PubMed Health⌕ Search

Biomedical subjects

J F Howard

Publications and source records attributed to J F Howard.

At least 19 recordsLinked to original sources
PubMed2005

Distal symmetric polyneuropathy: a definition for clinical research: report of the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.

The objective of this report was to develop a case definition of distal symmetric polyneuropathy to standardize and facilitate clinical research and epidemiologic studies. A formalized consensus process was employed to reach agreement after a systematic review and classification of evidence from the literature. The literature indicates that symptoms alone have relatively poor diagnostic accuracy in predicting the presence of polyneuropathy; signs are better predictors of polyneuropathy than symptoms; and single abnormalities on examination are less sensitive than multiple abnormalities in predicting the presence of polyneuropathy. The combination of neuropathic symptoms, signs, and electrodiagnostic findings provides the most accurate diagnosis of distal symmetric polyneuropathy. A set of case definitions was rank ordered by likelihood of disease. The highest likelihood of polyneuropathy (useful for clinical trials) occurs with a combination of multiple symptoms, multiple signs, and abnormal electrodiagnostic studies. A modest likelihood of polyneuropathy (useful for field or epidemiologic studies) occurs with a combination of multiple symptoms and multiple signs when the results of electrodiagnostic studies are not available. A lower likelihood of polyneuropathy occurs when electrodiagnostic studies and signs are discordant. For research purposes, the best approach to defining distal symmetric polyneuropathy is a set of case definitions rank ordered by estimated likelihood of disease. The inclusion of this formalized case definition in clinical and epidemiologic research studies will ensure greater consistency of case selection.

Clinical Protocols↗
PubMed2005

Distal symmetrical polyneuropathy: definition for clinical research.

The objective of this report was to develop a case definition of "distal symmetrical polyneuropathy" to standardize and facilitate clinical research and epidemiological studies. A formalized consensus process was employed to reach agreement after a systematic review and classification of evidence from the literature. The literature indicates that symptoms alone have relatively poor diagnostic accuracy in predicting the presence of polyneuropathy; signs are better predictors of polyneuropathy than symptoms; and single abnormalities on examination are less sensitive than multiple abnormalities in predicting the presence of polyneuropathy. The combination of neuropathic symptoms, signs, and electrodiagnostic findings provides the most accurate diagnosis of distal symmetrical polyneuropathy. A set of case definitions was rank ordered by likelihood of disease. The highest likelihood of polyneuropathy (useful for clinical trials) occurs with a combination of multiple symptoms, multiple signs, and abnormal electrodiagnostic studies. A modest likelihood of polyneuropathy (useful for field or epidemiological studies) occurs with a combination of multiple symptoms and multiple signs when the results of electrodiagnostic studies are not available. A lower likelihood of polyneuropathy occurs when electrodiagnostic studies and signs are discordant. For research purposes, the best approach for defining distal symmetrical polyneuropathy is a set of case definitions rank ordered by estimated likelihood of disease. The inclusion of this formalized case definition in clinical and epidemiological research studies will ensure greater consistency of case selection.

Electrodiagnosis↗
PubMed2001

Human thymuses express incomplete sets of muscle acetylcholine receptor subunit transcripts that seldom include the delta subunit.

In myasthenia gravis (MG) the muscle acetylcholine receptor (AChR) is the target of an immune response that might begin in the thymus. The thymus expresses binding sites for specific ligands of muscle AChR, a complex protein composed of alpha, beta, gamma (or epsilon) and delta subunits. The thymus expresses the AChR alpha subunit, but there is controversy regarding the expression in the thymus of the gamma, epsilon and delta subunits. We investigated the presence of messenger RNA (mRNA) for the different muscle AChR subunits in thymus tissue from 20 healthy subjects and 13 myasthenic patients. We detected mRNA for the alpha and epsilon subunits in all samples, for the beta subunit in all but one sample and for the gamma subunit in most samples although at lower levels than the epsilon subunit. Myasthenic thymuses expressed levels of gamma subunit mRNA similar to control thymuses but more abundant epsilon subunit mRNA. None of the myasthenic thymuses and only two control thymuses expressed detectable delta subunit mRNA. This supports the hypothesis that human thymus may express AChR proteins that do not include the delta subunit. Such receptors, which would have different antigenic structure than the muscle AChRs, might have a role in triggering the autoimmune response that causes MG.

Adolescent↗
PubMed2001

Use of intravenous gamma globulins in neuroimmunologic diseases.

Intravenous gamma globulin (IVIg) is used in the treatment of immunologic diseases that affect the entire neuroaxis, including the brain, spinal cord, peripheral nerves, muscles, and neuromuscular junction. The panel reviewed the available literature on the use of IVIg in order to evaluate the efficacy of this therapy in neuroimmunologic diseases. In prospective, rigorously controlled, double-blinded clinical trials, IVIg was found to have proven efficacy in the Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, dermatomyositis, and Lambert-Eaton myasthenic syndrome. It was found to be probably effective in myasthenia gravis and polymyositis, and possibly effective in several other neuroimmunologic diseases. Further studies are needed to evaluate the use of IVIg for neuroimmunologic diseases in which its efficacy is suspected but not proven and to elucidate its mechanisms of action.

Clinical Trials as Topic↗
PubMed2000

T cell recognition of muscle acetylcholine receptor in ocular myasthenia gravis.

We examined the proliferative response of blood CD4(+) cells to muscle acetylcholine receptor (AChR) subunits and the epitope repertoire of the epsilon and gamma subunits, in ocular myasthenia gravis (oMG) patients and healthy subjects. oMG patients seldom recognized all subunits. The frequency and intensity of recognition was the same for all subunits, irrespective of the disease duration. The responses in oMG were lower than in generalized myasthenia gravis. Healthy subjects had frequent, low responses to one or more subunits. oMG patients recognized several epitopes on the gamma and epsilon subunits, that partially overlapped those recognized in gMG. The subunits and epitopes recognized by individual oMG patients changed over time. Thus, oMG patients have minimal and unstable sensitization of anti-AChR CD4(+) cells, in agreement with their low and inconsistent synthesis of anti-AChR antibody.

Adult↗
PubMed1999

Myasthenia in SCID mice grafted with myasthenic patient lymphocytes: role of CD4+ and CD8+ cells.

OBJECTIVES: Acetylcholine receptor (AChR)-specific CD4+ cells are present in MG patients, and synthesis of the high-affinity immunoglobulin G (IgG) autoantibodies (autoAb) against the muscle AChR that causes MG symptoms requires intervention of CD4+ cells. The role of CD4+ cells in MG pathogenesis has been postulated but never proven. MG patients do not have anti-AChR cytotoxic phenomena, and it has been assumed that CD8+ cells do not have a pathogenic role in MG. However, CD8+ cells may facilitate rodent experimental MG, raising the possibility that CD8+ cells might be necessary also in MG. In this study we examined whether CD4+ and CD8+ cells play a role in the pathogenesis of MG and whether CD4+ cells specific for AChR epitope sequences recognized by most MG patients ("universal" epitopes) drive the synthesis of pathogenic antibodies. METHODS: First we characterized a chimeric human-mouse model of MG in severe combined immunodeficiency (SCID) mice engrafted with blood lymphocytes (BL) from MG patients. We used that model to determine whether CD4+ and CD8+ cells are necessary for transfer of MG symptoms. We engrafted SCID mice intraperitoneum with BL from 19 MG patients and 5 healthy controls. We engrafted some mice with either BL, BL depleted in CD4+ or CD8+ cells from the same patient, or CD4+ depleted BL reconstituted with CD4+ T cells from the same patient, specific for "universal" AChR epitopes or for two unrelated antigens, tetanus and diphtheria toxoids. We tested the mice for myasthenic symptoms for 7 to 18 weeks. RESULTS: Mice transplanted with BL, or CD8+ depleted BL, or CD4+-depleted BL reconstituted with anti-AChR CD4+ cells from MG patients frequently developed myasthenic weakness. The mice had human anti-AChR Ab in the serum and bound to muscle AChR. Mice transplanted with BL from controls, or CD4+-depleted BL from MG patients, or CD4+-depleted BL from an MG patient reconstituted with CD4+ cells specific for tetanus or diphtheria toxoids did not develop myasthenic weakness or anti-AChR Ab. CONCLUSIONS: CD4+ cells are necessary for MG pathogenesis; CD8+ cells may not be. CD4+ cells specific for "universal" AChR epitopes help the synthesis of pathogenic Ab.

Adult↗
PubMed1998

CD4+ T cell repertoire on the epsilon subunit of muscle acetylcholine receptor in myasthenia gravis.

We have identified sequence regions of the human muscle acetylcholine receptor epsilon subunit recognized by CD4+ T cells from myasthenia gravis patients. We tested the proliferative response in vitro of blood CD4+ cells from 18 myasthenic patients and 5 controls, to individual overlapping synthetic peptides spanning the epsilon subunit sequence. All patients recognized a complex epitope repertoire. The peptides recognized by the CD4+ cells included sequence regions of the epsilon subunit that were diverged as compared to the homologous sequences of the other receptor subunits. Recognition of epitopes formed by sequence regions unique to the epsilon subunit suggests a direct role of this subunit in sensitizing the CD4+ cells. Several epsilon subunit peptides were recognized by many patients. Thus the epsilon subunit, like other acetylcholine receptor subunits, forms 'universal' CD4+ epitopes. The healthy subjects recognized some epsilon subunit peptides sporadically and at a low level.

Adult↗
PubMed1998

TCR-Vbeta usage in the thymus and blood of myasthenia gravis patients.

In myasthenia gravis (MG) the muscle acetylcholine receptor (AChR) is the target of an autoimmune response. The anti-AChR response may originate in the thymus, which is abnormal in most MG patients and contains anti-AChR T and B cells. Microbial superantigens (sAg) may trigger autoimmune responses and in this study we sought clues as to whether sAg play a role in the pathogenesis of MG. We investigated the frequency of use of the different TCR Vbeta families by the thymus and blood T cells in MG patients and in control subjects, using a multi-primer PCR assay. Identical TCR-Vbeta usage was found in the thymi of MG patients and controls, except Vbeta2, which showed a small increase in MG patients' thymi. Blood T cells of MG patients used Vbeta4, Vbeta6, Vbeta15, Vbeta16 and Vbeta24 significantly more than those of the controls. Vbeta4 and Vbeta6 are the gene families most frequently used by anti-AChR CD4(+) cells in MG patients. Blood T cells from MG patients used Vbeta12, Vbeta14, Vbeta17 and Vbeta18 significantly less than controls. MG patients used Vbeta4 and Vbeta6 significantly more in the blood than in the thymus, while the opposite occurred for Vbeta7, Vbeta12 and Vbeta14. Controls used Vbeta17 more and Vbeta24 less in the blood than in the thymus. The preferential expansion of Vbeta4 and Vbeta6 in MG patients might reflect the immunodominance of certain AChR epitopes, or the action of a sAg outside the thymus. The minimal differences in the TCR-Vbeta usage in the blood and thymus of control subjects might be due to expansion of T cell clones specific for common antigens. Identical Vbeta usage in the thymi of MG patients and controls does not support an important role of the thymus as the location of anti-AChR sensitization when MG is clinically evident. The differences observed in the Vbeta usage in blood and thymi of MG patients are likely to be due to preferential Vbeta usage by the anti-AChR T cells in the blood.

Adolescent↗
PubMed1998

Successful treatment of headache related to intravenous immunoglobulin with antimigraine medications.

In order to investigate headache related to intravenous immunoglobulin, we studied a 36-year-old woman with a history of migraine receiving weekly intravenous immunoglobulin for refractory myasthenia gravis who experienced severe headaches with each treatment. Neurological examination, CT scan of the head, and a lumber puncture after the first headache were normal. Significant therapeutic response was based upon 50% reduction in pain and associated features. Headache features included throbbing pain which worsened with head movement and was associated with severe photophobia and nausea. Sumatriptan, 6 mg subcutaneous, reduced headache significantly with resolution of associated complaints. Treatment prior to intravenous immunoglobulin with dihydroergotamine mesylate resulted in development of only a mild dull ache without further development of severe head pain. Dihydroergotamine mesylate was also abortive in the few instances when the headache worsened. Headaches associated with intravenous immunoglobulin may have features of migraine and may be successfully prevented and/or treated with 5-HT1D receptor agonists.

Adult↗
PubMed1998

Intravenous immunoglobulin for the treatment of acquired myasthenia gravis.

Acquired myasthenia gravis (MG) is an autoimmune disorder characterized by exertional fatigue and weakness that is made worse with activity and improved with rest, only to recur with the resumption of activity. The pathology results from an antibody-mediated attack to several different epitopes of the acetylcholine receptor (AChR) complex. The consensus of an expert panel is that intravenous immunoglobulin (IVIg) is effective in reversing myasthenic weakness. Although the mechanism of action is not known, it is likely that there is a downregulation of antibody production. IVIg appears to have a role as an acute treatment intervention in rapidly progressive weakness or as a chronic maintenance therapy when all other treatment modalities have failed. Its response is similar to but slower than the response of plasma exchange (PE), but it offers advantages when therapeutic apheresis is not available or when vascular access is problematic.

Humans↗
PubMed1996

Mobius syndrome: electrophysiologic studies in seven cases.

Mobius syndrome is characterized by congenital facial diplegia, frequent impairment of gaze, variable involvement of other cranial muscles, and various musculoskeletal anomalies. The site of dysfunction remains debatable. We performed detailed electrophysiologic studies in 5 children and 2 adults with Mobius syndrome to better delineate the pathophysiology of this disorder. Sensory and motor conduction studies were normal in the extremities. Facial compound muscle action potential amplitudes were reduced in all patients. The blink reflex R1 responses were unobtainable unilaterally in 2 patients and unobtainable bilaterally in 3 patients. Otherwise, R1 and R2 latencies were variably prolonged. The jaw jerk and masseter silent periods, tested in 2 patients, were normal. Detailed electromyographic studies of facial muscles revealed multifocal, chronic neurogenic changes. The findings indicate a brain stem process predominantly affecting the facial nuclei and their internuclear connections rather than a supranuclear or muscular site of involvement.

Action Potentials↗
PubMed1996

One hundred consecutive thymectomies for myasthenia gravis.

BACKGROUND: Between June 1997 and November 1993, 100 consecutive thymectomies for myasthenia gravis were performed at University of North Carolina Hospitals in Chapel Hill. METHODS: A consistent, planned protocol involving preoperative, intraoperative, and postoperative care was followed. All thymectomies were performed through a median sternotomy with removal of all visible thymus and perithymic fat in the anterior mediastinum. RESULTS: There was no perioperative mortality or longterm morbidity. Mean postoperative hospital stay was 6.3 days (range, 3 to 18 days). Ninety-six percent of the patients were extubated the day of the operation, and all patients were extubated within 24 hours. Mean postoperative intensive care unit stay was 1.2 days (range, 1 to 4 days). After a mean follow-up of 65 months (range, 1 to 199 months), 78% of all patients are improved by at least one modified Osserman classification when their current status is compared with their worst preoperative disease severity. In fact, 69% of patients with mild disease preoperatively (class I, II, or III maximal severity) are in pharmacologic remission (asymptomatic without regular medication), whereas 29% of patients with severe disease (class IV or V) are in remission (p = 0.0001). CONCLUSIONS: Our programmatic approach to thymectomy through a sternotomy has shown minimal morbidity and mortality. It is beneficial to myasthenics at both ends of the age and severity spectrum.

Adult↗
PubMed1996

Spinal cord infarction: etiology and outcome.

We reviewed 44 cases of ischemia and infarction of the spinal cord at two university hospitals. Three patients experienced transient ischemic attacks. Etiologies of completed strokes were diverse and included rupture and surgical repair of aortic aneurysms, aortic dissection, aortic rupture and thrombosis, global ischemia, anterior spinal artery embolism, repair and thrombosis of spinal arteriovenous malformations, hematomyelia, epidural hematoma, cervical osteophytosis, celiac plexus block, systemic lupus erythematosus, coagulopathy, and decompression sickness. Motor function improved in 12 patients, was substantial in only one, and occurred largely within the first 2 to 4 weeks. Favorable ambulatory outcome correlated with improving neurologic examinations and relatively preserved strength in hip abductors and knee extensors. More extensive deficits without initial improvement portended a more severe prognosis. Autonomic dysfunction, pain, paresthesia, and depression were common and impeded recovery in some patients. The mean level of deficit was at T-8 and in cases of global ischemia was at T-9, which leads us to dispute the classical view of a midthoracic watershed zone of ischemic vulnerability near T-4.

Adolescent↗
PubMed1995

Immunoregulatory CD8+ cells recognize antigen-activated CD4+ cells in myasthenia gravis patients and in healthy controls.

CD8+ cells inhibiting the response of CD4+ cells exist in rodents, recognizing epitopes unique to a CD4+ clone (Ids) or expressed by all activated CD4+ cell (ergotypes). Stimulation of CD8+ cells recognizing ergotypes shared by all Ag-activated CD4+ cells would be useful for treatment of diseases involving undesirable CD4+ responses to ill defined Ags, such as many autoimmune diseases and allergies. As a first step toward demonstrating the existence of anti-ergotype CD8+ immunoregulatory cells in humans, we investigated here whether CD8+ cells recognizing Ag-activated CD4+ cells exist in autoimmune and healthy humans. CD4+ cells specific for human muscle acetylcholine receptor, tetanus, or diphtheria toxoids were propagated from patients with myasthenia gravis patients and healthy controls. Ag-activated CD4+ cells were irradiated and used as Ag to test the response of CD(4+)-depleted CD(8+)-enriched PBMC (CD8+ PBMC) from myasthenic patients and controls and to propagate short-term CD8+ cell lines from CD8+ PBMC. In both patients and controls CD8+ PBMC and CD8+ lines responded vigorously to autologous Ag-activated CD4+ cells. The CD8+ lines responded equally well to the Ag-activated CD4+ cells of different Ag specificity, suggesting that they recognized CD4+ ergotypes. They did not seem to respond to CD4+ cells activated by PHA. The CD8+ cells recognized class I-restricted epitopes, as their response to activated CD4+ cells was suppressed by anti-class I Ab. CD8+ cells recognizing Ag-activated CD4+ were present cells in the controls for 5 to 12 wk after immunization. In myasthenic patients, CD8+ cells recognizing activated anti-acetylcholine receptor CD4+ cells seemed to be always present.

Adult↗
PubMed1994

Myasthenia gravis. Residues of the alpha and gamma subunits of muscle acetylcholine receptor involved in formation of immunodominant CD4+ epitopes.

We propagated from myasthenia gravis (MG) patients by stimulation in vitro with synthetic sequences (alpha 48-67, alpha 304-322, gamma 75-94 and gamma 321-340) of the human muscle acetylcholine receptor (AChR), CD4+ lines against four 20-residue sequence regions of the AChR alpha and gamma subunits that are recognized by Th cells of most MG patients. Most lines secreted IL-2 and not IL-4, suggesting that they comprise Th1 cells. For three lines we verified that, as reported previously, AChR epitopes are presented by DR molecules: their response to the relevant peptide was abolished by anti-DR Abs. The DR molecules presenting AChR epitopes were identified by testing the response of the lines to the relevant peptide, using APC from donors homozygous for the different DR alleles of the line. We tested the lines with single residue-substituted analogues of the epitope sequence. The results of these experiments indicated that the lines were polyclonal and recognized overlapping epitopes. Their response was abolished by some substitutions, identifying residues common to all epitopes within a given region, whereas other substitutions reduced but did not obliterate the response, indicating residues included in some but not all epitopes recognized by the line. Comparison of the residues involved in epitope formation for different lines supported the conclusion that within the 20-residue immunodominant regions investigated here, the same sequence segment is involved in formation of epitopes, even in DR-discordant patients.

Adult↗