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Biomedical subjects

J M Schröder

Publications and source records attributed to J M Schröder.

At least 19 recordsLinked to original sources
PubMed2006

Antimicrobial skin peptides and proteins.

Human skin is permanently exposed to microorganisms, but rarely infected. One reason for this natural resistance might be the existence of a 'chemical barrier' consisting in constitutively and inducibly produced antimicrobial peptides and proteins (AMPs). Many of these AMPs can be induced in vitro by proinflammatory cytokines or bacteria. Apart from being expressed in vivo in inflammatory lesions, some AMPs are also focally expressed in skin in the absence of inflammation. This suggests that non-inflammatory stimuli of endogenous and/or exogenous origin can also stimulate AMP synthesis without inflammation. Such mediators might be ideal 'immune stimulants' to induce only the innate antimicrobial skin effector molecules without causing inflammation.

Animals↗
PubMed2006

Who is really in control of skin immunity under physiological circumstances - lymphocytes, dendritic cells or keratinocytes?

Our views of the skin immunity theatre are undergoing constant change. These not only reflect paradigm shifts in general immunology and skin biology, but also have profound clinical implications, which call for strategic changes in dermatological therapy. Nowhere can this be witnessed at a greater level of instructiveness and fascination than when addressing the question posed by this new Controversies feature. Thus, after a very long period of dominance by T cells and Langerhans cells as 'lead actors' on the skin immunity stage, the lowly keratinocyte has recently made an astounding theatrical appearance as a key protagonist of the innate skin immunity system, which may control even acquired skin immune responses. Further enhancing dramatic complexity and tension, the mast cell has entered as an additional actor claiming centre stage, and the epidermal Langerhans cell has slipped in a surprise appearance as the chief agent of immunotolerance. May you, esteemed reader, enjoy the spectacle offered here by selected immunodermatology authorities who double as 'stage managers' pushing their respective favourite actors into the limelight. You get everything you may expect from a good performance - complete with the impresario's overture that lures you into the theatre and sets the stage, competing divas, recently discovered new talents and even the critic's digest while the performance is still ongoing. By the time the curtain drops, you will have reached your own, independent conclusions on how to answer the title question of this play - at least for the time being...

Dendritic Cells↗
PubMed2005

Peripheral nerve and skeletal muscle involvement in CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by degeneration of vascular smooth muscle cells (VSMC) of nearly all tissues studied so far. The clinical phenotype of CADASIL shows great variability. The disease is caused by mutations of the Notch3 gene encoding the transmembrane receptor Notch3, which is expressed predominantly in VSMC. In some patients, neuromuscular symptoms have been described. To investigate the fine structural features of peripheral nerve and muscle biopsy specimens in more cases and greater detail, seven electron microscopically confirmed CADASIL patients showing a variable amount of granular osmiophilic material on the surface of VSMC were included in this study. Pathogenic mutations within the cluster region (exon 3 and 4) of the Notch3 gene were identified in six cases. Degeneration and regeneration of nerve fibers in the sural nerves, studied in four cases, was present, although moderate, in all nerve biopsy specimens, whereas an intramuscular nerve fascicle showed more severe changes. Enlarged mitochondria with needle-like calcium precipitates were repeatedly seen. In muscle biopsy specimens, some degree of neurogenic atrophy was apparent in addition to myopathic changes, including occasional ragged red fibers with abnormally large mitochondria, focal tubular aggregates, abnormal terminal cisternae, and myofibrillary abnormalities. Automated sequence analysis of the whole mitochondrial DNA performed in one patient revealed several nucleotide polymorphisms, which were not considered pathogenic. The findings suggest that in CADASIL degeneration of small blood vessels is initiated by defects of the surface membrane of VSMC. Dysfunction of these blood vessels may cause low-grade chronic ischemia with secondary hypoxidosis and a large variety of structural changes noted in skeletal muscle and peripheral nerves, although a primary influence of the underlying genetic defect can not be excluded.

CADASIL↗
PubMed2004

Actin myopathy with nemaline bodies, intranuclear rods, and a heterozygous mutation in ACTA1 (Asp154Asn).

Mutations in the skeletal muscle alpha-actin gene ( ACTA1) are associated by and large with three muscle diseases (1) congenital actin myopathy, (2) nemaline myopathy, and (3) intranuclear rod myopathy. More than 70 mutations have now been identified. The majority of ACTA1 mutations are dominant, a small number are recessive and most isolated cases with no previous family history have de novo dominant mutations. The present case, a boy of healthy Turkish parents, had a severe form of the disease of the latter type due to a heterozygous, presumably de novo mutation of the ACTA1 gene in exon 4 (Asp154Asn), with lack of spontaneous movements at birth requiring immediate mechanical ventilation. He died at the age of 9 weeks due to respiratory failure, secondary pneumonia, and chylothorax. The biopsy specimen of the femoral muscle was characterized by pleomorphic alterations with numerous muscle fibers showing accumulation of actin filaments, but, in addition, both nemaline bodies and intranuclear rod bodies. This was also seen in several other muscles investigated at autopsy. No developmental abnormalities of the central nervous system, and no loss of spinal motor neurons were detected despite atrophy or hypotrophy of a considerable number of muscle fibers. The peripheral nervous system, which has not been studied before in patients with ACTA1 mutations, showed no loss of motor or sensory myelinated fibers and no loss of sensory neurons in spinal ganglia.

Actins↗
PubMed2004

Apolipoprotein E and alpha-1-antichymotrypsin polymorphisms in sporadic inclusion body myositis.

Sporadic inclusion body myositis (s-IBM) is a progressive muscle disease of unknown aetiology. Characteristically, intracellular amyloid deposits are detectable, including beta-amyloid precursor protein, phosphorylated tau, alpha1-antichymotrypsin (alpha1-ACT) and apolipoprotein E (ApoE). Polymorphisms and mutations of the encoding genes have been identified in a variety of neurodegenerative diseases including Alzheimer's disease (AD). Beside other factors, polymorphisms may lead to protein accumulation in both diseases. In particular, polymorphisms within the ApoE and alpha1-ACT gene have been implicated in the aetiology of AD and s-IBM. We analysed ApoE and alpha1-ACT gene polymorphisms in 35 s-IBM patients. We could not identify any statistical significant correlation between distinct ApoE and alpha1-ACT genotypes and the risk of developing s-IBM. Additionally, ApoE and alpha1-ACT genotypes seem not to influence the onset age of s-IBM. A combination of different alpha1-ACT and ApoE genotypes appears not to enhance the risk of developing s-IBM. Therefore, allelic variations of alpha1-ACT and ApoE are unlikely to be genetic key factors in the aetiology of s-IBM.

Adolescent↗
PubMed2004

Optico-cochleo-dentate degeneration associated with severe peripheral neuropathy and caused by peroxisomal D-bifunctional protein deficiency.

The clinical, neuroradiological, neuropathological and biochemical findings in a patient with optico-cochleo-dentate degeneration (OCDD; OMIM 258700) are presented in a severe case succumbing at the age of 4 years. The electron microscopic and biochemical data showed for the first time that OCDD may occur as the phenotypic expression of D-bifunctional protein deficiency, i.e., a peroxisomal disorder. The boy was born as the first child of healthy, consanguineous parents of Turkish origin. No other family members were affected. The main clinical symptoms consisted of muscle hypotonia ("floppy infant"), generalized epileptic fits, hypacusis, rotatory nystagmus, insufficient pupillary reactions, and mental retardation. Fibroblast cultures revealed D-bifunctional protein deficiency. Neuropathological examination displayed moderate frontoparietal and insular microgyria, and atrophy of the cerebellum. Loss of neurons was severe in the granular layer, the Purkinje cell band of the cerebellum, and rather complete in the dentate nucleus. A corresponding loss of myelinated fibers associated with characteristic periodic acid-Schiff-positive macrophages was most prominent in the white matter of the cerebellum. There was additional severe loss of myelinated fibers in the central portions of the optic nerve, reduction of the nerve fiber density in the cochlear nerve, and reduction of myelinated nerve fibers by about 80-90% in the sural nerve, which has not been studied in previous cases. At the electron microscopic level, characteristic inclusions mainly in perivascular macrophages and astrocytes were the most prominent finding. The inclusions usually showed a bilaminar structure, whereas trilaminar structures, typically seen in adrenoleukodystrophy, and multilaminar structures were less frequently seen.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2004

Absence of KIF1B mutation in a large Turkish CMT2A family suggests involvement of a second gene.

BACKGROUND: Charcot-Marie-Tooth disease type 2A (CMT2A) was assigned to a 19.3-cM region on chromosome 1p35-36. A missense mutation in the kinesin family member 1B gene (KIF1B) was reported in a single CMT2A family. OBJECTIVE: To report the clinical and genetic data of a Turkish family with CMT2A. METHODS: Linkage to CMT2 loci was investigated in the family. Haplotype analysis of the CMT2A region was completed using additional single-nucleotide polymorphism and short tandem repeat markers. The KIF1B gene was sequenced on genomic DNA and cDNA in two patients. RESULTS: A recombination event narrowed the CMT2A locus to a 9.3-cM region flanked by D1S160 and D1S434. No mutation in KIF1B was found. CONCLUSION: The exclusion of KIF1B gene mutations in this family suggests the involvement of another CMT2A gene in the linked region.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Primary carnitine deficiency: adult onset lipid storage myopathy with a mild clinical course.

We studied two adult patients with myalgia and muscular fatigability during prolonged physical exercise. Serum creatine kinase was increased and muscle biopsy revealed a lipid storage myopathy affecting predominantly the type I fibres. Skeletal muscle carnitine content was reduced to 15% and 21% of the normal mean values, while serum carnitine levels were either normal or decreased. Four months of oral therapy with L-carnitine (3 g per day) resolved the clinical symptoms completely in both patients, and a subsequent muscle biopsy confirmed a marked reduction of lipid storage, along with increased muscle carnitine levels. The analysis of renal carnitine excretion and the exclusion of possible secondary carnitine deficiencies in both patients are compatible with mild defects of the carnitine transporter in one patient and of carnitine biosynthesis in the other. Since myalgia and muscular fatigue are frequent but unspecified complaints of otherwise clinically unremarkable adult patients, it is important to identify myopathies associated with primary carnitine deficiency because they may be amenable to treatment.

Adult↗
PubMed2004

NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression.

BACKGROUND: Mutations in NOD2, a putative intracellular receptor for bacterial peptidoglycans, are associated with a subset of Crohn's disease but the molecular mechanism linking this protein with the disease pathogenesis remains unclear. Human alpha defensins (HD-5 and HD-6) are antibiotic effector molecules predominantly expressed in Paneth cells of the ileum. Paneth cells also express NOD2. To address the hypothesis that the function of NOD2 may affect expression of Paneth cell defensins, we compared their expression levels with respect to NOD2 mutations in Crohn's disease. METHODS: Forty five Crohn's disease patients (24 with NOD2 mutations, 21 with wild-type NOD2) and 12 controls were studied. Real time reverse transcription-polymerase chain reaction was performed with mucosal mRNA for HD-5, HD-6, lysozyme, secretory phospholipase A2 (sPLA2), tumour necrosis factor alpha, interleukin 8, and human hypoxanthine phosphoribosyltransferase (housekeeping gene). Immunohistochemistry with anti-HD-5 and histological Paneth cell staining were performed in 10 patients with NOD2 mutations or wild-type genotypes. RESULTS: Ileal expression of HD-5 and HD-6, but not sPLA2 or lysozyme, were diminished in affected ileum, and the decrease was significantly more pronounced in patients with NOD2 mutations. In the colon, HD-5, HD-6, and sPLA2 were increased during inflammation in wild-type but not in NOD2 mutated patients. In both the colon and ileum, proinflammatory cytokines and lysozyme were unaffected by NOD2 status. Immunohistochemistry identified Paneth cells as the sole source of HD-5. CONCLUSION: As alpha defensins are important in the mucosal antibacterial barrier, their diminished expression may explain, in part, the bacterial induced mucosal inflammation and ileal involvement of Crohn's disease, especially in the case of NOD2 mutations.

Adolescent↗
PubMed2003

Inflammatory infiltrates in the spinal cord of patients with Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is defined as an acute inflammatory demyelinating polyradiculoneuropathy (AIDP) of the peripheral nervous system. Reports on central nervous system involvement in patients with GBS are rare and the histopathological analysis was usually restricted to conventional staining techniques. We were able to investigate four cases with GBS at autopsy in respect to the inflammatory infiltrates and histopathological changes in the spinal cord by immunohistochemistry using a panel of antibodies recognizing lymphocytes and different macrophage-activation antigens. There were increased inflammatory cell infiltrates comprising lymphocytes and macrophages in the spinal cord of two cases. In one of these two cases, GBS predominantly affecting the motor system similar to acute motor axonal neuropathy (AMAN) developed following hepatitis B vaccination; in the second one, GBS developed rapidly 4 days after onset of intravenous purified GM1-ganglioside application affecting the motor as well as the sensory system, resembling acute motor sensory axonal neuropathy (AMSAN). Impairment of the spinal anterior horn cells with their axons was suggested to be responsible for prolonged motor symptoms and the predominantly axonal type of neuropathy at least as a late-stage feature in these two cases with fatal outcome. Insignificant cellular infiltrates in the spinal cord were noted in the other two GBS cases. Focal cellular infiltration of spinal nerve roots and meninges was similar in all cases.

Adult↗
PubMed2003

Adult polyglucosan body disease: a postmortem correlation study.

Autopsy of a 50-year-old woman with adult polyglucosan body disease and missense mutations (Arg515His, Arg524Gln) in the glycogen branching enzyme gene (GBE) revealed accumulation of polyglucosan bodies in the heart, brain, and nerve. GBE activity was decreased in the morphologically affected tissues but was normal in unaffected tissues. GBE mRNA transcripts were similar in all tissues and in controls, which confirms the lack of tissue-specific GBE isoforms.

1,4-alpha-Glucan Branching Enzyme↗
PubMed2003

[Intraoperative histological sections in obstetric brachial plexus lesions--comparison of macroscopic appearance, HE staining and toluidine blue staining].

In brachial plexus lesions and their revision, evaluation of nerve stumps is very important for the reconstructive strategy. We intraoperatively perform cryostat sections, Haematoxilin-Eosin (HE) stained, and compare the clinical appearance of the nerves to the microscopic results. Toluidine blue staining is later used to validate the structural details. Intraneural fibrosis can be traced safely with both staining methods, in root avulsions a histology is helpful, too. For more proximal, intraforaminal lesions semithin section stained with toluidine-blue are less informative than are HE-stained cryostat sections. In these lesions the clinical control by electrical stimulation and evoked potentials is superior.

Adult↗
PubMed2002

Hypertrophic nerve roots in a case of Roussy-Lévy syndrome.

Hypertrophic radiculopathy is a rare feature of neuropathies. Single cases of enlarged nerve roots have been described in hereditary motor sensory neuropathies (HMSN) and chronic inflammatory demyelinating diseases (CIDP). This is the first description of hypertrophied nerve roots in a patient with Roussy-Lévy syndrome. MRI did not show contrast enhancement of the enlarged nerve roots or nodular lesions.

Charcot-Marie-Tooth Disease↗
PubMed2002

Congenital muscular dystrophy with adducted thumbs, ptosis, external ophthalmoplegia, mental retardation and cerebellar hypoplasia: a novel form of CMD.

At least six different forms of congenital muscular dystrophy are associated with structural changes of the central nervous system, and three of these have been mapped: merosin-deficient congenital muscular dystrophy on chromosome 6q2, Fukuyama congenital muscular dystrophy on chromosome 9q31, and muscle eye brain disease on chromosome 1p32. Walker-Warburg syndrome, congenital muscular dystrophy with calf hypertrophy, pontocerebellar hypoplasia, and normal eyes, and congenital muscular dystrophy with severe mental retardation and cerebellar cysts are nosologically distinct and have been excluded from the known congenital muscular dystrophy loci with structural changes of the central nervous system. Here, we describe a novel congenital muscular dystrophy syndrome which is phenotypically distinct from the recognized forms of congenital muscular dystrophy with brain involvement. Two siblings, a boy and a girl, were born to consanguineous parents from Sicily. Both children were born with adducted thumbs and toe contractures. They were floppy from birth, walked late, showed profound generalized muscle weakness including facial muscles, elevated creatine kinase levels of 200-700U/l, and histological changes compatible with muscular dystrophy. In addition, both showed ptosis, external ophthalmoplegia, mild mental retardation, and mild cerebellar hypoplasia on MRI. Immunocytochemistry showed normal expression of muscle membrane proteins including laminin alpha 2, laminin beta 2, and alpha-dystroglycan. Linkage analysis excluded the candidate loci on chromosomes 6q2, 9q31, and 1q32. The gene locus for congenital muscular dystrophy 1B, MDC 1B, on chromosome 1q42 was also excluded. Adducted thumbs are a distinct clinical sign that has not been reported in congenital muscular dystrophy before and should facilitate recognition of further patients with this disorder.

Blepharoptosis↗
PubMed2002

What is the 'true' function of skin?

Conventional textbook wisdom portrays the skin as an organ that literally enwraps whatever each of us stands for as a more or less functional, individual member of the mammalian species, and has it that the skin primarily establishes, controls and transmits contacts with the external world. In addition, the skin has long been recognized to protect the organism from deleterious environmental impacts (physical, chemical,microbiological), and is well-known as crucial for the maintenance of temperature, electrolyte and fluid balance. Now, ever more studies are being published that show the skin to also operate as a huge and highly active biofactory for the synthesis,processing and/or metabolism of an astounding range of e.g. structural proteins, glycans, lipids and signaling molecules. Increasingly, it becomes appreciated that the skin, furthermore, is an integral component of the immune, nervous and endocrine systems, with numerous lines of cross-talk between these systems established intracutaneously (e.g. Ann NY Acad Sci Vol 885, 1999; Endocrine Rev 21:457-487, 2000; Physiol Rev 80:980-1020, 2001; Exp Dermatol 10: 349-367, 2001). All these emerging cutaneous functions beyond the classical image of the skin as a barrier and sensory organ are immediately relevant for many of the quandaries that clinical dermatology, dermatopathology, and dermatopharmacology are still struggling with to-date, and offer the practising dermatologist attractive new targets for therapeutic intervention. Yet, many of these skin functions are not even mentioned in dermatology textbooks and await systematic therapeutic targeting. Following a suggestion by Enno Christophers, the current 'Controversies' feature brings together an unusually diverse council of biologists and clinicians, who share their thought-provoking views with the readers and allow us to peek into the future of research in cutaneous biology, not the least by reminding us of the -- often ignored -- evolutionary and embryonal origins of our favorite organ. Hopefully, this unique discussion feature will foster an understanding of the 'true' skin functions that is both more comprehensive and more profound than conventional teaching on this topic, and will stimulate more than 'skin-deep' reflections on the full range of skin functions.

Aging↗
PubMed2002

Occurrence and characterization of peripheral nerve involvement in neurofibromatosis type 2.

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder characterized by the occurrence of bilateral vestibular schwannomas, various brain and spinal tumours as well as peripheral nerve tumours, cutaneous tumours and juvenile posterior lenticular opacity. NF2 is caused by mutations in both alleles of a tumour suppressor gene coding for a protein called schwannomin or merlin. It is suggested that the development of NF2 tumours is caused by complete inactivation of the merlin/schwannomin gene. Interestingly, in a NF2 mouse model, peripheral nerve pathology was more frequently described than schwannomas. However, review of the literature shows that patients suffering from NF2 seldom have unexplained clinical features of peripheral nerve lesion unrelated to tumour masses. Single case reports describe sural nerve biopsies, which histologically show onion-bulb-like formations, seemingly originating from Schwann cells. We have conducted a systematic investigation to determine the occurrence and aetiology of peripheral nerve involvement in NF2 patients. We investigated 15 patients with definite NF2 and in 10 of these found electrophysiological evidence of neuropathy. In this study we present the classification of neuropathy, correlation to clinical findings, and histological findings of a sural nerve biopsy. We conclude that peripheral neuropathy, mostly of axonal type, is a common clinical finding in NF2. We hypothesize that the aetiology of this frequent peripheral neuropathy syndrome in NF2 is caused by compression effects of multiple tumourlets, originating along the length of the peripheral nerves on adjacent nerve fibres, by local influences of the endoneurial pathological cells on adjacent nerve fibres and/or the inability of these cells to properly adhere to, or ensheath, the axon.

Adult↗