigarettes and alcohol, we studied the reflux parameters, smoking habits, and alcohol consumption of 184 healthy, ambulatory outpatients who received endoscopy as the initial diagnostic procedure for workup of gastroesophageal reflux. Patients received endoscopic and histologic evaluations of the esophageal mucosa, prolonged ambulatory esophageal pH monitoring, and esophageal manometric determinations. Structural analysis was used to test the plausibility of various clinical theories concerning the most important factors contributing to the development of esophagitis. Statistical analyses revealed the following: (a) the lower esophageal sphincter pressure, acid contact time, and frequency of reflux episodes were highly associated with the presence of a hiatal hernia (p less than 0.003 for all parameters); (b) individuals with esophagitis had 16.5 times as many hiatal hernias as found in normal, healthy people; (c) cigarette smoking was not correlated with esophagitis but was significantly associated with increased lower esophageal sphincter pressure (r = 0.18; p less than 0.03); and (d) smoking was also not associated with increased acid contact time or increased frequency of reflux episodes. We conclude that (a) the presence of a hiatal hernia, not the pressure of the lower esophageal sphincter, is the most important predictor of reflux frequency, acid contact time, and esophagitis; (b) a decreased lower esophageal sphincter pressure, as suggested by structural analysis, is unlikely to be the cause of increased reflux episodes or esophagitis; and (c) if smoking and lower esophageal sphincter pressure are factors in the development of esophagitis, they damage the esophageal mucosa by mechanisms other than increased frequency of reflux episodes or increased acid contact time.

[High-grade tracheomalacia and tracheal stenosis in congenital esophageal atresia with lower esophagotracheal fistula (Type III b)]. / Hochgradige Tracheomalazie und Trachealstenose bei konnataler Osophagusatresie mit unterer ösophagotrachealer Fistel (Typ III b).

Stenosis and malacia of the trachea wall can provoke chronic stridor and/or chronic bronchitis, but usually stenosis and malacia only exist separately. The finding of an infant born with atresia of the oesophagus and a lower tracheoesophageal fistula which was cured by surgery on the 1st day of life are discussed. During the following 8 months we observed persistent stridor, chronic cough and (4-times) relapsing episodes of respiratory insufficiency ("nearly-sudden-infant-death-syndrome"/NSIDS) due to gastrooesophageal reflux (GER with aspiration) and severe tracheomalacia combined with tracheostenosis and bacterial infections (Pseudomonas aeruginosa). The strategy of therapy for GER and for the tracheal abnormality are discussed.

Identification of the functional promoter regions in the human gene encoding the myosin alkali light chains MLC1 and MLC3 of fast skeletal muscle.

The human gene encoding the alkali myosin light chains (MLC) 1 and 3 of fast skeletal muscle has been isolated. Two separate start sites for transcription have been identified by S1 analysis of muscle RNA. The nucleotide sequences of both proximal promoter regions have been determined and compared to the corresponding gene regions of other species. Several conserved promoter elements were located within 140 nucleotides upstream of the mRNA cap site, whereas further upstream no homologous sequences were found. Unidirectional 5' deletion mutants of both MLC promoters were used to direct bacterial chloramphenicol acetyltransferase activity in transient transfection assays of muscle and nonmuscle cells. Approximately 120 nucleotides of the MLC1 promoter and 80 nucleotides of the MLC3 promoter were sufficient for the transcriptional activation in primary myotubes and to a lower degree also in fibroblasts and hepatocytes. The preferential expression in muscle cells was not dependent on the conserved MLC consensus sequence, CCTTTTATAG, but it absolutely required the CCAT box or the CAT-like box in the MLC1 and MLC3 promoters, respectively. The weak activity of the MLC1 promoter was markedly enhanced in myotubes when DNA from the 3' gene flanking sequence was included in the chloramphenicol acetyltransferase constructs.

The alkali light chains of human smooth and nonmuscle myosins are encoded by a single gene. Tissue-specific expression by alternative splicing pathways.

Human smooth muscle and nonmuscle cells express closely related myosin alkali light chains which are different from the isoforms present in striated muscle tissues. To date no information on the amino acid sequence of these mammalian nonstriated muscle isoforms has been available. We have isolated full-length cDNA clones encoding the nonmuscle (lym4) and smooth muscle (GT6) myosin light chains (MLCs) from cultured human lymphoblasts and heart aorta smooth muscle cells, respectively. Here we present the complete nucleotide sequences for both cDNA clones, together with the deduced amino acid sequences for the peptides. Both cDNAs contain the same open reading frame for 151 amino acids with 5 amino acid differences located in the C terminus. These differences are encoded by a block of 44 nucleotides which is present only in the smooth muscle (SM) mRNA. To identify the human gene coding for the two MLC isoforms, we have isolated and sequenced the nonmuscle (NM)/SM MLC gene, together with several intronless pseudogenes. A single functional gene was found containing 7 exons which are utilized for the coding information of the SM MLC mRNA. In contrast, the NM MLC mRNA does not contain sequences encoded by exon 6 which corresponds to the 44 nucleotides expressed in SM mRNA. This genomic configuration suggests that both the smooth muscle and nonmuscle MLCs in man are generated from the identical primary transcript by alternative splicing pathways taking place in a tissue-dependent manner.