[Practical implementation of an integrated care model in mother-child treatment]. / Praktische Umsetzung eines integrierten Versorgungsmodells in der Mutter-Kind-Behandlung.

This article summarizes the specific treatment options in the combined mother-child treatment for women with postpartum psychiatric disorders. The incidence of postpartum mental illness is high, especially for postpartum depression that probably occurs in10-15 % of cases. Mental disorders not only have a negative impact on the mental health of the women affected, such as chronification and suicidal tendencies but can also adversely affect the mother-child relationship as well as the emotional and cognitive development of the child. For these reasons it is important, also under the aspects of a primary prevention with respect to the children of mentally ill mothers, to provide a needs-oriented, timely and disorder-specific interactional therapy, which also considers the long-term aspects of treatment. At the Celenus Klinik Carolabad in Chemnitz an integrated treatment model, the "Carola PLUS", could be established that caters for the particularly high demands of combined care and treatment for both mother and child.

[Gastrointestinal bleeding in liver cirrhosis at the ICU]. / Gastrointestinale Blutungen als Komplikation von Patienten mit Leberzirrhose auf der Intensivstation.

Due to portal hypertension and bleeding disorders, patients with liver cirrhosis are at increased risk for severe gastrointestinal bleedings (GIB), commonly requiring therapy at the intensive care unit (ICU). In order to identify epidemiological and prognostic factors for GIB in cirrhotic patients, we retrospectively analysed patients from our medical ICU from 1999 to 2010. Among 7376 critically ill patients, 650 (8.8 %) were diagnosed with liver cirrhosis. Hepatic cirrhosis was frequently found in ICU patients admitted due to severe GIB (23.2 % of 711 patients had cirrhosis). Moreover, patients with cirrhosis were at increased risk to develop severe GIB during intensive care treatment (40.9 % of 44 patients with GIB during ICU stay had cirrhosis). Besides the high rate of variceal bleedings (64.4 %) in cirrhotic patients, non-variceal haemorrhages were also common (28.5 %). We identified the MELD score and necessity of mechanical ventilation as independent risk factors for mortality in cirrhotic patients with severe GIB. Patients with liver cirrhosis and severe GIB had significantly impaired prognosis (case-related fatality rate of 26.1 % with cirrhosis vs. 6.8 % without cirrhosis), especially in cases of newly developed GIB during ICU therapy. Advanced therapeutic approaches and novel strategies are warranted to improve the critical prognosis of these high-risk patients.

Photo-induced effects on self-organized TiO2 nanotube arrays: the influence of surface morphology.

Self-organized TiO(2) nanotubes with packed, vertically aligned morphology and different lateral characteristics were grown on Ti metal substrates by controlled electrochemical anodization in phosphate/HF and ethylene glycol/HF electrolytes. The wetting, photo-induced superhydrophilicity, and photocatalytic activity of the nanotubular materials were investigated under ultraviolet irradiation. The photoactivity of the TiO(2) nanotube arrays was analysed in terms of their morphological characteristics that were determined by means of scanning electron microscopy and atomic force microscopy in conjunction with geometrical modelling. The wetting and the UV-induced superhydrophilicity could be accordingly modelled by the Cassie-Baxter mode arising from the large scale roughness of the nanotubular arrays in combination with the Wenzel mode due to the small scale roughness induced by ridges at the outer tube surface. The photocatalytic activity of the TiO(2) nanotube arrays was further found to correlate quantitatively with the variation of the geometric roughness factor, verifying the strong impact of morphology on the photo-induced properties of the vertically oriented TiO(2) tubular architecture.

[Cutaneous malignant peripheral nerve sheath tumor in neurofibromatosis type 1]. / Kutaner maligner peripherer Nervenscheidentumor bei Neurofibromatose Typ 1.

Patients with neurofibromatosis have an increased risk of developing malignant tumors in comparison to the general population. We describe a woman who developed a malignant peripheral nerve sheath tumor in a pre-existing neurofibroma.

[Juvenile hyaline fibromatosis]. / Juvenile hyaline Fibromatose.

Juvenile hyaline fibromatosis is a rare autosomal recessive disease of the connective tissue. We present the case of a 6-year-old normal mental developed boy with confluent pearly papules behind the ears and in the paranasal folds, firm nodules of the scalp, the back and metaphalangs, and severe gingival hypertrophy.

Topoisomerase II activities in AML and their correlation with cellular sensitivity to anthracyclines and epipodophyllotoxines.

We have developed a method to quantify topoisomerase (topo) II activities in partially purified nuclear extracts from human leukemia cells. By virtue of their different pH optima in the reaction buffer, two different topo II activities were found with activity optima at pH 7.9 and at pH 8.9 under high stringency conditions. The activities could be identified as topo II beta activity (pH 7.9) and topo II alpha activity (pH 8.9) by their different sensitivities to topo II alpha inhibitors, dephosphorylation experiments and immunoprecipitation with polyclonal antibodies. Seventy-two bone marrow or blood samples from patients with acute myeloid leukemias have been examined and their in vitro sensitivities to anthracyclines and epipodophyllotoxines correlated to the activities of topo II alpha and topo II beta. Although the topo II alpha activity could be directly inhibited by incubation of the cells with the mentioned drugs, no correlation between the topo II alpha activity and the sensitivity of the cells could be found. In contrast, the topo II beta activity which was not substantially inhibited by the drugs inversely correlated with the sensitivity of the cells. These findings were statistically significant for idarubicin (P= 0.017) and daunorubicin (P = 0.006). Vice versa, resistant cells (IC50 > median) had a higher topo II beta activity. Clinical relevance might be indicated by the finding that cells from patients that relapsed after initial treatment with anthracyclin-containing regiments had a significantly higher topo II alpha/beta activity ratio (P=0.0276). Obviously, the sensitivity of AML cells is substantially influenced by the activity of the resistant topo II (topo II beta) which gives evidence that the remaining topo II activity after treatment helps the cell to survive the DNA repair phase.

Topoisomerase II activities in AML blasts and their correlation with cellular sensitivity to anthracyclines and epipodophyllotoxines.

We have developed a method to quantify topoisomerase (topo) II activities in partially purified nuclear extracts from human leukemia cells. By virtue of their different pH optima in the reaction buffer, two different topo II activities were found with activity optima at pH 7.9 and at pH 8.9 under high stringency conditions. The activities could be identified as topo II beta activity (pH 7.9) and topo II alpha activity (pH 8.9) by their different sensitivities to topo II alpha inhibitors, dephosphorylation experiments and immunoprecipitation with polyclonal antibodies. Seventy-two bone marrow or blood samples from patients with acute myeloid leukemias have been examined and their in vitro sensitivities to anthracyclines and epipodophyllotoxines correlated to the activities of topo II alpha and topo II beta. Although the topo II alpha activity could be directly inhibited by incubation of the cells with the mentioned drugs, no correlation between the topo II alpha activity and the sensitivity of the cells could be found. In contrast, the topo II beta activity which was not substantially inhibited by the drugs inversely correlated with the sensitivity of the cells. These findings were statistically significant for idarubicin (P=0.017) and daunorubicin (P=0.006). Vice versa, resistant cells (IC90 > median) had a higher topo II beta activity. Clinical relevance might be indicated by the finding that cells from patients that relapsed after initial treatment with anthracyclin-containing regiments had a significantly higher topo II alpha/beta activity ratio (P=0.0276). Obviously, the sensitivity of AML cells is substantially influenced by the activity of the resistant topo II (topo II beta) which gives evidence that the remaining topo II activity after treatment helps the cell to survive the DNA repair phase.

Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of HSP linked to the SPG3A locus.

Hereditary spastic paraplegias (HSP) comprise a genetically and clinically heterogeneous group of neurodegenerative disorders characterised by progressive spasticity and hyperreflexia of the lower limbs. Autosomal dominant hereditary spastic paraplegia linked to the SPG3A locus on chromosome 14q11-21 accounts for approximately 10% of autosomal dominant hereditary spastic paraplegia (ADHSP). It is caused by mutations in the SPG3A gene encoding the protein atlastin. To date, only five disease-causing mutations in the SPG3A gene have been described. We analysed 13 SPG4-negative families for mutations in the SPG3A gene and identified a mutation in 38% (5/13). Two of the mutations are novel, c.481G>C (p.A161P) and c.740A>C (p.H247P). One of the novel mutations was found both in a family with early onset of symptoms and in a late onset family. Furthermore, we report on numerous polymorphisms detected in the SPG3A gene.

Autosomal dominant hypertension and brachydactyly in a Turkish kindred resembles essential hypertension.

We examined a Turkish kindred with a unique form of autosomal dominant hypertension that cosegregates 100% with brachydactyly and maps to chromosome 12p. Affected adults were 10 to 15 cm shorter than unaffected people; however, their body mass index (27 kg/m2) was not different. Blood pressure increased steeply with age in the affected people so that by age 40 years, they had a mean blood pressure of 140 mm Hg, compared with 92 mm Hg in unaffected individuals. Complete clinical, roentgenographic, and laboratory evaluation was performed in 6 subjects, including 24-hour blood pressure measurements and humoral determinations before and after volume expansion with 2 L normal saline over 4 hours followed by volume contraction on the following day with a 20-mmol sodium diet and 40 mg furosemide at 8 AM, noon, and 4 PM. Two affected men aged 46 and 31 years; 3 affected women aged 40, 31, and 30 years; and 1 unaffected man aged 29 years were studied. Systolic pressures ranged from 170 to 250 mm Hg, and diastolic pressures ranged from 100 to 150 mm Hg in affected people; the unaffected man had a blood pressure of 120/70 mm Hg. Thyroid, adrenal, and renal functions were normal; electrolyte and acid-base statuses were normal. Calcium and phosphate homeostasis was normal. Day-night circadian blood pressure rhythm was preserved. The subjects were not salt sensitive; renin, aldosterone, and catecholamine values reacted appropriately to volume expansion and contraction. Affected people had mild cardiac hypertrophy and increased radial artery wall thickness. Fibroblasts from affected people grew more rapidly in culture than from unaffected people. We conclude that this novel form of inherited hypertension resembles essential hypertension.

Phenotypic variation and genetic heterogeneity in Léri-Weill syndrome.

Léri-Weill syndrome (LWS) or dyschondrosteosis represents a short stature syndrome characterised by the mesomelic shortening of the forearms and lower legs and by bilateral Madelung deformity of the wrists. Recently, mutations in the pseudoautosomal homeobox gene SHOX have been shown to be causative for this disorder. This gene has previously been described as the short stature gene implicated in Turner syndrome (TS). We studied 32 Léri-Weill patients from 18 different German and Dutch families and present clinical, radiological and molecular data. Phenotypic inter- and intrafamilial heterogeneity is a frequent finding in LWS, and phenotypic manifestations are generally more severe in females. In males, muscular hypertrophy is a frequent finding. To test for SHOX mutations we used FISH, Southern blot and SSCP analysis as well as long-range PCR and sequencing. We identified (sub)microscopic deletions encompassing the SHOX gene region in 10 out of 18 families investigated. Deletion sizes varied between 100 kb and 9 Mb and did not correlate with the severity of the phenotype. We did not detect SHOX mutations in almost half (41%) the LWS families studied, which suggests different genetic etiologies.

Spectrum of mutations in the Fanconi anaemia group G gene, FANCG/XRCC9.

FANCG was the third Faconi anaemia gene identified and proved to be identical to the previously cloned XRCC9 gene. We present the pathogenic mutations and sequence variants we have so far identified in a panel of FA-G patients. Mutation screening was performed by PCR, single strand conformational polymorphism analysis and protein truncation tests. Altogether 18 mutations have been determined in 20 families - 97% of all expected mutant alleles. All mutation types have been found, with the exception of large deletions, the large majority is predicted to lead to shortened proteins. One stop codon mutation, E105X, has been found in several German patients and this founder mutation accounts for 44% of the mutant FANCG alleles in German FA-G patients. Comparison of clinical phenotypes shows that patients homozygous for this mutation have an earlier onset of the haematological disorder than most other FA-G patients. The mouse Fancg sequence was established in order to evaluate missense mutations. A putative missense mutation, L71P, in a possible leucine zipper motif may affect FANCG binding of FANCA and seems to be associated with a milder clinical phenotype.

6-Aryl-4,5-dihydro-3(2H)-pyridazinones. A new class of compounds with platelet aggregation inhibiting and hypotensive activities.

This paper reports on the synthesis and pharmacological activity of 6-aryl-4,5-dihydro-3(2H)-pyridazinone derivatives. The compounds exhibit an aggregation inhibiting action on human platelets in vitro and on rat platelets under ex vivo conditions, as well as a hypotensive action on rats. The strongest pharmacological effects were found with dihydropyridazinones, which have a 6-[p-[(chloroalkanoyl)amino]phenyl] substituent, together with a methyl group in the 5-position. The antiaggregation activity of compounds of this type is in vitro up to 16000 times and ex vivo up to 370 times greater than that of acetylsalicylic acid; the hypotensive action is up to 40 times as great as that of the comparative substance dihydralazine.

Two spatial memories for honeybee navigation.

Insect navigation is thought to be based on an egocentric reference system which relates vector information derived from path integration to views of landmarks experienced en route and at the goal. Here we show that honeybees also possess an allocentric form of spatial memory which allows localization of multiple places relative to the intended goal, the hive. The egocentric route memory, which is called the specialized route memory (SRM) here, initially dominates navigation when an animal is first trained to a feeding site and then released at an unexpected site and this is why it is the only reference system detected so far in experiments with bees. However, the SRM can be replaced by an allocentric spatial memory called the general landscape memory (GLM). The GLM is directly accessible to the honeybee (and to the experimenter) if no SRM exists, for example, if bees were not trained along a route before testing. Under these conditions bees return to the hive from all directions around the hive at a speed comparable to that of an equally long flight along a trained route. The flexible use of the GLM indicates that bees may store relational information on places, connections between landmarks and the hive and/or views of landmarks from different directions and, thus, the GLM may have a graph structure, at least with respect to one goal, i.e. the hive.

A new observation of two cases of acrofacial dysostosis type Genée-Wiedemann in a family--remarks on the mode of inheritance: report on two sibs.

We report on a Yugoslavian sibpair with postaxial acrofacial dysostosis type Genée-Wiedemann with some novel signs which broaden the spectrum of this syndrome. The manifestations of the present cases are compared with those of the previously described patients. Life expectancy, change of symptoms over time, and the mode of inheritance are discussed.

Five familial cases of opsismodysplasia substantiate the hypothesis of autosomal recessive inheritance.

We describe a family with two marriages of first cousins and a total of five children with opsismodysplasia. The diagnosis was based on clinical, radiological, and immunhistochemical findings. Helpful to the diagnosis was the testing with type I collagen antibodies, showing abnormally high levels in the hypertrophic area of growth cartilage. This observation supports the hypothesis of autosomal recessive transmission of opsismodysplasia.

Computer assisted diagnosis of malformation syndromes: an evaluation of three databases (LDDB, POSSUM, and SYNDROC).

Computer programs which can be used as an aid to diagnose multiple congenital anomaly syndromes have been used for many years, but up to now they have been evaluated very rarely. The diagnostic abilities of three of these systems [LDDB (London Dysmorphology Database), POSSUM (Pictures of Standard Syndromes and Undiagnosed Malformations), and SYNDROC] were analyzed. All three programs are based on an algorithm which defines a diagnosis by a set of phenotypic components all having the same weight (descriptive algorithm). A second algorithm is applied by SYNDROC to rank competing diagnoses in order of probability. This pseudo-Bayesian algorithm provides a coefficient of certitude (CC). For a test the clinical findings of 102 patients who had received a firm diagnosis were used. Two search strategies were tried: "novice's strategy" with all findings taken for a search and "expert's strategy" with a selected set of anomalies. Only those diagnoses that were suggested with the 1st rank, defined as the highest degree of agreement, or the highest CC were studied. The greatest resemblance between suggestions of the databases and the clinical diagnosis was obtained with the expert strategy. The highest number of matches were produced by SYNDROC (80 with expert strategy) and the lowest by POSSUM (54 with novice strategy). The overall agreement between the databases is about 40% for the 1st rank. This number reflects that different authors use different pivotal signs for the description of a syndrome. With the pseudo-Bayesian algorithm 59 cases obtained the highest CC value. Great difficulties exist with the subjective estimates for the calculation of these values; the absolute CC values seem to be meaningless. A small number of unusual cases with special combinations of anomalies provide serious problems for correct diagnosis.

Unilateral terminal aphalangia in father and daughter--exogenous or genetic cause?

Published cases of familial unilateral terminal transverse defects are scarce. We report on a morphologically similar defect of the hand in a father and his daughter. The hand anomaly is similar in both, but on the opposite side. Thalidomide was taken in the sensitive period of the pregnancy by the father's mother. To our knowledge this is the second description of unilateral terminal aphalangia in successive generations. In order to evaluate the possible genetic basis we analyze epidemiological studies in respect to the recurrence risk of cases with isolated limb reduction defects. We compare reports of familial occurrence concerning the degree of relationship as well as the pattern of malformation. The latter seems to be an important aspect from an evolutionary and a developmental viewpoint. For our observation an autosomal dominant transmission is the most likely although multifactorial determination cannot be excluded.

Phenotypic differences in Angelman syndrome patients: imprinting mutations show less frequently microcephaly and hypopigmentation than deletions.

Angelman syndrome (AS) is a relatively frequent disorder of psychomotor development caused by loss of function of a gene from chromosome 15q11-q13, a region subject to genomic imprinting. The AS gene(s) is exclusively expressed from the maternal chromosome. Several kinds of mutations have been found to cause AS. More than half of the cases exhibit a deletion of the maternal 15q11-q13 region. Recently, we and others described a new mutation type, the imprinting mutation, characterised by normal, biparental inheritance but aberrant methylation patterns of the entire chromosomal region. In AS, a paternal imprint is found on the maternal chromosome probably leading to functional inactivation of the AS gene(s). We have now compared the phenotype of 9 AS patients with imprinting mutation to that of nine age-matched ones with a maternally derived deletion. Both groups were evaluated for 19 common AS symptoms. All patients, independently of their molecular findings, showed classical AS symptoms such s mental retardation, delayed motor development, and absent speech. In contrast, for two signs, hypopigmentation and microcephaly, a different distribution among both groups was observed. Only one of nine AS patients with an imprinting mutation, but seven of nine in the deletion control group showed either symptom. Our results suggest that imprinting mutations, in contrast to deletions, cause only incomplete loss of gene function or that maternally derived deletions affect also genes not subject to genomic imprinting. We conclude that AS is caused by loss of function of a major gene that is imprinted but that there are also other genes that contribute to the phenotype when in hemizygous condition.

Homozygosity mapping in a family with microcephaly, mental retardation, and short stature to a Cohen syndrome region on 8q21.3-8q22.1: redefining a clinical entity.

A syndrome of microcephaly, progressive postnatal growth deficiency, and mental retardation was observed in two brothers and their cousin from a multiply consanguineous kindred of Lebanese descent. Hypotonia, chorioretinal dystrophy, and myopia were also identified. The severity of the condition varied among the closely related patients. Because of absence of a distinctive facial appearance, the degree of mental retardation, and short stature, the initially considered clinical diagnosis of Cohen syndrome was withdrawn and a novel genetic entity was assumed. Homozygosity mapping in this family assigned the gene to a 26.8-cM region on the chromosome band 8q21.3 -22.1, between the microsatellites at D8S270 and D8S514. The maximum two-point LOD score was found for marker at D8S267 (Zmax=3.237 at Omax=0.00). Intriguingly enough, the identified gene region overlaps the refined gene region for Cohen syndrome (COH1) [Kolehmainen et al., 1997: Euro J Hum Genet 5:206-213]. This fact encourages the hypothesis that the described kindred segregates for a variant of Cohen syndrome and suggests a redefinition of its phenotype.

Autosomal-recessive neural crest syndrome with albinism, black lock, cell migration disorder of the neurocytes of the gut, and deafness: ABCD syndrome.

We report on a macrosomic newborn girl with albinism, a black lock at the right temporo-occipital region, and retinal depigmentation. Bilateral deafness was confirmed by brainstem auditory-evoked potentials. In addition, the infant had a severe defect of intestinal innervation. Biopsy showed aganglionosis of the large intestine, and total absence of neurocytes and nerve fibers in the small intestine, indicating a total lack of sympathetic and parasympathetic innervation. The infant died of intestinal dysfunction at 5 weeks. She was the 14th child of consanguineous Kurdish parents. Four sibs of our patient had the same syndrome and died a few days after birth. The other 9 sibs are well, with an unremarkable phenotype. A syndrome of albinism, black lock, deafness, and a total lack of intestinal neural innervation has not yet been reported. It represents a new neural crest syndrome with autosomal-recessive inheritance.