Antibody to a zinc finger protein in a patient with paraneoplastic cerebellar degeneration.

In some patients with paraneoplastic cerebellar degeneration (PCD), autoantibodies against neural components have been identified. Here, we demonstrate a major 58 kd protein antigen in an immunoblot of human cerebellum by serum from a patient with PCD. Immunohistochemically, the serum recognized neural cells especially Purkinje cells in a human brain. To identify the details of the target antigens for the antibody, we isolated a cDNA clone from a human cerebellar library. Homology searches revealed a similarity with the zinc finger proteins. PCD related proteins reported here may be important to maintain neural cells especially those in the cerebellum, and further studies on this molecule may help us elucidate the causes of degenerative or autoimmune diseases in the cerebellum.     

Anti-Ri-associated paraneoplastic cerebellar degeneration. Report of a case and revision of the literature

Paraneoplastic cerebellar degeneration associated with anti-Ri antibodies mainly presents with opsoclonus-myoclonus-ataxia. We report here the case of a patient with anti-Ri-antibody paraneoplastic syndrome, who presented four years after treatment for small-cell lung cancer (SCLC) with oscillopsia and gait disorder. On neurological examination vertical nystagmus, ataxic gait and postural tremor of all four limbs was detected. He died one year after the onset of the symptoms because of a acute exacerbation of his severe chronic obstructive pulmonary disease. No SCLC relapse or new cancer has been detected during the one-year follow-up period.To our knowledge, our patient is the first case of anti-Ri associated disorder with oscillopsia and vertical nystagmus as the initially prominent clinical features. The findings of this case study support the variability of anti-Ri-antibody-associated paraneoplastic syndrome. Further studies must be directed to better characterize the mechanisms underlying this syndrome. Finally, paraneoplastic neurological syndromes should be kept in mind also when a neoplastic disease is not demonstrated.     

Subacute cerebellar degeneration associated with bronchogenic carcinoma

In surgical procedures for the improvement of function in lower extremities paralyzed by poliomyelitis, even the best that can be done will fall far short of normal function. But choosing and carrying out the operation best suited to the paralytic situation of the patient and to the kinds of function that will benefit him most, often can make the patients more self-sufficient, can make improvements that enable him to walk farther with less fatigue, to balance without support, to walk without grotesque limping, or that sometimes permit discarding a brace. Sometimes improving his ability to carry out even seemingly minor tasks of personal care is a definite positive service which to the patient is a boon.     

Targeting chemokine pathways in esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is one of the fastest growing malignancies in the US and needs newer therapeutic and diagnostic strategies. Chronic inflammation plays a role in the pathogenesis of EAC and contributes to the dysplastic conversion of normal esophageal epithelium to Barrett's esophagus and frank adenocarcinoma. Chemokines play important roles in mediating inflammation and recent evidence implicates these ligands and their receptors in the development and spread of various tumors. We demonstrated that the chemokines IL8, CXCL1 and CXCL3 are significantly overexpressed during esophageal carcinogenesis and accompanied by amplification and demethylation of the chr4q21 gene locus. We also demonstrated that IL8 levels can be detected in serum of patients with EAC and can serve as potential biomarkers. We now demonstrate that inhibition of IL8 receptor, CXCR2, leads to decreased invasiveness of esophageal adenocarcinoma derived cells without affecting cellular proliferation. Taken together, these studies reveal the important roles that chemokines play in development of esophageal cancer and demonstrate that these pathways can serve as potential therapeutic targets.     

Nigral degeneration correlates with persistent activation of cerebellar Purkinje cells in MPTP-treated monkeys

In the present work we analyze the cerebellum of chronic parkinsonian monkeys in order to clarify whether chronic mesencephalic depletion is associated with long term activation of the cerebellar neurons in chronic Parkinsonism. In our study, we observed a persistent activation of Purkinje cells in the cerebellum of chronic parkinsonian macaques, characterized by the expression of c-Fos, which correlated with dopaminergic degeneration. These results are compatible with the results observed in fMRI in Parkinson's disease patients, and may contribute to the understanding of additional alterations in the brain circuitry in Parkinsonism.     

Arachidonic acid metabolites in a nephroblastoma associated with paraneoplastic hypercalcemia

Blood concentration of PGE2, F2a, 6 keto PGF1a (6kF1a), TxB2 and 13, 14 dehydro 15 keto PGE2 (13, 14 OH 15 k E2) were measured in renal artery and vein of a patient with a PGs producing nephroblastoma. The tumor tissue produced PGs in the following order: PGF2a>PGE2>TxB2>6kF1a>13, 14 OH 15 k E2. However, renal artery concentration of the substances were as follows: 13, 14 OH 15 k E2>TxB2>6kF1a>PGF2a>PGE2. Since arterial concentration is critical to postulating a calcium mobilizing effect on bone tissue, PGE2 arterial level seems to be too low to exert a pathogenetic role on hypercalcemia, at least in the patient reported here.     

Arachidonic acid metabolites in a nephroblastoma associated with paraneoplastic hypercalcemia

Blood concentration of PGE2, F2a, 6 keto PGF1a (6kF1a), TxB2 and 13, 14 dehydro 15 keto PGE2 (13, 14 OH 15 k E2) were measured in renal artery and vein of a patient with a PGs producing nephroblastoma. The tumor tissue produced PGs in the following order: PGF2a greater than PGE2 greater than TxB2 greater than 6kF1a greater than 13, 14 OH 15 k E2. However, renal artery concentration of the substances were as follows: 13, 14 OH 15 k E2 greater than TxB2 greater than 6kF1a greater than PGF2a greater than PGE2. Since arterial concentration is critical to postulating a calcium mobilizing effect on bone tissue, PGE2 arterial level seems to be too low to exert a pathogenetic role on hypercalcemia, at least in the patient reported here.     

Loss of Wtap results in cerebellar ataxia and degeneration of Purkinje cells

N⁶-methyladenosine (m⁶A) modification, which is achieved by the METTL3/METTL14/WTAP methyltransferase complex, is the most abundant internal mRNA modification. Although recent evidence indicates that m⁶A can regulate neurodevelopment as well as synaptic function, the roles of m⁶A modification in the cerebellum and related synaptic connections are not well established. Here, we report that Purkinje cell (PC)-specific WTAP knockout mice display early-onset ataxia concomitant with cerebellar atrophy due to extensive PC degeneration and apoptotic cell death. Loss of Wtap also causes the aberrant degradation of multiple PC synapses. WTAP depletion leads to decreased expression levels of METTL3/14 and reduced m⁶A methylation in PCs. Moreover, the expression of GFAP and NF-L in the degenerating cerebellum is increased, suggesting severe neuronal injuries. In conclusion, this study demonstrates the critical role of WTAP-mediated m⁶A modification in cerebellar PCs, thus providing unique insights related to neurodegenerative disorders.     

Tocotrienols prevent hydrogen peroxide-induced axon and dendrite degeneration in cerebellar granule cells

It is well known that reactive oxygen species (ROS) attack several living tissues and increase the risk of development and progression of serious diseases. In neuronal level, ROS induce cell death in concentration-dependent fashion. However, little is known about the mechanisms of neuronal changes by ROS prior to induction of cell death. Here we found that treatment of cerebellar granule neurons (CGCs) with 0.5 μM hydrogen peroxide induced axonal injury, but not cell death. The number of dendrites remarkably decreased in hydrogen peroxide-treated CGCs, and extensive beading was observed on survival dendrites. In addition, an abnormal band of the original collapsin response mediator protein (CRMP)-2 was detected by Western blotting in hydrogen peroxide-treated CGCs. Treatment with each tocotrienol isoform prevented axonal and dendrite degeneration and induction of the abnormal band of the original band of CRMP-2 in hydrogen peroxide-treated CGCs. These results indicate that treatment with tocotrienols may therefore be neuroprotective in the presence of hydrogen peroxide by preventing changes to the CRMP-2 that occur before neuron death.     

Tocotrienols prevent hydrogen peroxide-induced axon and dendrite degeneration in cerebellar granule cells

It is well known that reactive oxygen species (ROS) attack several living tissues and increase the risk of development and progression of serious diseases. In neuronal level, ROS induce cell death in concentration-dependent fashion. However, little is known about the mechanisms of neuronal changes by ROS prior to induction of cell death. Here we found that treatment of cerebellar granule neurons (CGCs) with 0.5 μM hydrogen peroxide induced axonal injury, but not cell death. The number of dendrites remarkably decreased in hydrogen peroxide-treated CGCs, and extensive beading was observed on survival dendrites. In addition, an abnormal band of the original collapsin response mediator protein (CRMP)-2 was detected by Western blotting in hydrogen peroxide-treated CGCs. Treatment with each tocotrienol isoform prevented axonal and dendrite degeneration and induction of the abnormal band of the original band of CRMP-2 in hydrogen peroxide-treated CGCs. These results indicate that treatment with tocotrienols may therefore be neuroprotective in the presence of hydrogen peroxide by preventing changes to the CRMP-2 that occur before neuron death.