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T W Ho

Publications and source records attributed to T W Ho.

33 records · Page 2Linked to original sources
PubMed1996

Acute motor axonal neuropathy: an antibody-mediated attack on axolemma.

The acute motor axonal neuropathy (AMAN) form of the Guillain-Barre syndrome is a paralytic disorder of abrupt onset characterized pathologically by motor nerve fiber degeneration of variable severity and by sparing of sensory fibers. There is little demyelination or lymphocytic inflammation. Most cases have antecedent infection with Campylobacter jejuni and many have antibodies directed toward GM1 ganglioside-like epitopes, but the mechanism of nerve-fiber injury has not been defined. In 7 fatal cases of AMAN, immunocytochemistry demonstrated the presence of IgG and the complement activation product C3d bound to the axolemma of motor fibers. The most frequently involved site was the nodal axolemma, but in more severe cases IgG and C3d were found within the periaxonal space of the myelinated internodes, bound to the outer surface of the motor axon. These results suggest that AMAN is a novel disorder caused by an antibody- and complement-mediated attack on the axolemma of motor fibers.

Acute Disease↗
PubMed1996

Early nodal changes in the acute motor axonal neuropathy pattern of the Guillain-Barré syndrome.

The axonal patterns of Guillain-Barré syndrome, associated in many cases with antecedent Campylobacter jejuni infection, are now recognized as frequent causes of acute flaccid paralysis in some regions of the world. This study examined ultrastructurally the PNS of seven cases of the acute motor axonal neuropathy form of Guillain-Barré syndrome. In this disorder previous studies of advanced cases have found Wallerian-like degeneration of motor fibres in the spinal roots and peripheral nerves, with little lymphocytic inflammation or demyelination. The present study was focused on identifying early changes and establishing the sequence of changes. By electron microscopy the earliest and mildest changes consisted of lengthening of the node of Ranvier with distortion of the paranodal myelin, and in some instances with breakdown of the outermost myelin terminal loops. At this stage many nodes had overlying macrophages which extended their processes through the Schwann cell basal lamina covering the node and apposed the axolemma. Macrophage processes then extended beneath the myelin terminal loops, and the whole macrophage entered the periaxonal space at the paranode. Macrophage processes dissected the axon from the adaxonal Schwann cell plasmalemma and the macrophages advanced into the internodal periaxonal space, where they typically surrounded a condensed-appearing axon. At this stage the adaxonal Schwann cell cytoplasm regularly degenerated and disappeared, so that the periaxonal space was bounded by the innermost myelin lamella, and the axolemma of many fibres could not be seen. The internodal myelin sheath and the abaxonal Schwann cell cytoplasm remained normal. This arrangement appeared to be stable for some time, but in many fibres the axon subsequently underwent Wallerian-like degeneration. By interfering with impulse conduction, these nodal and periaxonal changes may explain paralysis in some pathologically mild cases. In addition, at early stages, these changes may be reversible, thus explaining the rapid recovery of some patients who become paralysed with acute motor axonal neuropathy. These observations, taken together with previous studies, suggest that acute motor axonal neuropathy is an antibody- and complement-mediated disorder in which the relevant epitopes are present on the nodal and internodal axolemma.

Adolescent↗
PubMed1995

Prolactin-immunoglobulin G complexes from human serum act as costimulatory ligands causing proliferation of malignant B lymphocytes.

Several lines of evidence indicate that immunoglobulin-bound prolactin found in human serum is not a conventional complex between an anti-prolactin antibody and prolactin but a different type of association of prolactin with the Fab portion of IgG heavy chains. The complex of prolactin with IgG was purified from serum by anti-human prolactin affinity chromatography and was shown to contain close to 1 mole of N epsilon-(gamma-glutamyl)lysine crosslinks per mole of complex, a characteristic feature in structures crosslinked by transglutaminase. Interestingly, the complex caused a proliferation of cells from a subset of patients with chronic lymphocytic leukemia, while it was inactive in a cell proliferation prolactin bioassay. By contrast, human prolactin stimulated the proliferation of cells in the bioassay but had no effect on the complex-responsive cells from the patients. Competition studies with prolactin and free Fc fragment of IgG demonstrated a necessity for engaging both the prolactin and the immunoglobulin receptors for proliferation. More importantly, competition for the growth response by free prolactin and IgG suggests both possible reasons for the slow growth of this neoplasm as well as avenues for control of the disease.

B-Lymphocytes↗
PubMed1995

Guillain-Barré syndrome in northern China. The spectrum of neuropathological changes in clinically defined cases.

The pathology of the Guillain-Barré syndrome remains controversial, and autopsied cases available for study by contemporary techniques are uncommon. Large numbers of cases clinically diagnosed as Guillain-Barré syndrome occur in northern China. In this study we examined the neuropathological changes in 12 autopsied cases from Hebei Province, China. Eleven died early in the course of their disease. In all cases tissue was specially handled and fixed for electron microscopy and for immunocytochemistry. Three of these 12 cases had typical acute inflammatory demyelinating polyneuropathy (AIDP) with lymphocytic infiltration and macrophage-mediated demyelination, reproducing the pathological picture most often reported in Guillain-Barré syndrome in North America, Europe, and Australia. Six cases had predominantly axonal involvement, characterized by Wallerian-like degeneration of nerve fibres, with only minimal demyelination and with minimal inflammation in five. Three cases, even though paralysed at the time of death, had only very mild changes in the spinal roots and sciatic nerves. Within the group of six predominantly axonal cases, there were important differences both in the severity of the abnormalities and in the classes of fibres involved. Three cases had extensive Wallerian-like degeneration of sensory as well as motor fibres [acute motor-sensory axonal neuropathy (AMSAN)], while in the other three cases the fibre degeneration affected the motor nerve fibres almost exclusively. These latter cases establish a structural basis for the clinical and electrophysiological picture termed the acute motor axonal neuropathy (AMAN) pattern. In both the AMAN and the AMSAN patterns, a prominent feature was the presence of macrophages within the periaxonal space, surrounding or displacing the axon, and surrounded by an intact myelin sheath. These studies show that the early pathological changes in cases clinically diagnosed as the Guillain-Barré syndrome are diverse and not restricted to the well-known pattern of AIDP, and that the predominant pathological patterns may differ in different parts of the world. The differences in pathological findings between acute inflammatory demyelinating polyneuropathy and the axonal patterns are likely to reflect differences in the pathogenetic mechanisms. The periaxonal macrophages in the axonal patterns suggest that an important epitope may be localized to the axolemma or periaxonal space. The mild cases indicate that severe paralysis can occur early in Guillain-Barré syndrome without prominent structural changes along the nerve, suggesting that physiological block or nerve terminal changes may be implicated.

Acute Disease↗
PubMed1995

Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies.

Guillain-Barré syndrome has been considered to be primarily an acute inflammatory demyelinating polyneuropathy (AIDP). Our experience with Guillain-Barré syndrome in northern China differs from the traditional concept. Electrophysiologically and pathologically, most of our patients have motor axonal degeneration with minimal cellular inflammation, which we have termed 'acute motor axonal neuropathy' (AMAN). The current studies were undertaken to characterize prospectively the clinical, electrophysiological, and serological features of Guillain-Barré syndrome, defined clinically, in northern China. In 1991 and 1992, we characterized by electrodiagnostic criteria 129 Chinese patients with Guillain-Barré syndrome. The AMAN form was present in 65% of patients, the AIDP form in 24% and 11% were unclassifiable. For the 38 patients who presented from January to October, 1992, we performed serological assays for antibodies to Campylobacter jejuni and to glycolipids. Of these 38 patients, 55% had AMAN, 32% had AIDP and 13% were unclassifiable. Sixty-six percent of the 38 had serological evidence of recent C. jejuni infection as compared with 16% of village controls (P = 0.001). Seventy-six percent of AMAN patients and 42% of AIDP patients were seropositive. IgG anti-GM1 antibodies were more frequent in Guillain-Barré syndrome patients compared with village controls (42% versus 6%; P < 0.01). However, no statistically significant correlations were found between the pattern of disease, AMAN or AIDP, anti-glycolipid antibodies, or C. jejuni antibodies. Based on electrophysiological criteria, Guillain-Barré syndrome in northern China can be divided into two predominant forms: AIDP and AMAN. The AMAN form is more common and predominates in the yearly summer outbreaks of Guillain-Barré syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

The clinical correlates of high-titer IgG anti-GM1 antibodies.

Serum IgG anti-GM1 antibodies have been reported to occur in a variety of disorders, including Guillain-Barré syndrome and chronic polyneuropathies. Of over 5,000 serums tested in our laboratory, high titers of selective IgG anti-GM1 antibodies (> 1:1,000) and without binding to sulfatide were found in 35 patients. Clinical correlation revealed that almost all patients had axonal, motor neuropathies. One subgroup was comprised of individuals with an acute motor neuropathy, described either as an acute axonal Guillain-Barré-like syndrome that was occasionally associated with a prodrome of Campylobacter jejuni enteritis or as Chinese paralysis syndrome. A second group of patients had chronic asymmetric lower motor neuron (LMN) syndromes with no conduction block or other evidence of demyelination. The presence of selective high-titer IgG anti-GM1 antibody reactivity in serum is uncommon but when present is strongly associated with acute axonal motor neuropathies or chronic asymmetric LMN syndromes.

Antibodies↗
PubMed1993

Acute motor axonal neuropathy: a frequent cause of acute flaccid paralysis in China.

In northern China, annual epidemics of acute-onset flaccid paralysis diagnosed clinically as Guillain-Barré syndrome have been recognized for at least 20 years. On the basis of an historical analysis of more than 3,200 patients, distinctive features include most cases occurring during the summer months among children and young adults, most of whom reside in rural areas. Of 90 patients with acute flaccid paralysis, 88 had a distinctive pattern that shares clinical and cerebrospinal fluid findings with demyelinating Guillain-Barré syndrome, but that differs from Guillain-Barré syndrome physiologically and pathologically. The clinical course is marked by rapidly progressive ascending tetraparesis, often with respiratory failure, but without fever, systemic illness, or sensory involvement. Cerebrospinal fluid is acellular, and elevations of protein content occur in the second or third week of illness. Electrodiagnostic studies show normal motor distal latencies and limb conduction velocities, but reduced compound muscle action potential amplitudes. Sensory nerve action potentials and, when elicitable, F waves are within the range of normal. Recovery is usually good. Autopsy studies have shown Wallerian-like degeneration of motor fibers. These studies establish that this is a distinctive syndrome, distinguishable from poliomyelitis and demyelinating Guillain-Barré syndrome.

Acute Disease↗
PubMed1993

Secretion of specific nonphosphorylated and phosphorylated rat prolactin isoforms at different stages of the estrous cycle.

The biological activity and immunoreactivity of serum prolactin (PRL) has been shown to fluctuate throughout the estrous cycle of the rat. Since the 24-kDa nonphosphorylated and phosphorylated isoforms from several species have also been shown to differ in their biological and immunoreactivities, we have investigated the possibility that the 24-kDa monomer isoform profile varied throughout the estrous cycle of the rat. The PRL isoform profile was assessed in homogenates of pituitaries and in short-term incubation media. Comparisons between homogenates, which always contained isoforms 1, 2, 3, and 3' (numbered according to increasing acidity), and media showed nonproportional release of the isoforms at all stages. Of great interest were the release of isoform 1 (a nonphosphorylated form) only at estrus and the lack of release of isoform 3' (a phosphorylated form) only in the afternoon of proestrus. This lack of release of 3' was accompanied by a marked increase in the release of isoform 2 (the unmodified polypeptide). These results suggest a unique function for isoform 1 during estrus and a role for increased isoform 2 and absent isoform 3' during the proestrus surge of PRL. Moreover, they suggest that fluctuations in the biological activity and immunoreactivity of serum PRL during the estrous cycle could be due, at least in part, to fluctuations in the isoform profile.

Animals↗
PubMed1992

Prolactin isoform 2 as an autocrine growth factor for GH3 cells.

Because PRL has growth factor activities in several tissues, we have asked whether it also has autocrine growth factor activity in pituitary GH3 cells. GH3 cells were grown at increasing densities in the presence or absence of antirat PRL (polyclonal and monoclonal) or nonspecific antibodies. Cell proliferation increased with increasing cell density, as did the concentration of PRL in the medium. Antirat PRL, but not control antibody, markedly inhibited but did not eliminate cell proliferation, and this effect was diminished with increasing PRL concentration in the medium. PRL receptors were demonstrated on 40-50% of the cells by indirect immunofluorescence using a specific antirat PRL receptor monoclonal antibody. Cell surface PRL was colocalized to the same 40-50% of the cells and copatched or cocapped along with the receptors. Absence or presence of PRL receptors did not correlate with stage of the cell cycle, as judged by ethidium bromide dual labeling. Cell surface PRL was found to be on PRL-containing cells. These data have fulfilled four criteria necessary for establishment of a substance as a secreted autocrine growth factor: 1) the factor must be secreted; 2) in log growth phase, increased cell proliferation should occur at increased cell densities; 3) the cells must display a receptor for the factor; and 4) there must be a growth response to the factor. Thus we have established that PRL is an autocrine growth factor for at least 40-50% of the GH3 cell population. This, to our knowledge, is the first example of autocrine growth factor activity of a major hormone normotopically expressed.

Animals↗
PubMed1992

50 kD prolactin binding protein in schizophrenics on neuroleptic medication.

Serum samples from 15 age-matched normal male subjects and 15 male schizophrenic patients on neuroleptic medication were subjected to immunoprecipitation with anti-human prolactin (PRL) and analysis of the immunoprecipitate by two-dimensional gel electrophoresis. We report the unexpected immunoprecipitation of large amounts of an approximately 50 kD protein in 12/15 of the schizophrenic patients. Preliminary analyses suggest that this 50 kD protein may be an IgG heavy chain. Since total levels of IgG and each of the IgG subclasses are the same in the normal and schizophrenic group, the increased amount of the 50 kD protein in the schizophrenics is clearly specific to anti PRL precipitation. Since the anti-PRL does not directly recognize either the 50 kD protein or any immunoglobulin light chains in the precipitate, we suggest that the 50 kD protein is precipitated because it is bound to PRL. Perhaps immunoglobulin binding of PRL is a mechanism used to compensate for chronically elevated PRL levels during neuroleptic treatment.

Adult↗
PubMed1991

Prolactin (PRL) processing by kallikrein: production of the 21-23.5K PRL-like molecules and inferences about PRL storage in mature secretory granules.

We have previously described a series of C-terminally-clipped forms of PRL, the 21-23.5K PRL-like molecules (PLMs). Because we noted estrogen (E2) induction of PLMs and E2 also induces a pituitary glandular kallikrein, we have investigated the possibility that processing of PRL by kallikrein is responsible for the production of the PLMs. Subcellular fractionation of pituitaries from control or E2-treated female rats showed total kallikrein to be concentrated 1- to 4-fold and 6- to 20-fold in the granules (vs. original homogenate) from control and E2-treated animals, respectively. Cleavage of purified PRL by kallikrein resulted in the formation of large quantities of a number of the PLMs. Incubation of secretory granules derived from control or E2-treated animals under the same conditions showed no cleavage of PRL in the absence of a limiting granule membrane and a small production of the PLMs in the presence of a granule membrane. Production in the latter instance was slightly greater in granules derived from E2-treated animals. Addition of purified kallikrein to secretory granules from control or E2-treated animals in the presence or absence of granule membranes, resulted in the additional production of large amounts of only the smallest PLM (PLM 9), indicating a lack of cleavage of the two most C-terminal sites for the enzyme. Increasing the concentration of beta-mercaptoethanol to 0.64 M, to ensure monomerization of the granule PRL, had no effect on endogenous kallikrein activity of the number of products resulting from the addition of exogenous kallikrein to granules. In summary: 1) purified kallikrein can cleave purified PRL to form products which run with the same isoelectric point and mol wt values as the PLMs; 2) kallikrein is present in PRL secretory granules; 3) some PLM production occurs in a membrane-bound secretory granule fraction, but none occurs after removal of the membrane; this intragranular production, like cleavage of purified PRL with purified kallikrein, is dependent on the presence of a detergent and a reducing agent; 4) cleavage of granular PRL by exogenous kallikrein is limited to a single site and the more C-terminal sites are protected; and 5) protection of the C-terminus is not removed by intermolecular and intramolecular disulfide bond reduction. We conclude: 1) that pituitary glandular kallikrein is a strong candidate for the enzyme responsible for the production of the PLMs, and 2) that there is some element of PRL storage, other than intermolecular disulfide bonds, which involves the C-terminus of the molecule.

Animals↗
PubMed1989

Production and secretion of the 21-23.5 kDa prolactin-like molecules.

We recently described the presence of a series of prolactin (PRL)-like molecules (PLMs) in the rat pituitary gland and showed that their formation was not due to artifactual proteolysis of 24 kDa PRL during extraction or to degradation of PRL in lysosomes. In this study we have found (1) in vitro translation of pituitary cell RNA to result in the production of only 24 kDa monomer isoform 2 and no PLMs, (2) that secretion of newly synthesized PLMs is differently regulated than at least a proportion of newly synthesized monomers, (3) that secretion of newly synthesized PLMs occurs after at least a 6 h delay, (4) that cysteamine (a) inhibits the release of the PLMs, (b) causes an increase in their amount versus isoform 2, and (c) causes an intracellular accumulation of pleiomorphic, immature secretory granules, and (5) that cells grown under degranulating culture conditions do not contain PLMs. These results, using normal anterior pituitary cells in primary culture, demonstrate the potential for differential release of the PLMs versus monomer PRL in vivo and are consistent with the production of the PLMs from 24 kDa monomer isoform 2 during secretory granule condensation.

Animals↗
PubMed1989

Mammotroph autoregulation: the differential roles of the 24K isoforms of prolactin.

In this study we have attempted to determine which of the secreted 24K isoforms was responsible for autocrine regulation of PRL secretion by comparing the isoforms synthesized and secreted by normal cells, which do autoregulate, with those synthesized and secreted by GH3 cells, which do not normally autoregulate. Comparable numbers of cells were washed free of serum and then extracted into Tris-buffered saline by sonication and detergent treatment. Proteins present in these cell extracts and in samples of culture medium were then precipitated with cold acetone (-20 C; 48 h) and subsequently dissolved in urea-lysis buffer for 2-dimensional (2-D) electrophoresis. The 2-D patterns for normal cells showed four 24K PRL isoforms inside the cells and three 24K PRL isoforms (designated 2, 3, and 3') secreted into the medium. The 2-D patterns for GH3 cells showed very little intracellular storage of PRL, but what was present was identified as 24K PRL isoform 2. The GH3 cells secreted large amounts of only 24K PRL isoform 2. Preparations of PRL containing only isoforms 1,2, and 3 (at a total radioimmunoassayable concentration of 5 micrograms/ml PRL) were capable of inducing autoregulation in GH3 cells, as evidence by decreased secretion of prelabeled intracellular PRL. Initiation of autoregulation in GH3 cells caused granulation and the intracellular production of isoform 3. Since a) a preparation containing isoforms 1, 2, and 3 was found to induce autoregulation in GH3 cells, b) isoform 1 is not a secreted form, and c) isoform 2 does not cause autoregulation (at least in GH3 cells), it is deduced that isoform 3 is an autocrine form of PRL. Since initiation of autoregulation in GH3 cells caused those cells to produce isoform 3, it is further deduced that the autoregulatory defect in GH3 cells lies in the actual lack of production of isoform 3 and not in an inherent inability of these cells to produce isoform 3.

Animals↗
PubMed1989

Biosynthesis of the secreted 24 K isoforms of prolactin.

PRL exists within the mammotroph population in a number of different molecular forms. Several of these forms are best described as isoforms, as they have the same mol wt (24 K), but differ in their net charges. In this study we have used in vitro translation assays to ascertain the number of 24 K translation products of normal pituitary messenger RNA (mRNA), and, finding only one, have used both in vitro translation assays and subcellular fractionation to determine the intracellular site of the posttranslational modification of this single translation product. Translation of mRNA from normal pituitary tissue or GH3 cells resulted in the apparent production of a number of pre-PRLs, but in only a single rough microsome-processed form of PRL, 24 K isoform 2. Longer term translation assays utilizing a variety of isotopes failed to show any evidence for rough microsomal posttranslational modification of isoform 2. Subcellular fractionation, using a discontinuous sucrose gradient, however, produced a membrane-bound large secretory granule fraction which, when isolated, contained essentially only isoform 2, and which had the capacity to convert isoform 2 to isoforms 3 and 3' by posttranslational phosphorylation.

Animals↗