Sensitivity of the sodium and potassium channels of Myxicola giant axons to changes in external pH.

Myxicola giant axons were studied using standard voltage-clamp techniques in solutions whose pH values ranged from 3.9 to 10.2. Buffer concentrations of 50 mM or greater were necessary to demonstrate the full effect of pH. In acidic solutions the axon underwent a variable depolarization, and both the sodium and potassium conductances were reversibly depressed with approximate pKa's of 4.8 and 4.4, respectively. The voltage dependence of GNa was only slightly altered by acidic conditions, whereas there occurred large shifts in GK along the voltage axis consistent with a substantial decrease in net negative surface charge in the vicinity of the K+ channels. The sodium and potassium activation rate constants were decreased by acidic conditions, but the results could not be described as a simple translation along the voltage axis.

Potassium current kinetics in Myxicola axons. Effects of conditioning prepulses.

In Myxicola giant axons the time constants for activation of the potassium conductance (GK) after prepulses less depolarized than a test pulse are comparable to the time constants for turn off of GK after prepulses more depolarized than the same test pulse. The absolute magnitude of the steady-state level of GK is also independent of prepulse amplitude in Myxicola. The results are contrasted with recent observations on voltage-clamped frog nodes.

Dapsone-induced peripheral neuropathy.

Peripheral neuropathy is a rare complication of dapsone therapy. This neuropathy appears primarily to be of the motor type, and recovery occurs on discontinuation of the drug therapy. The patient in this report developed a marked motor deficit as well as a selective marked loss of vibration sense shortly after the initiation of a relatively low dose of dapsone. Recovery was rapid on cessation of the therapy. This patient was found to be a slow acetylator of isoniazid, and therefore is probably a slow acetylator of dapsone. The possible mechanisms of the neurotoxicity of dapsone and the role of altered metabolism are discussed.

Mechanical fragility of erythrocytes in multiple sclerosis.

Erythrocyte fragility was measured by mechanical shaking in 82 normal individuals and 19 patients with multiple sclerosis (MS). On the average, fragility was significantly higher in the MS patients, although this increase did not correlate with the presence of serum neuroelectric blocking factors.

Complement-dependent serum: neuroelectric blocking activity in multiple sclerosis.

In attempting to discover a relationship between the neurologic and immunologic abnormalities in multiple sclerosis, we found a serum factor that inhibits the ventral root response in isolated, perfused frog spinal cords. This effect is correlated with disease activity. Blocking activity of the serum was lost by heating to 56 degrees C, restored by adding complement, and was found in the serum IgG fraction. There was no correlation of neuroelectric blocking activity with measles complement-fixing antibody. An antibody other than that to measles virus may thus have a role in the pathogenesis of multiple sclerosis.

Movement phosphenes in optic neuritis: a new clinical sign.

Positive visual phenomena (phosphenes) elicited by eye movements have been described in normal individuals and in myopes with vitreous opacities. In the present paper we describe eye movement-induced phosphenes that appear to be related to optic nerve involvement in patients with optic neuritis and multiple sclerosis. This phenomenon is not associated with vitreous or retinal defects, nor is it similar to phosphenes observed in normal individuals. Instead, it shares many characteristics with the well-known Lhermitte sign and is believed to represent a similar phenomenon.

Neuroelectric blocking activity and plasmapheresis in amyotrophic lateral sclerosis.

Neuroelectric blocking activity, similar in nature to that previously observed in sera from patients with multiple sclerosis, has been observed in sera from 18 patients with amyotrophic lateral sclerosis. Results concerning the application of plasma exchange to this patient population are also described.

4-Aminopyridine in multiple sclerosis: prolonged administration.

In an earlier study, we demonstrated efficacy of single oral doses of 4-aminopyridine (4-AP) in improving motor and visual signs in multiple sclerosis (MS) patients for a mean of 4.97 hours. We attempted to determine whether efficacy could safely be prolonged using multiple daily doses over several days by administering 7.5 to 52.5 mg 4-AP to 17 temperature-sensitive MS patients in one to three daily doses at 3- to 4-hour intervals over 1 to 5 days in a double-blind study. Nine of these patients were also tested with identically appearing placebo. Thirteen of the 17 patients (76%) given 4-AP showed clinically important motor and visual improvements compared with three of nine in the placebo group. Average peak improvement scores were 0.40 for 4-AP and 0.12 for placebo. Seventy percent of the daily 4-AP improvements lasted 7 to 10 hours. The improvements for two consecutive doses of 4-AP lasted a mean of 7.07 hours (83% of the average 8.53-hour treatment-observation period) compared with 2.36 hours for placebo (26% of the average 9.06-hour treatment-observation period). No serious side effects occurred. 4-AP is a promising drug for the symptomatic treatment of MS.

Lymphocyte subpopulations in multiple scerlosis: comparison with neuroelectric blocking activity.

Lymphocyte subpopulations were determined in patients with confirmed multiple sclerosis using a new technique in which immunoglobulin bearing (lg+) cells are rosetted directly with purified anti-light chain antibody-coated human erythrocytes, while T cells are first sensitized with specific anti-human thymus antisera prepared in b4b4 rabbits, and then indirectly rosetted with purified anti-rabbit light chain allotype antibody-coated human erythrocytes. In 45 percent of the patients, there was a striking decrease in the percentage of T lymphocytes and a reciprocal elevation of lg+ and N cells. In another 20 percent, T cell depression was not accompanied by Ig+ elevation. The remaining 35 percent had normal lymphocyte profiles as did all patients with nondemyelinating neurologic diseases. However, we found no significant correlation between the lymphocyte profiles and prospective clinical evaluation of these patients and no correlation between alterations in lymphocyte profile and the presence of neuroelectric blocking factors in the peripheral blood of multiple sclerosis patients.

Plasmapheresis decreases neuroelectric blocking activity in multiple sclerosis.

Serum neuroelectric blocking factor activity diminished after plasmapheresis in five of seven patients with MS but returned to baseline levels in 2 to 3 weeks. In the other two patients changes were insignificant. All patients studied had progressing symptoms. Five plasma exchanges of 2 liters were performed in 10 days. Two patients improved clinically, whereas five did not. There was no correlation between the level of neuroelectric blocking activity and changes in clinical status.

Disruption of the perineurium in amphibian peripheral nerve: morphology and physiology.

Removal of a small piece of perineurium in amphibian nerve causes a lesion consistent with the presence of extensive demyelination. Conduction velocity is reduced by 30 to 40%, and most of the fibers that still conduct are labile, with abnormally low blocking temperatures and unusual susceptibility to conduction block induced by changes in extracellular electrolytes. Application of drugs that inhibit the delayed K+ conductance restores conduction to fibers blocked by temperature elevation and ionic changes. This preparation may prove useful in studies of the pathophysiology of demyelinating diseases.

T cell-depleted autologous hematopoietic stem cell transplantation for multiple sclerosis: report on the first three patients.

Multiple sclerosis (MS) is a disease of the central nervous system characterized by immune-mediated destruction of myelin. In patients with progressive deterioration, we have intensified immunosuppression to the point of myeloablation. Subsequently, a new hematopoietic and immune system is generated by infusion of CD34-positive hematopoietic stem cells (HSC). Three patients with clinical MS and a decline of their Kurtzke extended disability status scale (EDSS) by 1.5 points over the 12 months preceding enrollment and a Kurtzke EDSS of 8.0 at the time of enrollment were treated with hematopoietic stem cell (HSC) transplantation using a myeloablative conditioning regimen of cyclophosphamide (120 mg/kg), methylprednisolone (4 g) and total body irradiation (1200 cGy). Reconstitution of hematopoiesis was achieved with CD34-enriched stem cells. The average time of follow-up is 8 months (range 6-10 months). Despite withdrawal of all immunosuppressive medications, functional improvements have occurred in all three patients. We conclude that T cell-depleted hematopoietic stem cell transplantation can be performed safely in patients with severe and debilitating multiple sclerosis. Stem cell transplantation has resulted in modest neurologic improvements for the first time since onset of progressive disease although no significant changes in EDSS or NRS scales are evident at this time.

Alkaloid synthesis using chiral delta-amino beta-ketoesters: a stereoselective synthesis of (-)-lasubine II.

[reaction: see text]A highly stereoselective asymmetric synthesis of the quinolizidinealkaloid (-)-lasubine II from a delta-amino beta-hydroxy ketone, a new polyfunctionalized chiral building block, is described.

Masked oxo sulfinimines (N-sulfinyl imines) in the asymmetric synthesis of proline and pipecolic acid derivatives.

[structure: see text]. On addition of Et2AlCN/i-PrOH, masked oxo sulfinimines give alpha-amino nitriles that afford oxo alpha-amino acids on hydrolysis. These amino acids cyclize and are reduced to cis proline and cis pipecolic acids derivatives in high ee and good yield. This new procedure avoids many of the limitations related to the preparation of oxo amino acids from proteinogenic amino acids.

Intramolecular Mannich reaction in the asymmetric synthesis of polysubstituted piperidines: concise synthesis of the dendrobate alkaloid (+)-241D and its C-4 epimer.

[reaction: see text] The intramolecular Mannich reaction of delta-amino beta-keto esters with aldehydes and ketones is a new methodology for the synthesis of polysubstituted piperidines and is illustrated by the concise asymmetric synthesis of the dendrobate alkaloid (+)-241D and its C-4 epimer.

Asymmetric synthesis of alpha-methylphosphophenylalanine derivatives using sulfinimine-derived enantiopure aziridine-2-phosphonates.

[formula: see text] 2-Methylaziridine-2-phosphonates were prepared from enantiopure sulfinimines and were demonstrated to be versatile synthetic intermediates for the synthesis of novel alpha-disubstituted and alpha,beta-trisubstituted alpha-aminophosphonate derivatives. The first asymmetric synthesis of both enantiomers of alpha-methylphosphophenylalanine is described.

Asymmetric synthesis of quaternary alpha-amino phosphonates using sulfinimines.

The addition of lithium diethylphosphonate to enantiopure ketosulfinimines is highly diastereoselective (>95%), affording the first examples of quaternary alpha-alkyl alpha-amino (arylmethyl)phosphonates.

delta-Amino beta-keto esters, a designed polyfunctionalized chiral building block for alkaloid synthesis. Asymmetric synthesis of (R)-(+)-2-phenylpiperidine and (-)-SS20846A.

[formula: see text] delta-Amino beta-keto esters 3 and 11 are designed polyfunctionalized chiral building blocks for alkaloid synthesis and are prepared in one step from the corresponding sulfinimine (N-sulfinyl imine). Concise highly enantioselective four-step syntheses of 2-phenylpiperidine (7) and SS20846A (14) from 3 and 11, respectively, are described.

Sulfinimine-mediated asymmetric synthesis of 1,3-disubstituted tetrahydroisoquinolines: a stereoselective synthesis of cis- and trans-6,8-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline.

[reaction: see text] The highly diastereoselective addition of lateral lithiated o-tolunitriles to sulfinimines followed by treatment of the resulting sulfinamide with MeLi, hydrolysis, and reduction represents a concise new methodology for the asymmetric synthesis of 1,3-disubstituted tetrahydroisoquinolines.

Medicare hospice benefit: early program experiences.

In this article, an overview of the Medicare hospice benefit is presented and selected preliminary findings from the Medicare hospice benefit program evaluation are provided. By mid-1987, about one-half of all community home health agency-based hospices were Medicare certified, compared with about one-fifth of all independent/freestanding hospices and one-seventh of hospital and skilled nursing facility-based hospices. Medicare beneficiary election of the hospice benefit increased from about 2,000 beneficiaries in fiscal year 1984 to about 11,000 during fiscal year 1986. Medicare reimbursed hospices an average of $1,798, $2,078 and $2,337 per patient during fiscal years 1984, 1985, and 1986, respectively.