Continuous vs thrice-daily ceftazidime for elective intravenous antipseudomonal therapy in cystic fibrosis.

BACKGROUND/AIM: We hypothesized that a continuous 24-h infusion of 100 mg/kg per day ceftazidime (treatment C) would result in equivalent or even superior anti-infectious efficacy in chronic Pseudomonus aeruginosa (PA) infection in patients with cystic fibrosis (CF) in comparison to the usual application of 200 mg/kg per day ceftazidime in three doses (treatment T). METHODS: This was a randomized crossover study comparing outcome after 14 days and 35 days. Tobramycin administered once daily (10 mg/kg per day) was administered concomitantly in both groups. The primary end-point was a decrease in the leukocyte count, and the secondary endpoints were clinical and lung function parameters, Pseudomonas quantification in sputum, and inflammation markers (immunogloblulin [Ig] G, C-reactive protein [CRP]) in serum. All patients received antibiotics electively as 14-day courses on a regular basis, not for acute exacerbations. RESULTS: Fifty-six patients (29 females, mean patient age 14.4 years, age range 5-37) initially received treatments C or T, followed by the alternative treatment after a mean interval of 37 (+/- 21) weeks. After 2 weeks of antibiotic treatment, the overall study group showed significant improvements compared to baseline for body weight, leukocyte counts, CRP, forced expiratory volume in 1 s (FEV(1)), FVC (forced vital capacity), and bacterial load in the airways, with no significant differences between treatment groups. Both regimens were well tolerated. Three weeks after cessation of antimicrobial therapy, leukocytes and PA density had returned to pre-treatment values. CONCLUSION: We conclude that continuous or thrice-daily dosing of intravenous ceftazidime, both combined with once-daily tobramycin, are equally effective application regimens for elective antipseudomonal therapy in clinically stable patients with CF.

Influence of the cyclooctadepsipeptides PF1022A and PF1022E as natural products on the design of semi-synthetic anthelmintics such as emodepside.

The 24-membered cyclooctadepsipeptide (CODP) PF1022A, the active metabolite of the fungus imperfectus Mycelia sterilia (Rosellinia sp.) isolated from the plant Camellia japonica in Japan, is described as a powerful broad-spectrum anthelmintic natural product with low toxicity in animals. Further CODPs such as PF1022B, C, D and E have been isolated from the same culture and their structures have been established. Both PF1022A and PF1022E serve as valuable starting materials for the synthesis of semi-synthetic CODP derivatives with improved intrinsic anthelmintic potency and broad-spectrum activity. It was found that in most cases the di-substituted PF1022A derivatives showed a greater (or equal) activity by oral application against the gastrointestinal nematode Haemonchus contortus compared to the corresponding mono-substituted PF1022A analogues as exemplified by emodepside. In order to get additional information on the bioactive conformation, emodepside was transformed into its mono- and tetra-thionated derivatives by isosteric replacement. In the light of the increased efficacy of these derivatives against H. contortus or Trichostrongylus colubriformis, it has been suggested that the asymmetric conformation clearly influences the anthelmintic activity of CODPs. Although useful synthetic pathways are available today for the preparation of the semi-synthetic CODP emodepside, the fermentative production of its bis-para-nitro and bis-para-amino precursors could be the process used for its industrial-scale production in the future.

Transmission of herbicide resistance from a monoecious to a dioecious weedy Amaranthus species.

The genus Amaranthus includes several important monoecious and dioecious weed species, and several populations of these species have developed resistance to herbicides. These species are closely related and two or more species often coexist in agricultural settings. Collectively, these attributes raise the concern that herbicide resistance might transfer from one weedy Amaranthus species to another. We performed research to determine if a dominant allele encoding a herbicide-insensitive form of acetolactate synthase (ALS) could be transferred from a monoecious species, A. hybridus, to a dioecious species, A. rudis. Numerous F(1) hybrids were obtained from controlled crosses in a greenhouse between A. rudis and herbicide-resistant A. hybridus, and most (85%) of these hybrids were herbicide-resistant. Molecular analysis of the ALS gene was used to verify that herbicide-resistant hybrids contained both an A. rudis and an A. hybridus ALS allele. Although hybrids had greatly reduced fertility, 42 BC(1) plants were obtained by backcrossing 33 hybrids with male A. rudis. Fertility was greatly restored in BC(1) progeny, and numerous BC(2) progeny were obtained from a second backcross to A. rudis. The herbicide-resistance allele from A. hybridus was transmitted to 50% of the BC(1) progeny. The resistance allele was subsequently transmitted to and conferred herbicide resistance in 39 of 110 plants analyzed from four BC(2) families. Parental species, hybrids, and BC(2) progeny were compared for 2C nuclear DNA contents. The mean hybrid 2C nuclear DNA content, 1.27 pg, was equal to the average between A. rudis and A. hybridus, which had 2C DNA contents of 1.42 and 1.12 pg, respectively. The mean 2C DNA content of BC(2) plants, 1.40 pg, was significantly (alpha < 0.01) less than that of the recurring A. rudis parent and indicated that BC(2) plants were not polyploid. This report demonstrates that herbicide resistance can be acquired by A. rudis through a hybridization event with A. hybridus.

Exercise inhibits epithelial sodium channels in patients with cystic fibrosis.

The aim of this study was to determine the effects of a single exercise bout on luminal Cl(-) and Na(+) conductance in the respiratory epithelium of patients with cystic fibrosis (CF). In nine patients with CF and nine healthy control subjects, the transepithelial electrical potential difference (PD) of the nasal respiratory epithelium was recorded, first at rest and then during moderate-intensity exercise. Under both conditions, PD was first measured while superfusing the epithelium with isotonic saline. Then, the effects of amiloride and amiloride plus low chloride plus isoproterenol were determined. Exercise resulted in a significant lower PD compared with rest in patients with CF (-6.6 +/- 16.6 mV versus -33.6 +/- 10.0 mV, p < 0.0001) and control subjects (0.1 +/- 8.7 mV versus -7.1 +/- 5.1 mV, p < 0.01). The effects of amiloride on PD were reduced during exercise compared with rest in patients with CF (+15.8 +/- 9.5 mV versus +26.1 +/- 11.0 mV, p < 0.01) and control subjects (+5.8 +/- 4.8 mV versus +10.0 +/- 3.1 mV, p < 0.01). There was no effect of exercise on chloride conductance in patients with CF and control subjects. We conclude that moderate-intensity exercise partially blocks the amiloride-sensitive sodium conductance in the respiratory epithelium. The inhibition of luminal sodium conductance could increase water content of the mucus in the CF lung during exercise and may, in part, explain the beneficial effects of exercise in patients with CF.

Bilateral deficit during short-term, high-intensity cycle ergometry in girls and boys.

Peak torque during an isokinetic bilateral knee extension or flexion is usually lower than the summed peak torque of two unilateral contractions, and this phenomenon is designated as bilateral deficit (BD). The objectives of this study were to determine whether a BD also exists for more complex, alternating movements (e.g., short-term, high-intensity cycling), and to assess the possible effects of gender and maturity. Forty children and adolescents performed two unilateral (ULWAnT) and one bilateral Wingate anaerobic test (BLWAnT). The highest power reached in any 3-s interval (peak power; PP), and the total mechanical work (TMW) performed during the test was determined. Individual BD for PP (BDpp, %) was calculated by dividing the PP in the BLWAnT by the sum of the PP values of both ULWAnTs. The BD for TMW (BDTMw) was calculated in the same way. The sum of PP generated during the two ULWAnTs was larger than the PP measured in the BLWAnT (P<0.000001). The same difference was observed for TMW (P<0.0001). Maturity did not affect the BDpp or BDTMW (P=0.34). However, the BD was more pronounced in females compared to males (P= 0.03). In conclusion, a BD is evident during cycling exercise.

Mutation reports: epidermolysis bullosa simplex associated with severe mucous membrane involvement and novel mutations in the plectin gene.

We report a novel case of epidermolysis bullosa simplex with severe mucous membrane involvement and mutations in the plectin gene (PLEC1). The patient suffered from extensive blistering of the skin and oral and laryngeal mucous membranes. Electron microscopy of a lesional skin biopsy showed cleft formation within the basal cell layer of the epidermis. Antigen mapping displayed entirely negative staining for plectin, a large (>500 kDa) multifunctional adhesion protein present in hemidesmosomes of the basal keratinocytes. Mutation analysis revealed compound heterozygous, previously undisclosed nonsense mutations, Q1713X and R2351X, of paternal and maternal origin, respectively, within exon 32 of PLEC1. Based on earlier reports, plectin deficiency is associated with late onset muscular dystrophy in patients with epidermolysis bullosa. No signs of muscle weakness have been observed during the 4 y follow-up of our patient. This case illustrates the fact that molecular pathological analyses have prognostic implications in identification and evaluation of patients who appear to be at risk for development of muscular dystrophy later in life.

Granulomatous cheilitis and Crohn's disease in a 3-year-old boy.

Granulomatous cheilitis and Crohn's disease are disorders of unknown etiology. There are case reports describing their coincidence and pointing out the necessity of ruling out systemic disorders once the diagnosis of granulomatous cheilitis is made. However, such reports are few and the causal association of both diseases is controversial in the literature. We report the youngest patient so far, a 3-year-old boy, who had granulomatous cheilitis and Crohn's disease simultaneously. This coincidence so early in life strongly suggests that both represent manifestations of the same disease.

Albumin, IgG, retinol-binding protein, and alpha1-microglobulin excretion in childhood.

Urine concentrations of two high molecular weight proteins, albumin and IgG, and two low molecular weight proteins, alpha1-microglobulin (A1M) and retinol-binding protein (RBP), were measured in 657 healthy children from birth to 18 years of age. The urinary levels of RBP and A1M suggest an age-dependent decline, whereas the levels of albumin and IgG show an uneven distribution. Reference values for albumin, IgG, A1M, and RBP for each group are reported.

Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase.

Peutz-Jeghers (PJ) syndrome is an autosomal-dominant disorder characterized by melanocytic macules of the lips, multiple gastrointestinal hamartomatous polyps and an increased risk for various neoplasms, including gastrointestinal cancer. The PJ gene was recently mapped to chromosome 19p13.3 by linkage analysis, with the highest lod score at marker D19S886. In a distance of 190 kb proximal to D19S886, we identified and characterized a novel human gene encoding the serine threonine kinase STK11. In a three-generation PJ family, we found an STK11 allele with a deletion of exons 4 and 5 and an inversion of exons 6 and 7 segregating with the disease. Sequence analysis of STK11 exons in four unrelated PJ patients has identified three nonsense and one acceptor splice site mutations. All five germline mutations are predicted to disrupt the function of the kinase domain. We conclude that germline mutations in STK11, probably in conjunction with acquired genetic defects of the second allele in somatic cells, cause the manifestations of PJ syndrome.

Autoimmune hepatitis following hepatitis A virus infection.

A 7-year-old patient is reported who suffered from fatigue and jaundice due to chronic hepatitis. He had acquired hepatitis A virus infection in his community and communicated the disease to his German family 4 weeks later. While the other family members recovered from acute viral hepatitis A, the patient presented 10 weeks after the onset of hyperbilirubinemia (12 mg/dl) with the histology of chronic hepatitis, absence of markers for viral persistence, presence of autoantibodies against smooth muscle (1:320) and the asialoglycoprotein receptor (1:600), and marked hypergammaglobulinemia (3700 mg/dl), leading to the diagnosis of autoimmune hepatitis. The patient received immunosuppressive therapy, symptoms of liver disease disappeared, and autoantibodies cleared from circulation. The case is discussed in the context of a putative virus-induced autoimmune hepatitis in childhood. Autoimmune hepatitis may be induced by an external trigger. Hepatitis A virus infection is one of probably several triggers that may induce autoimmune hepatitis in predisposed individuals.

[Specific gene deletion in patients with cystic fibrosis: pilot study of a small patient cohort]. / Spezifische Gendeletionen bei Patienten mit zystischer Fibrose: Pilotstudie an einem kleinen Patientenkollektiv.

Identification and molecular cloning of the cystic fibrosis (CF)-gene was a major progress in genetic counseling of families with one or more affected children. In caucasian families about 70% of the CF-patients show a homozygous or heterozygous deletion of one amino acid, that is phenylalanine at position 508 (delta F508). In a pilot study we examined the DNA of 14 CF-patients for F508 deletions. DNA was amplified by PCR and hybridized with a oligonucleotide-probe specific for the mutation containing CF-gene. Surprisingly all of the patients had a deletion of F508 of at least one allele (10 for both alleles, 4 for one allele). This method is of great importance for carrier-diagnosis. The finding of these or other deletions within the CF-gene may represent a prognostic marker for this disease.

[Severe liver involvement by Capillaria hepatica]. / Schwerer Leberbefall durch Capillaria hepatica.

Human hepatic capillariasis is a rare disease, which predominantly affects children aged 1 to 4 years and has a poor prognosis in extensive infections. This is the first case observed in Germany. The main symptoms are those of severe parasitosis: persistent high fever, hepatomegaly, and excessive hypereosinophilia. Diagnosis is confirmed by the finding of intracellular typical eggs in liver biopsy. There is a lack of established therapy; our 18 months old girl developed liver fibrosis. She survived under a prolonged treatment with high doses of Thiabendazole and two single doses of Ivermectine. Decortin was given to inhibit further granulomatous processes in the liver.

[Computerized perimetry in infants treated with ethambutol (author's transl)]. / Zur computergesteuerten Gesichtsfeldkontrolle bei Kindern mit Ethambutol-Medikation.

Computerized perimetry of the central visual field (Competer) was utilized in 12 eyes of children treated with Ethambutol because of tuberculosis to verify potential visual hazards of the drug. Visual acuity, visual field and the mean retinal threshold of the central field revealed no significant changes with increasing cumulative Ethambutol dose up to 166.5 g. The visual field was re-checked five times with a consecutive time lapse of 7 weeks. It can be concluded that the critical total dose of 150 g that is considered to be potential dangerous in adults does not affect the optic nerve of the infant either. Since this total dose can be exceeded in the continued treatment of the disease parents should be aware of the necessity of repeated visual field examinations or color vision testing. This concern is especially valid in infants suffering from renal tuberculosis because of higher plasma levels of the drug when excretion is prolonged.

[Continual observation of clinical and immunological parameters, in particular of salivary IgA, in tonsillectomised children (author's transl)]. / Verlaufsbeobachtung klinischer und immunologischer Parameter, insbesondere des Speichel-IgA, bei tonsillektomierten Kindern.

In 106 tonsillectomised children the following parameters were measured before and after operation: clinical parameters (length, weight, postoperative complications), haematological parameters (BSR, Hg, PVC, RBC and WBC), and immunological parameters (IgG, IgA, IgM and salivary IgA); in a number of children measurements were taken over a period of more than three years. Standard values of salivary IgA in relation to total salivary protein were determined in non-infected children of various age groups. Compared with the standard and initial values we found some statistically significant changes in the serum immunglobulin levels and in the salivary IgA, but no irreversible pathological decrease in the above-mentioned parameters.

Continual observation of clinical and immunological parameters, in particular of salivary IgA, in tonsillectomised children.

In 106 tonsillectomised children the following parameters were measured before and after operation: clinical parameters (length, weight, postoperative complications), haematological parameters (BSR, Hg, PCV, RBC, and WBC), and immunological parameters (IgG, IgA, IgM, and salivary IgA); in a number of children measurements were taken over a period of more than 3 years. Standard values of salivary IgA in relation to total salivary protein were determined in noninfected children of various age groups. Compared to the standard and initial values, we found some statistically significant changes in the serum immunoglobulin levels and in the salivary IgA, but no irreversible pathological decrease in the above-mentioned parameters.