bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuropathy Associated With Anti‐Chondroitin Sulfate C IgM Antibodies
Authors: Bossi B , Carpo M , Cappellari A , Allaria S , Scarlato G , Nobile‐Orazio E.
Published: March 2003

Chondroitin Sulfate C (ChS‐C), is a glycosaminoglycan present in the membranes of neurons and axons. Anti‐ChS‐C IgM antibodies have been reported in patients with predominantly sensory neuropathy (PN) often associated with IgM monoclonal gammopathy, but also in some neurological controls. In order to evaluate the frequency and clinical correlate of anti‐ChS‐C IgM antibodies, we tested them by a new Covalink ELISA technique in sera from 206 patients with IgM monoclonal gammopathy including 79 with PN (PN+IgM) with unknown IgM reactivity, 65 with PN with antibodies to the myelin‐associated glycoprotein and 62 without PN, and from 33 patients with PN of other causes, 30 with other neurological and non‐neurological diseases and 23 normal subjects. We only found high titers of anti‐ChS‐C IgM in two patients (1/128,000 and 1/256,000 respectively) with IgM monoclonal gammopathy: one had Waldenström Macroglobulinemia diagnosed seven years before and a 3 year history of slowly progressive limb weakness, finger paresthesias, unsteady gait and occasional nocturnal cramps. Neurological examination revealed a predominantly large‐fiber sensory neuropathy with mild distal atrophy and weakness in upper and lower limbs. Electrophysiological and morphological studies were suggestive of a predominantly demyelinating neuropathy. The other patient had IgM MGUS without PN at the time of antibody testing but developed finger paresthesias seven years later, when he had decreased position sense and abnormal sensory nerve conduction studies. In conclusion high titers of anti‐ChS‐C IgM, though infrequent, were always associated with the presence or development of sensory PN in patients with IgM M‐protein, supporting a possible role for these antibodies in the neuropathy.
Expression Of Matrix Metalloproteinases 2 And 9 And Of Tumor Necrosis Factor Alpha In Inflammatory And Non Inflammatory Neuropathies
Authors: Volpi N , Alessandrini C , Magi S , Venturini E , Giannini F.
Published: March 2003

Matrix metalloproteinases (MMPs), a family of endopeptidases engaged in remodeling of the extracellular matrix, are involved in processes of cell adhesion, endothelial and cytokine activation. In neuropathology they seem thus to be effective in demyelination and disruption of the blood‐neural tissue barrier. In CNS and muscle, MMPs are also related to deposition of amyloid proteins. Previous studies indicate an upregulation of MMP2 and MMP9 in chronic inflammatory demyelinating neuropathy (CIDP) and non systemic vasculitic neuropathy (NSVN). Tumor necrosis factor alpha (TNF‐α) is involved both in immune and non‐immune lesions of peripheral nerve, being produced by macrophages and T cells, and by mast cells and Schwann cells after mechanical injuries. TNF‐α is functionally related to MMPs, which activate its transmembrane precursor. We thus investigated by immunohistochemistry localization of MMP2, MMP9 and TNF‐α in sural nerves from inflammatory (CIDP, NSVN, vasculitic neuropathy in Churg‐Strauss syndrome (CSS)) and non inflammatory (myeloma associated amyloidotic neuropathy, neuropathy in monoclonal gammopathy, colchicine neuromyopathy and HMSN II) neuropathies. If available, soleus muscle was also examined. MMP2 showed in all cases a diffuse endoneurial and perineurial immunoreactivity (IR), with a stronger endothelial localization in presence of perivascular mononuclear cells. Conversely MMP9 was restricted to inflammatory cases, with localization in T cells and macrophages; endothelial expression, induced by activated T cells, was more evident in CSS. Endoneurial and perineurial detection of TNF‐α was also in dependence of the inflammation rate. In the amyloidotic neuropathy, we were unable to detect immunohistochemical colocalization of Ig light chains and MMP2. As previously pointed out, no correlation with severity of demyelination, as assessed by electrophysiologic and teased fibre studies, was evident. Comparison with muscle data support a correlation of MMPs and TNF‐α tissue expression with the activity of the inflammatory process. However, differences in MMP patterns for CIDP and NSVN are being outlined. Moreover, our cases indicate possible distinctive features in vasculitic neuropathies associated with systemic vasculitides.
Childhood Chronic Inflammatory Demyelinating Polyneuropathy: Clinical Course And Long‐Term Outcome
Authors: Ryan MM , Grattan‐Smith PJ , Procopis PG , Morgan G , Ouvrier RA
Published: March 2003

We reviewed the clinical history, electrophysiologic and pathologic findings, and response to therapy of 16 children with chronic inflammatory demyelinating polyneuropathy. The majority presented with lower limb weakness. Sensory loss was uncommon. The illness was monophasic in seven children, relapsing in six, and three had a slowly progressive course. All patients were treated with immunosuppressive agents. In 11, the initial treatment was prednisolone. All had at least a short‐term response but five went on to develop a relapsing course. Intravenous immunoglobulin was the initial treatment in four patients. Three responded rapidly, with treatment being stopped after a maximum of 5 months. In resistant chronic inflammatory demyelinating neuropathy, in addition to prednisolone and immunoglobulin, plasma exchange, azathioprine, cyclosporine, methotrexate, cyclophosphamide and pulse methylprednisolone were tried at different times in different patients. On serial neurophysiologic testing slowing of nerve conduction persisted for long periods after clinical recovery. Follow‐up was for an average of 10 years. When last seen 14 patients were asymptomatic, two having mild residual deficits. Childhood chronic inflammatory demyelinating neuropathy responds to conventional treatment and generally has a favourable long‐term outcome.
Anti‐Sulfatide Igm Antibodies In Peripheral Neuropathy
Authors: Carpo M , Meucci N , Allaria S , Marmiroli P , Monaco S , Toscano A , Simonetti S , Scarlato G , Nobile‐Orazio E.
Published: March 2003

Anti‐sulfatide IgM antibodies have been recently associated with neuropathy but the clinical and electrophysiological correlations of this reactivity remains unclear. We reviewed the clinical and electrophysiological features of patients with high anti‐sulfatide titers detected in our laboratory from 1991 to 1998. Of the 564 patients with different neurological diagnosis tested by enzyme‐linked immunosorbent assay (ELISA), 11 had high anti‐sulfatide IgM titers (>1/8000), 26 had titers of 1/8000 while 78 had titers of 1/4000. All patients with high anti‐sulfatide IgM titers had a chronic, dysimmune, mostly sensorimotor neuropathy that in seven was associated with IgM monoclonal gammopathy. In most of these patients electrophysiological and morphological studies were consistent with a predominantly demyelinating neuropathy frequently associated with prominent axonal loss. Antibody titers of 1/8000, though always associated with neuropathy, did not correlate with a particular form or cause of neuropathy, while lower titers were equally distributed in patients with different neurological disorders. Our study indicates that high anti‐sulfatide IgM titers (>1/8000) are highly predictive for a chronic, dysimmune, mostly demyelinating neuropathy often associated with IgM monoclonal gammopathy, and may therefore have potential diagnostic relevance.
Enhanced B7 Costimulatory Molecule Expression In Inflammatory Human Sural Nerve Biopsies
Authors: Kiefer R , Dangond F , Mueller M , Toyka KV , Hafler DA , Hartung HP
Published: March 2003

Objectives‐To define the role of the costimulatory molecules B7‐1 and B7‐2 in inflammatory disorders of the peripheral nervous system. B7 molecules are essential for effective antigen presentation and may determine the differentiation of T cells into a Th‐1 or Th‐2 phenotype, thus modulating immune response and disease course. Methods‐Forty nine sural nerve biopsies from patients with neuroborreliosis, Guillain‐Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), CIDP variants and hereditary neuropathies, and those with no detectable abnormality were investigated. The expression of B7‐1 and B7‐2 mRNA and protein was investigated by polymerase chain reaction (PCR) and immunocytochemistry. Results‐B7‐1 mRNA was strongly upregulated in both cases of neuroborreliosis, in two cases of GBS and one case of variant CIDP. Moderate to low levels were detected in the remaining GBS and CIDP biopsies and were rarely found in a noninflammatory control group consisting of hereditary neuropathy and normal nerves. At the immunocytochemical level, strong expression of B7‐1 protein was found in both neuroborreliosis cases, and moderate or low expression in six of eight GBS cases and seven of 17 CIDP cases investigated, whereas only one of five non‐inflammatory control nerves showed staining, which was very weak. In neuroborreliosis, B7‐1 protein was found very pronounced in epineurial infiltrates, whereas in CBS and CIDP, labelling was predominantly endoneurial and localised to putative macrophages. B7‐2 mRNA and protein were expressed only at low levels in neuroborreliosis and selected autoimmune neuropathy cases, and were essentially absent from noninflammatory controls. Conclusions‐B7 molecules are expressed in the peripheral nervous system and regulated during disease, and their presence in macrophages underlines the putative function of endoneurial macrophages as local antigen presenting cells in the immunopathology of peripheral nerve. B7‐1 rather than B7‐2 is preferentially upregulated, possibly promoting the induction of a Th‐1‐type T cell response within the nerve.
N‐MYC Downstream‐Regulated Gene 1 Is Mutated In Hereditary Motor And Sensory Neuropathy‐LOM
Authors: Kalaydjieva L , Gresham D , Gooding R , Heather L , Baas F , De Jonge R , Blechschmidt K , Angelicheva D , Chandler D , Worsley P , Rosenthal A , King RHM , Thomas Pk
Published: March 2003

Hereditary motor and sensory neuropathies, to which Charcot‐Marie‐Tooth (CMT) disease belongs, are a common cause of disability in adulthood. Growing awareness that axonal loss, rather than demyelination per se, is responsible for the neurological deficit in demyelinating CMT disease has focused research on the mechanisms of early development, cell differentiation, and cell‐cell interactions in the peripheral nervous system. Autosomal recessive peripheral neuropathies are relatively rare but are clinically more severe than autosomal dominant forms of CMT, and understanding their molecular basis may provide a new perspective on these mechanisms. Here we report the identification of the gene responsible for hereditary motor and sensory neuropathy‐Lom (HMSNL). HMSNL shows features of Schwann‐cell dysfunction and a concomitant early axonal involvement, suggesting that impaired axon‐glia interactions play a major role in its pathogenesis. The gene was previously mapped to 8q24.3, where conserved disease haplotypes suggested genetic homogeneity and a single founder mutation. We have reduced the HMSNL interval to 200 kb and have characterized it by means of large‐scale genomic sequencing. Sequence analysis of two genes located in the critical region identified the founder HMSNL mutation: a premature‐termination codon at position 148 of the N‐myc downstream‐regulated gene 1 (NDRG1). NDRG1 is ubiquitously expressed and has been proposed to play a role in growth arrest and cell differentiation, possibly as a signaling protein shuttling between the cytoplasm and the nucleus. We have studied expression in peripheral nerve and have detected particularly high levels in the Schwann cell. Taken together, these findings point to NDRG1 having a role in the peripheral nervous system, possibly in the Schwann‐cell signaling necessary for axonal survival.
Giant Axonal Neuropathy Locus Refinement To A < 590 KB Critical Interval
Authors: Cavalier L , BenHamida C , Amouri R , Belal S , Bomont P , Lagarde N , Gressin L , Callen D , Demir E , Topaloglu H , Landrieu P , Ioos C , BenHamida M , Koenig M , Hentati F.
Published: March 2003

Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder, characterised clinically by the development of chronic distal polyneuropathy during childhood, mental retardation, kinky or curly hair, skeletal abnormalities and, ultrastructurally, by axons in the central and peripheral nervous systems distended by masses of tightly woven neurofilaments. We recently localised the CAN locus in 16q24.1 to a 5‐cM interval between the D16S507 and D16S511 markers by homozygosity mapping in three consanguineous Tunisian families. We have now established a contig‐based physical map of the region comprising YACs and BACs where we have placed four genes, ten ESTs, three STSs and two additional microsatellite markers, and where we have identified six new SSCP polymorphisms and six new microsatellite markers. Using these markers, we have refined the position of our previous flanking recombinants. We also identified a shared haplotype between two Tunisian families and a small region of homozygosity in a Turkish family with distant consanguinity, both suggesting the occurrence of historic recombinations and supporting the conclusions based on the phase‐known recombinations. Taken together, these results allow us to establish a transcription map of the region, and to narrow down the GAN position to a < 590 kb critical interval, an important step toward the identification of the defective gene.
Phase II Evaluation Of Thalidomide In Patients With Metastatic Breast Cancer
Authors: Baidas SM , Winer EP , Fleming GF , Harris L , Pluda JM , Crawford JG , Yamauchi H , Isaacs C , Hanfelt J , Tefft M , Flockhart D , Johnson MD , Hawkins MJ , Lippman ME , Hayes DF
Published: March 2003

Purpose: To determine the efficacy, safety, pharmacokinetics, and effect on serum angiogenic growth factors of two dose levels of thalidomide in patients with metastatic breast cancer. Patients and Methods: Twenty‐eight patients with progressive metastatic breast cancer were randomized to receive either daily 200 mg of thalidomide or 800 mg to be escalated to 1,200 mg. Fourteen heavily pretreated patients were assigned to each dose level. Each cycle consisted of 8 weeks of treatment. Pharmacokinetics and growth factor serum levels were evaluated. Results: No patient had a true partial or complete response. On the 800‐mg arm, 13 patients had progressive disease at or before 8 weeks of treatment and one refused to continue treatment. The dose was reduced because of somnolence to 600 mg for five patients and to 400 mg for two and was increased for one to 1,000 mg and for four to 1,200 mg. On the 200‐mg arm, 12 patients had progressive disease at or before 8 weeks and two had stable disease at 8 weeks, of whom one was removed from study at week 11 because of grade 3 neuropathy and the other had progressive disease at week 16. Dose‐limiting toxicities included somnolence and neuropathy. Adverse events that did not require dose or schedule modifications included constipation, fatigue, dry mouth, dizziness, nausea, anorexia, arrhythmia, headaches, skin rash, hypotension, and neutropenia. Evaluation of circulating angiogenic factors and pharmacokinetic studies failed to provide insight into the reason for the lack of efficacy. Conclusion: Single‐agent thalidomide has little or no activity in patients with heavily pretreated breast cancer. Further studies that include different patient populations and/or combinations with other agents might be performed at the lower dose levels.
Induction Of Endothelin‐1 Expression By Glucose: An Effect Of Protein Kinase C Activation
Authors: Park JY , Takahara N , Gabriele A , Chou E , Naruse K , Suzuma K , Yamauchi T , Ha SW , Meier M , Rhodes CJ , King GL
Published: March 2003

Enhanced actions or levels of endothelin‐1 (ET‐1), a potent vasoconstrictor, have been associated with decreased blood flow in the retina and peripheral nerves of diabetic animals and may be related to the development of pathologies in these tissues. Hyperglycemia has been postulated to increase ET‐1 secretion in endothelial cells. We have characterized the mechanism by which elevation of glucose is increasing ET‐1 mRNA expression in capillary bovine retinal endothelial cells (BREC) and bovine retinal pericytes (BRPC). Elevation of glucose, but not mannitol, from 5.5 to 25 mmol/l for 3 days increased membranous protein kinase C (PKC) activities and ET‐1 mRNA in parallel levels by 2‐fold in BREC and BRPC. These effects were reversed by decreasing glucose levels to 5.5 mmol/l for an additional 2 days. Glucose‐induced ET‐1 overexpression was inhibited by a general PKC inhibitor, GF109203X, and a mitogen‐activated protein kinase kinase inhibitor, PD98059, but not by wortmannin, a phosphatidylinositol 3‐kinase inhibitor. By immunoblot analysis, PKC‐beta 2 and ‐delta isoforms in BREC were significantly increased relative to other isoforms in the membranous fractions when glucose level was increased. Overexpression of PKC‐beta 1 and ‐delta isoforms but not PKC‐zeta isoform by adenovirus vectors containing the respective cDNA enhanced in parallel PKC activities, proteins, and basal and glucose‐induced ET‐1 mRNA expression by at least 2‐fold. These results showed that enhanced ET‐1 expression induced by hyperglycemia in diabetes is partly due to activation of PKC‐beta and ‐delta isoforms, suggesting that inhibition of these PKC isoforms may prevent early changes in diabetic retinopathy and neuropathy.
Distribution Of Paclitaxel Within The Nervous System Of The Rat After Repeated Intravenous Administration
Authors: Cavaletti G , Cavalletti E , Oggioni N , Sottani C , Minoia C , D'Incalci M , Zucchetti M , Marmiroli P , Tredici G.
Published: March 2003

The distribution of paclitaxel (Taxol(R)) within the central and peripheral nervous system after repeated administration of this antineoplastic agent is still largely unknown. In this study we determined for the first time paclitaxel tissue concentration in the brain, spinal cord, dorsal root ganglia (DRG) and sciatic nerve using an experimental paradigm in the rat which reproduces the features of paclitaxel peripheral neurotoxicity in humans. Pathological confirmation of the onset of paclitaxel‐induced peripheral neurotoxicity was performed. In order to achieve reliable results even with low concentrations of paclitaxel, a newly reported analytical method (high‐performance liquid chromatography with tandem mass spectrometry) was used. We demonstrated that paclitaxel has easy access to the DRG, where it accumulates, while the lowest concentrations of the drug were measured in the brain. The intermediate concentrations of paclitaxel observed in the sciatic nerve and spinal cord may be due to paclitaxel transport along the centrifugal and centripetal branches of the DRG neuron axons.
Acute Deterioration Of Charcot‐Marie‐Tooth Disease IA (CMT IA) Following 2 MG Of Vincristine Chemotherapy
Authors: Hildebrandt G , Holler E , Woenkhaus M , Quarch G , Reichle A , Schalke B , Andreesen R.
Published: March 2003

Background: Severe up to life‐threatening neuropathy has been observed in patients with hereditary neuropathies receiving vincristine. Case report: A 52‐year‐old female painter suffering from high‐grade non‐Hodgkin's lymphoma (stage IVB) was treated with a total of 4 mg of vincristine during two courses of CHOP chemotherapy (cyclophosphamide, vincristine, adriamycin, prednisone). At onset of treatment no neurological problems were reported. There was good lymphoma response to chemotherapy. At the same time, however, the patient gradually developed dysphagia, dysarthria, muscular weakness of both lower and upper extremities, areflexia, paraesthesia of the fingertips and bilateral sensory impairment of feet and lower legs. These symptoms continually worsened over a period of seven weeks until she was unable to walk or to perform her work. Electrophysiological studies showed peripheral axonal and demyelinative sensorimotor neuropathy in correlation to histological findings. Molecular analysis revealed 17p11.2 duplication typical for Charcot‐Marie‐Tooth disease IA. While continuing chemotherapy without the use of vincristine the patient's neurologic symptoms slowly recovered within six months. Conclusion: Prior to administration of vincristine family and patient history as well as physical examination should be performed carefully to look for underlying hereditary neuropathy. For those patients with a clinical history or symptoms suggestive for CMT nerve conduction velocity studies and on an individual base even molecular genetic analysis are necessary to prevent serious neurologic complications.
PERIPHERAL NEUROPATHY IN SYSTEMIC LUPUS ERYTHEMATOSUS ‐ A LONGITUDINAL STUDY
Authors: Omdal R , Loseth S , Torbergsen T , Koldingsnes W , Husby G , Mellgren SI.
Published: March 2003

Objective ‐ Peripheral neuropathy (PN) is reported to occur in 5–27% of patients with systemic lupus erythematosus (SLE) mostly as a length‐dependent sensorimotor axonopathy. Studies over time have not been performed. Design ‐ Longitudinal study. Subjects and methods ‐ Thirty‐three Caucasian SLE patients consented to participate in the study and were subjected to clinical examination, laboratory tests, and nerve conduction velocity (NCV) studies. At the follow‐up 7 years later, 7 patients (21%) were dead, 4 refused to participate, and 2 did not want to perform NCV studies. Twenty patients were thus available for longitudinal study. Results ‐ When all SLE patients were considered on a group basis at follow‐up, 8 (33%) out of 24 NCV parameters showed significant deterioration despite correction for time, while 16 (67%) were unchanged. Analysis of change from baseline showed that, except for F ‐responses, several NCV changes were highly dependent (negative regression coefficients) on baseline levels at start of study. No demographic, laboratory, or disease associated quantitative factor was associated with these changes in NCV parameters over time. Nor was a consistent effect on NCV parameters from any qualitative demographic or disease associated factor confirmed by Repeated Measures ANOVA analyses. Conclusions ‐ A modest progressive neuropathic process exists in patients with SLE. Important is also the finding that, over time, the abnormalities of NCV parameters fluctuate in the individual patients, and the impairments are not necessarily irreversible. This study also shows no association to medication, demographic‐, or other disease associated factors.
Postvaccinal inflammatory neuropathy: peripheral nerve biopsy in 3 cases
Authors: Vital Claude , Vital Anne , Gbikpi‐Benissan Georges , Longy‐Boursier Maïté , Climas Marie‐Thérèse , Castaing Yves , Canron Marie‐Hélène , Le Bras Michel , Petry Klaus
Published: March 2003

Abstract  Autoimmune inflammatory polyneuropathy (PN) can be triggered by vaccination. We report 3 such cases. A 36‐year‐old female nurse presented 15 days after a hepatitis B vaccination (HBV) with acute sensory disturbances in the lower limbs. She had severe ataxia but no weakness. Cerebrospinal fluid (CSF) protein level was 84 mg/100 mL, with 3 lymphocytes. A 66‐year‐old man presented 21 days after HBV with severe motor and sensory PN involving all 4 limbs. A 66‐year‐old man presented 15 days after a yellow fever vaccination with progressive motor and sensory PN involving all 4 limbs and bilateral facial paralysis. CSF protein level was 300 mg/100 mL, with 5 lymphocytes. Six weeks later, a tracheostomy was performed. In these 3 patients, the nerve deficits lasted for months. In each case, peripheral nerve biopsy showed KP1‐positive histiocytes but no T‐lymphocytes in the endoneurium. On ultrastructural examination, there was axonal degeneration in the first 2 cases; in case 2, a few myelinated fibers exhibited an intra‐axonal macrophage but the myelin sheath was preserved. There was only 1 example of macrophage‐associated demyelination in case 2, but these were numerous in case 3. It is likely that in the first 2 cases, an autoimmune reaction against some axonal or neuronal components was triggered by HBV. It induced an acute sensory ataxic PN in case 1 and an acute motor and sensory axonal neuropathy (AMSAN) in case 2. The third patient had a chronic inflammatory demyelinating PN, likely triggered by yellow fever vaccination.
Antiganglioside antibodies in acute self‐limiting ataxic neuropathy: incidence and significance
Authors: Serrano‐Munuera C , Gallardo E , Rojas R , De Luna N , Gonzalez‐Masegosa A , Marti‐Masso JF , Martinez‐Matos A , Ortiz N , Rene R , Berciano J , Grau JM , Willison HJ , Graus F , Illa I
Published: March 2003

Antidisialosyl antibodies have been previously associated to chronic and acute ataxic neuropathies. We studied the presence of these antibodies in nine patients with acute self‐limiting ataxic neuropathy (ASLAN) using ELISA and TLC immunodetection. One patient showed serum IgG immunoreactivity against gangliosides GD3 and GQlb. The patient's IgG was able to bind to the nodes of Ranvier on frozen human dorsal root. Our studies confirmed that antidisialosyl reactivity is associated to ataxic neuropathy and its specific binding to the dorsal root could explain the predominant sensory involvement. Nevertheless, the low incidence of this reactivity indicates that a different pathogenic mechanism should be involved in most ASLAN patients.
Neurological complications of sepsis: critical illness polyneuropathy and myopathy
Authors: Hund E
Published: March 2003

Sepsis may cause not only failure of parenchymal organs but can also cause damage to peripheral nerves and skeletal muscles. It is now recognized that sepsis‐mediated disorders of the peripheral nerves and the muscle, called critical illness polyneuropathy (CIP) and critical illness myopathy, are responsible for weakness and muscle atrophy occurring de novo in intensively treated patients. CIP represents an acute axonal neuropathy that develops during treatment of severely ill patients and remits spontaneously, once the critical condition is under control. The course is monophasic and self‐limiting. Among the critical illness myopathies, three main types have been identified: a nonnecrotizing “cachectic” myopathy (critical illness myopathy in the strict sense), a myopathy with selective loss of myosin filaments (“thick filament myopathy”) and an acute necrotizing myopathy of intensive care. Clinical manifestations of both critical illness myopathies and CIP include delayed weaning from the respirator, muscle weakness, and prolonging of the mobilization phase. The pathogenesis of these neuromuscular complications of sepsis is not understood in detail but most authors assume that the inflammatory factors that mediate systemic inflammatory response and multiple organ failure are closely involved. In thick filament myopathy and acute necrotizing myopathy, administration of steroids and neuromuscular blocking agents may act as triggers. Specific therapies have not been discovered. Stabilization of the underlying critical condition and elimination of sepsis appear to be of major importance. Steroids and muscle relaxants should be avoided or administered at the lowest dose possible.
Molecular forms of NGF in human and rat neuropathic tissues: decreased NGF precursor‐like immunoreactivity in human diabetic skin
Authors: Yiangou Yiangos , Facer Paul , Sinicropi Dominick V. , Boucher Tim J. , Bennett David L.H. , McMahon Stephen B. , Anand Praveen
Published: March 2003

Abstract  Precursors of NGF have been shown to be the predominant forms of this neurotrophin in human brain and peripheral tissues, and proNGF has been shown recently to preferentially bind p75NTR with high affinity. In our studies of human and rat skin and nerve extracts, a 53 kDa band was detected by Western blot using antibodies against rhNGF or prepro‐NGF (−91 to −60), that could correspond to a previously described modified prepro‐NGF‐like molecule. The relative optical intensity of the 53‐kDa bands was markedly reduced in skin extracts from patients with subclinical diabetic neuropathy (diabetic: 1.5, 1.0–8.0, n = 6; controls: 52.0, 23.0–85.0, n = 6, p = 0.0022) but was increased in extracts of inflamed colon from patients with Crohn's disease (inflamed: median 12.0, range 0.1–12.0, n = 11: controls: 0.1, 0.1–3.0, n = 8, p = 0.0055). Antibodies to both rhNGF and prepro‐NGF immunostained basal keratinocytes in tissue sections of normal human and rat skin showed accumulation of immunoreactivity in nerve fibers distal to sciatic nerve ligation in rats. Prepro‐NGF antibody immunostained rat large/medium sensory neurons, whereas only small sensory neurons were stained with antibodies to mature rhNGF, suggesting that prepro‐NGF may be preferentially taken up and transported by p75NTR. The different molecular forms derived from prepro‐NGF are likely to be of importance in sensory mechanisms, and deserve further investigation.
HEREDITARY SENSORY NEUROPATHY TYPE I: HAPLOTYPE ANALYSIS SHOWS FOUNDERS IN SOUTHERN ENGLAND AND EUROPE
Authors: Nicholson GA , Dawkins JL , Blair IP , Auer‐Grumbach M , Brahmbhatt SB , Hulme DJ.
Published: March 2003

Hereditary sensory neuropathy type I (HSN1) is the most common dominantly inherited degenerative disorder of sensory neurons. The gene mutation was mapped to chromosome 9 in a large Australian family, descended from an ancestor from southern England who was a convict. Dawkins et al. recently reported gene mutations in the SPTLC1 gene, in this and other families. The first description of hereditary sensory neuropathy, by Hicks, was in a family from London and Exeter. To determine if the families in the present study that have SPTLC1 mutations are related to English families with HSN1 and, possibly, to the family studied by Hicks, we performed haplotype analysis of four Australian families of English extraction, four English families, and one Austrian family. Three Australian families of English extraction and three English families (two of whom have been described elsewhere) had the 399T→G SPTLC1 mutation, the same chromosome 9 haplotype, and the same phenotype. The Australian and English families may therefore have a common founder who, on the basis of historical information, has been determined to have lived in southern England prior to 1800. The sensorimotor neuropathy phenotype caused by the 399T→G SPTLC1 mutation is the same as that reported by Campbell and Hoffman and, possibly, the same as that originally described by Hicks.
ACUTE ONSET OF INFANTILE SPINAL MUSCULAR ATROPHY
Authors: Ravid S , Topper L , Eviatar L.
Published: March 2003

Two patients with acute generalized weakness and areflexia are presented. The electrophysiologic studies in both revealed evidence of decreased conduction velocity and mixed axonal and demyelinating neuropathy, suggestive of the diagnosis of Guillain‐Barré syndrome. The young ages of the patients and their failure to respond to immunoglobulin therapy were the major clues to the final diagnosis of spinal muscular atrophy type I. Blood for DNA study revealed homozygous deletion mutation in exons 7 and 8 of the survival motor neuron gene. This diagnosis should be considered in every child under 1 year of age who presents with acute weakness because Guillain‐Barré syndrome in this age group is rare.
METHYLPREDNISOLONE MAY IMPROVE LUMBOSACRAL RADICULOPLEXUS NEUROPATHY
Authors: Dyck PJB , Norell JE , Dyck PJ.
Published: March 2003

Objective: To report on an open trial of intravenous methylprednisolone (IV MP) in nondiabetic lumbosacral radiculoplexus neuropathy (LSRPN). Background. Lumbosacral radiculoplexus neuropathy is a subacute, unilateral or asymmetric syndrome of pain, weakness, and paresthesia of the lower extremity, which is attributed to ischemic injury from microvasculitis in lumbosacral roots, plexus, and nerves. Methods: Eleven nondiabetic patients with worsening LSRPN were treated ‐ ten with infusions of IV MP (1 gm/wk) for 8 to 16 weeks and one with an equivalent dosage of oral prednisone. The main endpoints evaluated were: 1) the Neuropathy Impairment Score (NIS), and 2) the Neuropathy Symptoms and Change (NSC) scores. Results: The median age of our patients was 67 years, range 49 to 86 years. Seven patients were women. All 11 patients reported improvement during treatment—nine reported marked improvement. The median NIS improved from 42 points (range 9 to 106 points) before treatment, to 20 points (range 5 to 57 points) (p = 0.005) after treatment. Pain was completely resolved in four patients and much improved in seven. The change subscore and the severity subscore of the NSC were statistically significantly improved after treatment. Prior to treatment, all patients had significant weakness with six confined to wheelchairs and four using mechanical devices to aid in ambulation. After treatment, the weakness was markedly improved in nine patients; only one still required a wheelchair and six walked independently (p = 0.03). Conclusions: 1) In LSRPN, pain and neurological deficits improved (often dramatically) with IV MP treatment. 2) Although our results should be interpreted with caution since this trial is uncontrolled, IV MP may favorably affect the natural history of LSRPN. 3) The results are sufficiently promising to provide a rationale for prospective, sham controlled, double blind trials.
DIAGNOSTIC INVESTIGATION OF PATIENTS WITH CHRONIC POLYNEUROPATHY: EVALUATION OF A CLINICAL GUIDELINE
Authors: Rosenberg NR , Portegies P , De Visser M , Vermeulen M.
Published: March 2003

Objective: (1) To evaluate a clinical guideline for the diagnostic investigation of patients presenting with signs and symptoms (present for longer than 6 weeks) suggesting a chronic polyneuropathy. (2) To investigate the contribution of electrophysiological studies to a focused search for aetiology in these patients. Methods: A chart review was carried out of a consecutive group of outpatients in 1993‐7 at a university department of neurology, with signs and symptoms suggesting a polyneuropathy in whom the diagnostic investigation had been carried out according to a recently introduced guideline. Diagnostic tests were performed and final diagnoses were made. Results: Unnecessary investigations were carried out in 108 (51%) of 213 patients and too few tests in 23 (11%) of these patients. In 82 (48%) of the 172 patients who fulfilled the inclusion criteria neurophysiological tests did not contribute to the final diagnosis. Neurophysiological criteria for demyelination were fulfilled in only 13 (8%) of the 172 patients. Conclusion: In patients presenting with signs and symptoms of chronic polyneuropathy the number of tests in the diagnostic investigation can be considerably reduced. In patients with signs and symptoms of polyneuropathy, providing the clinical phenotype is typical, in the presence of diabetes mellitus, renal failure, HIV infection, alcoholism, or use of potentially neurotoxic drugs further investigations are non‐contributory. The significance of electrophysiological studies in the investigation of patients with polyneuropathy is rather to separate sensorimotor neuropathies from pure sensory neuropathies than to distinguish between demyelinating and axonal neuropathies.
ROLE OF PROLINE ACCUMULATION IN RESPONSE TO TOXIC COPPER IN CHLORELLA SP. (CHLOROPHYCEAE) CELLS
Authors: Wu Jiunn‐Tzong , Hsieh Ming‐T. , Kow Lai‐Chu
Published: March 2003

The green alga Chlorella sp. (strain 2350) was found to accumulate proline, up to a maximum of 0.027 fmol·cell−1, under stressful concentrations of cupric ions. The function of the accumulated proline was studied with respect to its effect on copper (Cu) uptake. By induction with salt stress, cells with various levels of intracellular proline were used for this study. It is shown that the amount of Cu taken up by the cells was reduced when the intracellular proline levels were enhanced. When proline was exogenously supplied prior to Cu treatment, the adsorption of Cu was markedly reduced. When exogenous proline was supplied after Cu treatment, it resulted in a remarkable desorption of the adsorbed Cu immediately after the addition of proline. The results of the present study indicate that proline may exert some action on the cell surface and suggest that one function of accumulated proline is to reduce the uptake of metal ions. The accumulation of proline may be related to a tolerance mechanism for dealing with Cu stress.
ESTIMATION OF CHLOROPHYLL a FROM TIME SERIES MEASUREMENTS OF HIGH SPECTRAL RESOLUTION REFLECTANCE IN AN EUTROPHIC LAKE
Authors: Schalles John F. , Gitelson Anatoly A. , Yacobi Yosef Z. , Kroenke Amy E.
Published: March 2003

We acquired high spectral resolution reflectance data in Carter Lake, a eutrophic oxbow on the Iowa–Nebraska border, from April 1995 to April 1996. Chlorophyll a, total seston, sestonic organic matter, Secchi depth, and nephelometric turbidity were determined for each respective spectral measurement. Changes in algal taxonomic structure and abundance coincided with the development and senescence of a midsummer through autumn bloom of Anabaena. Taxonomic structure was more diverse in late winter and spring when Synedra sp. (diatom) and several chlorophytes and dinoflagellates were present. Overall, chlorophyll a varied from about 20 to 280 μg·L−1, Secchi transparency from 18 to 74 cm, and seston dry weight from 11 to 48 mg·L−1 in February and September, respectively. Particulate matter completely dominated lake water light attenuation. Dissolved organic matter had low optical activity. The most sensitive spectral feature to variation in chlorophyll a concentration was the magnitude of the scattering peak near 700 nm. The 700‐nm peak correlated to chlorophyll concentration through the relationships between algal pigment absorption near 670 nm and the cell biomass and surface‐related scattering signal in the near infrared. An algorithm relating the height of the 700‐nm reflectance peak above a reference baseline between 670 and 850 nm to chlorophyll a was accurate and robust despite large variations in optical constituents caused by both strong seasonality in the algal system and short‐term variations in seston from wind‐induced sediment resuspension. The present algorithms were successfully used in other systems with different seasonality and productivity patterns. The coefficients of the models relating chlorophyll a and spectral reflectance variables appeared to be ecosystem specific: both the intercept and slope for the models in this study were moderately lower than for several other recently published results. We validated our algorithm coefficients with a second, independent dataset. The standard error for chlorophyll a prediction was ±28 μg·L−1.
PHYLOGENY AND CLASSIFICATION OF REEF‐BUILDING CORALLINE ALGAE (CORALLINALES, RHODOPHYTA)
Authors: Bailey J.C. , Freshwater D.W.
Published: March 2003

The Corallinales includes ca. 40 genera of calcified red seaweeds. Species are of two distinct morphotypes; those that possess genicula (uncalcified nodes) and those that lack genicula. Most nongeniculate species take the form of crusts. The presence (or absence) of genicula, secondary pit connections, and tetrasporangial conceptacle features have traditionally been used as key characters for delimiting coralline subfamilies. In this study, nuclear encoded 18S and 26S rRNA gene sequences were determined and used to reexamine relationships among coralline taxa. Separate and combined phylogenetic analyses of these data yielded similar trees in which four major lineages are resolved. Heydrichia and Sporolithon (Sporolithaceae) are positioned at the base of the tree and appear to be distantly related to other species examined. Within the Corallinaceae, the nongeniculate Melobesioideae is resolved as a monophyletic group. All members of this subfamily produce mutiporate tetraspoangial conceptacles. The Corallinoideae, which are characterized by unizonate genicula, are resolved as sister to a clade containing species placed in the Lithophylloideae, Mastophoroideae and Metagoniolithoideae. The molecular data indicate that geniculate and nongeniculate species characterized by the presence of secondary pit connections are closely related. For example, both data sets robustly support a sister taxon relationship between Amphiroa and Titanoderma. Our results indicate that: 1) all taxa in which secondary pit connections are present should be referred to the Lithophylloideae and, 2) genicula are nonhomologous structures that are independently derived in Amphiroa, Lithothrix, Metagoniolithon and the last common ancestor of the Corallinoideae.
ENDOMEMBRANE ULTRASTRUCTURE AND POSSIBLE CHLOROPLAST PROTEIN IMPORT PATHWAY IN HETEROSIGMA AKASHIWO (RAPHIDOPHYCEAE)
Authors: Ishida K. , Cavalier‐Smith T. , Green B.R.
Published: March 2003

Chloroplasts in heterokont algae probably originated from a red algal endosymbiont which was engulfed and retained by a eukaryotic host, and are surrounded by four envelope membranes. The outermost of these membranes is called chloroplast ER (CER) and usually connects with the nuclear envelope. This information, however, is based mainly on studies on single‐plastid heterokont algae. In multi‐plastid heterokont algae, it is still unclear whether CER is continuous with the nuclear envelope. Since nuclear‐encoded chloroplast proteins are synthesized by ribosomes on the ER membrane, clarifying the ER‐CER structure in the heterokont algae is important in order to know the targeting pathway of those proteins. We did a detailed ultrastructural observation of endomembrane systems in a multi‐plastid heterokont alga: Heterosigma akashiwo, and confirmed that the CER membrane was continuous with the ER membrane. However, unlike the CER membranes in other heterokont algae, it seemed to have very few ribosome attached. We also performed experiments for protein targeting into canine microsomes using a precursor for a nuclear‐encoded chloroplast protein, a fucoxanthin‐chlorophyll protein (FCP), of H. akashiwo, to see if the protein is targeted to the ER. It demonstrated that the precursor has a functional signal sequence for ER targeting, and is co‐translationally translocated into the microsomes. Based on these data, we propose a hypothesis that, in H. akashiwo, nuclear‐encoded chloroplast protein precursors that have been co‐translationally inserted into the ER lumen are sorted in the ER and transported to the chloroplasts through the ER.
EXPRESSION PATTERNS OF THREE PUTATIVE SEXUAL‐SPECIFIC GENES IN THE CENTRIC DIATOM THALASSIOSIRA WEISSFLOGII
Authors: Koumandou V. , Armbrust E.V.
Published: March 2003

An intriguing feature of the diatom life cycle is that sexual reproduction not only generates genetic diversity but also controls cell size. Very little is known, however, about either the frequency or the potential ramifications of sexual events in field populations, due in large part to the difficulties associated with recognizing sexual stages. Our approach has been to identify genes involved in the diatom sexual cycle, with the goal of developing molecular probes to determine when and where sexual reproduction occurs. We are investigating the expression pattern of three genes identified in a sexual reproduction screen. The Sig1, Sig2 and Sig3 genes comprise a gene family, and encode proteins with strong sequence homology to extracellular matrix proteins. We have hypothesized that the Sig proteins are necessary for sperm/egg recognition. Using RT‐PCR, we have shown that transcription of the Sig genes is highly upregulated during the early stages of the sexual cycle, before any morphological changes are apparent. The three genes show significant differences in the exact timing and levels of expression, suggesting different roles for each member of the gene family. We are now employing quantitative RT‐PCR to study their relative transcription levels in more detail. We are also using antibodies made against a recombinant version of the Sig2 protein to look at protein expression levels before and after sexual induction, and to determine where the Sig2 protein localizes in the cell.
FLUID SHEAR‐STIMULATED DINOFLAGELLATE BIOLUMINESCENCE
Authors: Latz M.I. , Rohr J.
Published: March 2003

Bioluminescence studies provide insight into the properties of water motion that are stimulatory to flow‐sensitive organisms such as dinoflagellates, the most common sources of near‐surface oceanic bioluminescence. Previous laboratory studies employing steady flows have characterized the luminescent response of dinoflagellates in terms of shear stress. In the present study, computational and experimental approaches were used to investigate the contributions of shear and acceleration to cells responding in a laminar converging flow field, where regions of high acceleration and shear are spatially separated. Flow‐stimulated flashes by the dinoflagellates Lingulodinium polyedrum and Ceratocorys horrida were used as a near‐instantaneous monitor of cell response. By combining video analysis of flash trajectories with computational methods, the location of each stimulated cell was determined and flow parameters at that location were calculated. Based on several criteria, shear stress was considered the flow parameter most stimulatory to cells. For both dinoflagellates species and for all flow rates, essentially all cells responded downstream near the wall where shear stress levels were maximal, and levels of acceleration and extensional stress were as much as two orders of magnitude less than locations away from the wall. Minimum shear stress levels at the cell positions were consistent with response thresholds based on previous studies. Bioluminescence is an excellent tool for examining how organisms respond to flow at the small temporal and spatial scales relevant to planktonic organisms.
NOSTOCACEAN MACRO‐MORPHOGENESIS
Authors: Lazaroff N. , Eichelberger H.H.
Published: March 2003

A poorly understood feature of nostocacean growth and development is the formation of ordered macroscopic structures from microscopic cells, trichomes, and filaments. Using macro‐photography, time‐lapse micro‐cinematography, light and electron microscopy of Nostoc species in pure culture, it has been possible to demonstrate how motility, adhesion and aggregation of photo‐induced hormogonia result in macro‐morphogenesis of dendroid forms. Red‐light induced hormogonia from synchronized cultures aggregate rapidly on agar as tight flowing streams, in patterns responsive to the direction and quality of incident light. Unlike the even textured cell surfaces of heterocystous filaments, the cell walls of swarming hormogonia are covered with a striate mucoid layer containing pili attached to cells of adjacent hormogonia. During differentiation to an aseriate phase, cell wall fusions occur and a gelatinous matrix forms around the enlarging sub‐globose cells. Liquid suspensions of hormogonia aggregate in a solid mass following the net centripetal movement of interlaced loops of curved hormogonia attached by adhesive pili. In darkness or dim white light, compressed hormogonial aggregates form erect tree‐like (dendroid) macro‐structures by photo‐tactic reversal of streaming motility. Hormogonia within the aggregates re‐organize into streams that push upward into the light, forming structured, positively phototropic protuberances, several millimeters in length. Under weak illumination, the structures become branched with crowns of waving hormogonia. The dendroid morphology is stabilized by deposit of gelatinous material derived from successive cycles of cell‐filament development, liberation of heterocysts and formation of dormant cells and trichomes.