Inflammatory profile discriminates clinical subtypes in LRRK2-associated Parkinson's disease.

BACKGROUND AND PURPOSE: The presentation of Parkinson's disease patients with mutations in the LRRK2 gene (PDLRRK2 ) is highly variable, suggesting a strong influence of modifying factors. In this context, inflammation is a potential candidate inducing clinical subtypes. METHODS: An extensive battery of peripheral inflammatory markers was measured in human serum in a multicentre cohort of 142 PDLRRK2 patients from the MJFF LRRK2 Consortium, stratified by three different subtypes as recently proposed for idiopathic Parkinson's disease: diffuse/malignant, intermediate and mainly pure motor. RESULTS: Patients classified as diffuse/malignant presented with the highest levels of the pro-inflammatory proteins interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1) and macrophage inflammatory protein 1-ß (MIP-1-ß) paralleled by high levels of the neurotrophic protein brain-derived neurotrophic factor (BDNF). It was also possible to distinguish the clinical subtypes based on their inflammatory profile by using discriminant and area under the receiver operating characteristic curve analysis. CONCLUSIONS: Inflammation seems to be associated with the presence of a specific clinical subtype in PDLRRK2 that is characterized by a broad and more severely affected spectrum of motor and non-motor symptoms. The pro-inflammatory metabolites IL-8, MCP-1 and MIP-1-ß as well as BDNF are interesting candidates to be included in biomarker panels that aim to differentiate subtypes in PDLRRK2 and predict progression.

Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure.

Non-mosaic males with a 46,XY karyotype and a MECP2 null mutation display a phenotype of severe neonatal-onset encephalopathy that is distinctly different from Rett syndrome (RTT). To increase awareness of this rare disorder, we are reporting novel findings in a sporadic case, compare them to 16 previously reported cases and establish salient criteria for clinical diagnosis. The proband suffered from general hypotonia and hypoxia caused by hypoventilation and irregular breathing. He developed abnormal movements, seizures and electroencephalogram abnormalities. He failed to thrive and to reach any motor milestones and died at 15 months from central respiratory failure without a diagnosis. In a muscle biopsy, type II fibers were reduced in diameter, indicating central hypoxia. At autopsy, the brain was small with disproportionate reduction of the frontal and temporal lobes. Synaptophysin staining of synaptic vesicles was greatly reduced in cerebellar and spinal cord sections. Analysis of Golgi-stained pyramidal neurons from cortical layers III and V of the frontal and temporal lobes revealed drastically diminished dendritic trees. Post-mortem MECP2 mutation analysis on DNA and RNA from fibroblasts revealed a novel de novo 9-nucleotide deletion including the intron 3/exon 4 splice junction. The two nucleotides flanking the deletion form a new splice site, and the aberrantly spliced transcript lacks seven nucleotides (r.378_384delTCCCCAG), causing a frameshift and premature termination codon (p.I126fsX11). Males with congenital encephalopathy, not females with RTT, represent the true human counterpart for the commonly studied Mecp2-/y mouse model and provide unique insight into the mechanisms of MeCP2 deficiency.

[Follow-up control of ultrasonographic neonatal screening of the hip]. / Verlaufskontrollen von Hüftbefunden im sonographischen Neugeborenenscreening.

1656 newborns were examined by ultrasound for early diagnosis of CDH in a screening program. In 2.5% of the cases, dysplasia or dislocation of the hip was diagnosed and required treatment. In all cases the final outcome after adequate treatment showed a hip joint without any abnormalities. 11.3% of type IIa-hips (using Graf's classification) did not reach an alpha-angle of 60 degrees until the 12th week. They were then therefore classified as type IIb. 97% of all hip joints were judged as normal in the course of the 4th month. This study emphasizes the necessity of a general ultrasound screening program. It also demonstrated that early and adequate treatment leads to a normal development of the joint.

[Heparin-induced thrombocytopenia after elective hip joint replacement with postoperative prevention of thromboembolism with low-molecular-weight heparin]. / Heparin-induzierte Thrombozytopenie nach elektivem Hüftgelenksersatz unter einer postoperativen Thromboembolieprophylaxe mit niedermolekularem Heparin.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a severe side effect of the prophylaxis of venous thromboembolism with unfractionated heparin. The aim of the present study is to gain more information on the incidence of HIT during prophylaxis of venous thromboembolism with low-molecular-weight heparin in elective hip surgery. METHODS: 586 consecutive patients were included into the prospective study, who were admitted to hospital for elective hip replacement. The incidence of thrombocytopenia, clinically manifest venous thromboembolism and of the heparin-induced IgG antibodies were analysed during prophylaxis with low molecular-weight heparin. Patients received once daily subcutaneously low molecular-weight heparin for a mean of 28 days postoperatively. Platelet counts and clinical examinations for the presence of venous thromboembolism were done at days 0, 2, 7 (+/- 1) and 12 (+/- 2). Heparin-induced IgG antibodies were determined before and after a 12 (+/- 2) days prophylaxis with low molecular-weight heparin in 265 of 586 patients randomly. Patients were reexamined for thromboembolic complications after 3 and 6 months. The clinical suspicion of thromboembolic complication was documented objectively. RESULTS: None of the patients developed a decrease of platelets of < 50% of the initial value. Ten of 265 patients had elevated IgG antibodies against heparin/platelet factor 4 before prophylaxis (3.8%). After the 12 (+/- 2) days prophylaxis 13 of 265 patients had elevated IgG antibodies (4.9%). C14 serotonin assay was positive in 0 of 10 patients before treatment and in 3 of 19 patients at day 12 (+/- 2). Ten patients developed venous thromboembolism postoperatively (8 x deep venous thrombosis, 2 x pulmonary embolism, no fatal embolism). Only 1/19 patients with elevated antiheparin IgG titres developed venous thromboembolism. The C14 serotonin assay was negative in this patient. Two patients died in the postoperative phase due to underlying cardiovascular diseases. CONCLUSIONS: In patients with elective hip replacement prophylaxis of venous thromboembolism with low molecular-weight heparin was associated with a very low incidence of HIT, and hence screening for HIT antibodies is not required.

[Review of the results of the ARO multicenter study]. / Uberblick und Ergebnisse der ARO-Multicenterstudie.

The ARO multicenter study intended to show clinical and radiological differences with regard to different systems of fixation and designs of the prothesis in total hip replacement in patients with hip dysplasia, osteoarthritis and rheumatoid arthritis. In 1987 and 1988 5255 total hip prothesis were implanted by the 24 hospitals which took part in the study. 3133 prothesis (95.6%) were clinically and radiologically examined. The follow-up period averaged 6.9 years. The results of the Aro multicenter-study showed that despite difficult preoperative conditions especially in cases of rheumatoid arthritis the satisfaction rate improved remarkably. During the operation less complications arose in comparison to patients with hip dysplasia and osteoarthritis. Regarding the rate of infection after operation there were no differences between the 3 groups. Only the rate of post-operative luxation concerning rheumatoid patients turned out to be twice the number of the others. In our opinion this is due to the fact that these rheumatics were operated by posterior approach. Patients with rheumatoid arthritis were satisfied most with their surgeries. Results of rheumatic patients according to Harris hip score were slightly worse than the results of the two other groups. This was due to systemic involvement and bad preoperative function of the hip. As a result of the study there were no differences in using cemented or cementless techniques for rheumatic hip replacement. The decision for the method of fixation should depend on the patient's ability to relief the prothesis after operation. The study has shown that cementless implantation can also be used for young rheumatics provided that a suitable design of prothesis will be selected.

[Implant failure after total hip replacement. Comparison of patients with primary coxarthrosis, rheumatoid arthritis and dysplastic coxarthrosis]. / Implantatversager nach Hüft-TEP-Implantation. Vergleich bei Patienten mit primärer Koxarthrose, rheumatischer Arthritis und Dysplasiekoxarthrose.

The analysis of THR-failures showed that the acetabular component still is the main problem of total hip replacement. The acetabular cup fails more often than the stem. In the midterm analysis the failure rate is a little bit higher in cementless than in cement fixed cups. The known effect that the failure rate of cups fixed with cement increases exponentially 8 to 10 years after implantation, could of course not be seen in this study. The success of the cementless fixation was negatively influenced by the diagnosis rheumatoid arthritis, age over 70 and the fixation manner: the failure rate of threaded cups was higher than the one of press-fit cups although the Zweymüller-cup as well as the Link type V-cup showed good results. The midterm results of the stem were very good for the cementless as for the cemented technique. Some implants showed compared to others significantly worse results. The further implantation should be thought of, what partially has already happened. The results of cementless stem fixation in patients with rheumatoid arthritis, osteoarthrosis and dysplastic osteoarthritis is comparable, so that cementless fixation should be thought of in case of adequate conditions (ability of partial weight bearing for some weeks, age under 60).

Phase-I trial of intravenous continuous infusion of tumor necrosis factor in advanced metastatic carcinomas.

Fifteen patients with advanced metastatic adenocarcinomas were treated in a phase-I study with continuous intravenous 24 h infusion of recombinant tumor necrosis factor alpha (TNF-alpha) in order to determine the maximum tolerated dose (MTD) and associated side-effects. Patients received 40-400 micrograms/m2 TNF-alpha once (arm A) or twice (arm B) weekly for a scheduled treatment period of 2 months. The observed systemic side-effects resembled those reported for interferons and included fever, chills, fatigue, headaches, myalgias, thrombocytopenia, prostration, and malaise. Dose-limiting toxicities, resulting in a median MTD of 200 micrograms/m2 for 24 h, were fever, chills, fatigue, myalgias, and thrombocytopenia. Out of 15 patients, 11 showed tumor progression, and 3 sustained in no change for over 2 months of treatment. A minor response was seen in 1 patient with a colorectal carcinoma and liver metastases. To reduce side-effects, patients were treated either with paracetamol or indomethacin. Higher MTDs were observed in patients treated with indomethacin. No detectable plasma TNF-alpha levels or TNF antibodies were measured under therapy (plasma TNF-alpha less than 20 pg/ml). We conclude that TNF-alpha appears to have some antineoplastic activity in patients with adenocarcinomas since 4 patients remained in no change or showed a minor response.

The distribution of fibronectin in lymph nodes infiltrated by Hodgkin's disease. An immunoperoxidase study on paraffin sections.

The tissue distribution of fibronectin (FN) was examined using a commercial anti-FN serum, the peroxidase-anti-peroxidase (PaP) technique, and paraffin sections of 22 lymph nodes affected by Hodgkin's disease. Vascular basement membranes and reticulin fibres are selectively stained and their structural changes in this pathological condition become readily visible. In contrast to the normal lymph node and to Hodgkin's disease with lymphocytic predominance, cases of mixed cellularity disease contain individual and focally grouped cells displaying intracytoplasmic FN. In nodular sclerosis these cells with fibroblast morphology are consistently numerous in the marginal zones of the cellular nodes. Strongly reacting mastocytes probably absorbed the applied antiserum non-immunologically. All the other cell types giving rise to the varying appearances of Hodgkin's lesions are consistently negative with respect to intracellular FN, including all forms of Hodgkin cells. We conclude that in Hodgkin's disease the immigration of FN-secreting fibroblasts is an integral part of the early sclerosing reaction, which in itself is a defence/repair mechanism closely related to scar formation.

Conspicuous enterocytic binding pattern for peanut lectin and malignant histiocytosis of the intestine.

We present a case of a 33 year old male with a history of early childhood diarrhoea and more recently diagnosed gluten sensitive enteropathy, who died with active disease, ulcerative proctosigmoiditis and desquamative erythrodermia associated with toxin induced shock. Autopsy revealed a tumour restricted to lymph nodes of the mesentery and the retroperitoneum. This is considered to be malignant histiocytosis of the intestine (MIH). Immunohistological examination of the diagnostic jejunal biopsy showed a pathological binding pattern for peanut lectin (PNL) within the enterocytes. This may be an expression of disturbed production or secretion of a product rich in non-reducing terminal D-galactosyl residues.

J-chain-producing immunoblastic lymphoma in a case of Richter's syndrome. Immunohistochemical evidence for a gradual malignant transformation of a single B-cell clone and flow cytophotometric data.

A 66-year old male with Richter's syndrome died 52 month after diagnosis of chronic lymphocytic leukaemia (CLL). The clinical course was characterized by a marked IgM hypoglobulinaemia which paralleled a chronically relapsing Herpes simplex infection. Autopsy showed a large retroperitoneal and intraabdominal tumour mass and well defined supradiaphragmatic lymphomas. Histological examination revealed a composite tumour consisting of CLL B-cell type (B-CLL) and immunoblastic malignant lymphoma of B-cell type (B-IbL). The lymphocytes bear mu-chains on their surface and to a lesser extend within their cytoplasm, the obviously defective immunoblasts produce J chains exclusively. Flow cytophotometric data seem to indicate an identical diploid stem line of the two tumours. The majority of the cells are in G0/1 phase. The CLL rarely produces mitoses, however, the IbL has a mitotic rate of 7% and a considerable proportion (33%) of cells in the phase of DNA-synthesis. This is the fourth malignant lymphoma and the second immunoblastic lymphoma to be reported that produces J chain in the absence of immunoglobulin.