Update on glycopeptide use in german university hospitals.

BACKGROUND: A previous study has shown considerable variation in glycopeptide use from 1992 through 1994 among four university hospitals in southern Germany. Active antimicrobial management in one of the hospitals was associated with the containment of glycopeptide consumption in the medical and surgical service at < 1.5 defined daily doses (DDD)/100 patient days in the subsequent period. In the present study, more recent data on comparative glycopeptide use in German university hospitals were analyzed. MATERIALS AND METHODS: Hospital pharmacy records from 1998 through 2000 were evaluated. The number of DDD (definition according to the World Health Organization [WHO]/Anatomic and Therapeutic Classification [ATC] index) per 100 patient days was calculated to compare glycopeptide use in different medical and surgical service areas between eight German university hospitals. RESULTS: The 3-year averages in recent glycopeptide use for the eight hospitals ranged between 1.3 and 8.8 DDD/100 patient days in the medical services, and between 0.7 and 1.8 DDD/100 patient days in the surgical services. Only one of the eight hospitals showed medical service glycopeptide use of < 1.5 DDD/100 patient days. In most hospitals, glycopeptide use was higher in the medical intensive care units (ICU) (median 8.6; range 4.3 to 12 DDD/100 patient days, data for the year 2000) than in the surgical ICUs (median 6.7; range 1.2 to 8.6 DDD/100 patient days, data for the year 2000). High use was also observed for hematology-oncology services (median 7.5; range 2.7 to 15.7 DDD/100 patient days, data for the year 2000). CONCLUSION: These recent data from a larger hospital sample confirm large variations in glycopeptide use, identify hematology-oncology services as a significant prescribing source along with ICUs, and indicate areas of probable overuse of glycopeptide antibiotics. The data may be useful as a benchmark for further focused drug use control interventions.

A screen for mutations in human homologues of mice exencephaly genes Tfap2alpha and Msx2 in patients with neural tube defects.

BACKGROUND: Very little is known about the identity of genetic factors involved in the complex etiology of nonsyndromic neural tube defects (NTD). Potential susceptibility genes have emerged from the vast number of mutant mouse strains displaying NTD. Reasonable candidates are the human homologues of mice exencephaly genes Tfap2alpha and Msx2, which are expressed in the developing neural tube. METHODS: A single-strand conformation analysis (SSCA) mutation screen of the coding sequences of TFAP2alpha and MSX2 was performed for 204 nonsyndromic NTD patients including cases of anencephaly (n = 10), encephalocele (n = 8), and spina bifida aperta, SBA (n = 183). A selected number of SBA patients was additionally tested for specific mutations in MTHFD, FRalpha, and PAX1 already shown to be related to NTD. RESULTS: Two TFAP2alpha point mutations in individual SBA patients were silent on the amino acid level (C308C, T396T). On nucleic acid level, these mutations change evolutionary conserved codons and thus may influence mRNA processing and translation efficiency. One SBA patient displayed an exonic 9-bp deletion in MSX2 leading to a shortened and possibly less functional protein. None of these mutations was found in 222 controls. Seven polymorphisms detected in TFAP2alpha and MSX2 were equally distributed in patients and controls. Patients with combined heterozygosity of an exonic MSX2 and an intronic TFAP2alpha polymorphism were at a slightly increased risk of NTD (OR 1.71; 95% CI 0.57-5.39). CONCLUSIONS: Although several new genetic variants were found in TFAP2 and MSX2, no statistically significant association was found between NTD cases and the new alleles or their combinations. Further studies are necessary to finally decide if these gene variants may have acted as susceptibility factors in our individual cases.

A cross-sectional study of dehydroepiandrosterone sulfate in prepubertal children with myelomeningocele.

OBJECTIVE: To assess biochemical characteristics of adrenarche in patients with myelomeningocele (MMC), we examined serum levels of dehydroepiandrosterone sulfate (DHEAS) in prepubertal MMC patients. PATIENTS AND METHODS: The study included a total of 54 prepubertal patients with MMC and shunted hydrocephalus: 13 patients (2 m, 11 f; aged 4.6-10.1 years, mean 8.1 +/- 0.4) with isolated pubarche (Tanner stage PH 2-4, B1 or testes volume < or =3 ml) and 41 prepubertal MMC patients without pubarche (17 m, 24 f; aged 2.0-11.9 years; mean 6.8 +/- 2.5). DHEAS levels were measured directly by chemiluminescence immunoassay (Nichols, USA). Auxological data (supine length, body mass index (BMI), arm span) and bone age (BA) were recorded. RESULTS: (mean +/- SD): Basal DHEAS levels correlated with chronological age (CA) (r = 0.32, p < 0.05), BA (r = 0.65, p < 0.01; n = 23), BMI (r = 0.54, p < 0.01) and pubic hair stage (PH1 vs. PH2-4, r = 0.49, p < 0.01). 10/11 patients aged 2-4 years had DHEAS levels in the normal range, whereas 18/40 (45.0%) of the 5- to 9-year-old patients showed elevated levels (>+2 SDS). Ten patients with isolated pubarche (10/13; 2 m, 8 f; CA 8.3 +/- 1.5 years) and 9 patients without pubarche (9/41; 6 m, 3 f; CA 6.9 +/- 2.1 years) had elevated DHEAS levels (+6.34 and +4.05 SDS, respectively). The values correlated with BA/CA ratio (p < 0.05, n = 23). There was a trend to higher BMI SDS levels in patients with elevated DHEAS levels. CONCLUSION: Our data show an early and increased activation of adrenal androgen secretion in MMC patients.

Does growth hormone (GH) enhance growth in GH-deficient children with myelomeningocele?

GH deficiency (GHD) in patients with myelomeningocele leads to the question of whether these disabled patients should be treated with human GH. To date, only a few short-term reports of GH therapy are available in the literature, and long-term data for final height are lacking. We report auxological and laboratory data for seven prepubertal myelomeningocele patients with proven GHD (idiopathic GHD or neurosecretory dysfunction) during GH treatment. All patients (five males and two females; median chronological age, 6.6 yr) had shunted hydrocephalus and were treated with GH (0.5 IU/kg x week; 0.15 mg/kg x week; daily sc injections) over a median period of 38 months (range, 35-49 months). GH secretion was analyzed by measurement of spontaneous overnight GH secretion and two standard stimulation tests. Auxological parameters, bone age, serum levels of insulin-like growth factor I and insulin-like growth factor-binding protein-3, and neurological and orthopedic status were documented regularly. Median growth velocity of supine length improved during treatment (at start, 3.7 cm/yr; after 36 months, 5.7 cm/yr; P < 0.05), with highest levels 6 months after the start of therapy (8.1 cm/yr). The growth velocity of arm span was greater than these values. Supine length SD score for chronological age increased from -4.71 (at start) to -3.35 (after 36 months; P = NS), length SD score for bone age increased from -2.70 to -2.23 (P = NS), and arm span SD score increased from -2.98 to -1.75 (P < 0.05). The growth velocities of length and arm span remained significantly above the pretreatment values (P < 0.05). Symptomatic tethered cord associated with progression of scoliosis developed in two of seven children. GH treatment significantly improved the growth velocities of body length and arm span. However, the increase in length SD score was not significant, whereas arm span SD scores significantly improved over the study period.

Pharmacological properties of parenteral cephalosporins: rationale for ambulatory use.

Parenteral cephalosporins are among the most frequently used antibiotics in hospital therapy. They are characterised by an extended spectrum of activity against gram-positive and gram-negative bacteria, and some also have good activity against anaerobes. They kill proliferating bacterial cells rapidly, and generally show only a low tendency to select resistant mutants. However, there are cephalosporin compounds which induce cephalosporinases very rapidly in certain microorganisms. Together with other beta-lactam antibiotics, parenteral cephalosporins interfere with bacterial cell wall synthesis by inhibiting peptidoglycan cross-linkage. Because of this specific target, they are nontoxic to mammalian cells, and have a very favourable adverse effect profile. The chemical stability of parenteral cephalosporins in aqueous solution is good. After intravenous injection, high concentrations of these agents are achieved in serum and tissue. Most cephalosporins are eliminated unchanged via the kidney, with a half-life of 1 to 2 hours. But there are also derivatives with a serum half-life of more than 2 and up to 8 hours, allowing 12- or 24-hour dosage intervals. Because of their reliable efficacy and low risk of adverse effects, the parenteral cephalosporins offer a high degree of tolerability even in the setting of outpatient antibiotic therapy. In particular, the derivatives of the third generation are characterised by unique pharmacological properties.

Arm span, serum IGF-1 and IGFBP-3 levels as screening parameters for the diagnosis of growth hormone deficiency in patients with myelomeningocele--preliminary data.

UNLABELLED: Short stature is a common problem in patients with myelomeningocele (MMC) and hydrocephalus. We evaluated auxological and laboratory parameters to differentiate short stature due to neurological defect from short stature additionally caused by growth hormone deficiency (GHD). In a group of 38 prepubertal patients with MMC and hydrocephalus aged 3.8-11.0 years, auxological parameters, including arm span and bone age, and serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels were measured. Patients with normal supine length (n = 15) had normal arm span. Serum IGF-1 and IGFBP-3 levels were normal (> or = 10th percentile) in 14/15 patients. Twenty-three MMC patients had short stature (height SDS < -2), 11/23 patients had reduced arm span (SDS < -2), and 12/23 had normal arm span. Serum IGF-1 and IGFBP-3 levels were normal in 10/12 of short statured patients with normal arm span, but low (< 10th percentile) in those patients with reduced arm span (IGF-1: 8/11 patients, P < 0.05; IGFBP-3: 9/11 patients, P < 0.005). In 7/11 short statured MMC patients with reduced arm span and low serum IGF-1 and IGFBP-3 levels, growth hormone secretion was investigated. All had a disturbed growth hormone secretion (GHD: n = 4; neurosecretory dysfunction: n = 3). CONCLUSION: Arm span, serum IGF-1 and IGFBP-3 levels are estimated to be appropriate screening parameters for GHD in patients with MMC. Initiating growth hormone therapy should be considered not only according to endocrine findings but also with respect to neurological and orthopaedic anomalies.

Precocious puberty in children with myelomeningocele: treatment with gonadotropin-releasing hormone analogues.

In patients with myelomeningocele (MMC), growth is influenced by a large number of growth-retarding factors due to the neurological defect. Moreover, endocrine disorders have been found to contribute to short stature in MMC patients. Central precocious puberty (CPP) is a common problem. Due to growth disturbances and difficulties in obtaining standardized measurements, MMC patients have been excluded from gonadotropin-releasing hormone (GnRH) analogue studies in the past. We report on eight patients (six female, two male) with MMC, hydrocephalus, and CPP who were treated with GnRH analogues: triptorelin intramuscularly (N=5) or leuprorelin subcutaneously (N=3). Auxological data and hormone levels were assessed before treatment and every 6 months during treatment. The median chronological ages (CA) at the start of treatment were 8.6 years (females) and 8.4 years (males). Bone age (BA) was accelerated in all cases prior to treatment and two girls were already menstruating. Elevated gonadotropin serum levels and sex steroid levels decreased during treatment, although no complete suppression to prepubertal levels was reached. Progression of pubertal development and menses stopped in all patients. The tempo of BA acceleration (deltaBA:deltaCA) decreased, but no significant improvement in height standard deviation score BA and predicted adult height resulted. No side effects during treatment were observed. CPP in MMC patients has to be considered as early as possible to enable an early diagnosis and corresponding treatment. Further prospective studies on the effects of GnRH analogues in MMC patients are necessary.

Growth and pubertal development in patients with meningomyelocele: a retrospective analysis.

Our retrospective analysis of growth and pubertal development includes 109 children and adults with meningomyelocele (MMC) (52 M, 57 F) aged 3.2-21.0 years (median 8.9 years). Anthropometric data, growth-retarding factors and data on pubertal development were analysed in comparison to the normal population using standards from Prader et al. (1). The results (mean +/- SD) were as follows. Fifty patients (46.8%) had short stature (height SDS for chronological age (SDS CA) < -2). The supine length was influenced by the level of the lesion (height SDS CA: > or = L2 -3.13 +/- 1.62, < or = S2 -0.46 +/- 1.27), ambulatory status, skeletal deformities and pubertal stage. The mean adult height (n = 15, age 16.1-21.0 years) measured 141.3 cm for women (height SDS CA -3.83 +/- 1.79) and 159.2 cm for men (height SDS CA -2.27 +/- 1.81). In 82.6% of the subjects (n = 90), arm spans were within the normal range. Reduced arm spans (SDS < -2) as found in 19 patients (17.4%) with short stature (mean height SDS CA -3.29 +/- 1.29) may be caused by factors other than neurological lesions and skeletal deformities, and require further endocrinological studies. Out of 27 pubertal patients, central precocious puberty was diagnosed in five girls. The stages of puberty in MMC girls developed earlier than expected for the age-related group.

Inhibition of dihydrofolate reductase activity by alcoholic extracts from Fraxinus excelsior, Populus tremula and Solidago virgaurea.

Aqueous-ethanolic extracts of Fraxinus excelsior, Populus, tremula and Solidago virgaurea in a combination of 1: 3: 1 (v/v/v) are the components of the plant drug Phytodolor N (abbreviated as PD), which exhibits antipyretic, analgesic and antirheumatic activity. Similar to a broad variety of synthetic non-steroidal anti-inflammatories the mentioned plant extracts inhibit dihydrofolate reductase. The following concentrations as percentage in the test volumes represent the individual I50-values: F. excelsior = 0.26% (v/v); P. tremula = 0.46% (v/v) and S. virgaurea = 0.6% (v/v). The combined extracts in PD exhibit an I50 at 0.3% (v/v). Testing the activity of the water-soluble compounds of corresponding dry extracts, the activity of F. excelsior with an apparent I50-value of 0.008% (w/v) by far dominates the inhibitory overall effect of the combination (I50 = 0.014%, w/v).

Biochemical activities of propolis-extracts. III. Inhibition of dihydrofolate reductase.

Ethanolic and aqueous extracts of the natural compound PROPOLIS indicate substantial antiinflammatory functions as well as antibiotic activities in vitro and in vivo. The exact mode of physiological or biochemical mechanisms responsible for the medical effects, however, is all but clear. The standardization on the basis of quantitative determination of prominent components of these extracts have been substituted recently by simple biochemical model reactions including photodynamic properties. In this communication we report on the inhibitory activity of an aqueous extract of propolis on the enzyme dihydrofolate reductase. This activity may at least partially be due to the content of caffeic acid, as revealed by HPLC chromatography and comparative activity tests of representative ingredients of the propolis extract. This result may explain some of the protective functions of propolis, similar to those shown for several "non-steroidal antiinflammatory drugs", NSAIDs.

Inhibition of dihydrofolate reductase by mofebutazon.

Mofebutazon, in contrast to phenylbutazon, inhibits dihydrofolate reductase in a concentration-dependent manner. An apparent Ki for mofebutazon and dihydrofolate reductase in the presence of NADPH as electron donor and dihydrofolate as electron acceptor of approximately 0.2 mM was calculated.

[Surgical intervention on the thymus in children and adolescents]. / Operative Eingriffe am Thymus bei Kindern und Jugendlichen.

Our group of 17 thymus operated patients--aged between 2 months and 18 years--consisted of 4 girls and 13 boys. All 5 patients whose operations were connected with a treatment for myasthenia gravis showed clinical improvement. In 3 children with malignant tumours the extent of surgery determined their subsequent prognosis. In 9 patients thoracotomy was performed because of space-occupying growth, or for the purpose of ensuring diagnostic safety.

EMG and needle muscle biopsy studies in arthrogryposis multiplex congenita.

From 1979 to 1983, EMG and/or muscle biopsy studies were done in twenty-one of twenty-two patients seen in our institution for the first time for arthrogryposis multiplex congenita (AMC). Most of the muscle biopsies were done with a needle. As expected, the final diagnosis in these patients was very heterogeneous since it is well recognized that AMC can be due to any factor that interferes with fetal mobility. We found however a surprisingly high number of patients (9/22) affected by a myopathic disease. Based on these results, we feel that needle muscle biopsy should be included as a routine procedure in infants affected by AMC since by clarifying the diagnosis it helps in improving genetic counselling and prognosis in these patients. It is now widely accepted that arthrogryposis multiplex congenita (AMC) is not in itself a disease but is secondary to any factor that interferes with fetal movements. The joint deformities seen in these children can be due to mechanical factors (oligohydramnios for example), central or peripheral nervous system disorders, muscle diseases... (Dubowitz 1978, Hageman and Willemse 1983, Hall 1981, Swinyard 1982). However, the relative frequency of each etiologic factor remains unclear since in spite of the abundant literature on the subject, we found only three reports describing the findings of electromyographic (EMG) and muscle biopsy studies done systematically in unselected groups of children affected by AMC (Amick et al 1967, Bharucha et al 1972, Dastur et al 1972, Kullmann and Szijj 1973). Furthermore, each article reached different conclusions in regard to the occurrence of these various etiologies in their respective patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Determination of concentration of an antibiotic (Cefotaxim) in the vaginal mucosa after preoperative intravenous administration]. / Konzentrationsbestimmung eines Antibiotikums (Cefotaxim) in der Vaginal-haut nach präoperativer intravenöser Gabe.

In 11 patients in whom an antibiotic (Cefotaxim) had been applied preoperatively, the tissue concentration was determined in the vaginal mucosa where postoperative infections after gynaecological operations are most common. The tissue concentration is compared with the minimum inhibition concentration of the pathogens identified directly before the operation in the cervicovaginal flora. In the case of the aerobic pathogens--with the exception of Pseudomonas aeruginosa--the concentration is far in excess of the necessary MIC, whereas with the anaerobic pathogens the concentration is only partly greater than the MIC. Resistance exists against Bacteroides fragilis.

Comparative determination of cefotaxime and desacetyl cefotaxime in serum and bile by bioassay and high-performance liquid chromatography.

In rat serum as well as in human serum and bile after injection of cefotaxime (CTX), the parent compound and the active metabolite desacetyl cefotaxime (dCTX) have been demonstrated by quantitative analysis with high-performance liquid chromatography (HPLC). Simultaneous determination of CTX by bioassay using test organisms sensitive to both CTX and dCTX resulted in spuriously high concentration readings of CTX. Using dCTX insensitive test organisms concentrations of cefotaxime obtained by agar diffusion test and by assay with HPLC were highly correlated. In human serum and bile after i.v. injection of 2 g CTX, as may be administered therapeutically, high concentrations of dCTX were observed. dCTX has a longer elimination half-life than the parent molecule. It is concluded that the measurement of CTX in biological fluids should be performed by HPLC or by bioassay with a selective test organism in order to obtain correct pharmacokinetic parameters.