[Development of an ivermectin-containing syrup as an extemporaneous preparation for treatment of scabies in children]. / Entwicklung eines Ivermectin-haltigen Saftes als Magistralrezeptur für Kinder zur Therapie der Skabies.

BACKGROUND: Oral ivermectin can be used to treat scabies. Evidence for safe and effective use in young children in individual treatment situations has been developed and published. In order to also ensure a body weight-adapted dosage for children, an ivermectin-containing syrup was developed as an extemporaneous preparation. MATERIALS AND METHODS: Since ivermectin is not available as a pure substance for the formulation, tablets containing active ingredient were used as a basic material for development. The formulation was designed according to pharmaceutical, regulatory and use-oriented criteria. An HPLC (high-pressure liquid chromatography) method was developed and validated to demonstrate chemical stability. In order to facilitate the practical implementation, information on suitable packaging material and application aids was also developed and the formulation was evaluated. RESULTS: It has been demonstrated that the final formulation produced in the pharmacy was stable and can be stored for 3 weeks. No concerns were raised regarding the tolerability of the syrup formulation. The physicochemical properties and the taste of the formulation allow the intended use as a well-dosed syrup for children. CONCLUSION: The developed formulation meets the requirements of the Apothekenbetriebsordnung (Pharmacy Work Rules; Section 7 ApBetrO) and enables an exact, body weight-adapted dosage of oral ivermectin in young children. Studies on human pharmacokinetics or clinical studies to demonstrate tolerability and/or efficacy are not available for the formulation.

Neonatal alcohol exposure augments voluntary ethanol intake in the absence of potentiated anxiety-like behavior induced by chronic intermittent ethanol vapor exposure.

Individuals fetally exposed to alcohol have a disproportionate risk for developing lifetime alcohol dependence, an association that may be confounded by the presence of comorbid conditions, such as anxiety. Anxiety is also observed following fetal alcohol exposure and is known to exacerbate ethanol consumption, highlighting the utility of animal models to assess this relationship. The present study evaluated the impact of third-trimester equivalent ethanol exposure on ethanol consumption and anxiety-like, marble burying behavior in adult, male C57BL/6 mice following exposure to chronic intermittent ethanol vapor, proposed to model dependence. Neonatal mice (P5-6, 2.5-3.0 g) were administered one injection of saline or ethanol (2.5 g/kg, subcutaneously [s.c.]). Pre-vapor marble burying and limited-access two-bottle choice ethanol intake (15% v/v, 2 h) were comparable in adults (8 weeks of age) across neonatal treatment groups. Five consecutive drinking sessions were repeated 72 h after each weekly ethanol vapor exposure procedure for a total of five vapor/drinking cycles. Consistent with prior research, an increase in voluntary ethanol drinking was observed in vapor-exposed, neonatal saline-treated mice throughout the study starting after the second vapor cycle compared to both air-exposed control groups. In neonatal ethanol-treated mice, this increase in ethanol intake and preference following vapor exposure was accelerated, being observed after the first vapor cycle, and observed at an augmented level compared to vapor-exposed, neonatal saline-treated mice and air controls for both neonatal conditions. Conversely, marble burying was enhanced equivalently in vapor-exposed mice from either neonatal treatment group relative to their respective air-exposed controls. These data recapitulate clinical observations of enhanced sensitivity for alcohol dependence following developmental alcohol exposure, which may reflect enhanced motivational drive rather than potentiated negative affect. The present model will facilitate the future exploration of mechanisms that underlie increased risk for alcohol use after early developmental exposure.

Isolated recessive nail dysplasia caused by FZD6 mutations: report of three families and review of the literature.

Congenital abnormalities of the nail are rare conditions that are most frequently associated with congenital ectodermal syndromes involving several of the epidermal appendages including the skin, teeth, hair and nails. Isolated recessive nail dysplasia (IRND) is much rarer but has recently been recognized as a condition resulting in 20-nail dystrophy in the absence of other cutaneous or extracutaneous findings. A few case reports have identified mutations in the Frizzled 6 (FZD6) gene in families presenting with abnormal nails consistent with IRND. These reports have highlighted the role of Wnt-FZD signalling in the process of nail formation. We report three families presenting with features of IRND, in whom we identified mutations in FZD6, including one previously unreported mutation.

23-Year-Old Female with an Inflammatory Myofibroblastic Tumour of the Breast: A Case Report and a Review of the Literature.

Purpose: Inflammatory myofibroblastic tumours (IMT) are a subcategory of inflammatory pseudotumours (IPT). They arise most commonly in the abdominopelvic region, lung and retroperitoneum, but virtually any anatomical site may be involved. Predominantly children and adolescents are affected and there is a tendency for local recurrence. In the literature up to the present, 20 patients have been reported with an IPT/IMT of the breast. We would like to present another patient with this unusual tumour entity of the breast and discuss the literature. Patient and Examinations: A 23-year-old woman presented with a painless lump in her left breast. There was no history of breast cancer in her family. Sonography showed a hypoechoic heterogeneous solid mass with irregular margins. A core needle biopsy revealed a tumour of high cellularity and a densely collagenous background. Immunohistochemically, the spindle-shaped cells were immunoreactive to smooth muscle actin and ALK-1 protein. Additional FISH analysis proved ALK rearrangements on chromosome 2p23 leading to the diagnosis of an IMT. Wide surgical excision was performed with no evidence of local recurrence after 12 months. Conclusion: Three of the above mentioned 20 patients with IMT/IPT of the breast developed a recurrent tumour, none presented with distant metastasis. A significant recurrence rate of 15 % leads to a clinically and sonographically close follow-up in these patients.

Association of hormone receptor status with grading, age of onset, and tumor size in BRCA1-associated breast cancer.

BRCA1-associated breast cancer frequently presents with estrogen-receptor (ERalpha) and progesterone-receptor (PR) negativity, grade 3, and early onset. In contrast, in BRCA1-deficient mice, ERalpha is highly expressed in early tumorigenesis. In a retrospective cohort study on 587 breast cancer patients with deleterious BRCA1 mutations, the correlation of ER, PR status, grading, age of onset, and tumor size was investigated. ERalpha and PR expression decreased from 62% in ductal carcinoma in situ (DCIS) to 20% and 16% in pT3, respectively (p value for ER 0.025 and PR 0.035, Fisher's exact test). The percentage of grade 1/2 tumors decreased from 44% in DCIS to 17% in pT3 (p value 0.074). Moreover, ER/PR positivity increased with increasing age. Our data suggest that early stage BRCA1-associated breast cancers are more frequently ERalpha and PR positive and low grade than advanced stages.

Platinum sensitivity in a BRCA1 mutation carrier with advanced breast cancer.

Although BRCA1-associated breast carcinomas are frequently detected in nodal-negative stage, they typically present with an aggressive histopathological phenotype that is reflected by a poor prognosis and an increased risk for distant metastatic spread. Recent in vitro data suggest a high sensitivity of BRCA1-associated carcinomas to platinum-based chemotherapy and a lower sensitivity to anthracyclines and taxanes. This is explained by the key role of BRCA1 in DNA double-strand repair via homologous recombination, thereby leading to a higher sensitivity to DNA intercalating agents, such as platinum. Here we present the case of a woman suffering from BRCA1-associated metastatic breast carcinoma that was resistant to docetaxel, but responded strongly to cisplatin-containing chemotherapy. This supports the rationale of ongoing clinical studies.

DNA microarray analysis identifies candidate regions and genes in unexplained mental retardation.

OBJECTIVE: Because in most patients with mental retardation (MR), who constitute 2 to 3% of the population, the etiology remains unknown, we wanted to identify novel chromosomal candidate regions and genes associated with the MR phenotype. METHODS: We screened for microimbalances in 60 clinically well-characterized patients with unexplained MR mostly combined with congenital anomalies. Genome-wide array-based comparative genomic hybridization was performed on DNA microarrays with an average resolution of <0.5 Mb. We verified every nonpolymorphic array clone outside the diagnostic thresholds by fluorescence in situ hybridization and performed breakpoint analyses on confirmed imbalances. RESULTS: Six presumably causal microimbalances were detected, five of which have not been reported. Microdeletions were found in five patients with MR and distinctive facial features, who also had neurologic findings (three cases), brain anomalies (two cases), and growth retardation (two cases), in chromosomal bands 6q11.1-q13 (10.8 Mb), Xq21.31-q21.33 (4.0 Mb), 1q24.1-q24.2 (3.8 Mb), 19p13.12 (2.1 Mb), and 4p12-p13 (1.1 Mb). One microduplication was detected in 22q11.2 (2.8 Mb) including the DiGeorge syndrome critical region in a patient with mild MR, microcephaly at birth, and dysmorphisms. Three imbalances were shown to be de novo and two inherited. The Xq21 microdeletion in a boy with borderline intellectual functioning was inherited from a normal mother; the 22q11.2 microduplication was inherited from a normal father and was present in two affected siblings. CONCLUSION: We could identify novel microimbalances as the probable cause of mental retardation in 10% of patients with unclear etiology. The gene content of the microimbalances was found to correlate with phenotype severity. Precise breakpoint analyses allowed the identification of deleted genes presumably causing mental retardation.

Design of high affinity cyclic pentapeptide ligands for kappa-opioid receptors.

Using results from our previously reported cyclic opioid peptide series and reliable models for mu-, delta-, and kappa-opioid receptors (MOR, DOR, and KOR, respectively) and their complexes with peptide ligands, we have designed and synthesized a series of cyclic pentapeptides of structure Tyr-C[D-Cys-Phe-Phe-X]-NH2, cyclized via disulfide, methylene, or ethylene dithioethers, and where X = D- or L-Cys; or D- or L-penicillamine (Pen; beta,beta-dimethylcysteine). Determination of binding affinities to MOR, DOR, and KOR revealed that members of this series with X = D- or L-Cys display KOR affinities in the low nanomolar range, demonstrating that a 'DPDPE-like' tetrapeptide scaffold is suitable not only for DOR and MOR ligands, but also for KOR ligands. The cyclic pentapeptides reported here are not, however, selective for KOR, rather they display significant selectivity and high affinity for MOR. Indeed, peptide 8, Tyr-C[D-Cys-Phe-Phe-Cys]-NH2-cyclized via a methylene dithioether, shows picomolar binding affinity for MOR ( = 16 pm) with more than 100-fold selectivity for MOR vs. DOR or KOR, and may be of interest as a high affinity, high selectivity MOR ligand. Nonetheless, the high affinity KOR peptides in this series represent excellent leads for the development of structurally related, selective KOR ligands designed to exploit structurally specific features of KOR, MOR, and DOR.

Roles of residues 3 and 4 in cyclic tetrapeptide ligand recognition by the kappa-opioid receptor.

A series of cyclic, disulfide- or dithioether-containing tetrapeptides based on previously reported potent mu- and delta-selective analogs has been explored with the aim of improving their poor affinity to the kappa-opioid receptor. Specifically targeted were modifications of tetrapeptide residues 3 and 4, as they presumably interact with residues from transmembrane helices 6 and 7 and extracellular loop 3 that differ among the three receptors. Accordingly, tetrapeptides were synthesized with Phe(3) replaced by aliphatic (Gly, Ala, Aib, Cha), basic (Lys, Arg, homo-Arg), or aromatic sides chains (Trp, Tyr, p-NH(2)Phe), and with d-Pen(4) replaced by d-Cys(4), and binding affinities to stably expressed mu-, delta-, and kappa-receptors were determined. In general, the resulting analogs failed to exhibit appreciable affinity for the kappa-receptor, with the exception of the tetrapeptide Tyr-c[d-Cys-Phe-d-Cys]-NH(2), cyclized via a disulfide bond, which demonstrated high binding affinity toward all opioid receptors (Ki(mu) = 1.26 nm, Ki(delta) = 16.1 nm, Ki(kappa) = 38.7 nm). Modeling of the kappa-receptor/ligand complex in the active state reveals that the receptor-binding pocket for residues 3 and 4 of the tetrapeptide ligands is smaller than that in the mu-receptor and requires, for optimal fit, that the tripeptide cycle of the ligand assume a higher energy conformation. The magnitude of this energy penalty depends on the nature of the fourth residue of the peptide (d-Pen or d-Cys) and correlates well with the observed kappa-receptor binding affinity.

Unbalanced translocation 8;Y (45,X,dic(Y;8)(q11.23;p23.1)): case report and review of terminal 8p deletions.

A boy with a rare unbalanced de novo Y/autosome translocation is presented. Main clinical features in the boy comprised a psychomotor delay, talipes planus, a dolichocephalus, low set and retroverted ears, supraorbital fullness of subcutaneous tissue and a bulbous nasal tip. Chromosomal analysis on amniocytes showed a single X chromosome and a derivative 8p (Karyotype: 45,X,der(8)GTG). The following DAPI staining revealed the inactivated centromere of the chromosome Y located on 8p and the absence of heterochromatic material Yq. Microsatellite analysis on fetal blood DNA using markers between SRY on Yp and DYS 240 on Yq proved presence of the spermatogenetic relevant factors. A terminal deletion of 8p was confirmed by FISH postnatally. Molecular genetic reassessment revealed the monosomy 8p to be of maternal origin; the translocation can thus be proven to have occurred in the zygote. The breakpoint in 8p was localised distal to GATA4, a gene which is involved in heart development; the finding that our patient did not suffer from cardiac problems agrees with the disomic presence of GATA4. Only the application of FISH combined with microsatellite analysis allowed a precise correlation between clinical phenotype and a subtle deletion of terminal 8p; furthermore, a recurrence risk for the parents could be excluded.

Localization of a gene for syndactyly type 1 to chromosome 2q34-q36.

Syndactyly type 1 (SD1) is an autosomal dominant limb malformation characterized in its classical form by complete or partial webbing between the third and fourth fingers and/or the second and third toes. After exclusion of a candidate region previously identified for syndactyly type 2 (synpolydactyly), we performed a genomewide linkage analysis in a large German pedigree. We found evidence for linkage of SD1 to polymorphic markers on chromosome 2q34-q36, with a maximum LOD score of 12.40 for marker D2S301. Key recombination events in affected individuals defined a 9.4-cM region between markers D2S2319 and D2S344. The identification of the responsible gene will give further insights into the molecular basis of limb development.

[Psychosomatic medicine in dermatologic education]. / Psychosomatik im dermatologischen Unterricht.

Ten years' experience in handling psychosomatic aspects as part of dermatology courses in Göttingen have revealed an unexpected need for such courses among students. Our program includes lectures as well as work in small groups.

[The disease course and psychosocial events in inpatient treatment of atopic eczema patients--a pilot study]. / Krankheitsverlauf und psychosoziale Ereignisse während der stationären Behandlung atopischer Ekzematiker--Eine Pilotstudie.

Our pilot study deals with the systematic investigation of the clinical experience that, in correlation with psychosocial events, atopic dermatitis may take an unexpected course (deterioration or improvement) during hospitalization. We describe our procedures regarding the proposal of hypotheses, the operationalization of the variables "deterioration of eczema" and "psychosocial factor", and our methods in gaining the data required. In the evaluation of 19 courses of treatment, we first checked the possible correlations between individual deterioration of eczema and various psychosocial events. We had to rule out, however, that a positive reaction like this was purely coincidental. In this respect, the event "confrontation with every day life" has significantly been confirmed. We discuss possible further studies which may ensue from our psychosomatic research concept.

[Confronting the artefact patient with manipulative behavior]. / Zur Frage der Konfrontation des Artefaktpatienten mit seinem manipulativen Verhalten.

Patients with self-inflicted skin disorders form a rather heterogeneous group. Our paper is intended to provide the practitioner with some orientation concerning interaction and therapeutic procedure in patients with artefactual skin diseases. Basically, these patients should be differentiated according to what extent they are aware of their manipulations. This degree of awareness should then be the guideline for a well-dosed and sensitive confrontation with their manipulative behavior. In any case, a positive result of the confrontation largely depends on the confidential relationship between physician and patient.

[Short-term discharge as a diagnostic and therapeutic possibility in psychosomatically oriented treatment of the atopic eczema patient]. / Kurzbeurlaubung als diagnostische und therapeutische Möglichkeit in der psychosomatisch orientierten Behandlung des atopischen Ekzematikers.

70 patients suffering from atopic dermatitis and receiving in-patient care were discharged for one or two days upon achieving an improved and stable dermatological state. Back in hospital after their short-term demission, two thirds of these patients showed a deterioration of their cutaneous condition. The majority of them were able to perceive a connection between their worsened skin condition and the acute psychosocial constellation during their brief stay at home. A second short-term demission brought about more acceptable and steady skin conditions, especially in patients treated psychosomatically. Some of the patients declared definite changes in their own modes of behavior to be responsible for this stabilized improvement.