Vascular endothelial growth factor in CSF: a biological marker for carcinomatous meningitis.

OBJECTIVE: To determine the value of vascular endothelial growth factor (VEGF) in CSF as a marker for carcinomatous meningitis (CM). METHODS: The concentration of VEGF was measured by ELISA in matched samples of CSF and serum collected from 162 patients. These included patients with solid tumors with CM (n = 11) or brain metastases without concomitant CM (n = 12), paraneoplastic neurologic syndromes (n = 4), viral (n = 15) and bacterial (n = 20) meningitis, and a variety of non-neoplastic and noninfectious neurologic diseases (n = 100). Using CSF/serum albumin ratios, the VEGF index was calculated to estimate the proportion of intrathecally produced VEGF. Immunohistochemical staining for VEGF was performed in a brain metastasis from a mammary carcinoma associated with CM. RESULTS: High VEGF levels (median 6,794.8 pg/mL) were found in CSF of all patients with CM, whereas VEGF levels in matched sera were comparable to other disease groups. In patients with CM, the concentration of VEGF in CSF decreased significantly following antineoplastic treatment. In CSF samples from patients with brain metastases without concomitant CM, VEGF was not detectable. Median VEGF concentration in CSF from patients with acute bacterial meningitis was 38.6 pg/mL, with only 9 of these 17 patients showing detectable VEGF levels in CSF. The VEGF indices in patients with bacterial meningitis were significantly lower than in tumor patients with CM (<22.8 versus >62.3), suggesting that the proportion of intrathecally produced VEGF is much higher in patients with CM as compared with patients with bacterial meningitis. Patients without neoplastic or infectious neurologic disorders consistently showed VEGF levels in CSF below the assay detection limit of 25 pg/mL. Immunohistochemistry revealed strong cytoplasmic staining for VEGF in a metastatic lesion from breast cancer infiltrating the meninges. CONCLUSION: In patients with carcinomatous meningitis, significant amounts of VEGF are released into CSF. This study yields preliminary evidence that VEGF in CSF may be a useful biologic marker for both the diagnosis and evaluation of treatment response in carcinomatous meningitis.

CAG-repeat expansion in androgen receptor in Kennedy's disease is not a loss of function mutation.

Expansion of CAG trinucleotide repeats in androgen receptor gene is present in patients with a rare X-linked inherited form of motor neuron disorder termed Kennedy's disease or spinal and bulbar muscular atrophy (SBMA). This is a late onset progressive disease often associated with mild signs of androgen insensitivity. Defects in androgen receptor (AR) action have been linked to the expansion of the CAG trinucleotide repeats and postulated to be the cause of the disease. We have identified a trinucleotide repeat of 45 in the N-terminus of the AR in two brothers with SBMA and several members in their family (range in the general population is 11-35). Treatment of the patients with androgens failed to improve their clinical symptoms and provided no hint of an anomalous function of the AR. Consistently, functional analysis of the mutant receptor showed hormone binding, transactivation and transrepression potentials identical to that of the wild-type receptor. These results together argue against SBMA being a loss of function mutation of the AR.

Diffuse large B-cell lymphoma with infiltration-associated peripheral neuropathy and paraneoplastic myopathy with a prolonged course over seven years.

Rarely lymphoproliferative disorders (LPD) may be associated with peripheral neuropathy, based on different mechanisms of pathogenesis. Here, we report a case of a primary extranodal diffuse large B-cell lymphoma which showed a prolonged course with several recurrences manifesting as neuropathies, and long term remissions achieved by chemotherapy and involved field radiation. Repeated pathohistologic evaluations showed spread of lymphoma growth predominantly along nerve structures, suggesting neurotropism of the lymphoma cells.

[Space medicine and life sciences in space]. / Raumfahrtmedizin und Life sciences in space.

The examination of pathophysiological disturbances and the process of adaptation in man during space flight is not for optimizing of the biological systems during the training of cosmonauts and astronauts for their stay in space only. These results are also important for medical application on patients. In real microgravity disturbances of motor performances, coordination of movements, accuracy of movements, muscle function as well as structural changes in muscles is found in real microgravity. Spinal reflexes and the control of vestibular system on eye movements are also afflicted. Higher brain functions, especially associative reactions, critical abilities, memory, as well as high brain function like space orientation, body scheme control, geometric and arithmetic analysis and its reproduction, at last speech production, writing and reading are decreased. Vegetative disorders, bone decalcification, primary muscular atrophy occur as well as changes in sleep--wake regulation and diminishing of vigility. Disturbances of blood and body fluid circulation and biologic radiation damage are further effects of man space flight. Several problems of space adaptation can be studied with the methods of the simulated microgravity using the dry water immersion, examination and the bed rest model in special laboratories. The routine medicine is learning from the scientific results of the research in real and simulated microgravity.

Long-term cognitive and MRI findings in a patient with paraneoplastic limbic encephalitis.

This case study describes the long-term course of behavioral alterations and MRI findings in a patient with a combined limbic and cerebellar paraneoplastic syndrome, which was associated with a squamous lung carcinoma. Clinical equivalents were cerebellar ataxia, as well as severe anterograde memory loss, frontal executive dysfunction and behavioral alterations. MRI revealed inflammatory changes followed by progressive atrophy affecting the cerebellum and both temporal lobes. Tumor surgery yielded only a partial and transient recovery of neurological symptoms, and paraneoplastic atrophy continued to progress despite radical excision of the carcinoma. This case of paraneoplastic encephalitis suggests that the related atrophy may present as a chronic, progressive, multifocal encephalopathy and that the associated cognitive impairments may include several cognitive domains.

Linear scleroderma "en coup de sabre" coexisting with plaque-morphea: neuroradiological manifestation and response to corticosteroids.

A 24 year old woman in the 33rd week of pregnancy developed progressive neurological complications with right sided hemiparesis in association with the occurrence of linear scleroderma "en coup de sabre" (LSCS) and pre-existing plaque-morphea, already being treated by balneophototherapy. Further progression of neurological symptoms led to a caesarean section with the delivery of a healthy child. Brain magnetic resonance imaging (MRI) showed focal T2 signal increases in the left frontoparietal region directly adjacent to the area of LSCS. Cerebrospinal fluid analysis revealed oligoclonal bands, suggesting an intracerebral inflammatory process. Subsequent pulsed corticosteroid treatment led to a remission of neurological symptoms and to a marked resolution of the MRI lesions.

Vascular endothelial growth factor (VEGF) is elevated in brain tumor cysts and correlates with tumor progression.

Vascular endothelial growth factor (VEGF), a key regulatory protein in neoangiogenesis, is strongly expressed in a variety of primary brain tumors, particularly malignant gliomas. In previous studies, high levels of VEGF were also reported in tumor cysts of glioblastomas. Using an ELISA method we measured the concentration of VEGF in matched samples of aspiration fluid from tumor cysts and serum. Samples were collected from 14 patients with primary brain tumors of various histology (six glioblastomas, one protoplasmatic astrocytoma, two pilocytic astrocytomas, one ependymoma, one meningioma, and three craniopharyngiomas) and two patients with solitary cystic brain metastases from adenocarcinomas of the lung. Aspiration fluids of tumor cysts from all patients revealed high VEGF levels ranging between 882 and 1,263,000 pg/ml, which were 2 to more than 2,000 times higher than the corresponding serum levels. Maximum VEGF levels were detectable in cyst fluids from recurrent glioblastoma. Serum VEGF levels ranged between 125 and 716 pg/ml and did not differ from serum levels in 145 healthy volunteers. In a single patient with metastatic lung cancer the concentration of VEGF in serum and cyst fluid was determined during disease progression. During 60 days of follow-up VEGF concentrations in the cyst fluid collected by puncture of an Ommaya reservoir increased 650-fold, while serum levels remained rather constant. These findings indicate that immunoreactive VEGF is produced at the tumor site and abundantly released into the cyst fluid of primary and metastatic brain tumors. Interestingly, this abundant local release is not reflected in serum VEGF levels, even in the case of very high VEGF concentrations in tumor cysts. Thus, VEGF may be biologically relevant for the formation of tumor cysts in brain tumors and correlates with local disease progression.

[Movement disorders in weightlessness]. / Bewegungsstörungen in der Schwerelosigkeit.

The system MONIMIR has been developed to study the coordination of eye, head and arm movements as well as spinal reflexes in microgravity and was used during three spaceflights on board of the station MIR. The following investigations in the course of the experiment MONIMIR were performed: (1) slow head movements in three planes, (2.3) fast pointing movements of eyes, head and arm to acoustic and visual targets, (4) tracking movements of eyes, head and arm to visual targets, (5) head and arm movements based on short term memory and (6) patellar-tendon-reflex. In microgravity different functions and effectors showed different nature and degree of disturbance and different courses in adaptation; in most of the tests exactness and velocity of head and arm movement was decreased; head movements were more disturbed than arm movements; fast pointing movements were more severely affected than slow tracking movements which partly improved; visual controlled movements showed better adaptation as only proprioceptive controlled movements; the patellar-tendon-reflex was highly increased. Disturbances were most pronounced in the early stage of the spaceflights; at later stages most of the performances improved. Methods and results can be used not only for improvement of election and health control of cosmonauts/astronauts for future longterm space missions but also for diagnostics and research of adaptational processes in course of diseases or extreme conditions on earth.

Poor response to activated protein C as a prominent risk predictor of advanced atherosclerosis and arterial disease.

BACKGROUND: The potential role of activated protein C (APC) resistance in arterial thrombosis and disease is a matter of ongoing controversy. METHODS AND RESULTS: In the present population-based survey, a random sample of 826 men and women underwent high-resolution duplex ultrasound scanning of the carotid and femoral arteries. Response to APC was expressed in APC ratios. Subjects were tested for the factor V Leiden mutation. The risk of carotid stenosis increased gradually with decreasing response to APC (adjusted OR [95% CI] for a 1-U decrease of response to APC, 1.6 [1. 2 to 2.2]), as did the risk of femoral artery stenosis (1.7 [1.3 to 2.3]) and prevalent cardiovascular disease (1.4 [1.1 to 2.0]). The association between low APC ratio and atherosclerotic vascular disease applied equally to subjects with the factor V Leiden mutation and those without. Our study identified various nongenetic determinants of poor response to APC in the general population, including behavioral, hormonal, and environmental factors. CONCLUSIONS: The present study revealed an independent and gradual association between low response to APC and both advanced atherosclerosis (stenosis) and arterial disease. Resistance to APC due to factor V Leiden mutation was only one facet of this relationship.